Learning Center
Plans & pricing Sign in
Sign Out


VIEWS: 33 PAGES: 173


                               THIRD MEETING
                     Session One, Monday, June 18, 2007

The meeting came to order at 9:00 a.m. in Ballroom C of the Sheraton
Crystal City, Arlington, VA, Dr. Stephen James, Chairman, presiding.

STEPHEN P. JAMES, M.D., Chair, National Institute of Diabetes and
   Digestive and Kidney Diseases (NIDDK), National Institutes of Health
BRUCE R. BACON, M.D., St. Louis University School of Medicine
BARBARA L. BASS, M.D., The Methodist Hospital, Houston
RICHARD S. BLUMBERG, M.D., Brigham & Women's Hospital, Boston
JOHN M. CARETHERS, M.D., University of California, San Diego
MAURICE A. CERULLI, M.D., New York Methodist Hospital, Brooklyn
MITCHELL B. COHEN, M.D., Children's Hospital Medical Center,
MARGARET M. HEITKEMPER, Ph.D., R.N., University of Washington, Seattle
JANE M. HOLT, National Pancreas Foundation, Boston
DAVID A. LIEBERMAN, M.D., Oregon Health Sciences University, Portland
NANCY J. NORTON, International Foundation for Functional
   Gastrointestinal Disorders, Milwaukee
PANKAJ J. PASRICHA, M.D., University of Texas Medical Branch,
DANIEL K. PODOLSKY, M.D., Massachusetts General Hospital, Boston
KENTON M. SANDERS, Ph.D., University of Nevada School of Medicine,
ROBERT S. SANDLER, M.D., M.P.H., University of North Carolina, Chapel
JOANNE A.P. WILSON, M.D., Duke University Medical Center, Durham
EUGENE B. CHANG, M.D. University of Chicago
LISA BEGG, Dr.P.H., R.N., Office of Research on Women’s Health, Office
   of the Director, National Institutes of Health
BROOKS D. CASH, M.D.,FACP, MC, USN, National Naval Medical Center
DAVID P. GOLDMAN, M.D., M.P.H., United States Department of
   Agriculture (USDA)
RAJ K. GOYAL, M.D., VA Boston Healthcare System
GILMAN GRAVE, M.D., National Institute of Child Health and Human
   Development (NICHD)
CHRISTINE A. KELLEY, Ph.D., National Institute of Biomedical Imaging
   and Bioengineering
JAG H. KHALSA, Ph.D., National Institute on Drug Abuse
MARGUERITE KLEIN, M.S., R.D., National Center for Complementary and
   Alternative Medicine
DENNIS LANG, Ph.D., National Institute of Environmental Health
   Sciences (NIEHS)
SUSAN F. MARDEN, Ph.D., R.N., National Institute of Nursing Research
JOHN MILNER, Ph.D., National Cancer Institute
ANNETTE ROTHERMEL, Ph.D., National Institute of Allergy and Infectious
   Diseases (NIAID)

                      NEAL R. GROSS
                      1323 RHODE ISLAND AVE., N.W.
(202) 234-4433        WASHINGTON, D.C. 20005-3701

FRANCISICO SY, M.D., Dr.P.H., National Center on Minority Health and
   Health Disparities
SAM ZAKHARI, Ph.D., National Institute on Alcohol Abuse and Alcoholism
ELIZABETH L. WILDER, Ph.D., Acting Assistant Director, Office of
   Portfolio Analysis and Strategic Initiatives, Office of the
   Director, National Institutes of Health
ROBERT HAMMOND, Ph.D., Executive Director, NCDD
In addition to Commission members, others in attendance included NIH
staff representatives and interested members of the public. Attendees
included the following:

Anne Bicha, American Gastroenterological Association
A.J. Bownas, the Hill Group
Jill Carrington, Ph.D., NIDDK
Michelle Cissell, M.A.Cissell Consulting
Leslie Curtis, Office of Communications and Public Liaison (OCPL),
Sarah Dunsmore, National Institute of General Medical Sciences (NIGMS)
 [for Michael Rogers]
Carol Feld, Office of Scientific Program and Policy Analysis (OSPPA),
Erika Elvander, Office of Research on Women’s Health, Office of the
 Director, NIH [June 18 for Dr Begg]
Brian Harvey, M.D., Ph.D., Sanofi-Aventis
Eleanor Hoff, Ph.D., OSPPA, NIDDK
Joyce Korvick, M.D., M.P.H., Food and Drug Administration
Carina May, the Hill Group
Megan Miller, Ph.D., OSPPA, NIDDK
Helyn Oscanyan, the Hill Group
Sharon Pope, OSPPA, NIDDK
Anne Wright, Circle Solutions, Inc.

                     NEAL R. GROSS
                     1323 RHODE ISLAND AVE., N.W.
(202) 234-4433       WASHINGTON, D.C. 20005-3701

                                    List of Presentations

I. Welcome, Approval of November 6, 2006, Minutes, and
     Today’s Goals, Stephen James, MD and Robert Hammond, PhD ....... 4

II. Office of Portfolio Analysis and Strategic Initiatives (OPASI)
     Elizabeth Wilder, PhD ............................................ 8

III. Working Group Updates (in order of presentation)

           Inflammatory Bowel Diseases (WG 5) Daniel K. Podolsky, MD ....... 21

           Infections of the GI Tract (WG 3) Mitchell B. Cohen, MD ......... 34
           Cancers of the Digestive System (WG 4) John M. Carethers, MD .... 44

           Diseases of the Pancreas (WG 10) Jane M. Holt, Presented by
              Jay Pasricha, MD ............................................. 60

           Functional GI Disorders and Motility Disorders (WG 2)
              Kenton M. Sanders, MD ........................................ 74
           Diseases of the Oropharynx & Esophagus (WG 7) Jay Pasricha, MD .. 86

           Diseases of the Liver & Biliary System (WG 11) Bruce Bacon. MD .. 96
           Diseases of the Stomach & Small Bowel (WG 9) Eugene B. Chang, MD
              Presented by Maurice A. Cerulli, MD ......................... 106

           Diseases of the Colon & Rectum (WG 9) Joanne A.P. Wilson, MD ... 118

           Intestinal Failure & Regeneration, Nutritional Disorders &
              Support, Surgically Modified Gut, & Transplantation (WG 6)
              Barbara L. Bass, MD ......................................... 132
           Bioengineering, Biotechnology, & Imaging (WG 13)
              Barbara L. Bass, MD ......................................... 141
           Overview of the Digestive System (WG 1) Richard Blumberg, MD ... 152
Preparation for Day 2
     Stephen James, MD.............................................. 165

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
(202) 234-4433            WASHINGTON, D.C. 20005-3701

 1                                       P-R-O-C-E-E-D-I-N-G-S
 2                                                                  9:10 a.m.
 3   I. Welcome, Approval of November 6, 2006, Minutes, and Today’s Goals
 5                DR. JAMES: Why don't we get going. We're just a few minutes
 6   behind, but the introductions I think can go fairly quickly. Welcome
 7   everybody to Washington. As you can see we're in tropical summertime or
 8   we're about to be this afternoon if you wander up out on the street
 9   today, so gentlemen, you're allowed to take your coats off or even your
10   ties if you wish. We're in tropical mode. Although, I'd ask you to keep
11   them handy because we're going to do a group photo after lunch. I don't
12   think we have a group photo. We really need a group photo. Dan, you can
13   go out and buy a tie in the gift shop.
14          (Laughter)
15          DR. JAMES: I think we should. This thing is so important we
16   really must have a group photo and I guess we don't have one so far. So
17   that's - you can tell, Betsy, how important this Commission is. We're
18   thinking about photos and stuff.
19          I guess, should we go around the table? I'm not sure we need to.
20   I think everybody here is pretty familiar with who everyone is. We
21   haven't lost anyone and we only have a few changes in our ex officios.
22   I'm not sure we're making any announcements about people who are
23   changing institutions. If you choose to announce that by all means do
24   that when you do your own thing, but I'm not sure I'm allowed to
25   announce where people are coming or going.
26          Gene Chang hasn't made it yet. He's trying. He's on standby again
27   and we hope he'll be here either late this morning or this afternoon. So
28   we're going to change the agenda just a little bit. When we get to the
29   small bowels section, we'll just delay that and move everything up that
30   follows up by one slot and hopefully he'll be here after lunch. Gene
31   isn't going to be able to stay for the whole meeting anyway because he
32   is getting a major award at the University of Chicago, the first Arthur
33   Rubenstein Mentorship Award. So Gene has to be there tomorrow anyway.
34          We do have some changes in the ex officios. Barbara Bell at the
35   CDC has a new position, not at the CDC, and she has resigned. And we
36   have a replacement but she couldn't make it today. It's Dr. Laura Seeff.
37   Laura, as some of you may be aware of is an expert in colorectal cancer
38   and actually authored an important paper in the New England Journal I
39   believe is where it was. So I'm sorry she's not here. We were going to
40   try to arrange a phone connection but couldn't pull that off at the last

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   minute. Brian Harvey who is in the back row no longer is with the FDA
 2   and is now here as a public person. This meeting is open to the public.
 3   Joyce Korvick, his prior deputy, is now the Acting Division Director at
 4   FDA and she's here in the back. Welcome. Sue Marden has been appointed
 5   Program Director for the National Institute of Nursing Research's GI
 6   portfolio and she's going to represent the Institute in place of Alexis
 7   Bakos. So I want to thank people who are coming and those who have
 8   departed for their help in this effort. I think we have a new - is Lisa
 9   Begg here? Tomorrow. So Lisa Begg will be representing the Office of
10   Research on Women's Health and Erika Elvander - not here yet - will be
11   here today. Sarah Dunsmore will represent the National Institute of
12   General Medical Sciences in place of Michael Rogers who wasn't able to
13   come today. I have next to me Betsy Wilder who I'll introduce in a
14   minute and I'm sure you all will be very interested in her presentation.
15          The next order of business is to approve the minutes. The minutes
16   are in the package, the book that you have. If any of you have had an
17   opportunity to study them closely, as I'm sure you have, you would have
18   forwarded comments to us. After the fact you're always welcome to
19   forward any corrections that you might identify, but at this point I'll
20   take a motion to approve the minutes. Anyone want to make a stab at
21   that? Second? Any discussion of the minutes? All in favor of approving
22   the minutes?
23          (Show of hands)
24          DR. JAMES: Any opposed?
25          (No response)
26          DR. JAMES: Okay. I like to do business in this way. This is a
27   good way to get going. You want to do your announcements now, Bob?
28          DR. HAMMOND: Thank you, Steve. Some policy announcements. In
29   terms of conflict of interest all of the Commission members have
30   completed and have submitted conflict of interest statements which is a
31   requirement for membership on the Federal advisory committee. I'd like
32   to take this opportunity to remind the members not to speak individually
33   on the Commission's behalf or on activities not cleared by the
34   Commission. If you have any questions about this policy, please contact
35   me.
36          In terms of the meeting procedures today and tomorrow morning, we
37   have only a limited amount of time for comments and the members will
38   have priority since they are the only people here who are authorized to
39   vote on issues. The public is welcome to submit comments in writing
40   after the meeting. Instructions for doing so are on the Commission's

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   website and in the Federal Register notice which was published on March
 2   28. You'll notice that we do have floor mikes, at least one back there,
 3   in case we have time at the end of the meeting for public comments.
 4   Because we have a very full agenda with a lot of ground to cover, we'll
 5   be monitoring the times of presentations very closely. There's a timer
 6   up at the podium for the speakers and one minute before your closing
 7   time you get a little flashing light there to remind you to summarize
 8   your final points. Also, during discussion periods please allow Steve
 9   James to recognize you before you speak. This will help the discussions
10   move along, but also it will help the transcriber who's sitting right
11   behind me to identify the speakers in the transcription. So the mikes
12   are very important to use. Members have one mike for each two people and
13   you'll see, just press the button. When the red light is on, your mike
14   is live. This is not only so the people in the back can hear you, but
15   again so we can transcribe this.
16          Let me just go through the binder very briefly. This is the
17   binder for the members and ex officios. The first tab is simply the
18   agenda. The second tab has background materials like the charter, but
19   also there's a fact sheet, a one-page fact sheet which is very handy.
20   It's not new information, but it's information that's in several
21   different places on the web and we've used it for handouts at DD Week
22   and other places. It's a nice concise one-page document. The draft
23   minutes are the next tab which is now approved. Dr. Wilder's
24   presentation is in the fourth tab.
25          The fifth tab, this is the real heart of what we're doing, the
26   chair's presentations for the working groups. There's three slides to a
27   page so you can have notes and then we have the goals and challenges and
28   sample pages. Remember what we did for the information of the public
29   here, we had a spreadsheet constructed so we could have, rather than
30   simply looking at individual PowerPoints for each of the working groups,
31   try to map these across in a column format, and we actually assigned
32   some temporary keywords to be able to search on these. The keywords were
33   assigned and the spreadsheets were sent out about a week before this
34   meeting to allow the members to look for overlap, redundancy, so the
35   goal might be presented in one working group rather than multiple ones,
36   and common themes that might be consolidated into a single goal, either
37   as an overarching goal or conclusion in a single working group. So the
38   point now is to look at the most important goals of this meeting for
39   inclusion in the final long-range plan. The challenges and steps to
40   achieve the goals were also consolidated in a spreadsheet with keywords

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   to assist the members in looking at these. Of course, those will be
 2   driven by the actual research goals. So just be assured that the
 3   keywords are simply tools for us to sort these and will not appear in
 4   the official document.
 5          The advances, this large document, is in the seventh tab and this
 6   was collected say for the conference calls themselves when we asked
 7   people to look at research advances within the last few years, and also
 8   some updates after the conference calls. And the idea is we thought we'd
 9   put all of this in the unabridged format for everyone to look at. It's
10   really good reading material to look at what's going on in the other
11   fields. Again, this is not something we'd want to have presented today
12   so that's certainly off of the presentation docket. It would be very
13   time-consuming, but it is extremely good background information, and of
14   course only a few of these research advances will actually show up in
15   the final report, the ones that are aligned with the goals that are
16   going forward.
17          The last tab is the timeline which we'll cover tomorrow. This is
18   what happens after we leave tomorrow, and tomorrow by the way we have an
19   8:00 a.m. administrative session. So although the formal agenda starts
20   at 9:00, we'll actually start some of these things such as timeline and
21   some other overarching issues at 8:00 tomorrow as you'll see, and this
22   is open to the public as well. At the request of the Commission members,
23   our next meeting will be held Monday, November 19, 2007, in Chicago near
24   O'Hare International Airport. It will be a one-day meeting this time and
25   the date and place are included in your binders, and it's available at
26   the registration table also and we'll put this on the website as well.
27   Finally, for the members an expense form is included in the inside
28   pocket of the binder.
29          So I mentioned the microphones, very important to use those. If
30   you need any help at all, the Hill Group staff are at the table outside
31   and the restrooms are located just to the right. Just keep making right
32   turns, right around the corner. A final announcement. We'll have lunch
33   at 12:45. There will be a one-hour lunch break for the general group
34   here and the restaurant is right in the hotel lobby, although there are
35   some other places, but in the restaurant at the lobby area we have an
36   area cordoned off for the Commission members and ex officio members like
37   we did last time so we don't have to hunt for tables. Sit down and
38   network there if you'd like to, but we would like the Commission
39   members, the ones sitting at this table to return 15 minutes early -
40   that would be 1:30 - for our group photo. This is our one and only photo

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   of the group. Unless there are any questions, I'll turn the mike over to
 2   Steve. Thank you.
 4   II. Office of Portfolio Analysis and Strategic Initatives (OPASI), NIH
 6          DR. JAMES: As usual, all the details are taken care of by Bob. So
 7   thank you, Bob. So as you heard, the main agenda for today and tomorrow
 8   morning really is to come very close to focusing on what the real
 9   recommendations of this Commission will be, and without dictating at all
10   what they might look like, I think we do need to get very close to at
11   least in a draft form outlining what the important goals are going to
12   be. There's going to be quite a bit of work beyond that in terms of
13   crafting the final report. Michelle Cissell is taking notes and going to
14   be working over the summer, beginning the process of turning this into a
15   homogenous, very slick, glossy report that will be in good English and
16   hopefully have a major impact. But to get to the point of having
17   something that Michelle can really work on, we have to come very close
18   to settling what the real material will be in this report. So we have a
19   tremendous wealth of material to go over today and again tomorrow
20   morning in order to get to that point, but we do have quite a bit of
21   work to do.
22          But in preparation for that we thought it would be very
23   interesting to have someone speak to us about central efforts at NIH for
24   research planning and large-scale overarching research projects. So I'm
25   very happy that Dr. Elizabeth Wilder sitting next to me has agreed to
26   come and speak to us about OPASI and Roadmap. Betsy is currently the
27   Acting Associate [check title] Director of OPASI and she also
28   concurrently has a position in NIDDK where she has directed programs in
29   developmental biology and repair. She has been a participant in many
30   different trans-NIH efforts to facilitate collaboration. She was the
31   Acting Coordinator of the NIH Roadmap Interdisciplinary Research Teams
32   and co-chaired the Multiple Principal Investigator Policy Implementation
33   Committee. Committees can have very long names at the NIH. That's why
34   they all have acronyms and then nobody knows what they're really doing,
35   but Betsy really has it under control and knows what all this stuff is.
36   So I'm very pleased that she has come today and will tell us about
37   what's up in terms of very new things in terms of the organization of
38   the NIH and crosscutting research, and then we'll have plenty of time
39   for questions. I think we'll hold questions till after. Do you want to
40   hold questions, or do you want to do them as they?

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1                DR. WILDER: I'm flexible.
 2                DR. JAMES: Whatever you want to do. Okay. Thank you.
 3          DR. WILDER: So thank you for the invitation. It's nice to be
 4   here. Is this on? There. Let me know if you can't hear me. So I think
 5   what I'd like to do is just begin with a little bit of a historical
 6   background of Roadmap for you in case some of you are not aware of the
 7   history of it and exactly how we came to be where we are today with it.
 8   So the process for Roadmap really began several years ago, even before I
 9   came to the NIH, and it consisted of an IOM report that was published in
10   2003 which was generated by IOM and the Board of Life Sciences and
11   provided many recommendations for how the NIH should proceed. And
12   central among those was a recommendation that the NIH as a whole should
13   do strategic planning and think about what the agency as a whole needs
14   to do rather than a collection of institutes and centers.
15          So this report was published and there were really three kinds of
16   recommendations that were merged to form really the first iteration of
17   Roadmap. So the trans-NIH planning was the first one. There was also a
18   call for the NIH to think very hard about how best to stimulate
19   innovative research. So how to do innovation, how to stimulate it, how
20   to foster it has been an ongoing theme that we've been thinking about.
21   And the third major recommendation from that IOM report that has been
22   encompassed into Roadmap was a call to facilitate clinical research. So
23   those three broad recommendations were sort of folded into a planning
24   process that resulted in a series of initiatives that were designed to
25   facilitate research across the NIH. And so that became known as the
26   Roadmap. And the first grants funded via the Roadmap were funded in 2004
27   and now we're beginning to think about a new set of - a new cohort of
28   initiatives. And so that's really what I'm going to tell you about
29   today. If you have any questions about the first cohort, please let me
30   know.
31                So the idea with Roadmap initiatives is that they are supposed to
32   represent areas of research that are critically important for the NIH as
33   a whole, but there are many, many areas of research that fall into that
34   category and it's also true that any of these very broad crosscutting
35   areas are going to proceed for a long time in the future. So one
36   question that the IC directors and the NIH director had to grapple with
37   early on in the process was how to stimulate research in a number of
38   crosscutting areas, but not be nailed down to continuing to facilitate
39   research in that area forever because then it would just snowball and
40   get increasingly bigger. So the Roadmap is really intended to be a

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   short-term type of support to get something going that's critically
 2   important for the NIH. And we refer to that as incubator space. So the
 3   Roadmap is - do I have a pointer? It's easier for me to talk if I have a
 4   pointer. Well, I will just point.
 5          (Laughter)
 6          DR. WILDER: But that gets me away from the microphone, I'm sorry.
 7   So the incubator space is really a concept that includes the fact that
 8   programs - oh, thank you - because they're crosscutting and complex they
 9   warrant concerted attention from NIH as a whole. And so although there
10   are many crosscutting initiatives that one could imagine, the NIH
11   Roadmap is intended to really do things, jump-start things in a way that
12   institutes couldn't do together. So in preparation for the transition of
13   the first cohort of initiatives out of the incubator space, the NIH
14   began a process of soliciting ideas for a new cohort. And it's important
15   to recognize that ICs often collaborate on many, many topics of shared
16   interest, and so in order to limit the world of what the Roadmap might
17   fund the IC directors established special criteria for use of the Common
18   Fund. And so I'll just point out here that the Common Fund is somewhat
19   synonymous with the Roadmap. The Common Fund we refer to as the money,
20   the Roadmap as the programs.
21          So the criteria that Roadmap initiatives should meet first and
22   foremost is that they should be expected to be truly transforming. So
23   initiatives that come out of the Roadmap should be expected to transform
24   the way we do research and that of course is subjective, but all of the
25   potential ideas for Roadmap go through an extensive vetting process and
26   the things that come out are felt to have high potential to dramatically
27   affect the way we do research across biomedical and behavioral research.
28   It's important that the outcomes should synergize with the work of the
29   institutes and centers. So the Roadmap initiatives are not very likely
30   to be disease-specific, but they should synergize with disease-specific
31   research funded by the institutes, and I'll come back to that in a
32   moment. They should require participation from NIH as a whole and/or
33   address areas of science that do not fall within the mission of any one
34   IC or OD program office. And this is not an incredibly exclusive
35   criterion since most research I would say spans the mission of at least
36   two institutes, but we do expect that Roadmap initiatives will be value-
37   added to research funded by many institutes. And then finally, Roadmap
38   initiatives should be something that no other entity is likely to do. So
39   we don't want to redo what pharmacy is doing. We don't want to redo what
40   the NSF is doing. So we try to take a careful look at what other

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   agencies and what other institutes are doing out in the world and find a
 2   specific niche that NIH can fill.
 3          So the Roadmap 1.5 process, and I will also just step back to
 4   tell you why we call it 1.5. The funds that will fund this new cohort of
 5   initiatives are within the funds originally set aside for Common Fund.
 6   So the Common Fund is not growing beyond what we expected it to be with
 7   the first cohort of initiatives, it's just a redirection of the funds.
 8   Last summer we had a very broad idea-gathering process. We gathered
 9   ideas from expert panels, from the NIH staff and from the broad
10   community via a request for information. We coordinated a group of
11   people from across the NIH to take a very careful look at those
12   initiatives and decide which met all of the criteria that I outlined for
13   Roadmap initiatives, and so which were responsive to those criteria. We
14   did a portfolio analysis of some of those topics looking at what the NIH
15   was currently funding with respect to these potential ideas, and then
16   that information was passed to the IC directors for their consideration
17   in prioritizing the possible ideas for the Roadmap. And that led to a
18   meeting in January where the IC directors selected a number of topics to
19   be further developed. Those ideas were reconsidered in May and the IC
20   directors selected a final set of initiatives to move forward.
21          So in January the first set of prioritization actually led to not
22   only ideas that needed to be funded via the Roadmap, but continuing
23   trans-NIH co-ordinating processes that the NIH really needs to consider
24   in a coordinated way even if they are not funded via the Common Fund. So
25   I'd like to go through some of these issues with you. So certainly they
26   prioritized major areas that the Roadmap and the Common Fund should
27   fund. We refer to these as major Roadmap initiative areas and these were
28   broad areas where you could imagine a number of possible initiatives.
29   And these were the microbiome, inflammation phenotyping, proteome and
30   protein capture tools and epigenetics. But importantly, this process of
31   very broad idea-gathering highlighted areas that are very broadly
32   applicable across the institutes and centers, but are perhaps not very
33   well coordinated. And so these potential areas for coordination are
34   areas where the NIH just needs to get together all the ICs, see what
35   we're doing and try to figure out if there is a better way to coordinate
36   across the agency to eliminate redundancies, to facilitate cross-
37   communication amongst investigators, amongst staff within the NIH. And
38   so these coordination areas that were highlighted via the Roadmap
39   process were regenerative medicine, pharmacogenomics and bioinformatics.
40   So trans-NIH groups for each of these areas have formed and I think this

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   long-term coordination process will be ongoing for the next few years.
 2          The IC directors also recognized that there could be small pilot
 3   programs that would very much be useful for institutes and centers
 4   across the agency to test very highly innovative ideas, but perhaps not
 5   ready for a major initiative, but to test whether research in this area
 6   might be useful or ready for a major initiative in the next few years.
 7   And so in January, two areas were selected as potential pilot topics.
 8   One is a connectivity map and transient molecular complexes. And if
 9   you'd like to know more information about what exactly these mean I can
10   come back to that if you'd like.
11          So finally, the Roadmap process identified broad areas that are
12   very complicated and will need a lot of concerted thought to see how or
13   whether we can better coordinate our efforts across the agency. And so
14   we refer to these as Roadmap emphasis areas, or strategic planning
15   areas. So training and careers is a topic that came up many, many times
16   in the idea-gathering phase. As individual ideas would say you know, we
17   need better training in this, or we need this type of investigator to be
18   supported, or young people in this area fall out very quickly because of
19   X. And so there were so many possible ways to facilitate training,
20   facilitate young investigators, that the thinking of the IC directors
21   was that we need to take a very coordinated look at the types of
22   training programs that we currently sponsor, figure out what our
23   workforce needs to look like, what the current problems are across the
24   workforce and then design better training programs if needed. Or maybe
25   we're doing the best that we can and these problems are intractable. But
26   the working group that has formed to think about training is first
27   taking a look at the workforce engaging many academic institutions as
28   well as NIH staff to try to figure out where we need to be and then
29   we'll design programs to figure out how to get there. Health disparities
30   is of course a very complicated topic. We have a whole center at the
31   NIH, the National Center for Minority Health Disparities that
32   coordinates this centrally, and yet within the Roadmap process many
33   ideas were put forward that would enhance our research in health
34   disparities. So we are currently working with NCMHD to try to figure out
35   whether there are things that can be done better to better coordinate
36   research in this area, but this ultimately will go through NCMHD.
37          Finally, science of science administration is a somewhat unwieldy
38   topic. It's the question of how - what are the best ways to administer
39   research, and this is a question that's centrally interesting to NIH
40   people, of course. The types of questions that are being considered here

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   deal with review, what's the best way to review science, particularly
 2   interdisciplinary science is a big interest. How do we review
 3   innovation? Do our current review practices stifle innovation? And so we
 4   have a whole task force at the NIH who are considering review issues. So
 5   the Roadmap process will probably not deal so much with review, but with
 6   other administrative types of questions. If we want to encourage young
 7   investigators, what are the most effective ways to put a new
 8   investigator into independence and promote their careers, et cetera. So
 9   this will be an ongoing probably long-term strategic planning area.
10          Okay, so for the major Roadmap initiatives, the ones that will be
11   funded via the Common Fund, there were five topics that came out of the
12   January prioritization process and two of them have now been approved
13   via a May prioritization process for immediate implementation. And I
14   would imagine that you guys are particularly interested in the
15   microbiome. And the Human Microbiome Project - so the microbiome could
16   have potentially involved a number of studies including many animal
17   models, but the focus here for the Roadmap will be on the Human
18   Microbiome Project. It will consist of a number of initiatives that are
19   collectively designed to get us to the point where we understand the
20   importance of the microbiome to human health and whether we can
21   manipulate the microbiome to improve human health. And so the starting
22   point for this is sequencing of the microbiome. So one initiative that
23   will be begun for 2008 funding is a major effort to sequence the
24   microbiome at a number of sites. The thinking is that this will require
25   developing new technologies, so we'll also have an initiative to develop
26   new tools and technologies for this. And then finally I think very
27   important for the human health side of this is trying to determine the
28   extent to which the microbiome correlates with human disease and whether
29   that can be manipulated to improve health.
30          The second major area that has been approved for immediate
31   implementation deals with epigenetics, and this is somewhat similar to
32   the microbiome. The general question is to what extent do epigenetic
33   changes correlate with disease and can that be manipulated to improve
34   human health. So really similar questions, but two different genomes
35   that we're looking at. Well, actually I guess microbiome is a gazillion
36   genomes, but - so in this case a primary thrust is trying to determine
37   what the default epigenome is in a healthy human person in a number of
38   cell types, and then trying to determine whether the epigenome is
39   changed in disease. So this will also involve a series of initiatives,
40   an international consortium that will sequence reference epigenomes.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   This will be transferred into a publicly available database, and again
 2   the thinking is that we will need new tools and resources to facilitate
 3   this type of research ongoing into the future.
 4          There were two other topics that were given a conditional
 5   approval for moving forward as Roadmap initiatives and the thinking for
 6   these two areas were that the proposals as put forward in May needed to
 7   be re-scaled and scoped a bit, and they will be implemented in stages.
 8   So the first is phenotyping services and tools. This again has a human
 9   focus and the initiatives would encourage the development of resources
10   to catalogue human phenotypes for a characterization of complex
11   diseases. This is echoed many times during the Roadmap - the idea-
12   gathering process, that we need better ways to say what a human
13   phenotype is and to share the data across many institutions and to have
14   standardized ways of describing disease. And so this, the first part of
15   this initiative will essentially address that.
16          Protein capture tools and proteome tools. This will be a series
17   of initiatives trying to generate tools that will allow investigators to
18   identify and study individual proteins. And the first part of this will
19   be to support the development and availability of high-quality probes
20   specific to every protein in human and animal models. This is a little
21   bit of an overstatement and I think this is why the proposal needed to
22   be re-scoped. I think this is going to be very difficult to do within
23   the incubator space period that the Roadmap supports. So this again has
24   come to have a human focus and so I think the initiatives that
25   manufacturer will be focused on - I mean, the specific initiatives will
26   be focused on human tools. This Roadmap initiative would also develop
27   tools and resources to identify and isolate the proteins. And so this
28   series, all of these initiatives on this slide will move forward
29   probably in either late `08 or early `09.
30          The - so let me just go back to make one clarification because I
31   think this slide is confusing. These are distinguished from what we
32   refer to as Roadmap pilots because they're not really pilots. This is a
33   staged implementation. So we expect things to move forward in stages
34   with later stages contingent upon success of the earlier stages. So when
35   you see things that are Roadmap pilots, those are described here and
36   they're not staged. We just envision a single pilot study here. So the
37   only pilot project that was approved to move forward was the
38   connectivity map and this initiative is designed to discover and
39   demonstrate linkages between diseases, drug candidates and genetic
40   manipulation. It aims to provide common language in the form of gene

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   expression profiles to facilitate interactions among - I don't need to
 2   read this. If you have questions about what's up here, please let me
 3   know. I think the critical thing to point out here is that because of
 4   the early stage analysis of this type of initiative it is moving forward
 5   first via workshop to gather more feedback from the community about the
 6   best way to proceed with this, and then a pilot project will be on the
 7   order of a two-year program. So the next steps for this process are that
 8   an internal NIH committee will review the RFAs that are put forward by
 9   trans-NIH groups that are working on each of these topics and the fall
10   of 2007 RFAs will be released. We expect awards to be made in summer `08
11   and then activities of the working groups for the coordination and
12   strategic planning areas as I mentioned are ongoing.
13                Let's see. I've already pretty much described those. Here's the
14   timeline that we've been working under. We're already way over here.
15   This simply refers to the types of things that we consider to be
16   important in trans-NIH planning and put it up here even though we've
17   gone through this process to highlight that the role of OPASI really is
18   to gather ideas, look at our portfolio, provide the IC directors with
19   the information they need to prioritize and then to get these - work
20   with the ICs to get them funded. And that's all I have. I'm open to
21   questions.
22          DR. JAMES: Dan Podolsky.
23          DR. PODOLSKY: I wonder if you could tell us if there is any more
24   detail about the approach to looking at the training and careers issues?
25   You know, has there been a group already comprised, and if so what's the
26   plan for moving the whole effort forward?
27          DR. WILDER: Right. So it's gotten off to a bit of a slow start.
28   So the problem is that there are so many training efforts ongoing and so
29   the first steps of that group were really - so let me just back up. A
30   trans-NIH group has formed. It's under the leadership of Dr. Storey
31   Landis who's IC director at NINDS, the Neurology Institute and also
32   Norka Ruiz-Bravo who is the head of the Office of Extramural Research.
33   So Storey and Norka have formed a group of representatives across the
34   NIH to think about how to tackle this problem. And their first efforts
35   were to think about all the things that we have. And it clearly - I mean
36   it quickly became obvious that what we need is to define the workforce.
37   And so the plan is to conduct a series of workshops probably across the
38   country interacting with professional societies as well as academic
39   institutions, deans, et cetera, to - as well as you know postdoctoral
40   groups, things like that - to define what we want our workforce to look

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   like and what really is the need. And so these series of - I'm sorry,
 2   excuse me. These workshops will probably begin this fall. And the scope
 3   of that group is such that I expect that to take on the order of six to
 4   nine months to gather this information and put it together in something
 5   that we are comfortable with in defining what we want our workforce to
 6   look like. The IOM has also spent a fair amount of time thinking about
 7   this and so - anyway, I think over the course of the next year we'll be
 8   in a position to determine whether we need any new training initiatives.
 9                DR. JAMES: Mitch.
10                DR. COHEN: I think I understand that the two initiatives that
11   were approved RFAs will result in funding for those two. I'm not quite
12   sure I understand what the next steps are for either the stage pilot or
13   the one pilot that was approved.
14          DR. WILDER: So the groups that have been working to define what
15   the initiatives should be for both phenotyping and protein capture were
16   asked to go back and focus a bit and come up with a staged
17   implementation plan and that's currently where we are. So the timing for
18   the implementation of those initiatives has not been determined yet
19   because the groups have yet to make a second proposal for those topics.
20   My guess is that they will be funded in either `08 or `09. I mean
21   certainly `09, but perhaps `08.
22          And then - oh, you asked about the pilot. So the workshops for
23   the - to determine really the best way to move forward with the
24   connectivity map will be held maybe as soon as late summer, but maybe in
25   the fall.
26          DR. JAMES: Maurice.
27          DR. CERULLI: Thank you for the update. My question is of the five
28   broad areas you mentioned plans for four of them, but did not mention
29   anything about inflammation. Are they still working on that? What is the
30   idea? It's a very broad area, certainly.
31          DR. WILDER: Right. So it is a very broad area and at the May 18
32   meeting of the IC directors the IC directors had to prioritize and felt
33   that funding in the area of inflammation was so robust and so broad that
34   really what was needed was a better coordinated approach rather than
35   following through with the proposal that the working group had come up
36   with. And so I think that this is going to be an ongoing issue of how
37   best to foster work in the area of inflammation. Are there things that
38   could be better coordinated? And I think one area of emphasis is to
39   coordinate the efforts of the NIH intramural program with the extramural
40   program as well to try to bring groups of people together in a better

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   way. So this is not dead and gone, it's just a question of how best to
 2   proceed. And my guess is that this will come back, but the thinking of
 3   the IC directors was that some other proposal needed to come forward
 4   that was more coordinated.
 5          DR. JAMES: John.
 6          DR. CARETHERS: Thank you. The Roadmap to my understanding takes a
 7   certain percentage of the NIH budget to set aside and I was just
 8   wondering with the coming RFAs I assume, what is the type of mechanism
 9   that will be used? Is it an existing mechanism, or is it a new
10   mechanism, i.e., you know center-type grants or whatever? And these are
11   - I assume these are designed to be multidisciplinary, across multiple
12   institutions, or how is that going to be structured?
13                DR. WILDER: So the - to address your issue with the budget. Just
14   this is a bit of a tangent perhaps to what you're asking, but the
15   Roadmap for `07 and probably for `08 will not be collected from the ICs
16   but is a separate appropriation in the budget. So it's currently about
17   1.7 percent of the NIH budget.
18          The mechanisms that will be used are varied and with the first
19   cohort of initiatives we had many different mechanisms. We had P20s, we
20   had P30s, we had you know several different kinds of centers, we had
21   R01s, there were R21s, there were workshops, there were novel mechanisms
22   that were generated, training mechanisms and I don't expect Roadmap 1.5
23   to be any different. So my guess is that the broad descriptions that
24   I've given you of these initiatives will appear in several different
25   types of mechanisms from centers, contracts, R01s, R21s, workshops, et
26   cetera. But I don't know because the specific proposals haven't come
27   forward yet.
28          DR. JAMES: Rick.
29          DR. BLUMBERG: Rick Blumberg. The microbiome is obviously
30   critically important - you alluded to that - for many of the members of
31   this commission. Just two questions. One is the obvious question, if you
32   can give us a little bit more information, a little bit more detail, a
33   little bit more granularity to what is to be considered in the RFA that
34   is going to be coming out later this year presumably for the microbiome,
35   and also, mechanisms of funding that you're considering.
36          And the second question is getting - alluding to Dan's question
37   is how is there integration in some of these crosscutting endeavors?
38   Microbiome is a very, very good example where there's a lot of
39   crosscutting in terms of connectivity, especially people power in terms
40   of making sure that we train the generation of investigators that will

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   be needed to make sure this priority can be carried on to the future for
 2   the various manifestations that it's going to have an effect upon.
 3          DR. WILDER: The microbiome - I'll address your last point first -
 4   doesn't have a training component and so training won't be a part of
 5   this initiative. The initiative that will move forward first is a
 6   sequencing initiative. So the thinking is that the determination of
 7   whether the microbiome correlates with disease, whether it can be
 8   manipulated to improve health needs to come after we have more
 9   sequencing data. So the first initiative that will move forward from
10   this working group is a sequencing initiative and it will be probably a
11   network type of thing. I don't think I can tell you mechanisms or I'd
12   have to kill you or something, but the - I think for any large
13   sequencing program it has to be done as a network of people working
14   together. And I think perhaps this is what you're referring to in terms
15   of integration. There will be an effort to sequence the microbiome from
16   a number of sites, the gut, the ears. I mean, you know all the sites
17   better than I do. And so I think that although I don't know that each
18   center or whatever group that's funded to do the sequencing will be
19   site-specific, it will be a collection of sequencing people. Does that
20   answer your question well enough? Okay.
21          DR. JAMES: We tend to be a little coy. Once we're in the process
22   of drafting an RFA internally we're not really allowed to tell people
23   what the content is. That would lead to - or in bits and pieces because
24   that would lead to unfair competitive advantage. Or if you knew then you
25   couldn't submit an application, so if we told you, you and your
26   institution can't apply. So you don't want to know too much. David?
27          DR. LIEBERMAN: Thanks again for your presentation. I have just a
28   general question about the Roadmap. When I participated in the initial
29   Roadmap discussion several years ago there was a lot of interest in
30   clinical databases. Where has that gone, because I certainly don't see
31   it here, or where do you see it going in the future?
32                DR. WILDER: Well, so the clinical databases are supposed to be
33   components of the CTSA, so the Clinical Translational Service Awards. So
34   all CTSAs have a bioinformatics component. And the - we have recently -
35   "we" like I have any say-so - the IC directors have recently voted to
36   add additional support to that by funding or by enabling supplements to
37   the CTSAs to allow better cross-communication between the CTSAs for
38   sharing of data. And to make their data systems more compatible with
39   each other so to facilitate that sharing of information. So it's all
40   done within the context of CTSAs even if you don't see it as a separate

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   initiative.
 2          DR. JAMES: Yes, Gilman.
 3          DR. GRAVE: Betsy, can you hear me? Is the microphone on? That was
 4   a wonderful clear presentation. I appreciate it. In the interest of full
 5   disclosure I was on the failed inflammation work group, so if it didn't
 6   work out it might be my fault. But I'm curious about the
 7   phenotyping/genotyping connection because everybody has their own
 8   phenotype. So there's 6 billion phenotypes in the world. How in the
 9   world are you going to - and then if you go back to Garrett and
10   alkaptoneuria, that phenotype has black urine. So that's a very clear,
11   specific phenotype, but what else are you going to do with phenotypes?
12   How is it really going to work?
13                DR. WILDER: Well, I think the desire is to standardize what you
14   call any particular disease, and I'm not a clinician so I'm not going to
15   give you really good examples, but something that I do understand is
16   blood pressure. So I go to the doctor and I get my blood pressure taken,
17   and I would think that you know 110/70 is 110/70, but apparently it's
18   not that simple. So I think the desire is to either have agreement
19   across the community about how one gathers data so that when you say
20   something it means the same thing as when you say something in a
21   different institution, or either agree on a way to do it or agree on a
22   way to describe the phenotype. And so this has received a lot of
23   interest from many, many people during the idea-gathering process that
24   it's impossible to compare the results of one study to the next because
25   the way that data are gathered are not the same. And so really that's
26   the goal of that initiative.
27          DR. BASS: I mean, at the risk of being naïve, which I suspect I
28   am in this area, the microbiome program is to actually sequence the
29   microbiome in all conditions of health and disease?
30                DR. WILDER: Oh no.
31                DR. BASS: What - can you tell us a little more about what this
32   is? It sounds almost wacky to me.
33                DR. WILDER: So that's what Roadmap is all about. The idea is to
34   sequence the microbiome from a number of healthy individuals and to
35   catalogue the types of species that we have living in us, or to
36   determine really what the microbiome looks like in a number of sites.
37   And so the sampling will be not from a single individual, but from a
38   number of healthy individuals. So the questions are how variable is it
39   and can we determine how variable it is amongst healthy individuals. So
40   if your microbiome looks very different from mine then it's going to be

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   hard to determine when I get sick whether that's a significant
 2   correlative change or whether it's just a change. So I think there is a
 3   very large informatics problem here that is at a stage now where it's
 4   handle-able and so I think that's why the program is moving forward
 5   right now. But the informatics will be staggering because the microbiome
 6   for any one individual is complicated, it's likely to vary depending
 7   upon what you eat and so the challenge is to determine what the
 8   variability is in health and then ultimately to determine whether any
 9   changes correlate with disease. So I think this is a very ambitious
10   program, it's slated to be a 5-year program and we'll see how far they
11   get in five years. But the thinking of the community is that the time is
12   right to begin the process.
13                DR. JAMES: Well, thank you very much. We're right on time and I
14   want to thank you. I think this is very helpful to hear how central NIH
15   planning and now Betsy is very modest. I think some of you may know
16   there was a very important NIH reauthorization bill passed at the end of
17   last year which really put in place in law the structure, the
18   administrative structures to do this and also an appropriation funding
19   line specifically for the Common Fund so it's not a tap on individual
20   institutes. But I think it's also very important to think about as we
21   develop a report to the NIH director how will it complement and fit in
22   with other types of planning efforts which are going on now of many
23   different types and what specifically do you want to accomplish and how
24   will it compliment other types of planning activities. So thank you
25   Betsy very much for coming.
27   III.         Working Group Updates
29                And with that I think we can move right into the main agenda.
30   Joanne wants to get her pointer back. It has your memory chip in it too.
31   Ah. That's key. If you lose your pointer and your memory at the same
32   time. So the main agenda now is that we're going to go through reports
33   from the individual working groups. We have circulated all of the slide
34   presentations at least as they were developed at the point they were
35   sent around. These are being continually updated I think. You'll notice
36   by the way that we - although they are numbered 1 to 13 there's no
37   number 12 I guess. And I think at the next meeting we will renumber. We
38   thought it would be too confusing to change the numbers this time. And
39   the process that led to that was that 12 was really a placeholder for
40   things that were left over and it wasn't clear in the initial planning

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   that they would have a home. So in the meantime as the groups developed
 2   their specific agendas it was clear that we had a good home for all the
 3   things that needed a home. We still of course will be always looking for
 4   did we leave something out that's really important, but I think that we
 5   decided as a group that we didn't need to have Chapter 12 which I was
 6   very happy about because I might have had to be the chair of that, so. I
 7   worked real hard to find homes for everything.
 8                So I think with that we'll move right into the first
 9   presentation. Again, about 15 minutes. You don't need to do them
10   verbatim. I think some of the items will be very clear in terms of what
11   they mean. If people present things that are really unclear but you
12   think it's an important goal then I guess it's very important to clarify
13   what it means so that we all have a good understanding. I think it's
14   another one of the ground rules is that you as a group, the commission
15   members are the ones who are going to really decide which are the most
16   important things to move forward in. We will reach out again in the
17   future to the public at large and to the investigator community with our
18   draft report for further comment, but I don't think we should be at the
19   stage where well, here's what I have, but I need to go back to my
20   working group and we're going to discuss it some more for another couple
21   of months and then come back and present it again. I think we really do
22   have to move forward with a reasonable set of goals that seem to be the
23   ones that we should start putting things down on paper about. So I don't
24   want to take too much of Dan's time. I already took a minute or two. So
25   we have in total about 25 minutes for the presentation and the
26   questions.
28   Inflammatory Bowel Diseases (WG 5) Daniel K. Podolsky, MD, Chair
30          DR. PODOLSKY: Thank you very much, Steve. I can only guess in
31   looking over the whole agenda that the logic in having working group 5
32   present first was that we are the group with the fewest slides. So sort
33   of inverse proportion to the importance of the topic. And I'm here to
34   tell you if I get this right about the collective wisdom of the group
35   shown here who I think you'll all appreciate in the aggregate represent
36   an important and I think comprehensive continuum of different
37   perspectives on the challenges of inflammatory bowel disease. And in
38   drafting our set of recommendations we really endeavored to approach it
39   from the point of reference that should be foremost in our minds, namely
40   what are we trying to accomplish for patients and individuals who would

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   be patients. So the overall goals of any research plan in here, and I'm
 2   sure the same will be said for each of the other working groups, is to
 3   really do what we can to manage disease when it is manifest and wherever
 4   possible to prevent it from occurring in individuals in the future.
 5          That said, we identified a number of goals and I'll briefly
 6   overview them without going through them each in great detail as Steve
 7   has suggested. But really I think in this group in particular we'll see
 8   a number of points of strong connection to what we heard about the
 9   Roadmap initiatives that are planned going from this point forward from
10   Betsy. And apropos of one of the last questions asked there, I think in
11   IBD area it's especially true that one of the things that has held back
12   progress has been the ambiguity of phenotype and perhaps more properly
13   the variability of the range of clinical manifestations. And so a first
14   goals that really emerged as essential to accomplish those overarching
15   goals of better health in the future are to develop at a number of
16   different levels a defined approach characterizing patients which would
17   have an immediate benefit in clinical management, a more precise
18   diagnosis, but also to be enabling of all the other research goals which
19   I'll go on to describe.
20          And so you see here a list of what we thought were the most, by
21   broad category, key areas for definition with respect to the
22   inflammatory bowel diseases. And again, some of these have an immediate
23   thrust in clinical application and others are enabling of I'll say not
24   just basic research, but translational research. For example, I point to
25   the last bulleted comment here, the development of correlative and
26   predictive biomarkers would be not only important in clinical
27   management, but for really accelerating the ability to - for clinical
28   development of new therapeutics.
29          This is a particularly timely juncture in thinking about the
30   genetic contribution of inflammatory bowel disease. Since this group
31   convened by teleconference and really just within the last weeks we've
32   seen published the results of the NIDDK consortium and in just this week
33   of the Wellcome Trust Consortium. And arguably between those two we've
34   now identified something close to the full set of genes, maybe not
35   epigenetics, but the full set of genes which confer risk. So in some
36   ways that first bullet might be largely accomplished, though it's
37   important to say not necessarily in all patient populations. So there's
38   still more work to be done to understand variations among different
39   ethnic, racial groups, et cetera. But now the task is on to really
40   understand what those genes contribute by way of mechanism to the

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   eventual emergence of what we recognize as inflammatory bowel disease,
 2   and then of course to understand how that occurs in the context of an
 3   interaction between the genetic factors and the life experience, the
 4   environmental factors, given that we know that we can identify risk, but
 5   risk is not the same thing as disease development. And so you see here a
 6   set of sort of subcomponents of that overarching goal of developing an
 7   ability to individualize our assessment of risk for the disease, and as
 8   a correlate of that we hope insights into how an individual might be
 9   most effectively treated among the various therapeutic options that
10   otherwise would be among the armamentarium available.
11          Here we come to a point of very obvious connection to what we've
12   already heard about the Roadmap. And I think everybody here will have
13   some sense that there has been an emerging, really converging
14   appreciation that there may be genetic susceptibility, but there are a
15   clear requirement for environmental factors and among those if not the
16   sole one, certainly a major one is the nature of the microflora with
17   which the mucosa and the immune system interacts. And so clearly in this
18   disease area in particular, understanding the microbiome and having
19   approaches to do that across a number of different axes if you will was
20   viewed as being central to what will be goals over these next 10 years.
21   I guess the only hesitation I have, and this is sort of personal
22   editorial comment, is there's such unanimity of opinion on this whole
23   thing that I become concerned that it's wrong just because it's now
24   become such sort of conventional wisdom. But without actually being able
25   to, you know to challenge it beyond that philosophical point it's a
26   compelling part of what we think needs to be done. And that's not to say
27   a daunting one, given the complexity of the flora as was touched on by
28   Barbara in her comment, and the fact that to be meaningful it's going to
29   be important to understand variation across niches within individuals,
30   across individuals, across different environmental you know life
31   circumstances.
32                A fourth goal relates to what has of course been one of the more
33   longstanding foci or focus of these disorders and still seems really
34   essential to achieve an ability to understand the disease pathogenesis
35   and ultimately intervene effectively, and that is to characterize the
36   immune system so you could modulate it to prevent or ameliorate IBD. We
37   propose here really a framework for the comprehensive delineation of
38   immune responses, especially as in recent years we've come to be
39   particularly focused on the role of the innate immune system and nuances
40   in its workings may play in the very, very earliest phases of

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   inflammatory bowel disease. And so that's a fourth set of goals which
 2   are outlined in this report.
 3          And with that all as backdrop really the group came to consensus
 4   around an importance to understanding the mucosal surface. This is to a
 5   degree a little code for epithelial biology, what maintains the
 6   integrity of that surface, how is that functional integrity as well as
 7   anatomic integrity compromised in relationship to these diseases and how
 8   can its effectiveness be restored. I think it's noteworthy that even if
 9   our understanding of any one of the genes identified to confer risk of
10   IBD remains to be fully defined, virtually all or perhaps even I can say
11   all the genes are expressed within the epithelial compartment giving
12   sort of further emphasis to the value of this being part of a scientific
13   strategic plan to getting to an understanding of the pathophysiology of
14   IBD, and so what you see here is a set of sub-aims that are targeted to
15   achieve that overarching goal.
16          And in relationship to that, but really in a somewhat more global
17   sense it's important to develop the means to promote repair. It's fair
18   to say that certainly in the short term we don't presume that we will
19   have the means absolutely to prevent disease from actually occurring. We
20   still will be in the mode of how to best treat people who have manifest
21   disease, and one of the important goals therefore it follows is to have
22   strategies to foster physiologic recovery from inflammation and the
23   sequelae of inflammation. And so here are a set of sub-aims that if
24   achieved would allow one to promote, repair, restore normal function to
25   the individual who has experienced the impact of inflammatory bowel
26   disease.
27          A seventh goal which I know will have its counterparts in any one
28   of these, perhaps with the exception of the working group charged with
29   the overarching basic science so to speak of the GI tract, is in the
30   need to have effective tools for clinical evaluation and intervention.
31   This goes back in part to the original goal of having a phenotyping that
32   enables more consistent diagnosis and prediction with respect to natural
33   history, but goes on to really talk in slightly more detail about
34   specific components for clinical evaluation, intervention which are
35   central - which essentially will be dependent on advances in clinical
36   investigation and the strategy. So these include for example new
37   technologies to evaluate disease activity using those biomarkers which
38   we already touched on as well as non-invasive or novel endoscopic
39   imaging techniques, and to then on the basis of those diagnostic and
40   evaluative techniques to have more effective, more physiologic

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   interventions. Whether that's through conventional surgical approaches
 2   or endoscopic approaches, you know that would be to be defined. And so
 3   we identify here a number of really key components of unmet medical need
 4   that our clinical investigator community should be focused on.
 5          And before I think turning to the topic of major challenges, we
 6   have a final goal here with respect to the specific challenges of -
 7   specific needs of the pediatric population affected by these diseases
 8   and which we know, quite aside from the disease mechanisms that we've
 9   already touched on and effects of inflammation, there are in addition an
10   overlay of what it means to become ill as a youngster or an adolescent,
11   and both the psychosocial development issues as well as the growth -
12   impact on normal growth and development that were identified as very
13   important to an overall goal to ameliorate and prevent these effects in
14   children and adolescents.
15          So with that let me go to the major challenges and steps to
16   achieve these goals. The order here is a little bit - a little less than
17   consistent. Let me say that in general they fall into three types of
18   challenges. One is organizational, the need for large-scale
19   collaborations to achieve many of those goals. Second is technological,
20   needs for new tools to achieve these goals. And the third are related
21   just to the challenges of dealing with the human as the model organism
22   in clinical investigation. So I'll just run through these very quickly.
23   Some of these as you can see are the needs, they're sort of a
24   restatement of what the goals that we know the challenges are. We don't
25   currently have standards for endpoints for example in clinical trials
26   for acquisition of samples. And this is going to be enabling ultimately
27   of a number of those goals that I've outlined.
28          With respect to technological challenges there's a need, and
29   these are listed not on this slide, but somewhere on the next two to
30   follow, for more robust in vitro and in vivo animal models with
31   validated relevance to human diseases. This has been a long-recognized
32   limitation within the IBD research community and continues to be a major
33   hurdle. The other sort of broad swath of technological need is in
34   relationship in particular to the microbiome. It's one thing to say
35   you're going to go ahead and sequence it, but in fact there really
36   aren't the powerful computational tools necessary to do that in a way
37   which one can be confident in the end you can derive useful information,
38   actionable information. And so that's a really key sort of - a key set
39   of technological barriers.
40          As mentioned, an overarching type of challenge is the

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   organizational one and in particular the need for a national and
 2   international scale to achieve many of the genomic and clinical studies.
 3   I think that's already evidenced in the success of the NIDDK consortium
 4   and the Welcome Trust, but as we go deep to that to understand it across
 5   broader types of populations and truly to understand natural history,
 6   the translational component to the initial identification of risk, this
 7   becomes only more important. And I think in the same way, scale is self-
 8   evident as important to achieve projects like the microbiome as was
 9   already touched on by Betsy in her presentation.
10          Finally, I mentioned clinical. Some of that as I've said already
11   is around the need to coalesce around standards of diagnosis and of
12   patient stratification and characterization. But there are other
13   dimensions to this as well which are highlighted on this slide. That is
14   the need to really engage our patients as partners and the challenges
15   that any clinical investigator has encountered in getting enrollment
16   into studies, and this is particularly a challenge in the pediatric
17   population. So this, you know without going through them in each detail
18   because you have them there in front of you, are the broad set of
19   challenges which the IBD working group saw as really gating points for
20   achieving the goals that the group identified.
21          So let me just conclude with a few comments about initial goals.
22   This is a fairly nuclear list you see here. In an earlier version, I
23   can't remember if everybody saw that, we had like many groups, a very,
24   very long list and when we started to get through the exercise of
25   stratifying them as long-term, intermediate and short-term basically
26   they all regressed to a mean of being short- to medium-term and so we
27   went away from that degree of parsing. And also there were just so many
28   of them that we felt it was perhaps most productive, having identified
29   the overall goals and the components of those overall goals, the major
30   hurdles, to talk about what we could do to begin with to get on the
31   right path to achieve all that. So those initial steps are shown here,
32   one, to get over the issue of the power of scale that's going to be
33   necessary to answer some of the most important question is to focus on
34   getting the right consortia, to study the functional impact of the
35   genomic associations and to position the community as consortia around
36   clinical and translational investigators similarly. And again, we have
37   examples of just how powerful that can be by what's been accomplished in
38   the genome-wide scans. Apropos again of what's already been stated, we
39   saw a short-term - a very initial goal of getting the microbiome project
40   off the ground as really particularly key and to emphasize again that

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   some of the most important initial steps are not going to be to think
 2   you're going to sequence you know in a comprehensive way the whole
 3   microbiome before you have really developed the computational tools to
 4   do that most efficiently and most powerfully.
 5          And third among these initial steps was to convene a summit as it
 6   were of all the stakeholders to try to get to a common view on how to
 7   move forward with clinical trials, agreement around patient phenotyping,
 8   clinical phenotyping and otherwise, and clinical endpoints as a first
 9   step to expediting clinical investigation, and then in a general way of
10   the areas that I've touched on to really target some of the methodologic
11   development that will be enabling of the functional goals outlined you
12   know in our working group's report. And I think Steve that concludes my
13   report. Hopefully I've covered the ground in enough time to allow some
14   comment.
16   Discussion
18          DR. JAMES: That's great. Thanks very much. I'll open it up for
19   comments and questions. Yes, so Michelle, do you want to - Michelle
20   Cissell who is our science writer and is going to have to do some of the
21   heavy lifting is going to put down bullets and comments and things to
22   help organize this discussion I hope. And by the way, what we're going
23   to do is again, we'll try to narrow the goals. The reason for the day
24   and a half meeting is the expectation that some of you may want to go
25   back to the drawing board tonight and reformulate some of your goals,
26   and then talk about some of the implementation, or the beginning of
27   implementation more tomorrow. Okay? Yes, Rick?
28          DR. BLUMBERG: So Dan, that was very good. The question I have is
29   mainly for Steve though, is one of process and how we're going to begin
30   to talk about the overlaps, and how we're going to manage them. I mean,
31   some overlap as we said from the very beginning of this project is good
32   and I assume we want to focus on that overlap. And if you can give us
33   some guidance here.
34          DR. JAMES: Yes, I think that again just like giving a lecture you
35   can say something at the beginning, what you're going to tell somebody,
36   tell them and then tell them again at the end. The idea that there will
37   be redundancy, I think it's almost inescapable. If you look at this you
38   could easily insert other important disease areas and some of the
39   details are going to be different, but the overall approaches may have a
40   lot of commonalities. Therein I think is a lot of strength. My view

                           NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   would be that each individual area, likely special groups will look at
 2   that and maybe only look at that and see what is in there for my
 3   interest, and it should be a relatively complete story that's
 4   comprehensible. But then I think one of the things that I thought we'd
 5   talk about tomorrow as I put together a little slide set is just
 6   starting to collect the things that look like obvious overlapping areas
 7   and there are many of them. The approaches could be that we might even
 8   want to create a separate chapter just describing the extent of all the
 9   overlaps in very generic terms and bringing them to attention and maybe
10   I guess we could create a connectivity map showing how all the - many of
11   the themes interact among all these different topical areas. But I think
12   we also want to be sure that each one of them stands on its own to some
13   extent. If it's so cross-referenced that you would have to look at seven
14   other chapters to understand what Dan is saying about IBD I don't think
15   it would have the same impact. I think they should be little gems in
16   themselves and then we can also in a separate way, perhaps either as an
17   executive summary or even an overarching chapter deal with all the
18   connections and overlaps. I think that would be an obvious way to try to
19   handle it.
20          DR. PODOLSKY: Steve, I was going to at some point raise a sort of
21   somewhat related point in terms of process in that it would seem that we
22   would be aiming for something like consistency in the granularity or
23   generality of each of these reports. So you know, where is that
24   homogenization going to happen? I think you don't I think in the end
25   want one chapter which gets into excruciating detail and another one
26   which is you know one slide, we're going to cure this disease, so.
27          DR. JAMES: No. I think to have a common look and feel and
28   consistency is essential for it to have its ultimate major impact.
29   Michelle of course is primarily interested in how we're going to go
30   about doing that. And it's really our job to help achieve that in
31   putting up a reasonable number of goals in a same sort of way so that we
32   can begin collectively to write them. So I'm not going to dictate how
33   that has to be. My view is the fewer the better, that simple is better
34   than too complicated, but also not trivial either. I think it is
35   possible to write very pithy things with short statements. They should
36   be positive. In looking at the hurdles it became very apparent to me
37   because you mixed different ways of doing it that probably in the end
38   we'll talk about the challenges and hurdles, but we shouldn't be stating
39   them as lack of something because that often falls on deaf ears. They
40   should be stated in the positive. We need to do. But these are stylistic

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   things that we can handle. Rick?
 2          DR. BLUMBERG: Do I need to state my name for the record or it's
 3   not necessary?
 4          DR. JAMES: Yes.
 5          DR. BLUMBERG: Okay. Rick Blumberg. So just, now having that
 6   information, if I could then weigh in on a couple of very specific
 7   things in Dan's presentation. So with respect to the microbiome and
 8   Dan's hope to homogenize, I'd make a recommendation that for example
 9   with the microbiome which is so obviously overlapping with a lot of us
10   and certainly with my section in particular, that Abigail's section
11   focus mainly on generating the tools and the databases and so forth and
12   so on and leave the disease-related aspect to working group number 5 is
13   a very simple way to handle that overlap. And Abigail had, we'll see,
14   put in some disease implications of the processes that she had proposed
15   to get us to - help us help the community get us to some kind of
16   recognizable information about the microbiome, but leave the disease-
17   related aspects of it to the various subsections. And it's a little bit
18   more difficult than the mucosal immunity part because mucosal immunity
19   has because of the importance of IBD and the elegance of the human model
20   and the problem, IBD has become in many respects mucosal immunity, but
21   the similar kind of statement could be made there as well.
22          DR. JAMES: Yes. We left you to last on the agenda just because
23   your job is the hardest I think and because there's overlap with
24   essentially everything. But I think the way I hear you is that there's
25   still a way to on the one hand a somewhat clinically or translationally
26   oriented group will talk about the more translational issues in the
27   clinical research of where - how the technology will be used, whereas
28   your chapter could delve or more specifically talk generically about the
29   technology and the science of regulatory cells in and of themselves
30   without having to justify why we're interested. Because the connectivity
31   will be there. But I think you're right, you wouldn't write them the
32   same way in two different chapters. Other comments? Yes, Margaret.
33                DR. HEITKEMPER: I noticed in your presentation that you dealt
34   with the psychosocial issues related to children, but I didn't hear much
35   about how as the individuals progress into adulthood and all the issues
36   about coping and behavioral intervention. And given that this is going
37   to be a trans-NIH document, and thinking about different institutes that
38   might be more focused on the issue and how we help people just manage
39   their condition I wonder if you brought that into adulthood and not just
40   leave it entirely with the child, although that's obviously important.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. PODOLSKY: I think you know this gets at sort of a central
 2   issue is how much to lump and how much to split. In the course of the
 3   initial discussions and formulations as I've said already you know we
 4   had a lot more specificity and a lot of things which drop out in the
 5   formulation you've seen here in being explicitly mentioned. And among
 6   those was the consideration of these other dimensions to the clinical
 7   impact and clinical needs going forward. It didn't drop out of the
 8   consideration in the pediatric population just because it's such a
 9   prominent part of all that. And so I'm not sure how best to resolve that
10   because I don't know how deeply you know, a lot of these things could be
11   deconstructed into four and five different points except that I probably
12   would deal with it by being sure that there's an emphasis - and people
13   have to understand it for what it implies in the total care of the
14   patient and the family and so forth. But I'm a little concerned that if
15   you start to get back to specificity you'll have - there's another way
16   to approach it, but my own personal view and I thought some of the sense
17   that I had was so that people wouldn't be numbed reading a chapter with
18   too many recommendations, that you know we came to the judgment to do it
19   this way. I think there would be a way to parse the language and
20   certainly in the written report itself to elaborate on what "total care"
21   means to hopefully -
22          DR. JAMES: I think probably, I suspect what Margaret might be
23   alluding to is that looking up at the makeup of the working groups,
24   they're heavily oriented towards either clinical researchers,
25   traditional clinical researchers and basic scientists. And admittedly
26   you know, at NIH we're always looking for behavioral and social science
27   investigators because it's a rather thin crowd in short supply. And that
28   I think it's true that we probably will want a little expertise in
29   helping to, just like everything else in a very specific, carefully
30   crafted way make some strong statements about the importance of
31   behavioral and social sciences research so that it's meaningful and
32   means something to the community of investigators we'd like to
33   encourage. Because I think it's quite clear that it wasn't for the many,
34   many things that people wanted to cover that wasn't - you only could
35   have six or eight people. That often falls off the list and that's -
36   therein is the problem for this area. It's important to many areas of
37   research, but then never rises to the occasion of quite making it on the
38   list. So I think I hear your comment quite well and I think that we will
39   need to look at that in the final report to be sure -
40          DR. PODOLSKY: And I will say that I would hope that you, others

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   here will read the draft text of the chapter, make sure that it is you
 2   know adequately you know addressed in that.
 3          DR. JAMES: Yes. David?
 4          DR. LIEBERMAN: Can I just add a comment to that? I agree with
 5   this and I'm wondering if - I mean that's going to fall I think into one
 6   of these overarching theme kind of areas because several of the
 7   diseases, coping with cancer, coping with esophageal disease, whatever,
 8   are going to be behavioral issues, and I wonder, have you envisioned
 9   having some sort of a overarching theme sort of chapter where this type
10   of issue could be highlighted as important? It's not going to come out -
11   I agree with Dan's prioritization actually, so it's not going to bubble
12   up in that part of the report, but it seems like it's going to be an
13   issue with each one of the working groups that are clinical.
14          DR. JAMES: Yes, as I started out I think it seems that we're
15   going to be headed toward having some kind of additional replacement for
16   Chapter 12 with a chapter - we might call it an executive summary or
17   something else that deals with the overarching areas. This in a way
18   would be kind of like our own Roadmap areas that touch on everything,
19   but no one area is able to do it on its own and this would be a
20   particularly good example of that kind of issue, and that's why it never
21   gets done. So I hear you and I think that we'll want to focus as we move
22   forward on specific plans for how we would put such a chapter together.
23   But I think we have to have a fairly clear idea of the individual ones
24   first. And so certainly in many areas the issue of patient-oriented
25   research, behavioral issues, in IBS it will come to the fore certainly
26   and how to handle that will be important. Jay.
27          DR. PASRICHA: Thanks. Jay Pasricha. That was a very nice
28   overview. I really like the way you organized it. My question
29   specifically was to the slide that you have some initial steps. I wonder
30   how you arrive at that process because the number of steps that you've
31   shown is really out of proportion to the number of goals and it doesn't
32   really cover most of the goals that you wanted. And some of this is
33   relatively vague. I think, for instance target methodological
34   development. What specifically do you mean by that?
35          DR. PODOLSKY: Yes Jay, I mean it's certainly a fair comment and
36   you know, each of those really was a summary of which there are now
37   going to be several specific. So the methodologic - and I, when we get
38   into the chapter I think these will then be spelled out - spelled out
39   are some of the things I touched on you know that go back to the
40   original goals of developing the computational tools, developing in

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   vitro models, developing in vivo models. So what I attempted to do here,
 2   you know it may have been a bit misguided, was to take what was a list
 3   of about 50 things literally and you know give them what the - you know,
 4   the categories they seemed to fit into and also which ones really you
 5   know were fairly immediate as opposed to dependent kinds of things, like
 6   forming these large-scale consortia. So all I can say is that when we
 7   get into the writing, within the limits of the length practical for the
 8   chapters that those will be then further deconstructed.
 9          DR. PASRICHA: So I would have thought that this is true for all
10   the working groups, that the initial steps that we recommend are going
11   to be probably those that are not covered currently by traditional NIH
12   mechanisms. A lot of the goals for instance that you have are covered by
13   R01 mechanisms for others. But there are some steps that we don't have a
14   good mechanism within the NIH to cover, and whether we should be
15   thinking about putting those steps in a separate category.
16          DR. JAMES: Well, I don't think it's probably too smart to focus
17   so much on mechanisms as to what we think needs to be done. And some of
18   the things we think need to be done can be done through - in fact a lot
19   of them through existing mechanisms as long as they receive priority
20   and/or maybe sometimes it's developing a research community and
21   organizing it to do something doesn't necessarily mean you need to
22   create a new mechanism. But then again as they're doing in Roadmap
23   they're looking at what's the goal and then figuring out what's the best
24   way to get there, and sometimes it might require creating an entity that
25   doesn't exist. The CTSAs would sort of be an example of that, trying to
26   invent something to really do work in a new sort of way. But I think
27   we're perhaps getting a little ahead to worry about that part of it. I
28   think we should focus today on getting the goals down.
29          DR. PODOLSKY: But just to your point Jay, otherwise what I had as
30   a first version was in fact just a repetition of essentially all those
31   things listed under the goals. For example you know, characterizing all
32   of the T-cell populations and so on and so forth which is - it seemed,
33   if anything tended to camouflage what might be done as different than
34   business as usual and that's where I got to that overarching set of four
35   or five things.
36                DR. JAMES: Kenton.
37                DR. SANDERS: I wanted to ask about reciprocity between the
38   microbiome and the mucosa. It seems like it's an ongoing sort of
39   cultural interaction that may not be, you know, knowing something about
40   the microbiome and knowing something about the mucosa. But as these

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   things develop there are influences back and forth that go on and that
 2   becomes a much more complicated problem than just knowing what the
 3   cellular component or modeling of the mucosa is in reaction to the
 4   microbiome, or what the microbiome does and how it predisposes the
 5   mucosa to disease.
 6          DR. PODOLSKY: Yes, it's certainly an important point. I'd have to
 7   say that in a couple earlier drafts of this the microbiome showed up on
 8   every single slide, mostly with that thought in mind. I'm just looking
 9   back at it, seeing that in my effort to sort of try to hone in on - or
10   try to diminish the repetitiveness of it that you know it came out of a
11   couple. But it's there in specific relation to the immune system and the
12   interactions there. You see the importance of understanding the impact
13   of the immune system on the - excuse me, the microbiome on the immune
14   system and vice versa. But perhaps you know, to make - I may have
15   overdone it in sort of editing this out to underplay that point, so I'll
16   make sure that gets into the final report because it's a very important
17   point.
18          DR. JAMES: And John Milner?
19          DR. MILNER: John Milner of the National Cancer Institute. Quick
20   question related to your comment about the pharmacokinetics of
21   pharmacology treatment, and I wonder if within that you're actually
22   thinking about using drugs for prevention as well as therapy. That's one
23   aspect, and then the other aspect is have you broadened that to include
24   naturally occurring compounds that would be in the diet? Thinking about
25   calcium and a variety of other things that may in fact modify the
26   inflammatory response. If you're not aware, we do have an RFA that is on
27   the street actually to deal with this area.
28          DR. PODOLSKY: Well, on the latter point we didn't really think in
29   a particularly focused way about what range of therapeutic options might
30   be, you know whether naturally occurring compounds versus chemical
31   entities versus you know biologics or beyond that. So our assumption is
32   that there's no prior bias as to what kinds of things would be studied.
33   And I'm sorry, your first?
34          DR. MILNER: Well, I think then if you actually put in something
35   to mention prevention as well as something to mention naturally
36   occurring compounds I think you know, with cancer.
37          DR. PODOLSKY: Yes. Of course one of our two overarching main
38   goals, one of our two was prevention. Certainly one of the hopes will be
39   that out of the identification or risk alleles that there will be the
40   ability to identify those individuals where you could have intervention

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   ahead of time. I have to say it's an unproven hypothesis as of yet, but
 2   that's clearly one of the long-term essential applications of that
 3   insight.
 4          DR. JAMES: Michelle is quite familiar with Type I diabetes having
 5   written that report I guess, and that of course being an overarching
 6   goal to try to prevent that disease from developing. So thanks very
 7   much. We do need to move on and I think Mitch, you're in the spotlight.
 9   Infections of the GI Tract (WG 3) Mitchell B. Cohen, MD, Chair
11          DR. COHEN: Thank you very much. It's always a tough act to follow
12   Dan, but I think he set a high bar and very overarching goals and so I
13   will try to address some modifications as we go forward to keep the
14   model. As was already mentioned there is great wisdom in the crowds and
15   this was a great crowd of people representing a number of different
16   intestinal infections and we tried not to deconstruct into specific
17   taxa-related goals. So without too many exceptions, I think we were
18   successful.
19          In general, our overarching goals were to identify etiologies of
20   intestinal infection, to improve the prevention and treatment of
21   intestinal infection, to understand and modulate non-intestinal
22   consequences of intestinal infection and lastly, continuing the theme,
23   to understand and modulate the human microbiome to promote health, end
24   disease. This used to be called host microbial interactions, but I think
25   as we just heard from Kenton and then from Dan it really is a cultural
26   community and we need to learn to modulate that as part of intestinal
27   infections as well as part of other disease-specific entities.
28          So in rapid order, and I will try to not read all verbatim, one
29   important goal organizationally was to establish criteria for
30   accessible, potentially renewable archives of enteric specimens in a
31   panel of disease states and to establish a repository for patient
32   samples to be used for research into prevention and intervention. This
33   falls in the category of organizational goals. We also thought, again
34   this is our first use of the microbiome, that we needed to augment
35   microbial sentencing capacities of intestinal microbiota. I think even
36   before we have the computational efforts we need to understand that
37   there are still not a uniform way of approaching this in an unbiased
38   fashion, and that this includes, but it does not uniquely include
39   bacteria. We also need to develop an understanding of the intestinal
40   microbiome in the host genome on microbial colonization and to

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   understand the consequences of the host microbial interactions.
 2          We as others thought it was important to develop animal models to
 3   manipulate the microbial community and to understand the mechanisms of
 4   action of probiotics. I mention this separately. Dan voiced some concern
 5   that maybe the human microbiome may be the new fad of this next few
 6   years just as probiotics may have been the most recent fad. We shall
 7   wait to see. It was important to perform well-designed, case-controlled
 8   pathogen discovery projects in case-controlled host microbiota
 9   investigations. We thought it was important to develop new point-of-care
10   diagnostics to easily and rapidly diagnose known infectious agents of
11   diarrheal diseases. We are still using way outmoded technology in the
12   clinical setting to diagnose this.
13                Again, as a short-term goal we thought it would be important to
14   conduct epidemiologic investigations using state of the art molecular
15   techniques to establish the true incidence of various agents of
16   diarrheagenic diseases, to understand the health impact of acute and
17   persistent enteric infection in both normals and distinct subgroups of
18   patients, including immune-compromised patients. We thought it would be
19   important to perform studies to understand how common conditions such as
20   age, malnutrition and diabetes modify mucosal innate and adaptive
21   immunity and physiology, and to understand the role of host genetics in
22   the response to GI infections.
23          Among the last short-term goals we again now have a taxa-specific
24   or a micro-specific thing - goals here. Perform clinical trials to
25   define effective therapies, and again both antibiotic and non-antibiotic
26   for acetafaceal and to understand the mechanisms of the most common
27   intestinal function, rotavirus, to provide new approaches to the
28   treatment and also as a paradigm for other viral infections. We thought
29   it continued to be important both as a short-term and long-term goal to
30   understand the burden and impact of enteric infections on cognition and
31   health. This relates to both parasitic infections as well as viral and
32   bacterial, and to develop comprehensive outcome measures to guide and
33   standardize assessment of the impact of this burden in different
34   populations. This is also a biopsychosocial component to intestinal
35   infections. And we thought it was important to identify and characterize
36   enteric parasitic strains with increased virulence in humans as a goal
37   to - as a mechanism to determine key antigens for inclusion in long-term
38   goals of vaccine trials. And lastly, we thought it was important to
39   establish localized, centralized networks for healthcare professionals,
40   including primary physicians to promptly report suspected bioterrorism.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   This was our bioterrorism charge.
 2          In terms of intermediate goals, we thought it would be helpful
 3   once the technology was in place to assay the population of bacteria in
 4   the gut in a variety of disease states, and we needed to develop and
 5   utilize the computational power that would be needed to do this. This is
 6   our microbiome goal. We thought it would be important to move forward
 7   with vaccination strategies against high-frequency bacterial enteric
 8   disorders, recognizing that few are as of today fit this mold, but that
 9   cholera and possibly enterotoxigenic E. coli infections are the most
10   advanced and would lend themselves to immunoprophylaxis.
11          Another intermediate goal was to determine the role of GI
12   viruses, both those less well studied as well as those better known,
13   including rotavirus and other viruses in causing gastroenteritis. That
14   we are learning more about genetic polymorphisms, i.e., host genetics on
15   influencing susceptibility to enteric infections and that understanding
16   the host genetics may identify important immune pathways for protective
17   immunity as well as inform long-term research goals for rational vaccine
18   development.
19          In the intermediate timeframe we hope to complete the genome
20   projects for human enteric ailments and to initiate clinical testing of
21   a new generation of enteric parasite vaccines. And lastly, to develop -
22   not lastly, but to develop animal models for the study of enteric
23   infectious pathogenesis, including new therapeutic agents not limited
24   specifically to antibiotics or probiotics, but also testing prototype
25   vaccines. Another set of intermediate goals included identification of
26   correlates of immunity, development of candidate enteric vaccines to be
27   used in a human challenge model and to learn if intestinal -
28   gastrointestinal biota, both pathogenic and non-pathogenic cause non-GI
29   human diseases. So extraintestinal manifestations really of both GI and
30   non-GI diseases. We also thought it would be critical to identify
31   biomarkers to predict the development of systemic diseases secondary to
32   exposure to enteric pathogens.
33                Another intermediate goal was to pursue evidence for alterations
34   in microbiota under conditions relevant to various diseases such as IBD
35   as Dan mentioned, but I'm sure as will come up during the course of the
36   next day, other diseases that have now come to the forefront, including
37   obesity as a possible association with the human microbiome. And to
38   develop a central database repository where all known actions of
39   probiotics could be sent and compiled to further advance knowledge about
40   the mechanism of action and function of probiotics.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          Long-term goals: that once we had identified the candidates and
 2   done some intermediate testing we next thought it would be important to
 3   disseminate vaccines for enteric infections to susceptible populations;
 4   to initiate trials of interventions to modulate the gastrointestinal
 5   bacteria microbiota to prevent systemic and intestinal diseases,
 6   assuming that the short-term and intermediate term goals have proved
 7   valid and successful; to learn how to attenuate the host response to
 8   specific human infections even if we couldn't prevent them; and to
 9   determine if currently unknown gastrointestinal infectious agents exist,
10   to identify them and eradicate them. We thought that expansion of
11   studies to look at the long-term impact on enteric infection on both the
12   physical as well as cognitive and biopsychosocial development in all age
13   groups was important, and to integrate measures to control parasitic
14   infections, especially worldwide distribution of vaccines and mass
15   treatment protocols, including de-worming, et cetera, and to develop
16   efficient, cost-effective approaches to address environmental factors
17   that contribute to the burden of enteric parasitic diseases.
18          We thought it would be important over the long term to develop
19   various tools in the armamentarium to combat enteric infections of
20   immunocompromised hosts and translate the basic science understanding
21   from animal models developed in the short and intermediate term in terms
22   of Phase I and then Phase II and III human trials. We thought that
23   studying the feasibility of developing vaccines against non-pathogenic
24   bacteria as a way to implement the human microbiome may in fact be a
25   long-term goal, but at this point maybe is more theoretic; that we
26   needed to develop large-powered placebo-controlled trials to develop the
27   safety and efficacy of non-microbial - anti-microbial treatments, and to
28   explore the boundaries of genetically modified organisms for delivery of
29   biologically relevant therapeutics, whether for inflammatory bowel
30   disease or other approaches as well.
31          What were the major challenges? We did not take the higher level
32   view that Dan so nicely articulated, but in many ways reemphasized and
33   recapitulated some of the goals in the form of challenges. I think they
34   form three different categories. One is organizational, that goes to
35   structure, development of consortia and an adequate pool of talented
36   researchers, two is technological, the need for new tools, and three is
37   prioritization, the will to provide resources to do some things that are
38   technically doable now. We identified as the major challenges: the lack
39   of repositories and databases; the continued use of archaic bacterial
40   detection technology which really hasn't changed much in the last 50-

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   plus years; the need for understanding pathways triggered by specific
 2   pathogens in the gut; the need for understanding the genetics and
 3   replication systems of viral pathogens in order to develop the next set
 4   of antiviral therapies and vaccines; technologically the fact that most
 5   soluble antigens are poorly immunogenic; that vaccines for some enteric
 6   pathogens will require multiple antigens because of their multiple
 7   pathogenicity factors and antigen determinants; the fact that immunity
 8   to some enteric pathogens may be strain-specific and that critical
 9   antigens for some very important infections are yet to be identified.
10          We have very few correlates of protective immunity and this is
11   again a technological challenge so that most trials require large field
12   studies or human challenge models. Another technological challenge is
13   the fact that vaccines are less immunogenic when given to the people who
14   need them most, specifically those in developing countries and children.
15   And from a potentially organizational and prioritization factor, it
16   still is very difficult to get pharmaceutical companies interested in
17   developing vaccine products when the return on investment is limited
18   because the populations who will benefit mostly from them are in
19   developing countries. This could be an important conceptual challenge
20   that NIH could undertake by underwriting some of these costly
21   development opportunities or partnering with private foundations.
22          Another challenge is our limited understanding of the intestinal
23   microbiota and microbiome as well as the need to - the computational
24   power to identify the results we get from dissecting the human
25   microbiome, the paucity of small mammal models or in vitro models, the
26   need for new in vivo technology and imaging systems to apply to these
27   animal models in human diseases, the need to identify silent epidemics
28   and outbreak of enteric pathogens. We only really know the tip of the
29   iceberg here. Again, here's an organizational model that is achievable.
30   The listing of probiotics as food supplements impairs the understanding
31   of how or whether or not these probiotics work. And the training and
32   education pipeline is something that needs attention for the development
33   of multidisciplinary teams of researchers.
34          So in summary I think that we dovetailed very nicely, and I
35   assume there was not wisdom in the crowds, but wisdom in the organizers
36   by putting the intestinal functions right behind IBD. I think they
37   dovetail very well as they would with immunity and several other factors
38   as well. And I'm happy to take questions.
40   Discussion

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 2                DR. JAMES: Right on time. Comments? Thank you. Very nice. That
 3   was a spectacular group. They had a lot of great ideas. Jay?
 4          DR. PASRICHA: That's very nice, Mitch. One of the things that
 5   perhaps was conspicuous by its absence was helicobacter. I don't know
 6   whether you're supposed to cover that in this or not.
 7          DR. COHEN: It was conspicuous because we ceded it to stomach.
 8                DR. PASRICHA: The other aspect is the relationship of intestinal
 9   infections to - you mentioned non-GI chronic diseases, but also GI
10   diseases. There's Irritable Bowel Syndrome.
11          DR. COHEN: Right. It was actually on the bullet list of IBD, IBS,
12   et cetera, so absolutely. So both chronic manifestations of GI and non-
13   GI diseases. Absolutely. Although we - there is an overlap between that
14   and another working group, but we definitely will include it at some
15   level in our report.
16          DR. JAMES: Dan?
17          DR. PODOLSKY: I'd like to put out for discussion sort of what in
18   the end might be a philosophical touch point for all this which is
19   around the role - around the incorporation within these reports of sort
20   of actual therapeutic development. So in putting out a 10-year plan for
21   research and the goals therein for the Congress and the NIH, obviously
22   in each one of these areas I mean the ultimate goal is better treatments
23   you know for patients. And here you include some explicit goals you
24   know, advocating for development of vaccines and actual I guess not a
25   therapeutic, but anyway. So you know, for intervention. I'll say in the
26   IBD group it was sort of finessed in the sense that we're talking about
27   the research which of course, the long-term benefit of which is to
28   develop more important therapeutics. But how much should we be taking as
29   ownership within this report and saying we want to develop the actual
30   treatments versus the enabling science behind those treatments where
31   obviously historically there's a divide between what is done in the
32   public sector versus by industry.
33                DR. COHEN: Do you want me to respond?
34                DR. JAMES: Certainly.
35                DR. COHEN: Well, I hear the concern and I think we really do want
36   to stay away from favoring a particular product. By the same token, I
37   think with the understanding that we need to promote the clinical and
38   translational applications of these things in broad strokes. I think we
39   probably need to be able to hang our that or sink our teeth into a
40   particular approach. And I think you're right, finesse will be important

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   and that's why we may want to stay away from targeted organisms or
 2   specific vaccines, except to point out where the scientific advances
 3   are. I think in contrast to inflammatory bowel disease where companies
 4   are falling over each other to get a competitive advantage at times, in
 5   the area of intestinal infections companies are shying away from the
 6   issue in large part because of the lack of return on investment. If you
 7   charge $10,000 for treatment in IBD you may get it paid. If you charge
 8   $10,000 for a vaccine, you won't get it to market in the United States.
 9   And so I think you know, the bottom line is we won't be effective unless
10   we push the agenda, and I think to mention these things may be necessary
11   in specific areas, but being always aware of the danger of stepping over
12   the boundary and suggesting a competitive advantage and being tainted by
13   so doing.
14          DR. JAMES: I would just point out that this topic comes up all
15   the time. What should be the role of NIH vis-a-vis industry or even
16   independent - other organizations. And I think it's fair enough to say
17   that the goals here are patient benefit, health benefits, and that we're
18   obligated to point out opportunities to partner and to - and not try to
19   say here's an area in which NIH should work, but there are other areas
20   where we shouldn't because industry should do it. Absolutely not. I
21   think we should be pointing out opportunities and even raise questions
22   about how to partner more effectively for translational goals if that
23   was the question. I thought this chapter was specifically missing other
24   than parasites much about pharmaceutical development and it concentrated
25   more on vaccines which I think is fine. Maybe the question is was that
26   left out on purpose, or just because - I think if something is not
27   economically feasible I don't think we necessarily should not say that
28   there aren't any goals there.
29          DR. PODOLSKY: Just in follow-up, I think there may well be
30   something that's distinctive - you know, the continuum between the -
31   into the development of actual vaccines. And vaccines may be sort of
32   different by nature than thinking about you know as new mechanisms are
33   identified, getting into sort of more if you will conventional drug
34   development, small molecules and the like. But Steve, if it is the case
35   that you want to be sure that we should be thinking about this report
36   encompassing all that, then you know one of the things that we should
37   get back to as a crosscutting theme is how, you know is what we should
38   be doing as a research community and as a publicly funded vision to
39   foster that, whether it's you know centers for chemical biology that tie
40   into this or whatever. Because otherwise you're talking about a whole

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   dimension that historically you know has not been part of our own
 2   research paradigm. It's the interface with the industry research and
 3   development paradigm.
 4          DR. JAMES: I don't think that anything is out of balance in terms
 5   of what you would recommend as important areas. I mean again, this
 6   report is to the director of the NIH who has a very central role in
 7   trying to be the interface between government and our many partners in
 8   improving health. And if you have cogent, important things that you can
 9   recommend they should be recommended. The difficulty of course is in
10   figuring out how to administratively do it, but again, vaccines of
11   course are an important paradigm for things that aren't necessarily
12   commercially attractive in the United States, but I doubt that anyone
13   would have any question about their importance as a research goal. And I
14   don't think that really necessarily requires any finessing or excuse
15   that, well it might not be commercially feasible. If you're getting to
16   the issue of how it - well, Dr. Yamada of course made some very cogent
17   points at the DDW about how one could encourage areas that might seem to
18   be off limits through creative administrative approaches.
19          DR. COHEN: So Steve, just to respond to your comment, I think we
20   probably should go back and review and make sure we have adequate
21   emphasis for other therapeutics throughout here. We made a conscious
22   effort however not to list specific therapeutics or even topics such as
23   probiotics, wanting it to be more enduring and being concerned that five
24   years from now it may look silly to have recommended a strategic plan on
25   probiotics. So for example, and I just picked up one, "perform clinical
26   trials to define effective therapies, antibiotic and non-antibiotic" is
27   our buzzword for a broad swath.
28          DR. JAMES: One question I would have is that you really have a
29   large number of goals.
30                DR. COHEN: Yes.
31                DR. JAMES: Some of the goals are actually more processes to
32   implement, such as forming a repository or something. So I wouldn't
33   think that a repository is going to make Joe Public feel particularly
34   comfortable that this is going to help me with my disease. We understand
35   how that would help. But I would tend to certainly reformulate and
36   describe the goals in research terms of what one wants to get out of it
37   rather than something that's needed to get there, such as a repository.
38          Also, I think that you have an awful lot of goals and I wonder if
39   they, like the IBD one, can be sort of assembled into some more
40   overarching smaller number of things. For bugs we know about, can we

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   understand more about how they cause disease and find targets to
 2   intervene? Can we prevent diseases with vaccines? Can we discover new
 3   causes of diseases? So that type of idea. Then you have a wealth of
 4   many, many things that are associated with each of these topics, but I'm
 5   wondering if the goals should be more like these overarching sorts of
 6   ideas for which there will be many, many specific sub-bulleted things of
 7   ways to address those in a somewhat different fashion. As presented it's
 8   an awful lot of goals, and some of them do seem to be duplicative or
 9   just restatements in a somewhat different way of the same idea. Does
10   that sound right?
11                DR. COHEN: Yes.
12                DR. JAMES: Do you think you can work on that?
13                DR. COHEN: Yes.
14          DR. JAMES: Kenton.
15          DR. SANDERS: I wonder if there's much emphasis at this point on
16   sort of long-term or residual effects of infection. And you know, are
17   there maintained inflammatory responses that go on, or are there defects
18   from remodeling of cells due to the infection and how to reverse these
19   long-term changes?
20          DR. COHEN: I think if it wasn't clear it's because it wasn't well
21   stated, but that was clearly a topic of discussion. So it will need to
22   be emphasized.
23          DR. LIEBERMAN: Like Dan I wanted to wax philosophical for a
24   minute. When I was thinking about this topic I kind of approached it
25   from a public health view. Worldwide, diarrhea is one of the leading
26   causes of death and in the United States, and I think Bob and Jay have
27   looked at this, in terms of economic impact it's a huge impact. And I
28   guess as I think about it from that perspective what would be the
29   priorities? And it seems like worldwide the priority would be a
30   development of simple prevention measures. So since most of the diseases
31   worldwide are waterborne, coming up with very simple, inexpensive things
32   that would reduce the risk. A great example of that is research that's
33   been shown with just the impact of very inexpensive mosquito nets and
34   the impact that has on malaria. Something like that would be something
35   appropriate here.
36          In the United States it seems like looking at issues related to
37   transmission, we just - we had the recent E. coli and spinach thing.
38   Well, that has a huge economic impact. You know, one little batch of
39   spinach gets infected and then the marketplace goes crazy. You know,
40   trying to understand these transmission factors better so that this sort

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   of thing can be prevented would have I think an enormous impact on the
 2   public.
 3          And then the last point which was actually just raised which will
 4   probably come up in the functional bowel disease is the post-infectious
 5   IBS issues. We're seeing a lot of this now in post-Iraq veteran
 6   populations, very young male populations coming up with new GI symptoms
 7   that would appear to fall into this functional category.
 8                DR. JAMES: I think one of your goals did actually touch on that
 9   in terms of talking about non-GI manifestations, and they could be
10   chronic manifestations, of GI infections, and so certainly that is -
11   you've already got some of that in there. Dr. Sy?
12          DR. SY: Francisco Sy with National Center on Minority Health and
13   Health Disparities. Our center has collaboration with the Fogarty
14   International Center and Fogarty have this initiative called Framework
15   on Global Health. And some of this global health initiative are focused
16   on intestinal parasitic infections. So I'm wondering if your commission
17   - I know that one of the challenges you mentioned is the lack of
18   interest from the pharmaceutical companies in terms of vaccine
19   development because they're targeting - a lot of these diseases are
20   found in developing countries. But there are some examples though of
21   pharmaceutical companies that collaborate in terms of supplying some of
22   the medication. In fact, some of the Gates Foundation initiatives are
23   focused on this de-worming in some of these developing countries. So I'm
24   wondering could the commission have some of its goal in terms of
25   collaborating with foundations or Fogarty in terms of this global
26   initiative on de-worming or targeting mass treatment of let's say
27   schoolchildren in some specific infection in developing countries.
28          DR. JAMES: All right. Those are very cogent points. Again, I
29   think that just to have some boundaries around our report, that they
30   ought to be couched in terms of NIH research, and that is I think that
31   we don't want to merge into providing global health. But certainly we
32   are in the business of generating the knowledge that will inform how to
33   better deliver health interventions throughout the world. So I think one
34   has to be careful that one could say that we should get engaged in
35   developing clean water programs, or machines that provide clean water in
36   a village, but I think that's a little bit out of bounds of what at
37   least our institute does. Maybe your institutes does, Dennis? Do you
38   want to address that?
39          DR. LANG: My comment was something else. Sorry. I'm wondering
40   whether the commission at all - it was brought to my attention with

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   Mitch's talk, but something maybe that you might consider. It seems to
 2   me there's an opportunity for the intersection of data that's going to
 3   be happening fairly shortly I would think over the probiotic issue in
 4   general, the definition of the gut microbiome and its variability among
 5   populations, to really think about better defining what has been termed
 6   the hygiene hypothesis and its role in developing a balanced immune
 7   response, and in addition to characterizing that information. I think
 8   there might be an opportunity to combine the idea of probiotic treatment
 9   with an early, essentially early in childhood trying to mimic if you
10   will an antigenic stimulation that would create a balanced immune
11   response and hopefully ameliorate several complex diseases that we could
12   all identify as being possibly related to that with the idea that you
13   could do that without incurring infection and pathogenesis by proper
14   identification of the right antigenic stimulus in the absence of an
15   intestinal infection that would be life-threatening. It's an opportunity
16   not specific to this particular topic, but one I thought maybe would
17   resonate with several of the other topics in the agenda.
18          DR. JAMES: That is a good thought. So as we eliminate parasites
19   it's going to further you know worldwide the problems of the developed
20   world. I don't know. Did you deal with the hygiene hypothesis in Chapter
21   1? So that's a good point I think in terms of on balance one has to
22   always remember as we do things that are intervening to provide health
23   that we also don't create new problems, or try to understand the ones
24   that go along with that. That's a very good point. Other questions or
25   comments to help? So tomorrow you'll want to go through a revised
26   version of this quickly I think. Can you do that?
27          DR. COHEN: Yes.
28          DR. JAMES: Good. Okay. We should take a break now Bob says. We're
29   a little behind, but that's - I think we're still learning how we're
30   going to do this, but I think both presentations were terrific. And
31   we've got some more work to do, but it's getting much more focused.
32   Thank you all. Back at 11:30.
33                (Whereupon, the foregoing matter went off the record at 11:17
34   a.m. and went back on the record at 11:37 a.m.)
36   Cancers of the Digestive System (WG 4) John M. Carethers, Chair
38          DR. JAMES: John? Again, Gene hasn't appeared yet so we're going
39   to postpone that. Yes, why don't you go ahead. People who are getting
40   coffee can listen while you're speaking.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. CARETHERS: Okay, so I'll go ahead and start. I'm Working
 2   Group 4, Digestive Cancers. And just to let you know this was a daunting
 3   task since this is a very broad area and covers a lot of different organ
 4   systems. So just like any other section we had our subgroup chaired by
 5   individual leaders that talked to as many as 35 people in the community,
 6   researchers, PhD's, community leaders to get information. So myself and
 7   Bob Sandler are the chair and co-chair. These are the members that's
 8   listed. And we decided to keep an organ-based approach to this because
 9   there's some differences, although you'll see at the end there's some
10   overlap with some of the cancers. So we have a basic cancer mechanism,
11   esophageal, stomach, pancreatic, colorectal, and then we have what I
12   call orphan cancers which didn't fit anywhere else. And as you notice,
13   hepatocellular carcinoma is not on this list because it's with the liver
14   section.
15          So each individual area ranked short-, medium- and long-term
16   goals. And I hope you can read this. I decided to put it in a table. I
17   thought it would be a little bit easier presentation, although the
18   lettering is a little smaller. And then a subsequent emailing went out
19   and asked everyone, particularly the subgroup chairs, to rank their top
20   two or three items that they would like to see hopefully implemented
21   down the line. So we tried to focus this down a little bit. So in the
22   first group, the basic cancer mechanisms, short-term goals include these
23   five items, define epigenetic mechanisms which as you heard in the NIH
24   Roadmap presentation was ranked by those co-chairs as the number one
25   thing in the short term to figure out and understand. And secondly
26   highest ranked was to characterize the tumor niche. So again, this is
27   across all cancers, just basic mechanisms. And what that means, the
28   tumor niche means is the mesenchymal epithelial environment and how that
29   interplay occurs. For intermediate goals we had less, three goals listed
30   here, but the number one ranked by the subgroup chairs was a targeted
31   approach based on single transduction for treatment. So this is aka the
32   Gleevec story where if you understand the basic mechanisms you can
33   perhaps develop targeted therapies. And second highest ranked for
34   intermediate goals was the biological properties of stem cells in the
35   micro-environment. It comes out characterizing the tumor niche in the
36   short-term goals, but this has been a hot topic lately, particularly
37   with organ - presumably organ-based stem cells. And for long-term goals
38   we had three ranked for basic mechanisms. The highest was sensitivity
39   and specific serum-based biomarkers for early detection and prediction
40   response to treatment. That implies that we would understand all the

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   biomarkers for the different organ-based cancers, and as you'll see this
 2   is a theme throughout all the organ-based cancers. And also develop
 3   population-based strategies to screen and prevent. And even though we
 4   have that well for colon cancer, we don't have it as well, except for
 5   certain targeted populations, for instance with pancreatic and
 6   esophageal cancers.
 7          So some of the major challenges for implementing these are
 8   development of high-throughput in genomic and proteomic facilities to
 9   compliment the CGAP project. Develop high throughput drug discovery
10   programs based on targeted approaches to cancer biology. And some of
11   this you can argue is done by industry, but we still have to understand
12   the biology to get through that. And there are certain limitations.
13   Establishment of databases that correlate clinical information with
14   biological information. And it's again nice to hear the Roadmap
15   presentation. And then development population-based screening with
16   biomarkers that prove sensitive and specific for a given cancer, because
17   we just don't have as many right now. So these are the major challenges
18   for those.
19          Now switching to esophageal cancer, going down the line we had
20   several short-, medium- and long-term goals. Again, these were ranked by
21   the subgroup leaders. Number one, and I just got these like two days ago
22   so I hope I put it correct because it wasn't in my email, but develop
23   population-based risk models for cancer assessment. And surprisingly,
24   this is - even though we know a lot about Barrett's cancer, this is not
25   real well known who's going to get cancers, and how do you predict even
26   what person with Barrett's will get cancer. Genome-wide scans for cancer
27   characterization. So to understand what is going on at the genomic
28   level.
29          Intermediate goals. Use pre- and post-treatment biopsies to
30   determine molecular abnormalities associated with treatment resistance.
31   And again, this is akin to what I mentioned in the basic mechanisms.
32   Number two ranked was develop risk assessments that can be detected in
33   blood. Again, the biomarker story. And this one had a third one, develop
34   minimally invasive imaging or molecular techniques for pre-malignant
35   changes. And we have rudimentary processes to either stain the
36   esophageal epithelium, and those need to be improved. One of the
37   subgroup leaders combined these two. I'm not sure if they can be
38   combined, but certainly a randomized trial looking at NSAIDs because
39   there's data now that NSAIDs can slow down the growth or maybe even
40   prevent the growth of cancer coming out of Barrett's, as well as a

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   randomized trial of ablation technologies that a lot of groups are
 2   performing now. But we still don't have good studies to address how well
 3   that works.
 4          So some challenges to implementing these. Implementation of
 5   pathways for clinical goals followed by translational studies. This is
 6   what one of the working group members calls the translation continuum.
 7   So this is a challenge because this hasn't always happened in this
 8   manner. Improving technology for imaging as I mentioned. Develop an
 9   implementation of preclinical models for esophageal cancer. So to
10   understand - to develop some of these biomarkers for instance, and
11   understanding some of the genetics. There aren't very good preclinical
12   models. And diagnosis and treatment options for esophageal cancer remain
13   relatively poor. Except for surgery, if you're lucky enough to find it
14   early many of these patients have a high mortality rate.
15          So going down to stomach cancer. Again, several short-,
16   intermediate- and long-term goals ranked by the subgroup leaders. Number
17   one is to develop a complete molecular profile of gastric tumors from
18   various locations in the stomach and the different types. So there's
19   different types characterized by the histology, intestinal and diffuse,
20   and including not only just the genomics, but the epigenomics. And
21   again, it was nice to hear the Roadmap talk this morning. Tools to
22   execute transgenic studies in the stomach. So these are essentially
23   mouse models to understand gastric cancer better. And begin more defined
24   registry with analysis of tumor location cell populations, cell type in
25   populations with a high prevalence of cancer.
26          Intermediate goals. The number one ranked was a wider application
27   of a transgenic approach to further understand again animal models.
28   Number two was molecular target database to identify small molecules
29   analyzed for chemotherapy, and third was the validation of the stem cell
30   hypothesis that hit science about two or three years ago. And then long-
31   term goals, refine risk stratification for investigation of screening
32   and surveillance of gastric cancer, and then coordinate the United
33   States investigators with those in endemic areas, for instance in China,
34   Iran, et cetera, because of their higher incidence of cancer and having
35   a larger study population.
36          Some challenges. I'll go through these briefly. Developing a
37   molecular roadmap that coordinates with the various phenotypes, again
38   using some animal studies, and these have to be developed. Establishing
39   a reliable tumor registry, and this is a theme amongst all the cancers.
40   Develop a screen for small molecules. Again, you could argue that this

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   could come from pharma, but in some cases this can also be done in
 2   certain laboratories. This may be more related to the H. pylori
 3   infection stomach group, but to determine if Menetrier's is related to
 4   H. pylori. This was one of the ones that wasn't as highly ranked.
 5   Phenotype patients that do not respond to genetic-based therapies.
 6   Again, profiling patients for treatment. And then develop clinical
 7   protocols for clinical trials that utilize both surgical and medical
 8   therapies.
 9          So moving to pancreas. Pancreas is indeed a challenge because of
10   the very high mortality ratio for those who get pancreatic cancers. So
11   one of the short-term goals was to create a new foci of researchers for
12   developing a critical mass. And this was based again off the pancreatic
13   cancer program review group from about six years ago. And accelerate
14   research into the genetics and familial patterns for molecular designed
15   therapies. So this again is developing essentially some type of database
16   or registry to get a good compendium of patients to really study them.
17   For intermediate goals, the number one ranked by the subgroup leaders
18   was improve access of researchers to novel therapeutic compounds because
19   we have very few compounds that prolong life, if any, in pancreatic
20   cancer, and develop risk stratification tools. Can you determine who's
21   going to best benefit. And then this comes down to again biomarker as
22   well as genomic studies.
23          For long-term goals, determine effective early diagnostic methods
24   applicable to the general population. So if one is targeting people who
25   have certain genetic diseases such as Potyager's disease, but perhaps
26   other high-risk groups such as those with diabetes if there was an
27   algorithm to determine that. Determine major epidemiologic risk factors
28   using modern study design. Some of these risk factors are from older
29   studies and to refine that with some of the new tools is one of the -
30   was suggested.
31          So some of the major challenges. And I whittled down some of the
32   ones that were directly due to what I call the f-word, the funding word.
33   Systemic therapies have been ineffective to date and we don't have any
34   good therapies for those who unfortunately develop pancreatic cancer.
35   Lack of surrogate markers to evaluate therapy. So if we could follow if
36   they're going to improve or not, or even predict. Our imaging technology
37   is getting better with endoscopic ultrasounds, certain CT slices, but
38   it's still not quite there yet. Some of these - if you can find cancers
39   when they're small, when they're curable and that's been the challenge.
40   Problems development a tissue repository to study these. Again, getting

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   a compendium of patients with familial disease. Even though there are
 2   some now transgenic models of pancreatic cancer, they may not fully
 3   replicate the human disease. Low-impact discoveries for patient care. So
 4   some of the discoveries that have come across in pancreatic cancer
 5   haven't fully transformed this into can we improve the life of the
 6   patient. And again this ties into number one, there's no effective
 7   treatment.
 8                So colon cancer. Again, several, particularly on the short-term
 9   goals. I was surprised actually by the ranking a little bit and I'll
10   tell you why in just a second. So number one is to integrate non-
11   invasive screening into practice. And this stems from the fact that we
12   are screening people, but still only about 40 percent of the people who
13   are eligible are getting screened. And are there other techniques that
14   can be approved in the short term to intermediate term that can improve
15   screening and reduce risk. Number two, determine the ability of selected
16   nutrients to protect was ranked second. Third was race and colon cancer.
17   The surprise one, I thought that was going to be high, was the natural
18   history of small polyps because of the imaging policy. But again, this
19   was just ranked by the subgroup leaders.
20          Intermediate goals. Number one was the clinical trials of
21   nutripreventive agents and this is again another hot topic now as we
22   start understanding how some of these agents work. Not just the aspirin
23   and NSAIDs, but other nutripreventive agents. Number two, to improve
24   needs to identify patients, colons or premalignant lesions that give
25   rise to - colorectal cancer. We know that only a small percentage of for
26   instance adenomas or any other lesion in the colon will turn into
27   cancer. What determines that is what we don't know. Identify certain
28   genetic factors, i.e. SNPs, that can link low-level family risk. We know
29   some of the high-risk genes that give you a 60 to 100 percent
30   penetrance, but there's a huge group of familial cancers that we don't
31   understand that at all.
32                Long-term. Number one, number two were integrate preventive
33   programs for high-risk. Even though we have a lot of suggestions that
34   people follow, there hasn't been a defined program that people have
35   studied rigorously. And develop SNP analysis to perfect the role of
36   colon cancer in individuals.
37          Major challenges, I'll go - brief. Colorectal cancers that appear
38   in old age and assessment or prevention may be difficult. In other
39   words, their life span is short after you prevented it and are you
40   really affecting that, although there is some evidence that we are

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   coming into the general population. I'm going to skip the other ones.
 2   I'm going to skip the orphan because they're small. So I'm going to go
 3   to some common goals. Most of the subgroups broke down to what we define
 4   as the short-, intermediate- and long-term. And they developed tools in
 5   the short term, apply those tools in the clinical trials for long-term.
 6   Another common goal is understand the basic biology of each cancer
 7   including the stem cell niche. Number three, genetic/epigenetic
 8   characterization of each cancer and/or the patient for eventual focus
 9   therapy and prognosis. And that's another hot topic. Getting adequate
10   tissues, particularly of high-risk patients to really understand this
11   better. Understanding more the familial and the environment,
12   particularly the diet. And you can also argue the microbiota that
13   contributes to perhaps the cancer, who knows. That should be determined
14   for each cancer, particularly colon cancer. Targeted approaches and
15   improve imaging technology is our common theme.
16          So lessons learned. Even though of all these cancers because we
17   have access to the premalignant stage for colorectal cancer, colorectal
18   cancer is still the best studied, but other cancers and research often
19   borrow techniques from that best studied cancer. But even - we still
20   don't understand fully the biology of colorectal cancer. For instance,
21   this whole epigenetic issue particularly with what's defined as CINP
22   tumors. It's not understood. And secondly, discovery for major advances
23   in treatment patients moving at a measured, slow pace. Once you get the
24   cancer, can we improve the therapy. I mean, we're still doing things
25   that we've done for the last 20 years or longer and there appears to be
26   no coordinated national effort to put groups of research together to
27   tackle the treatment aspect. That was the general feeling. So the last
28   question, last slide is could there be an NIH structure to coordinate
29   some type of multidisciplinary or multi-investigator studies on the
30   pathogenesis, genomic identification and biomarker discovery as well as
31   treatment for GI organ-based cancer. And I'll stop there.
33   Discussion
35                DR. JAMES: Thanks John, that was terrific. Comments, question?
36   David?
37                DR. LIEBERMAN: John, I have a question. I guess I was a little
38   surprised on colorectal cancer - it's really the 800-pound gorilla of GI
39   cancers - that there wasn't an emphasis in the short-term goals and
40   maybe intermediate on new markers of risk. So using genomics or

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   proteomics or other things. Maybe I missed it?
 2          DR. CARETHERS: Well, it's on here, but it just wasn't - I mean,
 3   this was just a working group leader's ranking. So I put it on here
 4   because we still may include it, but it just wasn't ranked by that
 5   leader. So it's definitely here.
 6          DR. LIEBERMAN: Okay. Yes, because I mean it strikes me that I
 7   mean the Holy Grail of screening is going to be some relatively simple,
 8   non-invasive method of risk stratification.
 9          DR. CARETHERS: And if you look at this, for instance this wasn't
10   ranked, but certainly in intermediate - it was in intermediate.
11          DR. PODOLSKY: I was going to make a comment on more or less the
12   same general topic that David has raised, but just to go into one degree
13   of specificity. That there doesn't seem to be anything in the short-term
14   goals that relates to you know what clearly is one of the most important
15   things in evolution, sort of alternate screening through CT colonography
16   and so on. So does that -
17          DR. CARETHERS: This is kind of in this -
18          DR. PODOLSKY: So we're calling that - that's part of the non-
19   invasive?
20          DR. CARETHERS: Yes.
21          DR. PODOLSKY: So we consider - it starts with the assumption,
22   integrating them into it. Do we know already what is the right role for
23   which of those? I mean, there just seems to be implicit that's something
24   that isn't yet fully established. We're coming to understand what is
25   optimal screening with available technology.
26          DR. CARETHERS: So yes. So this might be a little bit premature as
27   a short-term goals. This might be more of a long-term if the technology
28   warrants it. So I agree with you on that. So we can actually move that.
29          DR. PODOLSKY: So I would say that somewhere in the very short-
30   term should be really validating an optimal approach and the true role
31   of the options available into screening.
32                DR. CARETHERS: Right. Okay.
33                DR. PASRICHA: That's a very nice job. A couple of questions. One
34   was did your group attempt to give any kind of weightage to these
35   various cancers? Because I notice you spent a lot of time on gastric
36   cancer in comparison to some of the other cancers. The clinical problem
37   at least in this country is relatively small, and not knowing whether
38   that will figure in your final list. That's one question I had.
39          DR. CARETHERS: So you know, we didn't - not specifically, because
40   each group had two subgroup leaders, but in relative incidents you know

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   colon cancer is the most common of these cancers. But when we did the
 2   initial discussion it wasn't discussed that we were only going to focus
 3   you know, put 20 topics on colon cancer and only two topics on
 4   esophageal cancer or something like that. That's something that I think
 5   that we would refine over time.
 6          DR. PASRICHA: And the other comment I had was in terms of the
 7   prevention, nutripreventive, nutraceutical approach. I think there's an
 8   opportunity here for linking this to some of the microbiome,
 9   particularly in terms of the prebiotics that perhaps your group could
10   highlight a little bit. That didn't really come out as clearly.
11                DR. CARETHERS: So you're saying in addition to for instance -
12                DR. PASRICHA: So there is a component of this nutripreventive
13   approach that actually is a prebiotic approach. In addition to some of
14   the supplements there is a prebiotic approach that may alter the
15   microbiota and that may - I guess the connection between the microbiome,
16   colon polyps, colon cancer, is something that perhaps is for the
17   researcher.
18          DR. CARETHERS: So looking at the environment in colon cancer, I
19   meant there's - we don't fully understand - we know for instance certain
20   agents may reduce your risk epidemiologically. There's some biological
21   evidence. The other question is you know, everything from the presence
22   of bile, the presence of bacteria, the colonic motility, I mean how do
23   those influence. And so I guess if we focus - and maybe I'm taking this
24   out of context or not, but maybe just on the microbiota which I agree
25   with you may have a role, but would you suggest that that be, you know,
26   an intermediate, or would you suggest that that would be more fully
27   understood in one of the other groups and then link that to developing?
28          DR. PASRICHA: Well, I'm not getting into a specific mechanism,
29   but I'm just saying this is an opportunity here to sort of identify this
30   as another potential link to the overarching theme of microbiology in
31   the gut.
32                DR. CARETHERS: So better understand the?
33                DR. PASRICHA: Interaction between the intestinal microbiome and
34   the predisposition to colorectal neoplasia or epithelial health in that
35   regard.
36          DR. CARETHERS: So I'm still trying to figure out how close that -
37   I mean, so just evaluating it now because we don't have a good specific
38   link? You're saying just evaluate?
39          DR. PASRICHA: As a research goal I thought this may fit here.
40   Something - as we go forward in the future I think it would be something

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   worth looking at.
 2          DR. CARETHERS: And are you suggesting only for the colon?
 3          DR. PASRICHA: That's the most obvious I think. Amongst all the
 4   cancers that's the most obvious link, but it of course could apply to
 5   others too.
 6          DR. JAMES: Yes, in looking at your goals and just actually
 7   thinking of practical things of how you envision writing this up, it
 8   seems reasonable that you would have a little piece on each of these
 9   specific big areas of cancer because they're so important. But also
10   clearly as you started out, the crosscutting ones that are common to all
11   of them, imaging, biomarkers, role of environment, neoplastic factors. I
12   think you'll be able to carve out some that touch on everything and
13   highlight them in that way perhaps. And for many, I'm not sure, often -
14   we realized midway through this exercise that a lot of the groups got
15   very hung up on short-, mid-term and long-term goals and trying to be
16   sure that they had a whole sequence that meshed together when in fact we
17   really just wanted to be sure that the long-term goals were good ones.
18          Rick has had his hand up for awhile.
19          DR. BLUMBERG: Thank you. One thing that is certainly a very hot
20   area in immunity right now, immunology and it crosscuts here is
21   inflammation and cancer development, and the mechanisms that transition
22   from inflammation to cancer. In Dan's he focused on the end stage,
23   detecting it. It might be appropriate in your chapter to focus on the
24   mechanisms that get to that point.
25          DR. CARETHERS: Right. I couldn't agree with you more. We were
26   careful not to include things like ulcer colitis and stuff because of
27   the other groups, but you're absolutely right. Esophageal - yes, there
28   is - okay, we don't specifically say it, but we can specifically say it.
29          DR. BLUMBERG: This would be a place where sort of certain
30   inflammation as a mechanism of cancer is probably -
31          DR. CARETHERS: You're absolutely right. So I guess the question -
32   I mean linking that to cancer is absolutely right. I mean, every organ
33   in the GI tract has inflammation cancer. I guess the - I don't know,
34   maybe I'm slightly wrong because we were trying not to step on toes of
35   the other, because there's a stomach one.
36          DR. JAMES: I think as we pointed out there's going to be
37   crosscutting areas where Chapter 1 may talk about basic immunology, but
38   not necessarily gearing it towards the role in altering the epithelium
39   and contributing to carcinogenesis and there certainly is plenty of
40   latitude to have it in both places.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1                DR. CARETHERS: Okay.
 2                DR. JAMES: Don't worry about stepping on toes.
 3          DR. PODOLSKY: At the risk of perseverating I wanted to come to a
 4   specific but then go from that to a general. What I noticed looking
 5   further on that colon cancer slide that we had before, you know that you
 6   had in there the note, but not ranked as a priority the natural history
 7   of small polyp. The more specific comment I was going to make, it was
 8   following on the question I posed before which is there's a lot of new
 9   modalities for screening. I think there is a lot of data coming out as
10   to their sensitivity and specificity, and the pivotal point as to how
11   you, you know, how they really have clinical value, will in large part
12   depend on understanding what's the natural history of particularly the
13   small lesions. So I would say that that's as a specific a particularly
14   pivotal first - a short-term goal.
15          DR. CARETHERS: I couldn't agree with you more. I was surprised
16   that the subgroup leaders didn't write that.
17          DR. PODOLSKY: So that's relatively specific. I know David has
18   given a lot of thought to that. I'm sure Bob has comments as well. And
19   then I guess you could expand that to a more general overarching
20   possibility of saying we need to define the true biological risk,
21   clinical importance of premalignant conditions. So that is polyps,
22   that's Barrett's, which still remains highly uncertain and so on. So
23   maybe that's also a way to - ultimately you want to get to the higher
24   picture here of incorporating that. So natural history of premalignant
25   conditions.
26          DR. CARETHERS: Thanks.
27          DR. PASRICHA: I just want to go back to the colorectal cancer. I
28   think there's still a lot of - there's a big gap right now still about
29   how effective our technology is for screening. Even if you take
30   colonoscopy as the gold standard, there's more and more literature
31   coming out that it's not as effective in practice as we think. I think
32   we should have something towards that as a goal that more research needs
33   to be done into improving the effectiveness of colorectal cancer
34   screening, even if it's colonoscopy. I know you have something about
35   non-invasive screening, but even colonoscopy is not perfect and we still
36   are not fully understanding what is responsible for - you know, there
37   was a paper just this month in Gastroenterology from the Canadian group
38   that looked into the factors responsible for missing lesions in
39   colonoscopy. There's a lot of that that needs to be covered I think.
40          DR. CARETHERS: So we can add that here, or should that be

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   included in imaging?
 2          DR. PASRICHA: Well, there's overlap, but I think this is an
 3   example of where a very specific issue, I mean this being the most
 4   important GI cancer in this country, that the specific issue probably
 5   needs to be highlighted.
 6                DR. CARETHERS: Okay.
 7                DR. JAMES: Margaret.
 8                DR. HEITKEMPER: I'm afraid I'm going to start sounding like a
 9   broken record, but I'm concerned about the psychosocial aspects of this.
10   These are - patients have symptoms prior to, during and following
11   treatment. They often end up with surgical procedures and ostomies. Do
12   we have short-term goals about enhancing the quality of life while we're
13   trying to figure out where the disease comes from and cures it? And then
14   the other aspect of that, especially in thinking about something like
15   the state of the science in esophageal cancer is end of life care, and
16   do we really have enough research done in enhancing the quality of
17   people who aren't going to improve with the therapies that we're going
18   to develop. I don't know whether that falls into that, you know, large
19   overview chapter that we're going to have, but I think there has to be
20   some attention to quality of life issues in this category.
21          DR. CARETHERS: No, I agree. Our approach was to have the subgroup
22   leaders come up with the top ten things and then try to limit it down
23   because I mean, my understanding was we were going to try to - I don't
24   know how comprehensive you guys want us to be, or are we going to try to
25   list you know the top two, three, four things that - go for the bang.
26   Now, I mean we could actually come up with probably even a more
27   comprehensive list than this. So I'm kind of trying to walk a balance.
28          DR. JAMES: I think first off that as some of the things that if
29   people felt they could only pick one and left off others is a little bit
30   too -
31                DR. CARETHERS: Too stringent?
32                DR. JAMES: Too stringent. That things that clearly would resonate
33   with many groups as being important goals should be in there.
34                DR. CARETHERS: Okay.
35                DR. JAMES: And I think that you've heard from this group a few
36   that we're surprised were not there and you thought. And I think just
37   because of the way the question was asked of the group you know that's
38   what you got. But the fact that they're on here means that they clearly
39   had traction and people thought they were important. So I think the
40   issue will be how to formulate this in as reasonably a concise way that

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   doesn't leave out these important ideas.
 2          DR. CARETHERS: Okay. I certainly - for instance, at least the
 3   natural history of small polyps, I would have ranked that personally
 4   much higher, so.
 5          DR. JAMES: Joanne?
 6          DR. WILSON: I would say that issues like end of life and
 7   generalized care don't - wouldn't necessarily fall as a disease-specific
 8   investigation. So for instance would have organizations like the
 9   geriatrics and so forth focusing on it. Now, if we wanted to be totally
10   overarching, obviously good nutrition and so forth and so on. But I
11   think that from the standpoint of specific GI work, that that's not a
12   GI-specific in the management. You know, maybe it should be, but as a
13   practicing gastroenterologist we insert the people in the right ways,
14   but they typically are not under our specific purview.
15          DR. CARETHERS: Margaret, you also mentioned things like -ostomies
16   and stuff, and that affects probably IBD probably maybe more than colon
17   cancer, for instance. Esophagectomies and how people get strictures, and
18   how they deal with that. I mean, so I agree with you those are
19   absolutely - we can certainly add that if.
20          DR. JAMES: Jay?
21          DR. PASRICHA: John, one of the I guess lessons from colorectal
22   cancer that might be worth emphasizing is that despite having the most
23   well-characterized genetic roadmap from adenoma to carcinoma of all the
24   GI cancers there's no therapy that has emerged either for prevention or
25   treatment based on that, and whether that's a lesson for other cancers
26   in terms of directing research.
27          DR. CARETHERS: Yes. So this, again this is not just for colon,
28   but this is one of the common themes to try to develop targeted
29   approaches to cancer diagnosis and treatment. And you're absolutely
30   right, the oncologic aspect has not progressed very much at all. I mean,
31   look at pancreatic cancer, look at esophageal cancer, colon cancer, I
32   meant the primary therapy is still surgery for those cancers if you get
33   them early enough. So looking into new - I mean, you can look into other
34   chemotherapy agents, or you can try to develop target agents, or some
35   type of comprehensive approach I think is right.
36          There have been very few advances for instance specifically for
37   esophageal or pancreatic cancer. We've had - I skipped over the orphan
38   diseases. I mean, the GIS tumors do not have a therapy although they can
39   get resistance. MALT lymphomas, you can treat people with antibiotics if
40   you catch it early enough. Colon cancer, even colon cancer has had a

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   couple of new therapies, particularly targeted therapies with the anti-
 2   Rb2 and anti-VEGF and in the last years they've added Oxalplatin and
 3   Irinotecan which are relatively new drugs compared to - but still, our
 4   basic therapy is still 5-FU-based. So that's right. So do you want to
 5   phrase this a little bit different than?
 6          DR. PASRICHA: I guess the point I was making was that despite
 7   knowledge at relatively specific levels of the pathways and genetic
 8   aberrations, that has not translated into specific therapies. Some of
 9   the advances that you're talking about in terms of chemotherapy are
10   relatively non-specific, whether that's VEGF or Erbi -
11          DR. CARETHERS: Right. So that's why most people thought that you
12   know if you understand the biology you might develop a targeted
13   approach, just like the Erbi and the VEGF therapies.
14          DR. JAMES: I'm not sure what you're suggesting. What's the
15   alternative? Certainly areas of research which haven't given the answers
16   yet. That doesn't mean we're going to stop pursuing the question.
17          DR. PASRICHA: No, I'm not saying to stop. I'm just saying maybe
18   it's a push towards saying, you know, further justification for looking
19   at epigenetics for other -
20          DR. CARETHERS: Sure. Sure, absolutely. I mean that's -
21          DR. PASRICHA: I mean, I think it's just something -
22          DR. JAMES: I think as a strategy for saying why we want - it's
23   self-evident where we stand with diseases that we don't have to justify
24   that we need to move forward. I don't think we need to look backward and
25   say look at the things that didn't work, or the dead ends in research
26   avenues that didn't work. I think that's the nature of research. You
27   pursue things and don't necessarily get answers. I don't think that's
28   necessarily a strategy for goal-setting.
29          DR. CARETHERS: Sorry. I mean Jay, are you okay with number 6 as a
30   common? Okay.
31          DR. JAMES: Maurice.
32                DR. CERULLI: I have two comments, one on colon cancer. It seems
33   that the colon cancer in IBD and ulcerative colitis may have a different
34   mechanism, not through the APC gene as in the sporadic colon cancer. I
35   think that would be something worthwhile to sort of exploit as well as
36   explore. And the second is on - there's an increasing incidence of death
37   from pancreatic cancer, increasing numbers of people dying, and also the
38   increasing incidence of adenocarcinoma of the esophagus over the last 30
39   years. Can we somehow highlight that in your goals because I think those
40   are important. The epidemiology is telling us that something is

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   happening out there that we need to study.
 2          DR. CARETHERS: So, I mean I didn't go over that, but certainly
 3   those points are going to be included. So for esophageal cancer, the
 4   subgroup leaders had highlighted different aspects to try to improve
 5   screening and detection as well as some randomized trials to try to
 6   address that. So you're suggesting some more epidemiologic tools which
 7   if I remember right was on here somewhere.
 8                DR. JAMES: I think you might be alluding to - so remember, we
 9   have a parallel effort to have a burden of diseases report which we're
10   not going to hear about today, but that is ongoing and we'll hear about
11   that actually at the next meeting. And in fact you're absolutely right,
12   we want to be able to certainly incorporate nubbins of information in
13   that report and cross-reference it as useful, but we're not going to
14   actually have that ready to present now.
15          DR. CARETHERS: And your point on colorectal cancer IBD is well
16   taken, so.
17          DR. JAMES: Barbara.
18          DR. BASS: I just want to get back to Margaret's point again, and
19   perhaps it falls under this burden of disease report that's going to
20   articulate the sort of silent plague that GI diseases have, but
21   particularly in something like oncology. I think one short-term goal
22   that it's almost sort of public health and sort of standard of care, but
23   one thing is to sort of address that our standard of care for patients
24   requires multidisciplinary management and we actually don't have
25   structures and processes in place across this country in many
26   communities to deliver what is really for all of the places where we
27   live basic care. And I think somewhere, while it may not be - it's more
28   public health research than it is science here, but I think we need to
29   at least address that as an early short-term win that we could get in
30   something like oncology or IBD or other complex GI disorders.
31          DR. JAMES: Right. I have mixed views, but I think that in general
32   anything that's couched in terms of research is fair game and that one
33   would not necessarily use this report as a way to advocate for certain
34   types of healthcare delivery, but certainly the business of evaluating
35   different approaches to figure out which is better through research is
36   fair game. AHRQ tends to do more of that, but ever-increasingly, you
37   know what do we do beyond Phase III randomized controlled trials and
38   have like in Hepatitis B a number of drugs to choose from. We need more
39   research to help answer those questions and this would be, in terms of
40   multimodality, multidisciplinary approach, those are perfectly viable

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   research questions that need to be answered. The fact of when you have
 2   the answers how to put them into healthcare is another matter I think.
 3          Okay, I think yes, Dr. Sy. Sorry, you've been standing for
 4   awhile.
 5          DR. SY: Yes. I just wanted to comment about the second bullet
 6   under lessons learned and anticipated challenges where you mention
 7   there's a lack of national coordinated efforts to put groups of
 8   researchers together to tackle cancer treatment barriers more rapidly.
 9   One way we have addressed this is our center is working with NCI in
10   putting together the cancer research summit which is happening every
11   year. And this year it's July 16 - 18 and we're bringing different
12   cancer researchers from different states together, including the
13   community. In fact, NCI have 25 community network programs. Our center
14   has about 25 community-based participatory research that we have
15   supported. So the goal there is really to bring them together to discuss
16   these different issues about barriers, treatment. So this - we realize
17   this and we're addressing this issue.
18          DR. CARETHERS: Okay, thank you.
19          DR. JAMES: Again, I think just as a general guide that for the
20   final report it's always better to say we want to do something to
21   achieve a goal rather than to say something doesn't exist. Somebody in
22   the world is going to find - take issue with when you put something in
23   the negative I think in general. So thank you, that's very helpful.
24   Other comments? Yes, Raj.
25          DR. GOYAL: Excellent presentation. I just have a minor point. You
26   mentioned in one of your slides for follow-up and diagnosis - what was
27   that?
28          DR. CARETHERS: Common goals?
29          DR. GOYAL: No, can you go on? On your next slide. Next.
30                DR. CARETHERS: That was it.
31                DR. GOYAL: Okay, that's it. So there is - basically what I was
32   going to say is that I don't think you mentioned chromosomal instability
33   as a cause of certain types of cancers in the GI tract.
34                DR. CARETHERS: Yes -
35                DR. GOYAL: And so your focus on just looking at -
36                DR. CARETHERS: This covers all types of genomic instability.
37                DR. GOYAL: Including chromosomal?
38          DR. CARETHERS: Yes.
39          DR. GOYAL: But in other slide you said that the markers that we
40   are looking at is simply - what is the marker?

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1                DR. CARETHERS: You mean like something like this, or?
 2                DR. GOYAL: Next one. Next.
 3          DR. JAMES: I think you might be addressing the issue that
 4   biomarkers shouldn't exclude genetic markers.
 5          DR. GOYAL: What I was trying to say, that markers, what you
 6   mentioned is specific, but it should be broader. And it may be
 7   chromosomal instability or other kinds of markers other than just one.
 8                DR. CARETHERS: Oh, absolutely. I mean, when we say genomic - I
 9   mean, when we say markers, biomarkers, that could mean genomic markers,
10   it could be other tumor markers. So it wasn't a specifically type of
11   markers, just whatever markers predict the presence and/or treatment
12   response of a tumor. Wasn't specific to any -
13                DR. GOYAL: Okay, maybe I misread it. Essentially that's what I
14   was going to say, that since the biomarkers are so broad we should not
15   specify one.
16          DR. CARETHERS: Oh yes, I agree.
18   Diseases of the Pancreas (WG 10), Jane M. Holt, Chair; P. Jay Pasricha,
19   MD, Vice Chair
21          DR. JAMES: Okay, very good. That's terrific John, thank you.
22   Jane, do you want to pre-lunch? Pre-lunch is always the best
23   opportunity. People are starting to wake up and really get energized,
24   getting hungry.
25          MS. HOLT: My name is Jane Holt. Most of you don't really know me.
26   I'm not a scientist and not really familiar with all of this like you
27   are. I am a patient and Nancy Norton and I are the two patient
28   representatives on this commission. But as a patient I felt it was
29   important for me to talk just a minute and give you a perspective on
30   pancreatic disease from a patient's point of view.
31          I think that the most important thing that you need to realize
32   about pancreatic disease is our needs and research are really incredibly
33   basic. So far we don't even have guidelines for the diagnosis of chronic
34   pancreatitis. We've been working on it, we've been trying hard, but we
35   still don't have guidelines. We know ways that we don't - things that we
36   don't want to use for the diagnosis, but we don't have the guidelines.
37          As far as treatment for chronic pancreatitis, there is none. For
38   a patient that has chronic pancreatitis, the only thing they can do is,
39   which I did last week, is put the patient in the hospital, put them on
40   heavy fluids, no foods, heavy pain medication and wait for the pancreas

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   to calm down. And eventually it does calm down and we go home and wait
 2   again for the next time we enter into the hospital. For patients with
 3   acute pancreatitis if you're lucky enough to be in an emergency room
 4   where you get diagnosed quickly and are in a hospital that knows the
 5   correct treatment and gives them to you quickly you're in a better
 6   situation, but the problems are that the diagnosis is difficult, the
 7   treatment is difficult and most hospitals are not totally current on
 8   what needs to be done. And as John, even though it's not part of our
 9   thing, as John quickly alluded to, with pancreatic cancer 98 percent of
10   the patients that are diagnosed this year will die in six months to a
11   year because so little is known about the disease. So as I say, our
12   research needs are incredibly basic.
13                Not only is it a frustrating disease, but it's also a very
14   expensive disease because there's constant hospitalization, constant
15   doctor visits, expensive CAT scans, MRCPs and diagnosis treatments, and
16   for many patients there are visits to psychiatrists, to pain clinics and
17   it's very expensive medications that need to be used for the disease. In
18   the 18 years that I have had chronic pancreatitis there have been very
19   few advances. The technology has improved a bit. We have EUS, we have
20   MRCPs, we have better CAT scan and a little bit of genetics has been
21   done, but not much has been done to change the whole treatment of
22   patients.
23          Basically the only plea that I have is we need to start funding
24   more research and we need to figure out some of the basics so the people
25   can at least figure out why I have chronic pancreatitis. Nobody knows
26   yet why I have it, or if my children or grandchildren are going to have
27   it and when they do or if they do how to treat it. So it's my plea as a
28   patient to all of you that we do something to change the research in
29   pancreatitis.
30          Now, as chair of this working group - did I do the wrong button?
31   As chair of the pancreatitis and as a patient there was only one thing I
32   could do and that was to gather the best minds I could across the
33   country to help us out. And you see we had a really good working group.
34   And everybody on the working group really reached out to their
35   colleagues and to get information from them. We were also able to get in
36   touch with 75 different researchers across the country and gather a
37   group of 40 to kind of go through all of the things that were needed for
38   research. And I really feel comfortable that what we came up with today
39   is a consensus of really all the researchers across the country as to
40   what really needs to be done in the future for research in pancreatic

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   disease. And again, as I'm not a scientist I don't think that I'm the
 2   best person to present this to all of you, and I have to thank Jay who's
 3   been my vice chair and done a tremendous amount of work to get us to
 4   where we are. So I think Jay, if you don't mind I would have you come up
 5   and do the rest of the presentation.
 6          DR. PASRICHA: Thanks Jane. I particularly appreciate the fact
 7   that you were in the hospital until yesterday and came here. It's a
 8   testimony to how important you think this is. I also want to thank you
 9   for organizing the pancreatic working group and the one-day symposium
10   that we had. Much of what I'm going to talk about is actually reflected,
11   much of that is actually reflected in what I'm going to talk about.
12          So as Jane pointed out, the level of understanding of pancreatic
13   pathophysiology in disease is fairly rudimentary compared to some of the
14   other groups. And this is going to be reflected in some of our research
15   goals which are pretty basic. The first part of this talk is going to be
16   along the lines of how we had organized the working groups. The first
17   group was acute pancreatitis, pathogenesis and pathophysiology, and
18   these are the basic goals that we have. Again, these are not stratified
19   on a timeline, but these advances we felt are the most important. Early
20   cellular and molecular events in pancreatic injury, derangements in
21   acinar cell secretion in acute pancreatitis, and then perhaps most
22   importantly, mechanisms of acinar cell recovery following injury,
23   including lessons from pancreatic development and stem cells. And
24   related to this, and something that I haven't highlighted but I need to
25   is pathways that take a particular pancreas towards necrosis and other
26   pathways that take it to recovery or simply interstitial pancreatitis,
27   and that's part of this general goal.
28          We also had a working group on chronic pancreatitis, pathogenesis
29   and pathophysiology. And here the three major goals were to develop
30   models of chronic pancreatitis that were robustly valid and capable to
31   be used to study risk factors in humans. Understand the mechanism of
32   endocrine and exocrine cell loss and regeneration, including signaling
33   mechanisms, cell to cell interactions. And then specifically in terms of
34   chronic pancreatitis, understand mechanisms of fibrosis, its prevention
35   and reversal, and I think like the liver, this is sort of an
36   extraluminal organ where fibrosis is perhaps much more important than
37   other parts of the GI tract. This is something that may be a common
38   theme with the liver group, but certainly needs more understanding. In
39   that regard, the role of the pancreatic stellate cell which is of course
40   a type of cell that's found in almost all organs in modulating health

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   and disease. And then focusing on ethanol which is the commonest cause
 2   of acute and chronic pancreatitis in this country. And emerging evidence
 3   that obesity is also linked to the development of pancreatic injury.
 4   That's another goal. And then finally, elucidation of the
 5   neurobiological mechanisms that are not only responsible for normal
 6   pancreatic physiology, but are also reflected in disease states and can
 7   lead to pain, but by themselves can also contribute to inflammation. And
 8   as Jane pointed out, the most - the greatest unmet need in chronic
 9   pancreatitis at least is pain and the working group focused on that to a
10   large extent.
11          As far as clinical aspects of acute pancreatitis is concerned,
12   the group decided that a major goal would be development of
13   comprehensive population- or hospital-based databases to define
14   mortality, morbidity and reliable prognostic factors of severity at
15   admission that can be utilized to stratify patients. And it can also be
16   used to enroll patients in studies for new therapies. And related to
17   that is to really push the envelope as far as new therapies are
18   concerned. We know this is an acute inflammatory condition and there is
19   a whole plethora of drugs available for inflammation in the rest of the
20   body. Very few of these actually have been tried in the setting of acute
21   pancreatitis which is one of the few conditions that can kill you
22   acutely. So the group felt that there needs to be a push towards
23   studying these therapies, whether they're anti-cytokine or endoscopic as
24   pancreatic stents, or even surgical, such as treatment of necrosis. None
25   of this has really been well studied and the outcomes are not fully
26   known.
27          Chronic pancreatitis. As Jane pointed out, one of the biggest
28   challenges is diagnosis, particularly diagnosing early chronic
29   pancreatitis where it's often confused with other conditions or vice
30   versa such as gastroparesis or other GI problems. There needs to be a
31   better tool for recognizing fibrosis, whether it's invasive or non-
32   invasive. An example of an invasive technique that could help diagnose
33   early chronic pancreatitis would be the development of a true-cut biopsy
34   or the equivalent. We also need to do a better job in defining
35   derangements in pancreatic function that occur at an early stage rather
36   than at the end stage as we're all accustomed to seeing and which is
37   fairly straightforward to diagnose. And then there is a growing
38   recognition of this entity called autoimmune pancreatitis, and we really
39   need to develop better diagnostic tests, or screening tests even for
40   this condition.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1          The natural history of chronic pancreatitis needs better
 2   understanding, particularly for those factors that we consider are
 3   important in the development of fibrosis or recurrent pancreatitis. We
 4   know that everybody who drinks excessive alcohol, most people don't get
 5   chronic pancreatitis. What is it that defines that patient? Whether it's
 6   genetic or some other environmental factor needs further understanding.
 7   We also need to understand better the natural history of patients with
 8   chronic pancreatitis, especially the ones with alcoholic chronic
 9   pancreatitis. They tend to be difficult to follow and there is no real
10   good snapshot over various periods of time as to how they do. And then
11   there was a consensus that came given the growing evidence that
12   autoimmune pancreatitis, AIP, is important, that we need to figure out
13   how to better treat it. The role of steroids may - really needs more
14   work because it may be effective in the short term if we don't really
15   know what to do with these patients in the long term. And so whether
16   other forms of chronic immunosuppressive therapy are important remains
17   to be studied. And then finally - I've already mentioned this -
18   understanding genetic and environmental factors that enhance the risk of
19   disease development and disease progression.
20          Chronic pancreatitis also has several other unmet needs in
21   clinical goals. There needs to be development of reliable measures of
22   pain and quality of life, and this goes back to the burden of disease
23   and quantification of suffering that was alluded to earlier.
24   Establishing the value of various interventions on pain, in particular
25   pharmacology endoscopy surgery with prospective randomized controlled
26   trials has really not been done in any systematic manner. There are some
27   trials from Europe, but there is really no large-scale study in this
28   country that evaluates any one of these modalities for the treatment of
29   pain. In this regard with respect to total pancreatectomy there is some
30   interest in the use of total pancreatectomy with autologous ILAR cell
31   transplantation and whether this is an effective method of treating both
32   the pain and can provide replacement therapy for insulin remains to be
33   established. And then finally we need to identify novel targets for the
34   treatment of pain because clearly what we have today in the form of
35   narcotics isn't very effective.
36          Genetics plays an important role in pancreatitis, particularly in
37   the past few years as we've seen. The discovery of specific genes can
38   predispose - the specific genes can predispose to acute and chronic
39   pancreatitis, but clearly that's only a small spectrum of the patients
40   who have this problem. And more research needs to be done in the

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   discovery of other genes, particularly understanding how these genes
 2   interact with toxic factors such as alcohol or other environmental
 3   factors. This may be applicable both to adult forms of pancreatitis, but
 4   also cystic fibrosis and in this regard one of the goals is to develop
 5   animal models based on human genetic discoveries. We also had a section
 6   on cystic fibrosis and a lot of that was actually spent on issues that
 7   were not directly related to the pancreas such as lung transplants, but
 8   clearly we need to have more research done into childhood pancreatic
 9   disease as a whole and focusing on pathways that lead to exocrine
10   failure fibrosis in cystic fibrosis.
11          Finally, there was a section on endoscopic approaches and some of
12   these issues have already been dealt with, but there were issues related
13   to diagnosis, ability to access tissue, define whether there are
14   specific endoscopic or histological markers, issues like sphincter
15   abnormalities, better delineation of cystic lesions, technological
16   innovations such as elastography that could be used towards the pancreas
17   and perhaps most importantly in this is the ability to distinguish
18   between chronic pancreatitis and neoplasia, especially when the
19   neoplasia is at an early stage. There's still lots of research that
20   needs to be done on the effectiveness of endoscopic therapy. Even though
21   these have become established in our armamentarium I think they have not
22   been rigorously studied and there was a consensus that more research
23   needs to be done in the role of these therapies for both stone
24   strictures, acute inflammation, necrosis and chronic pain. And the very
25   tool that we use to actually treat or diagnose the pancreas by itself
26   can cause a major problem, that is post-ERCP pancreatitis. And there was
27   consensus among the endoscopists that they needed to do something to
28   prevent this and make this procedure safer.
29          So what I've done at the end is really summarize all these goals
30   into the most important ones, and these are as follows. The first is
31   develop methods for obtaining tissue from the pancreas. This could help
32   with earlier diagnosis and improved understanding of disease
33   pathogenesis progression. This is something that we lack and this is one
34   of the few organs that's left in the body where we don't have ready
35   access to tissue. And just as liver biopsies have transformed
36   hepatology, we feel that this could be very important in taking
37   pancreatic research to the next level. Also there needs to be other non-
38   invasive improvements in the ability to diagnose chronic pancreatitis at
39   an early stage - we've talked about that - and develop reliable
40   surrogate markers for chronic pancreatitis and activity and progression

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   of disease. Develop reliable surrogate markers for mortality, necrosis
 2   and systemic complications in acute pancreatitis. Determine the
 3   biological and genetic factors involved in the pathogenesis of acute
 4   pancreatitis, with particular emphasis on mechanisms of necrosis and
 5   systematic complications. And a subset of this would include post-ERCP
 6   pancreatitis. And determine the biology of pancreatic fibrosis and
 7   chronic injury, particularly with respect to the role of alcohol. There
 8   really needs to be a push towards developing animal models, current
 9   animal models for alcohol-related injury to the pancreas. They're not
10   satisfactory. And finally, neurobiology of the pancreas with respect to
11   mechanisms of pain and neurogenic inflammation. Neurogenic inflammation
12   is a theme that's emerging throughout the body, but recently there has
13   been a lot of literature on the pancreas and this needs to be researched
14   further. And based on all of the above, identification of novel
15   therapeutic targets for providing effective treatment for pancreatic
16   disorders which we hope will be not just a long-term goal, but something
17   achievable in the next few years. Thanks.
19   Discussion
21                DR. JAMES: Very good. Bob?
22                DR. SANDLER: - more of an observation, but we've heard several
23   talks this morning about how we don't understand the natural history of
24   basic common diseases and we've been blinded by modern technologies like
25   genomics and proteomics and metabalomics, and we sort of haven't gotten
26   ourselves organized to just study basic things like the natural history
27   of polyps. So maybe one of our overarching themes might be some call to
28   arms to try to be able to do that.
29          And sort of a small point. And I'm just glad you mentioned
30   natural history, but once a person presents to the doctor it's never the
31   natural history anymore because they're manipulated. And so maybe
32   clinical course is - for at least one of those slides might be a better
33   term than - it becomes the unnatural history once they see the doctor.
34          DR. JAMES: You have a slide, it's Acute Pancreatitis Clinical and
35   it starts with developing a comprehensive database. But I would actually
36   transform that. The goal is to conduct comprehensive epidemiological
37   studies of the sort that you suggest. Joanne?
38          DR. WILSON: I think one of the problems is the basic one in your
39   roadmap of phenotypes because that becomes the obstacle to studying any
40   natural history because we're not studying the natural history of one

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   disease, but multiple. So it becomes a definition of disease and then
 2   application of that. And we may quickly have the natural history if we
 3   can define the disease.
 4          DR. JAMES: Dan, did you have a comment?
 5          DR. PODOLSKY: I was thinking, you know following Jane's initial
 6   comments and the first PowerPoints that Jay covered. You know, really
 7   why are things still at such a basic level you know? And it appears to
 8   me there are a few things which I think you touched on, but I would have
 9   guessed have been particularly important. One is you know that there is
10   so much dependence on the human model and it's really difficult, and so
11   giving even more importance in this area to having good in vitro and in
12   vivo animal models as being enabling of the kind of intense experimental
13   accessibility that's just difficult when you're talking about the
14   pancreas. And then the other is, and it's probably related to that, is
15   attracting people to - it's a relatively small community of
16   investigators and that's been I think probably limiting as well. So I
17   think somehow this should be also emphasized in the report.
18          DR. PASRICHA: I stopped because the light went off, but let me
19   just tell you these are things that I - we put down in terms of the
20   major challenges. So let me know if you agree with that. It emphasizes
21   the points that you made. So there's a lack of reliable and valid
22   standards for diagnosis of organ dysfunction, lack of ready access to
23   tissue - there are inadequate and poorly validated animal models. There
24   are inadequate tools to study pain and quality of life, insufficient
25   number of patients seen at any one center. The size of the investigator
26   pool is disproportionate to the magnitude of the problem. And actually
27   in this field particularly more than anything there's a disconnect
28   between the interventionalists and the scientists. So - and then you
29   know we have this, but I didn't have time for that because a lot of this
30   is actually very common to some fields. Does that address?
31          DR. PODOLSKY: Yes, I might have come personally with a slightly
32   different weighting and knowledge - I'll say that last point, for
33   example, being an important one, I still you know don't know that that's
34   been the real barrier.
35          DR. JAMES: I think the barrier to research has been that the
36   opportunities haven't been there compared to other ways. So if somebody
37   is interested in a research career and they look at areas where they're
38   likely to be able to publish papers and get a grant this doesn't seem to
39   be the best area because no tissue, no animal models. Well, what are you
40   going to do to publish a paper and get a grant? So I think that there

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   are some very, very important hurdles.
 2          DR. PODOLSKY: - one is there's no in vitro or in vivo if you ask
 3   me. And then the effect is what you said.
 4          DR. PASRICHA: That's not completely true. I mean there are - I
 5   mean the bulk of the pancreatitis researchers are funded from the NIH
 6   based work on in vitro, activation. There are animal models, it's just
 7   not necessarily - just like an IBD they're not very well validated as
 8   being representative of human disease. But your point is well taken. I
 9   think the pool of scientists going into this field is very limited and
10   part of it is because as a specialty in gastroenterology we've taken out
11   the procedure from the disease and we kept it separate. So the people
12   who do ERCPs by and large are not pancreatologists. That's one of the
13   disconnects that we have. That's why I wanted to emphasize that because
14   actually I think that is a structural barrier and I've argued with the
15   AGA for taking - not having separate ERCP training programs unless
16   they're in the context of studying the pancreas as a whole. That doesn't
17   happen in our specialty.
18          DR. JAMES: Well, I think in terms of manpower if you look at
19   other disease areas, the majority of research actually being done in IBD
20   is probably by PhD scientists, many of whom are immunologists and so
21   forth and so on, oncology and other fields. But the issue is the
22   research opportunities are there for many disciplines to get engaged and
23   I think the simple lack of tissue to study for people who want to study
24   tissue, or lack of a robust animal model for people who can do that in
25   the laboratory, but if you don't have one then there's nothing to work
26   on. So I think you know, maybe with a few genetic discoveries, if we get
27   clever about rapidly turning those into animal models that generate
28   testable hypotheses that that would certainly open up these fields. And
29   I think if that were done people would come you know with facilitation
30   from research administrators, but there has to be the opportunity there
31   to bring the field. You can't create a cadre of investigators if there's
32   nothing to work on.
33                DR. PASRICHA: On the flip side, this is one area, I guess apart
34   from liver this is one area where there's another institute, that is the
35   NIAAA, which is equally dedicated to this problem. So there are actually
36   dual channels for funding which I think we need to emphasize.
37          DR. JAMES: Oh by the way, I keep reminding everyone this should
38   never be called the NIDDK commission. It is not. There are many
39   partners. In fact, the largest institute funding research in digestive
40   diseases is the NCI, not the NIDDK. We just happen to be the happy

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   people facilitating this commission and we certainly have many partners
 2   at NIH. John?
 3          DR. CARETHERS: So Jay, nice presentation. A couple of things. You
 4   mentioned a lot about maybe developing ethanol models and you mentioned
 5   briefly about autoimmune pancreatitis and CF. So I mean should there be
 6   some thought in just developing, if you need to developing other
 7   preclinical models that are not just ethanol-based? Because obviously
 8   that's a very important area for causing chronic pancreatitis, but
 9   there's other etiologies as well. That was one point.
10          The other thing is there's been some emerging evidence, and I
11   don't know if this should be included or not, about a lot of these
12   precursor lesions that develop out of pancreatitis that may be going
13   towards transformation. And I don't know if there's any - I didn't know
14   whether they included in ours or not, but whether some of these lesions
15   are reversible if you control the pancreatitis? In other words, you
16   develop some of these early you know in situ type intraductal lesions
17   that might - I have no idea if they're reversible or not, and I don't
18   know if those - if that should be looked at. And then there's some
19   recent evidence that what we call, you know some of these things that
20   lead to ductal cancers from out of the setting of inflammation aren't
21   really ductal cancers. They're really acinar cancers that take the
22   histology of ductal. There's some work from stem cells on that. And what
23   we're calling ductal cancer may, you know we say 90 percent of
24   pancreatic cancer is ductal cancer. But again, this kind of overlaps
25   with ours, but some of this comes out of the setting of inflammation and
26   so I didn't know whether that should be included with your stuff or our
27   stuff.
28          DR. PASRICHA: I was hoping you'd cover that, but I think it's an
29   important area of overlap. I think the last point you're making is the
30   issue, the pancreatic intraepithelial neoplasia, PIN lesions. What do
31   they really mean and whether they progress. Are they reversible. Because
32   if you look at some of the studies that have come out, 70 percent of
33   normals will have PINs. And so I think that is an emerging area and
34   perhaps - I thought it was more appropriate to be in the cancer, but I
35   think this is something we can emphasize because clearly there is a link
36   between chronic pancreatitis and cancer. It's not as robust as in some
37   of the other conditions, but it's certainly there.
38          Animal models, I agree with you, it's more than just alcohol and
39   some of those are emerging. Some of the trypsin mutation are just being
40   published now.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1                DR. JAMES: Rick?
 2                DR. BLUMBERG: I just want to just focus on - this may be too much
 3   detail and I apologize for that. But just, and it's probably buried in
 4   here, but you might want to reveal it out a little bit more, is the - I
 5   think the autoimmune pancreatitis, you jump right to treatment, but I
 6   don't think we really know what it is. And I think it's probably buried
 7   in this whole idea of natural history. The autoimmune pancreatitis is
 8   probably the tip of the iceberg of a variety of different immunobiologic
 9   and/or developmental and/or whatever-based abnormalities of the pancreas
10   that will ultimately distill into inflammation. But I think that buried
11   in that to bring that concept out of trying to define these issues both
12   epidemiologically as we were talking about with respect to natural
13   history, but also I think that just to find some better definitions of
14   what these diseases are. I just heard a very interesting talk for
15   example at the federation meetings for clinical immunology, an Italian
16   investigator for example who using expression cloning has found some
17   molecular mimicry perhaps between H. pylori and auto-antigen carbonic
18   anhydrase isoform in the pancreas for example. He's got to vet that out.
19   But you know I think there's a number of opportunities and that, just to
20   bring that idea out a little bit more in that one slide.
21          DR. PASRICHA: I note your point. Thank you.
22          DR. JAMES: John.
23          DR. MILNER: John Milner again from NCI. Thanks for that comment
24   about NCI. You know I think this is a really important issue, but I know
25   we have a PA out on the street and we have been trying to get
26   applications and we're not getting those applications. NCI has modified
27   the pay line so that we can fund more of these applications, but we're
28   not getting those applications. So something needs to be done because I
29   think we know the issues. But the scientists are not out there to
30   embrace these issues.
31          DR. PASRICHA: You're talking specifically about pancreatic
32   cancer?
33                DR. MILNER: Specifically about pancreatic cancer, yes.
34                DR. CARETHERS: We'll send them all your phone number.
35                DR. MILNER: But I'm just wondering is there a way that we can
36   identify you know, additional patients that we can examine, additional
37   groups? Are there some white papers that we can write to showcase these?
38   There's got to be something that we can do to get additional scientists
39   involved in this area. Clearly we're dealing from the standpoint of a
40   dietary component. Ethanol has surfaced many, many times, even in this

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   presentation, but there are other factors out there that modify.
 2          DR. JAMES: I think there was a PRG on pancreatic cancer from the
 3   NCI. Jane? Jane and - the problem is that that happened just about the
 4   time the budget doubling ended and so forth. So some of the - many of
 5   those ideas are still perfectly germane, just they haven't.
 6          DR. PASRICHA: You had the equivalent of that with the NIDDK and
 7   David Lieberman and I were involved when we first advocated studying
 8   clinical pancreatology, particularly the role of ERCP. I mean, I chaired
 9   that study section for a few years and we were always sort of appalled
10   by the lack of interest in the GI community, what we perceived to be a
11   lack of interest in really applying for those grants. So there is a
12   problem in the investigator pool here that's perhaps more acute than
13   some of the other fields and that I think needs more special emphasis
14   here.
15          DR. JAMES: Administratively what that translates into for people
16   like us at NIH is that when somebody does come along we - I try to bend
17   over backwards to give them extra special help with whatever it is
18   they're trying to do, I mean to the extent that we're able. When we
19   recognize there are these gap areas we're - a lot of work needs to be
20   encouraged. Jane, sorry.
21          MS. HOLT: There are so many things that I want to address at the
22   same time I'm not sure where to start. But I mean there's a little bit
23   of what comes first, the chicken or the egg, and the problem has
24   historically been is there hasn't been enough funding for research, so
25   therefore I don't think the best and the brightest have been as inspired
26   to get involved in it. I think now, at least in the last 10 years I've
27   seen a huge change where a lot more very interested, intelligent
28   researchers are getting much more involved. And what I've found when
29   we've been gathering these doctors recently is that there is much more
30   interest in trying to work together and get multi-center studies put
31   together. And it takes a lot to organize it and a lot of getting it
32   together, but that's the only way we're going to be able to do research
33   in pancreatic disease I think, is to get multi-center studies together.
34   And I think that there's a great interest among researchers right now in
35   doing that, and I think that a lot of what we've found from having the
36   opportunity to bring people together to present this roadmap is that
37   people do really want to work together and have wonderful, interesting
38   ideas, and I think things are going to change considerably.
39          I also - while I have the mike, I also want to clarify one point
40   because it came up during all of our work group conversations, and that

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   is the idea of pancreatitis and the IPMNs, and should it be - I mean, I
 2   agree it needs to be included somewhere and I think because the cancer
 3   group is so large that maybe it should be included in our group. And we
 4   did have presentations on it. I know Dr. Sarr did a whole thing on it,
 5   not realizing it wasn't going to be part of it. But we can very easily
 6   include it in our group if it's felt appropriate.
 7          DR. JAMES: I think that's something to work out offline as to
 8   where it belongs, but clearly it belongs.
 9                MS. HOLT: Yes.
10                DR. JAMES: You're right. Dan?
11          DR. PODOLSKY: I just wanted to as a placeholder say that there's
12   an element in here that probably belongs as part of a very general theme
13   in the same general spirit of natural history or clinical course of
14   disease and that's around fibrosis and pathological tissue response. In
15   thinking about chronic pancreatitis, stenosis, and IBD - you know -
16   critical to chronic liver disease so somewhere I would hope when we get
17   to the report that'll be one overarching thing, research really focused
18   on understanding tissue response to injury and how that could be
19   translated into avoiding the real morbidity of these things that result
20   from the response, in particular fibrosis and related activities.
21          DR. JAMES: Right, certainly, again the Liver Disease Action Plan
22   was a very prominently featured theme. But it crosses organs and
23   certainly renal disease is an issue as well.
24          DR. BACON: If you crack that nut you solve lots of diseases
25   because you don't have to worry about treating Hepatitis C if you can
26   inhibit fibrosis. You don't have to worry about, just over and over,
27   every organ system if you can regulate fibrogenesis you can change the
28   natural history.
29          DR. JAMES: Did we give you enough to work on? I think there is
30   some redundancy in some of this slide presentation in terms of being
31   able to present in five minutes.
32                DR. PASRICHA: Yes, actually the last two or three summary slides
33   were really what -
34          DR. JAMES: Yes. I think maybe tomorrow we'll want to be able to
35   re-hear because - and have them stated as positive goals. And I think
36   certainly natural history, this would be an area to tie in as well
37   perhaps. But.
38          DR. PASRICHA: So the question I was going to ask you related to
39   the other issues about not having enough interest in the applications.
40   Is this something that the NIDDK would consider organizing a, you know,

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   one-day conference on devoted to the pancreas? I think it's been done
 2   for almost every other disease area.
 3          DR. JAMES: Sure. How could I say no? No, sure. I think if there's
 4   a potential investigator community interested we're always there to try
 5   to help flesh out ideas with some of the resources because you're right.
 6   Sometimes to get a group activated to work on something you have to
 7   bring them together and allow them to focus. Some networks, by the way,
 8   are started as R01 applications and people form a network. There is one
 9   in pancreas as you know. But it needs a little jump-starting.
10          DR. PASRICHA: I mean, I think that the clearest message the NIH
11   gives is if they organize a conference. Then everybody suddenly perks up
12   and says this is an area that we want to get into.
13                DR. JAMES: Well, I think we're keeping you busy with
14   gastroparesis because that's what we did, right? Okay. I think we
15   probably really ought to break for lunch. Gail, do you -
16          DR. GRAVE: One last comment?
17          DR. JAMES: Okay.
18          DR. GRAVE: Well, I keep hearing about these multi-center
19   consortia and Steve was alluding to some. We took an inventory in our
20   institute, Child Health Institute, found out that there are 55 of them
21   and they're getting very, very expensive. And I think that we at least
22   at our institute are beginning to clamp down on the proliferation of
23   this, no matter how important. I wanted to start one in necrotizing
24   enterocolitis and unless I can do it on a shoestring we're not going to
25   get it done. So I just want to warn you that there's - the tide is
26   beginning to turn against these multi-center consortia networks because
27   they're very expensive.
28          DR. JAMES: Well, I think there are ways of doing them. There are
29   many kinds across NIH and you're right, we have to deal year by year
30   with the amount of money we have to spend just like the way you run your
31   household, so. But I think there are innovative ways, for example that
32   we're trying to greatly increase the efficiency with which we put these
33   things together as we learn more about how to do it and help
34   investigators not waste a year or a year and a half getting something up
35   and running. We can help them do it a lot faster. There are overarching
36   issues like IRBS and INDs and other things that hopefully we'll be able
37   to streamline some of this sort of stuff that really is an impediment.
38          DR. GRAVE: Well, that might be the most important thing you've
39   said because we've found typically that there's a 2-, 3-, even 4- or 5-
40   year lag before anybody even gets enrolled.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. JAMES: Well, this is particularly a problem of course in
 2   pediatrics where nobody - you know, the extra high you know hurdles for
 3   IRBs to do any kind of research.
 4          DR. GRAVE: That's true.
 5          DR. JAMES: Anyhow, you're absolutely right, but I think that
 6   doesn't mean we're not going to try to do collaborative approaches to
 7   research when that's clearly what's needed. Genetics is a terrific
 8   example that the collaborations aren't just national, they're actually
 9   now clearly have to be international to get the answers efficiently. So
10   I think it can be done. So time for lunch, right? Do you want to give us
11   - you can speak.
12          DR. HAMMOND: Okay, I've got the notes here. So we are having
13   lunch. The restaurant is at the lobby level if you'd like to use that.
14   There's other restaurants as well, but we do have an area reserved for
15   seating for the commission. We'd like to have the commission members
16   back here in 45 minutes. So that would be 1:45. Everybody else - we'll
17   restart the meeting actually at 2 o'clock. Okay? Thank you.
18          (Whereupon, the foregoing matter went off the record at 1:00 p.m.
19   and went back on the record at 2:04 p.m.)
21   Functional GI Disorders and Motility Disorders (WG 2), Kenton M.
22   Sanders, PhD, Chair
24          DR. JAMES: Okay. We're going to go ahead with Working Group 2,
25   switching gears a little bit and we're going to try to - really like to
26   do each group in about 25 minutes. So we have eight more I think? And so
27   those of you who would like to either eat or exercise tonight, you'll
28   get a chance. So I hope we can finish by about 6 o'clock at the rate
29   we're going. But if you really pick it up - we know how study sections
30   work. If you're the unlucky person whose grant is at the end they get
31   five minutes of review. So go ahead. You're on.
32                DR. SANDERS: Great. So this is Working Group 2 on functional
33   gastrointestinal disorders and motility disorders. And the makeup of
34   this committee is Nancy Norton is the vice chair of the committee and
35   then these people were employed to give their opinions and ideas for the
36   substance. The process that we engaged in was to have a couple of calls,
37   conference calls, after the reports were turned in, but then also I
38   engaged the opinions of about 40 people. A good number of the people
39   that are on the list of funded investigators in motility and GI that
40   were sent out to us, and then also a fair number of people that I

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   consider to be international leaders in this area. And so from that we
 2   got - we started out with long-term goals and we managed to put together
 3   about 45 long-term goals that were then developed into intermediate and
 4   short-term goals, but all of this material is far too much to present
 5   today. So what I've done is to organize this talk basically as 10
 6   general research goals. There are a number of questions that are listed
 7   underneath this, but I'm not going to really have time to go through all
 8   of these, but I just thought I'd include them for your consideration.
 9   Hopefully these will be able to be developed more fully in the report.
10          So the first research goal is to understand the molecular and
11   cellular events that yield normal motility and sensory behavior in the
12   GI tract, and the pathophysiology of functional GI disorders and
13   motility disorders. And then also to develop the means to repair or
14   replace damaged cellular components. So the general idea here is that
15   there's not enough known about the cells that actually produce normal
16   and abnormal behavior and so more extensive cell biology studies will be
17   necessary in the future. And again, there are a number of research
18   questions that are directed toward this topic.
19          The second major goal is to understand the development of the GI
20   tract and brain-gut interactions, and to determine how the aging process
21   and differences in gender affect gut development and function and brain-
22   gut interactions. So when I speak about development, there clearly is
23   development going on throughout life and it's under the influence of a
24   large number of environmental and sex issues and stress, et cetera, et
25   cetera, and a large amount is needed to be known about the plasticity of
26   the GI tract and how it contributes to these diseases.
27          The third major goal is to understand the components and
28   functional interactions of the peripheral, that is the autonomic and
29   enteric nervous systems both, and the central nervous system in normal
30   physiology and in functional GI and motility disorders. Clearly the
31   behaviors that are manifest in motility and functional GI disorders have
32   a very strong neural component, and frequently what appears to occur for
33   instance in diarrhea-predominant IBS or constipation-predominant IBS is
34   the wrong motor program runs at the wrong time and so therefore there is
35   inappropriate motility. And so understanding how the brain and the
36   central nervous system and the enteric nervous system and the peripheral
37   nervous system all interact together and signal is a very important area
38   of investigation.
39          Turns out that the tunica muscularis like the mucosa is a
40   substantial immune organ in the bowel and therefore the fourth goal that

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   we came up with is to understand the immune functions of the tunica
 2   muscularis, integration between mucosa and muscle immune responses and
 3   how inflammatory processes contribute to the pathogenesis and
 4   maintenance of functional GI and motility disorders. This is I think
 5   quite a new and exciting area of investigation, but there's much to be
 6   learned about this.
 7          The fifth goal is to understand peripheral and central pain in
 8   sensory pathways and how these pathways are affected in functional GI
 9   and motility disorders. This obviously is an important feature in
10   several of the chapters. And this management of pain and how pain
11   develops and becomes chronic seems to be an overarching theme for this
12   entire endeavor.
13                The next is again another sort of overarching theme that we've
14   seen several times already today and that is to understand the
15   microflora in functional GI and motility disorders. Obviously there's
16   growing information now that there is signaling between the microflora
17   and the enteric nervous system, and the enteric nervous system and the
18   brain, and reciprocity between the brain and the enteric nervous system.
19   So this is, as I said, a very new and exciting area that needs further
20   investigation.
21          Goal seven is to use information from studies of animal models
22   and cellular physiology to understand the integrated function of the
23   tunica muscularis and intrinsic and extrinsic nervous system. Clearly
24   we've learned a lot from cell biology already. Unfortunately a lot of
25   this comes from animal models only and there's not enough known about
26   the phenotype of the human GI tract. But there is need for sort of the
27   reverse of reductionism at this point in time is to develop sort of a
28   picture of the integrated function of the GI tract and the central
29   nervous system control of it.
30          Understand the - oh, sorry, I went backwards instead of forwards.
31   That's not good. Number eight, Goal eight is to determine how the
32   genotype contributes to or predisposes patients to the development of
33   functional GI disorders and motility. I mean, this again is a theme
34   that's been present in several talks already and that is is that there
35   may well be information within us all that determine whether or not
36   we're predisposed to these disorders, or we'll react to something that
37   occurs in our lifetime poorly so that these disorders develop. And it
38   would be nice to understand what that is.
39          Goal nine is that new technologies and therapeutic approaches
40   must be developed to effectively treat patients with functional GI and

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   motility disorders. There are a number of exciting things on the horizon
 2   and obviously research needs to continue into development of new
 3   approaches.
 4          Goal ten is a more rigorous evaluation of therapeutic outcomes
 5   and the impact of doctor-patient interactions are needed to determine
 6   what is effective in treating functional GI and motility disorders.
 7   There's a great deal more that needs to be known about effective
 8   evaluation, effective treatment, et cetera, et cetera, on these
 9   disorders.
10          Okay, so now the next area that I'm going to go into and spend a
11   little bit more time is what I consider to be major challenges, or what
12   the group considered to be because these were all turned in by people in
13   the group. Okay, so the first challenge here is that GI motility and
14   functional GI disorders are complex and a product of functional defects
15   in a variety of cell types. A better understanding is needed of the cell
16   biology, the many cell types in play to produce normal motility and an
17   appropriate level of GI sensation. So in a way this is a restating of
18   one of the goals, but we definitely need additional studies into the
19   cell biology of GI cells. This includes muscle cells, extrinsic and
20   intrinsic neurons, glial cells, interstitial cells of Cajal and as I
21   said, a variety of immune cells, both the resident cells that exist
22   within the bowel wall and those that are recruited during an
23   inflammatory response or in response to a food allergy, et cetera, et
24   cetera. Secondly, better techniques to isolate and identify specific
25   types of cells from healthy and diseased gut samples are needed. And
26   again, I think this is sort of a very broad theme that has been
27   mentioned. It's difficult to really understand the molecular and
28   cellular events and even the genetics of cells within the gut unless you
29   can get pure populations of these cells. And so I think it's very
30   important to continue with developing techniques to get specific
31   populations of cells from the GI tract. With proper cell isolation
32   techniques, modern technologies such as genomic and proteomic analysis
33   can be applied. It can be applied in a very specific way rather than
34   just on chunks of tissue.
35          This is another I think major problem that faces the motility and
36   also functional GI area, but also is quite - more broad than that. In
37   many cases the phenotypes of GI cells involved in motility and neural
38   responses are not conserved in cell culture because the microenvironment
39   is important in establishing and maintaining specific cellular
40   phenotypes. This makes large-scale genomic and molecular and cellular

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   biology studies very difficult. So we need I think better techniques to
 2   manipulate genetic expression of GI cell types, and to do this while the
 3   cells are still in their native environment rather than putting them
 4   into some cultured environment where they change. We definitely need to
 5   enhance targeting of transgenic methodologies to create better cell-
 6   specific - and I also mean inducible knockouts of genes in GI cells.
 7   This is - whereas it's occurred very beautifully in the central nervous
 8   system and in cardiac and liver, et cetera, this has really fallen way
 9   behind in GI, that we can't really control the molecular biology, the
10   genetic expression of cells within the GI tract very well at this point.
11   We need to develop the means to effectively turn on and turn off
12   expression of specific genes in adult animals and that would by far be
13   the best so that you don't have compensatory things going on that mask
14   the real effect of particular gene expression.
15          A huge area that is lacking, and again very broadly lacking I
16   think in GI physiology is we need to understand the mechanisms of
17   nociception and sensitization of afferent fibers in the gut. At this
18   point in time most research into the mechanisms controlling excitability
19   of afferent neurons is focused at cell bodies, but these regions of the
20   cells are likely to have different populations of receptors and ion
21   channels and signaling pathways than occur at sensory nerve terminals.
22   And it's going to be difficult to fully understand the normal
23   activation, integration and sensitization of gut afferents until we
24   understand the physiology of nerve terminals specifically.
25          There needs to be a - steps to achieve this are we need to
26   develop a means to discriminate between different classes of nerve
27   terminals and to clearly identify nociceptive nerve terminals in living
28   tissues. And that's difficult to do, impossible to do at this point in
29   time. We can't tell one afferent terminal from another really. We need
30   to develop dynamic imaging techniques to study the behavior of afferent
31   nerve terminals in the lamina propria and tunica muscularis. This is
32   where a lot of the business end of the nervous system occurs at these
33   afferent terminals and we just have a very poor understanding of that
34   system. We need to develop a detailed understanding of the mechanisms of
35   generator potentials in nociceptive neurons, what actually causes
36   nociception in the gut.
37          The next challenge is as information is gathered about the
38   physiology of specific cellular components of GI muscles we need to
39   understand how cellular events integrate to produce whole system
40   physiology and learn how cellular events contribute to

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   pathophysiological behaviors. And again, I think this is a key issue all
 2   the way from the periphery to the central nervous system. We don't
 3   really know how these cells interact very well. We need to develop
 4   models or a conceptual framework that unifies morphology, anatomy,
 5   histology, histochemistry, molecular biology with physiology, that is
 6   the functions of cells at the tissue and organ level as well. We need to
 7   further develop dynamic imaging techniques which is a convenient way to
 8   look at how many cells function together to facilitate studies of
 9   interactions between GI cellular components to understand the various
10   cellular components that contribute to the function of these tissues and
11   organs.
12          The next challenge is a better understanding of the integration
13   between the brain and gut axis in pathophysiologic conditions is needed.
14   We also need to understand how intrinsic and extrinsic neurons
15   communicate and how they integrate information. Steps to this are we
16   need to establish better recording methods to measure activity of the
17   autonomic nervous system in conscious experimental animals and to
18   correlate this neural activity with motility. We need to establish a
19   means of recording from central nervous system in conscious experimental
20   animals and correlate this activity with peripheral nerve activity and
21   motility. And then we need to understand the links between disorders of
22   GI function such as constipation and diarrhea and pain and discomfort in
23   the gut.
24          Next challenge is we need to establish more suitable animal
25   models for functional GI and motility disorders. It's likely to be
26   difficult to establish a cause and effect relationship between a
27   suspected pathophysiological factor and the development of symptoms and
28   disease without proper animal models. It's important to understand what
29   can and cannot be extrapolated from animal models to humans. This
30   process obviously helps refine the animal models if you get to that.
31   Studies need to be performed on human tissues - and again that's
32   something that has not been emphasized but needs to be emphasized in
33   this particular chapter - and cells to determine whether cellular and
34   molecular components and pathways that have been identified in animal
35   models actually are relevant in human tissues. We need better means of
36   monitoring GI function, autonomic function and brain function and
37   genetic models need to be developed. We also need genetic screens to be
38   applied to specifically identify defective GI motility, autonomic and
39   CNS phenotypes, and genes linked to defective motility phenotypes should
40   be inactivated in mammalian transgenic models as well.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1          Just a couple more of these. I know my light is blinking here. We
 2   need to develop molecular definitions for functional GI disorders and
 3   motility disorders, and develop biomarkers for each entity. Again, we've
 4   heard this in probably each talk. And I think I'll skip the specifics on
 5   this because I'm running out of time. Model systems are needed that
 6   allow rapid determination of functional effects of genetic variations in
 7   candidate genes that are reputed to alter motor and sensory function, as
 8   well as somatization manifesting in GI tract symptoms or diseases,
 9   testing of functional genomics in other words. And I think one of the
10   problems has been that not only have we not identified specific genes
11   that are important, but when that occurs, when that begins to occur as
12   is beginning to occur now, rapid screening techniques are really
13   necessary.
14          The area of transplantation of stem cells is obviously a very
15   important area. We need to determine how to replace regions of defective
16   bowel. Better transplantation therapies are needed, possibly including
17   solutions based on stem cell therapies and tissue engineering. And I
18   want to just get through these last two. Clinical assessments and
19   treatments of functional GI disorders and motility disorders need to be
20   standardized. Center to center frequently there are different
21   definitions of these diseases and therefore treatment is difficult to
22   communicate between centers without standardization of these disorders.
23   I think I'll just stop at that point. I went through some points, but
24   I'm running late so.
26   Discussion
28                DR. JAMES: Great, thanks. Big topic. Comments? David?
29                DR. LIEBERMAN: Yes, it's a huge topic and that was a very elegant
30   presentation. I guess as somebody who's not an expert in that area if
31   you did have to say prioritize your goals, and let's say you had to come
32   up with three goals, what would be the top ones? I couldn't tell for
33   sure reading through this whether there was really a clear
34   prioritization.
35          DR. SANDERS: Well, you have to understand that I'm not a
36   clinician so -
37          DR. LIEBERMAN: I understand.
38          DR. SANDERS: - it's difficult for me to prioritize clinical
39   goals. I think the second issue there is that as I said in the talk in
40   November, this is a collection of at least 20 clinical entities. So you

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   could definitely set priority based on patient burden or some criteria
 2   like that, but it's very difficult to say which is the most important
 3   thing to concentrate on here unless you come up with some - and that's
 4   actually one of the feedback issues that I raised.
 5          DR. JAMES: Nancy.
 6          MS. NORTON: Going back to the natural history, I think that's an
 7   issue that we face with the functional GI and motility disorders. We
 8   just don't understand natural history either. So I think that's a point
 9   of concern even though it wasn't really mentioned here, but we addressed
10   it.
11          DR. SANDERS: Yes. That was in the points at the end there that I
12   didn't go through, but I think that's a very important issue.
13                DR. JAMES: Jay?
14          DR. PASRICHA: A couple of points. I think one of the priorities
15   from my perspective as a clinician taking care of these patients is sort
16   of similar to what I mentioned in disease of the pancreas is the ability
17   to access tissue from humans. That's been very difficult. We just can't
18   get beyond the epithelium with current techniques. I think it would be
19   an enormous advance if we could reliably endoscopically get access to
20   muscle and enteric nervous system tissue in patients with suspected
21   functional and bowel motility disorders. That for me I would push as one
22   of the top priorities. With some very concrete achievements we can
23   actually - and this may overlap with the technology section. That's
24   something I would really like to emphasize.
25          DR. SANDERS: I've always made the distinction there that you
26   know, it's one thing to look at the anatomy of these tissues, I mean to
27   do pathology, but the whole point behind functional disorders is that
28   supposedly there aren't gross changes in structure. There are changes in
29   function. Secondly, you know you can get tissues and do molecular
30   studies on them and that's an interesting possibility at this point in
31   time, but to actually do functional studies to find out whether the
32   neurons work correctly, whether afferent neurons work correctly, whether
33   the muscle, et cetera, et cetera, work correctly, it's difficult to do
34   unless the centers match up with the groups that are studying these
35   things.
36          DR. PASRICHA: Right. No, but on the first step, I mean I agree.
37   How you study them is a separate thing, but the first step just as a
38   sort of technological thing would be to get the tissue and then you can
39   figure out what the best way to study them is. The - sorry. Didn't mean
40   to knock your glasses off, Dan.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1                DR. SANDERS: There will be plenty of time for questions, so.
 2                DR. PASRICHA: The second point I think which perhaps may not have
 3   been emphasized as much is the flip side of the interaction between gut
 4   tissue and nerves which is neurogenic inflammation. That's an
 5   overarching theme that's going to probably be important in many
 6   diseases, but I think it has a home here as well. You talked about the
 7   afferents and the spinal afferents and what they're doing in terms of
 8   pain transduction, but I think it's becoming increasingly obvious that
 9   they may play a role also in modulating the inflammatory response
10   locally.
11          DR. SANDERS: I also want to comment on the - there's been some
12   controversy within the working group about emphasis. And I mean there is
13   you know a strong comment about more emphasis on clinical treatment and
14   less emphasis on basic science because there's a need at this point in
15   time, there's a large patient population affected and there's a need for
16   treatments, or at least alleviation of symptoms. And so the balance in
17   this report is something that you know we're going to continue to work
18   as a working group as the document gets put together to see if we can
19   come up with a balanced document where there is enough there that will
20   interest you know the development of treatment for symptoms and to
21   relieve suffering really.
22          DR. PASRICHA: The biggest holdup for treatment is there are no
23   validated targets, and you know so where do we start. We don't have
24   access to human tissue, we don't have reliable animal models, so it's
25   really hard to come up with targets. I mean, so I think it's - you're
26   serving the clinical needs by going back and asking those questions.
27          DR. SANDERS: Yes, I mean I agree with you and I think that one of
28   the comments on the challenges to get this done properly was that I
29   think it is difficult to come up with very specific hypotheses about the
30   diseases without a better understanding of what causes them. But that
31   being said, there are people in the community that believe that they're
32   closer to treatment or they're closer to effective treatments. I mean
33   for instance there are treatments that are not necessarily at the cause
34   of the disease, but more at the symptom. Nancy may want to elaborate
35   more on this as well, but.
36          MS. NORTON: Well, I think you know treatments have been directed
37   at the periphery and the whole brain-gut piece hasn't been elucidated to
38   the point where I think some of the people in the field would like to
39   see the research carried. So there is - we are struggling as a group to
40   try to you know find that place where we all come together in the basic

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   science and the clinical aspect is coming together.
 2          DR. PASRICHA: I agree with that, and I think one of the examples
 3   of that where better basic research has led to some targets, for
 4   instance in the brain-gut axis is you know the CRF story and the
 5   receptors for that. That's something that has emerged from developing
 6   the animal models that could correlate stress with periphery, and that
 7   has led to potential new targets which are going to address both the
 8   brain-gut issue, but also perhaps some of the peripherals. But those are
 9   the kinds of studies I think that are probably priorities right now is
10   to get that library of targets out there and validated. We don't know
11   enough yet about that.
12          DR. JAMES: Margaret.
13                DR. HEITKEMPER: I have a little bit different comment and it
14   really is something that I've noticed throughout, not just with this
15   particular working group. But for example, your Goal 10. If there was
16   ever an area that required an interdisciplinary approach it's the
17   functional bowel and so when I look at your Goal 10 and I see doctor-
18   patient interactions and yet the behavioral therapies for problems such
19   as IBS have been shown to be effective, and those are often delivered by
20   psychologists or advanced practice nurses who also need training and to
21   have this sort of systematically delivered across centers. So I would
22   advocate to move away from specifically targeting MD-patient
23   interactions, but rather healthcare provider interactions and how we can
24   work as an interdisciplinary team to go about that.
25          But I would also say that yes, that the basic biology is
26   definitely needed, but we also need novel behavioral treatments that
27   utilize some of the newer technologies that allow us to better look at
28   that interrelationship between stress and symptom experiences of the
29   people who have these conditions. So I do think it is - we need both
30   fronts to be moving forward.
31          DR. SANDERS: Thank you for articulating that because I completely
32   botched it, but you said exactly what I meant to say.
33                DR. JAMES: I think we recorded that. That was very well put. One
34   of the things I think is apparent, particularly from David's initial
35   question, is that this would be a chapter if the goals look as somewhat
36   like the goals here that a background introduction will be crucial to
37   point out. Reading this, it looks a little bit more like a chapter one
38   and the relevance of these important goals to a large number of
39   complicated diseases is a little bit lost. So I think one way is
40   actually to craft the goals so that it's inherent in the goals that

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   there are diseases, but the other would be to craft this with a very
 2   strong introduction that points out some of these clinical issues that
 3   are very important.
 4          The other would be perhaps some of this could be captured - I
 5   wasn't sure trying to go back through this - by having a bullet that
 6   basically is called a phenotyping goal which is in a comprehensive way
 7   which can include many things, the biology of individual cells, the
 8   brain-gut imaging, physiology, genetics. Phenotyping really captures a
 9   whole lot of things and that's certainly essential and I think an
10   inherent problem in studying these diseases is defining you know Roam 3
11   is entirely I guess a symptom-based for the most part approach, but it's
12   sort of inherent that you are excluding diseases at the same time. So I
13   think we still have a long way to go in terms of phenotyping patients
14   with these disorders as one of the fundamental problems to sorting them
15   out. So maybe that could be captured too. Dan?
16          DR. PODOLSKY: Before coming onto a comment that picks up on that,
17   just to the discussion about targets. I don't know how this might
18   otherwise be incorporated, but in thinking about those therapeutics
19   which have become available. They have eventually all foundered on -
20          DR. SANDERS: They cause heart attacks and things.
21          DR. PODOLSKY: Well yes and adverse events, so safety. I mean
22   somehow you know getting those critical safety/efficacy ratios you know
23   are particularly important in this area. In reading it you know I found
24   that the challenges to a degree sort of really were a refrain of the
25   goals. And maybe another way to be thinking about it is around some of
26   the things that have been touched on. So if all those are goals that
27   major challenges are need for consistent patient phenotyping, need for
28   kind of tissue that - human tissues that Jay was saying and so on.
29   Because I think you could distill the challenges to accomplishing those
30   goals to a series of barriers that exist right now as the reasons why
31   they haven't been achieved yet.
32                DR. SANDERS: No, I agree.
33                DR. JAMES: John.
34          DR. CARETHERS: So just to touch on that. So I guess what you're
35   trying to say is a benefit/risk ratio for - you were talking about
36   safety of drugs. I had another question and maybe it's kind of embedded
37   in here because you mentioned in a couple of places about animal models,
38   how to study this, and I was wondering, and again I'm not an expert in
39   this field at all, about post-infectious induction of irritable bowel
40   syndrome, either tied in with the infectious group or the pediatric

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   groups.
 2          DR. SANDERS: Yes, I mean there are clearly post-infectious
 3   symptoms, motility symptoms, but whether or not they actually produce
 4   Irritable Bowel Syndrome is really difficult to say because that seems
 5   to have you know such a central role and the pain issue as well that - I
 6   mean, you can show aladenia. You can show sensitization of afferent
 7   neurons in animal models post disease. You can show remodeling of
 8   enteric neurons, et cetera, et cetera, et cetera. But is that IBS?
 9          DR. CARETHERS: Is there any - or long goals, long-term goals or
10   studies to look at at least the epidemiology of it?
11                DR. SANDERS: Sorry?
12                DR. CARETHERS: To look at the epidemiology of it? I have no idea.
13                DR. SANDERS: No, we don't have any specific goals at this point
14   in time about epidemiology. That's probably something that should be
15   there although I think there's going to be - isn't this?
16          DR. JAMES: Well, I guess the issue is how to weave that into
17   this. So Goal 6 does deal with sort of selective aspects of microflora,
18   but again since he's kind of trying to address 20 diseases. It's not
19   meant to be an IBS chapter. It's quite difficult to cover everything,
20   but you are right.
21          DR. PASRICHA: There are - to answer your question, there are
22   cohorts of patients who are being followed post-infectious who have IBS-
23   like symptoms. I guess that's where the - what Kent said about studying
24   the genetics, that's really where the thrust should be is what
25   predisposes 20 percent of patients with post-infectious symptoms to
26   develop IBS.
27          DR. JAMES: Rick?
28          DR. BLUMBERG: Yes. So just to talk about the elephant that's in
29   the room for me. So this is a beautiful presentation and it's very
30   fundamental. So from the vantage point of the patient it's about 100,000
31   feet which is what Group 1 has been charged with. So I'm trying to -
32   we'll talk about this later when I give my own report how we weave some
33   of the beautiful angles that you brought into this, try to merge the
34   documents, but then taking that and landing, coming down more to ground
35   level. Maybe it's buried in here as well, but the regionality of some of
36   these fundamental mechanisms, stomach for example and esophagus perhaps,
37   I'm not sure if that's going to be discussed in other places, which may
38   be very, very unique. And in a phenotypic way or a measurement way
39   electrophysiology. I don't know if that's buried in here as well. From a
40   novice in this area can we get - you know, aim to get an EKG essentially

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   so to speak, metaphorically of this system for diagnostic purposes and
 2   measurement purposes and assessment purposes in the clinic.
 3          DR. SANDERS: Yes, that was in some of the sub-questions in these,
 4   but just not time to go through all this. I mean, I totally agree that
 5   there may be some things, just as Steve said as well, there may be some
 6   things here that need to be really in your chapter because they're too
 7   specific. But what I did not want to lose in this is that exactly what
 8   Jay said, is that we don't actually know the cause of many of these
 9   things, okay? Many of these entities we really cannot put our finger on
10   what the etiology is. So therefore studying not just the cell, but the
11   pathophysiology, the remodeling that goes on in disease situations in
12   response to infection, et cetera, et cetera, et cetera could be key. I
13   mean I say could be key because we just don't know.
14          DR. BLUMBERG: And follow-up to that is that just points out just
15   how little we know about this area.
16          DR. SANDERS: Yes.
17          DR. BLUMBERG: And this is another reason why the microbiome came
18   up as another good example all over the place, virtually every
19   presentation because it's something we just know so little about.
20          DR. PASRICHA: Kent, I wonder if you have any comments in terms of
21   the challenges regarding the manpower issue for research? Just as we
22   talked about in the pancreas, I mean this is arguably 40 to 50 percent
23   of all GI diseases as a group and do we have enough manpower to research
24   that?
25          DR. JAMES: Well, I think we'll probably address this tomorrow.
26   We're going to talk about training and career development, and I think
27   these issues are generic. They're different in different scientific
28   disciplines, but I think the generic issues of manpower and training
29   just as Betsy pointed out this morning are truly crosscutting and nearly
30   everybody in one way or another is involved in issues. No matter how
31   robust or how small your area of research is there always seem to be
32   manpower and training issues. So I think maybe we should leave that for
33   a more general discussion.
34                DR. SANDERS: I agree with you.
36   Diseases of the Oropharynx and Esophagus (WG 7) P. Jay Pasricha, Chair
38          DR. JAMES: Okay. I think we should move on and next we have
39   Number 7. It's a good thing I had somebody to whisper in my ear. Jay.
40   It's you.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. PASRICHA: Yes. Thanks. So this actually is probably the first
 2   example of a very large group of very different disorders and until now
 3   we'd either been dealing with sort of common disease processes or a
 4   small organ like the pancreas. Now we're going to get into some of the
 5   challenges trying to put all this together, something like oropharynx
 6   and the esophagus. So this was our working group. Our vice chair is
 7   David Lieberman and these are the members of the working group. As you
 8   can see they represent amongst them pretty much all the thought leaders
 9   in this field.
10          So we broke this down into several different subsections. And
11   some of it was anatomical and some of it was pathophysiological. So the
12   first subsection is the oropharynx and the aerodigestive tract. And we
13   had a few goals here. The first research goal was to understand the
14   neurobiology of central swallowing mechanisms in health and disease and
15   mechanisms of recovery. So this probably, as you know strokes are the
16   commonest cause of dysphasia and particularly in the elderly, and this
17   is relatively very poorly researched and poorly studied. We thought this
18   field would benefit from the development of useful animal models of
19   central swallowing disorders, but particularly focusing on the
20   neurobiology of recovery and plasticity of those brain areas that are
21   responsible for swallowing.
22          Research Goal 2 was really focusing on the special place of this
23   region in the interface between the airways and the GI tract. And there
24   are several diseases or syndromes that are generated at this interface.
25   And this was directed at that, to study the physiological and
26   pathological communication between different functional components. So
27   for example, the effects of gastroesophageal reflux on the airways
28   including the larynx and bronchi which of course has implications for
29   patients with asthma, and the effects of sleep abnormalities on upper GI
30   tract physiology. And this is a growing concern because of the obese
31   population and the fact that they may have sleep disturbances that
32   further predispose them to reflux. And then the third goal in this area
33   is to identify novel molecular, physiological and anatomical targets
34   with the development of more effective treatment, or - and this goes
35   back to some of the other aspects - is functional - better ways to
36   achieve functional rehabilitation of patients with CNS-related disorders
37   of swallowing. So that is the first subsection.
38          The second subsection is of course the big one in this area which
39   is gastroesophageal reflux and the first goal here was to investigate
40   the pathobiological mechanisms of events leading to and/or associated

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   with GERD. And even though we think GERD is a pretty straightforward
 2   disease it's actually surprising that its pathophysiology is still
 3   relatively poorly understood and so there are specific examples under
 4   this research goal such as transient LES, relaxations of TLESRs,
 5   biomechanical factors in terms of the modeling of the gastroesophageal
 6   junction and the role of the various layers of the GI tract, the muscle
 7   and so on. We don't really fully understand what leads to the
 8   pathogenesis of hiatal hernia. Perhaps it's biomechanical remodeling,
 9   but we're not sure. And then the pathogenesis of motility abnormalities
10   that are increasingly being recognized in GERD and which may be
11   responsible for a larger section of patients who are refractory to
12   current therapy.
13                Research Goal 2 under gastroesophageal reflux is to validate and
14   develop more effective and less invasive long-term approaches to GERD.
15   So there is a subset of patients that is significant and substantial
16   given the total prevalence of GERD that needs something more than just
17   standard PPI therapy and these are the patients who typically undergo
18   anti-reflux surgery, and there are lots of issues with that. And as you
19   know these last few years have seen a boom in non-invasive methods to
20   treat GERD, but they have not been well studied. And the group felt that
21   this whole area needs to be better studied in a prospective manner.
22          Research Goal 3 here was to understand the clinical spectrum,
23   outcomes and natural history of childhood reflux. So this was an area we
24   felt has not been well studied and particularly in terms of its
25   relationship to adult GERD. Childhood reflux has actually become GERD
26   and what are the implications for the health, both as children but also
27   long-term as they grow up.
28          Research Goal 4 is kind of a generic goal. It's to develop better
29   targets for the treatment of GERD. Currently even though PPIs are
30   effective they're a really symptomatic treatment and they don't go to
31   the heart of the pathophysiology. And then this fifth one was somewhat
32   minor, but still felt to be important enough to be included. It's to
33   develop reliable and simple methodologies to give better insight into
34   what's happening to the esophagus and stomach during reflux.
35          The third subsection in this chapter is esophageal injury,
36   inflammation and repair. And the first goal here was to understand the
37   mechanisms responsible for esophageal injury with particular emphasis on
38   the interactions between the various components of the esophageal wall
39   as they relate to health and disease. Again, some of these are pretty
40   generic, can be applied to any part of the GI tract, but specifically

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   there are issues related to increased permeability in the esophageal
 2   epithelium which is felt to be one of the first factors that are
 3   deranged in the development of GERD-related injury. We would like to
 4   understand how this leads to changes in esophageal nerve and muscle, and
 5   the theme I keep going back to in terms of neurogenic inflammation, how
 6   esophageal injury is intermodulated by neural and perhaps muscular
 7   events such as what Kent talked about. And there are lots of other sort
 8   of examples that we'd like to study in injury/inflammation repair and
 9   some of this has to do with this emerging entity of use in esophagitis.
10   How do allergens in food, in the air or in the environment cause this
11   particular kind of injury, studying the immune basis for this,
12   identifying the antigens and basically getting into greater mechanistic
13   approaches into the pathogenesis of how eosinophils infiltrate the
14   esophagus and cause dysfunction.
15          We were also interested in the final bullet point here,
16   mechanisms of repair because some of these conditions can lead to
17   strictures which by themselves are difficult to treat. And again, this
18   may be a common theme which Dan has alluded to earlier. It encompasses
19   several organs. And then finally, the group felt that eosinophilic
20   esophagitis at least for the moment is such a fast-growing or fast -
21   increasingly recognized disease that it's important really to give it
22   some standalone emphasis and that is to understand the host factors,
23   genetic profiles, determining susceptibility to injury in this
24   particular disease as an example. We went into several examples of what
25   we needed to do for eosinophilic esophagitis and the epidemiology,
26   natural history particularly in adults. It's not well understood. And in
27   novel targets for more effective and rational approaches to inflammatory
28   disorders. Again, most of this is directed against eosinophilic
29   esophagitis.
30          The other section here now is Barrett's metaplasia and dysplasia
31   which was given to us as a group. And this is a big topic by itself, but
32   the first research goal here was to understand the initiation of
33   Barrett's with particular emphasis on identifying the putative stem cell
34   and studying its biology. The group feels strongly that this is one of
35   the sort of landmarks that needs to be achieved in this area.
36          Research Goal 2 is to understand the contribution of the
37   etiopathogenic role of environmental and genetic familial factors in the
38   development of Barrett's. Research Goal 3 is to understand the natural
39   history of Barrett's metaplasia. And again we had this argument. What is
40   the natural history anymore since a lot of these patients are getting

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   their Barrett's ablated? But to still understand what the long-term
 2   clinical course is and identification of risk factors associated with
 3   progression and development of carcinoma.
 4          And Research Goal Number 4 is to develop and validate reliable,
 5   simple and inexpensive methods for screening and surveillance. That
 6   includes both endoscopic and non-endoscopic approaches. This is an area
 7   of overlap with the technology group.
 8                So Barrett's is a sort of big disease, has lots of research
 9   goals. To identify novel targets, therapies for chemo-prevention. This
10   is a disease which it should be eminently susceptible to chemo-
11   prevention. Patients at risk for Barrett's progression to carcinoma.
12          Research Goal Number 6, to identify novel molecular targets for
13   pharmacological approaches to restoring a stable epithelial phenotype in
14   patients with Barrett's esophagus, and Number 7, to promote the
15   development of novel methods of the physical removal of Barrett's when
16   it's indicated, study their efficacy, cost-effectiveness, safety and
17   durability.
18          Finally, the last section in this chapter is motor and sensory
19   neural mechanisms. And this is an example of what Kent's chapter does
20   and we take it down to a more specific level for an individual organ. So
21   the first goal here is to identify and validate methodologies for
22   studying esophageal neuromuscular function that better predict
23   underlying pathology and/or symptomatic phenotype. This includes better
24   physiological tests and imaging, also methods for sampling ENS and
25   muscle in the esophagus which I talked about.
26          Research Goal Number 2 is to understand the etiopathogenesis,
27   genetic predisposition of risk factors for esophageal motility and
28   function disorders, understand the role of autoimmunity, environmental
29   factors such as Barrett's relationship to GERD and genetic factors,
30   molecular candidates. Some of these have recently been discovered such
31   as the Aladdin gene which is responsible for the AAA system, Achalasia,
32   Alacrima and ACTH resistance.
33                Research Goal Number 3 is to understand the clinical spectrum,
34   outcomes and natural history of esophageal motility disorders and their
35   relationship to each other. So even if you take the prototype Achalasia,
36   very little is known about the long-term outcome of these patients
37   because there really hasn't been any prospective cohort here that has
38   been followed for that period of time.
39          Research Goal Number 4 is to identify novel therapeutic targets
40   for pharmacological cellular, such as stem cell or physical endoscopic

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   approaches for more effective and rational treatment for esophageal
 2   motility disorders. Again, this is just a specific illustration of what
 3   Kent's group has already pointed out. Again, this is a repetition of the
 4   overall theme to understand the neurobiology of normal and abnormal
 5   sensation as it applies to the esophagus. And then finally, to identify
 6   novel molecular targets for more effective and rational treatment of
 7   esophageal hypersensitivity associated with disorders such as non-
 8   cardiac chest pain and non-erosive reflux disease.
 9          So the major challenges and steps to achieve these research goals
10   were felt to be as follows. Inadequate understanding of the underlying
11   path of the biology, and there are many factors that contribute to that.
12   There's a lack of convenient, valid experimental models, small number of
13   patients seen by any one center, absence of uniform diagnostic criteria,
14   lack of generally available and reliable methods of physiological
15   testing and inaccessibility of tissue for histopathological correlation.
16   Other challenges is a true epidemiological and clinical picture of these
17   disorders has been difficult to obtain. There are variations in the
18   clinical practice and so this is left to the necessity of planning
19   studies to elucidate pathogenic mechanisms and improve on current
20   therapeutic strategies. A good example of this is actually eosinophilic
21   esophagitis. We still don't have a consensus on how many eosinophils it
22   really takes to make the diagnosis.
23          Another challenge is the lack of cross-fertilization amongst
24   disciplines. A very good example is swallowing disorders which is
25   secondary to CNS pathology. This is really a neuroscience problem from
26   that perspective, although its manifestation is in the GI tract. And
27   there doesn't seem to be enough interaction between these two groups in
28   terms of studying the underlying biology of these problems. Another
29   example of course is eosinophilic esophagitis. It's traditionally been
30   considered an allergic disorder and only recently gastroenterologists
31   are recognizing it.
32                And there are challenges peculiar to Barrett's. There's enormous
33   variability in disease definitions, histological grading. One of the
34   problems we are facing as clinicians is that you have these companies
35   springing up with technologies either directed at diagnosis or treatment
36   and they're already being disseminated without even asking the question
37   should these patients have the ablation in the first place. And this
38   really has led to some issues with looking at these patients. And then
39   we have some methodological issues which is that so far everybody has
40   been looking at patients with chronic GERD, Barrett's esophagus and

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   cancer as if that's the only spectrum of patients that actually develops
 2   Barrett's and adenocarcinoma. We know a large segment of Barrett's for
 3   instance does not necessarily have GERD-like symptoms.
 4          So recommended general step is a theme that has been repeated
 5   many times, is to establish multi-center consortia, recognizing that may
 6   be expensive but it's really we feel necessary, particularly in diseases
 7   such as Barrett's for all the reasons that are mentioned here. That
 8   would include collection of annotated tissue and serum specimens. Some
 9   specific measures also include bringing together investigators across
10   relevant disciplines for cross-fertilization that we have said. And then
11   we think this is particular area because with the general accessibility
12   of the esophagus, it's so easy to get into that technological
13   breakthroughs may contribute to some of the research goals we have.
14          Lessons learned. I didn't quite know what to do with this, but my
15   understanding is that - I mean, this is my take on it about lessons
16   learned. The esophagus because of its limited length and easy access can
17   be viewed as a model to test hypotheses of a more generalizeable nature.
18   For instance, visceral hypersensitivity, much of it has been really
19   studied in the esophagus since it's a relatively easy organ to work
20   with. Similarly if you have a stem cell approach, it's relatively easy
21   to do it in a disease like Achalasia where it's a very small segment,
22   couple of centimeters involved. And if you can restore nitric oxide to
23   that area you can really use that as proof of principle for a variety of
24   other approaches in the GI area.
25          And then just the lesson I learned from doing this exercise which
26   is what I thought you wanted us to comment on was when I went to the
27   CHRIS database it was just much easier than the information I received
28   there. And I think - I also think a summit get-together at DDW next year
29   should be organized to present the NCDD mission process. It would be a
30   very useful exercise. Thank you.
32   Discussion
34                DR. JAMES: Very good. Questions? Comments? John.
35                DR. CARETHERS: Just a quick one. I noticed you mentioned some
36   epidemiologic studies in your major challenges. Would you address, or
37   maybe the section address the issue about if you would the natural
38   history if you will of Barrett's? Because I mean that's obviously a big
39   thing that we do, and I don't think it was in your specific - I don't
40   remember seeing it.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. PASRICHA: I may have gone over that relatively quickly. It's
 2   Research Goal Number 3. Did that address your?
 3          DR. CARETHERS: I was - okay, yes, I didn't see that. I was
 4   thinking more epidemiologic as well.
 5          DR. PASRICHA: Yes. So we have our - specifically I think there
 6   needs to be a better definition of the prevalence of - we're getting
 7   there with recent studies. We emphasize really the long-term outcome of
 8   these patients really is not known. It needs to be understood.
 9          DR. JAMES: Yes. Perhaps the question is you really need it in a
10   population-based group rather than a selected. That's really one of the
11   hearts of many issues is we do find patients who have histories of GERD,
12   but what about all the other patients who may not have that risk factor.
13                DR. PASRICHA: That's a good point. I think I'll include that.
14          DR. JAMES: Maurice.
15          DR. CERULLI: I might also point out that the rectum is also
16   easily accessible and you don't have to sedate the patient for you know
17   looking at various aspects of therapeutic measures. Also, again the
18   point is raised about having a multi-center type of network. Perhaps we
19   should have one network for oral, intestinal, liver disease and then -
20   and have a structure formed, and then have like some of the ASLD, ASGE.
21   They have something called SIGs, special interest groups, that could
22   become modules within this overall network. It might be less costly and
23   sort of everybody would know there's one place to go and then find your
24   appropriate SIG. Getting back to my rectal point, but thanks.
25          DR. PASRICHA: Did you have a comment on that, Steve?
26          DR. JAMES: Well, I think that would be a fairly ambitious goal. I
27   think we tend to do things more incrementally just as a practical
28   matter. The NIDDK for example has started a repository that has
29   everything, tissues, DNA, any kind of information that can be stored
30   with the plan that that would be made available to anyone who wants it.
31   Whether you could really have a consortia of consortia has been
32   attempted. It can become administratively unwieldy to manage that. So I
33   think the groups that are most successful have a very clear purpose and
34   goal that - and also, the larger the groups get it becomes very unwieldy
35   if you're trying to mix and match many different diseases in one
36   setting. So I would be - I think the concept is okay. I think how to
37   bring it off is another matter which is why I think we should focus on
38   the goals. And again, different institutes at NIH have different ways of
39   getting the same thing done, and may be better equipped to do it in one
40   way than another. The Cancer Institute for example has cancer centers

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   and they tend to want to work through them, so you know, I think that
 2   one recipe of doing it may not work.
 3          DR. PASRICHA: Maybe - sorry, just to follow up on that. Maybe
 4   what you're saying is that the AGA - or societies like the AGA or the
 5   ASGE should think of partnering with the NIDDK to defray the cost of
 6   setting up consortia.
 7          DR. CERULLI: That could work too since they already have sort of
 8   a mechanism set up.
 9          DR. JAMES: It's a little cumbersome, but yes, we're always happy
10   to share other people's money, so. Constrained by laws that don't give
11   us total freedom to do what we want. Bob? Yes.
12          DR. SANDLER: Your recommendation to get annotated specimen is
13   reminiscent of something that came out of the esophagus PRG, the
14   Progress Review Group, and my recollection is they never did it. Is
15   there some - it looks like a good idea to me. Do you have any
16   information about why that wasn't done, or does that dissuade you from
17   recommending that?
18          DR. JAMES: Is John Milner still there? I think the - yes, there
19   was a PRG on Barrett's and I was actually at that one. You were too, I
20   believe. And there were a lot of good ideas and they simply never came
21   to fruition. There were different reasons for that, but that doesn't
22   mean that - I think the goals remain and we can keep trying to achieve
23   them. Kent?
24          DR. SANDERS: What I said about the difficulty in manipulating the
25   rest of the gut from a molecular point of view is particularly a problem
26   in the esophagus from the neuromuscular standpoint because the
27   neuromuscular arrangement in animals that we know the genome of and that
28   we make transgenics for is so different from human. And so I would think
29   that you know, another sort of obstacle or whatever, a challenge would
30   be to perhaps develop a good animal model with a more human-like
31   esophagus that could be dealt with in a transgenic and molecular
32   approach, although I don't think anybody's going to spend too much money
33   doing the genome of the possum.
34                DR. PASRICHA: Or the pig.
35                DR. GOYAL: I understand this has been done.
36                DR. SANDERS: Oh, has it?
37                DR. GOYAL: I just wanted to make one point. I think one of the
38   major problems in studying natural history of Barrett's esophagus is
39   that our diagnostic criteria of dysplasia. We really don't know what it
40   is. No two pathologies agree with each other and they usually say it's

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   only I and my friend agree that it's dysplasia, low-grade or high-grade
 2   dysplasia. So I think this is obstacle that might be overcome by some
 3   kind of a short-term goal to really somehow come to a vigorous
 4   definition, a pathological definition of dysplasia and its grade.
 5          DR. JAMES: Could that be accomplished with - we don't necessarily
 6   need to be beholden to like microscopic appearances. More sophisticated
 7   approaches to morphology and/or expression or rays or whatever may be
 8   what's needed. A really more comprehensive molecular definition of what
 9   we're calling Barrett's probably would be better than subjective ones
10   that require a panel of pathologists to agree what they're looking at.
11          DR. GOYAL: Yes, I agree. I think it really requires a
12   comprehensive approach with molecular biology as well as histology.
13                DR. JAMES: Any other comments? Very good.
14          DR. PASRICHA: Thank you.
15          DR. JAMES: Thanks very much. We're going to move on to liver now.
16   Bruce? Yes, sorry. John.
17          DR. CARETHERS: I just want to make a general comment. I mean,
18   some of the things that have come up thus far, particularly some of the
19   major challenges. I remember we're going to discuss this tomorrow. I was
20   just wondering, is there any rationale to having for instance an NIH or
21   a national IRB for some of this stuff versus local stuff? I mean, as one
22   -
23          DR. JAMES: Yes, I can cut that short just by saying that this
24   gets a lot of discussion at NIH and the best venue are currently -
25   focused attempt to do something about harmonizing IRB approaches and
26   issues is through the CTSA program because among the things they've
27   chosen as high priorities are common definitions of clinical things,
28   common types of databases, that is medical electronic record, and
29   harmonizing some of the things that are seen as tremendous barriers to
30   clinical research. IRB is one of them. FDA processes might be, getting
31   INDs and other basically sorts of procedural and administrative things.
32   So a lot of people have talked about that. For the most part there are
33   still many hurdles out there to overcome that are not at all disease
34   area-specific. It's quite generic. So I'm not sure that we need to
35   devote - a lot of people are working on these things. I'm not sure -
36   other than certainly recognizing that it's a problem for us too is any
37   more than what we need to do.
38          DR. CARETHERS: I'm sorry, I was thinking about more for some of
39   these potential discussions on these consortiums. For instance, recently
40   I understand - I don't know if it was the NIH, or CDC, I forgot who it

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   was, about heart attack victims in emergency rooms that was approved at
 2   a national level. Because it doesn't - because people aren't going to
 3   give consent. But I was wondering if something like that could be done
 4   for some of these consortium-type things. I was just curious.
 5          DR. JAMES: Yes, that's I think a really difficult informed
 6   consent issue, and that's yet another part of the package of OHRP and
 7   other things that are a little peripheral I think to our mission here.
 8   Okay. Bruce, you're on.
10   Diseases of the Liver and Biliary System (WG 11) Bruce R. Bacon, MD,
11   Chair
13                DR. BACON: So just go to the first. This is the group of people
14   who worked together. And we had several conference calls and struggled
15   with how our working group recommendations and goals would relate to the
16   Liver Action Plan. We had the advantage of having a 180-page booklet
17   with 16 chapters in it describing what we should do for liver disease.
18   We had the disadvantage of trying to get that into 15 minutes. So we
19   struggled with this a little bit and many of the people who you see on
20   the list here were actually a part of the Liver Action Plan. I suspect
21   all of them at one point, is that right Jay? All of these people I think
22   were involved at one point with the Liver Action Plan.
23          So we first tried to recreate the Liver Action Plan and we
24   realized that that was impossible, and then realized that we should
25   really develop something that would be modified from the Liver Action
26   Plan. And we had kind of an epiphany phone conference one time when we
27   decided we would split up the chapters from the Liver Action Plan and
28   divide up amongst the appropriate individuals and then come up with a
29   number of research goals and areas. So most of the research goals that
30   we've come up with are actually linked to the action plan. We feel
31   that's the best way to provide a unified approach in liver and biliary
32   diseases. And initially we had 64 goals identified, but of course we
33   don't have that much time, so we've reduced that down to 31 I think
34   which is still a lot, but we'll go through them.
35          So one of the first topics was just basic cell and molecular
36   biology of the liver. And the recommended goals were to elucidate intra-
37   and extracelluar events, determining hepatocyte polarity and examining
38   different culture systems starting with human oval cells and fetal
39   hepatoblast to verify the relevance of a precursor cell line to human
40   cholangiocyte biology. So there's something for those interested in

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   hepatocytes and something for those interested in cholangiocytes. And
 2   again, that was distilled down from a number of recommendations that
 3   were initially there.
 4          This gets into a little bit overarching pathophysiological
 5   processes amongst all of the organs that we deal with, this set of goals
 6   related to liver injury, inflammation, repair and fibrosis. And to
 7   identify individual liver cell type and inflammatory cell type and
 8   organelle-specific responses to inflammatory mediators, endogenous and
 9   pathogen-derived signals and liver injury, inflammation, regeneration
10   and fibrosis. To delineate genetic host and environmental determinants
11   of disease risk and progression in both acute and chronic liver injury.
12   And then to identify individual specific extrinsic and intrinsic
13   cytotoxic signaling and apoptosis, and define and develop anti-fibrotic
14   and anti-apoptotic strategies.
15          In the area of developmental biology and regeneration to develop
16   new models to study liver development. This was considered a short-term
17   goal originally and some of these, you'll see some carryover of short-
18   and long-term goals from the action plan. And to develop practical gene
19   or cell therapy for metabolic liver diseases.
20          Related to bile, bilirubin and colostatic diseases, to define
21   structure-function relationships of genes involved in regulation of bile
22   formation and secretion. Identify potential targets for therapy for
23   colostatic liver diseases. To determine if polymorphisms of major bile
24   and bilirubin transporters are modifier genes for other liver diseases
25   and for drug-induced colostatic liver disease.
26          Within the huge area of viral hepatitis, much of the work in
27   viral hepatitis is done - a lot of it's done by the pharmaceutical
28   industry and what we are increasingly running into now is aspects of
29   resistance from the various products that are being developed. So a
30   research goal in this area was to define the molecular basis for both
31   Hepatitis B and C treatment resistance, including to interferon and the
32   specific antiviral compounds that have been proposed. And then of course
33   to develop a Hepatitis C vaccine, that's everybody's apple pie and
34   motherhood, and to develop a therapeutic Hepatitis B vaccine. I think
35   there will be difficulties with the Hepatitis C vaccine that have been
36   encountered already.
37          One thing related to HIV and liver disease, to define efficacy of
38   existing and novel anti-HCV and anti-HBV treatments. This was in special
39   populations, but includes HIV-infected patients and recipients of
40   transplants and injection drug users. So this is actually a much broader

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   research goal, but was put down under the HIV and liver disease chapter.
 2          Fatty liver disease is an increasingly common problem in America
 3   with the obesity epidemic. And the research goals that were identified
 4   of many that were proposed were to evaluate the utility of the currently
 5   described different animal models and develop more accurate models for
 6   further studies on pathological mechanisms and treatment strategies in
 7   both alcoholic and non-alcoholic fatty liver disease. To evaluate
 8   epigenetic effects of alcohol on the components of the metabolic
 9   syndrome that contribute to fatty liver and steatohepatitis. And then to
10   develop non-invasive means to distinguish between steatosis and
11   steatohepatitis. Currently, liver biopsy is required to make that
12   differentiation. To identify molecular mechanisms that determine which
13   patient will transist from steatosis to steatohepatitis and to link
14   those who will have progression of disease to more severe chronic liver
15   disease. Try and identify those patients who are at risk for disease
16   progression.
17          Within the area of drug and toxicity, again another request for
18   collaborative databases, here with the pharmaceutical industry. To
19   analyze all prodrugs, drugs and drug metabolites associated with
20   abnormal liver tests and overt liver injury to identify structural
21   activity relationships predictive of hepatotoxicity. Again, that sounds
22   easy to write a sentence like that, but a much more difficult exercise
23   to conclude. Also, there is an initiative within NIDDK now called the
24   DILI network, which is Drug-Induced Liver Injury. And there are some
25   programs in place now to recruit cohorts of patients with drug-induced
26   liver injury comparing their genomic and proteomic profiles with those
27   of control patients using the same drugs without DILI. So some of this
28   is ongoing. It's a matter of adding to it.
29          In the area of autoimmune liver disease there are several
30   diseases that autoimmune hepatitis, PBC and PSC are in that category of
31   autoimmune diseases. I'm not sure they're all immune-mediated and it's
32   not sure what really sets those diseases off. But the request here of
33   the group was to create an international network of clinician
34   investigators to provide sera, mononuclear cells, pathological
35   specimens, clinical details to be used in the studies of the etiology
36   and pathogenesis of each of these diseases. There are no animal models
37   for studying any of these disorders, so the work has been done in
38   clinical databases. And then furthering on that line, establishing a
39   network of American investigators from an international - or an
40   international consortium to identify patients for future studies of more

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   sensitive and specific diagnostic tests, genomic, proteomic and
 2   metabalomic profiles of each disease, epidemiology in the United States,
 3   genetics in randomized controlled trials. These diseases really aren't
 4   studied very much because there are no single centers that have large
 5   numbers of patients and it really will take collaborative work for doing
 6   that. And frankly, autoimmune hepatitis is fairly easy to treat for the
 7   majority of patients and there's not an incentive to try and get new
 8   therapies. But PBC and PSC definitely would benefit from this.
 9          Pediatric liver disease. Dr. Sokol has come up with a couple
10   things here. Determine a thorough understanding of the etiology and
11   pathogenic mechanisms causing biliary atresia. On this basis, new
12   preventive and treatment strategies could be developed and tested. And
13   to develop animal models for the major genetic causes of colostatic
14   liver diseases in infants.
15          Genetic liver diseases. In the area of hemochromatosis and
16   disordered iron metabolism, to elucidate the interactions between these
17   newly discovered genes and their proteins hepcidin, HFE ferroportin,
18   hemojuvelin, I could add in there DMT-1 and transferrin receptor 2. And
19   then to define the genetic modifiers of Wilson's disease and the
20   porphyrias using animal models and clinical cohorts of patients. Again,
21   no one place has large enough numbers of these various diseases to do
22   this and there are no good animal models for these disorders.
23          Liver transplantation. What surfaced to the top as being most
24   important, develop novel ways to prevent recurrence of Hepatitis C
25   infection in the allograft. Define and improve mechanisms involved in
26   liver regeneration after live donor transplant. One area was
27   complications of chronic liver disease, and again what surfaced was
28   identify and develop small molecule targets leading to better controlled
29   portal hypertension which is the major complication that we see in
30   patients with end-stage liver disease. And to better define the natural
31   history. Again, we hear about natural history of hepatopulmonary
32   syndrome or portal pulmonary hypertension and determine whether early
33   detection and aggressive management would be beneficial.
34          Liver cancer. To identify molecular targets for potential therapy
35   of hepatocellular cancer which is one of the most rapidly rising cancers
36   that we see in the United States today, all related to the Hepatitis C
37   epidemic. And cholangio-carcinoma and gallbladder cancer. And to
38   translate genomic profiles into the clinical practice for individualized
39   therapy for hepatocellular cancer, cholangio-carcinoma and gallbladder
40   cancer.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1          In the area of gallbladder and biliary disease, to develop
 2   molecular and functional imaging techniques for disease and function of
 3   the biliary tract. That is a pretty broad goal. And to develop chemo-
 4   preventive approaches for gallstones in high-risk populations.
 5          Now, the major challenges and steps to achieve some of these
 6   goals are listed over the next few slides. So to recognize that the
 7   quantitative isolation of progenitor cells from diseased adult liver may
 8   prove difficult, suggesting that there are methods for isolating non-
 9   parenchymal cells could yield a representative sample. And it's expected
10   that complex culture conditions may be necessary for propagating
11   progenitor cells ex vivo.
12          Related to hepatic and biliary cancers, comprehensive banks of
13   tissue and serum for hepatocellular and bili-tracked cancers linked to
14   demographic and clinical data would be required to develop biomarkers.
15   Validate molecular signatures in individualized therapy. This again will
16   require large databases and collaborative work amongst numerous
17   investigators. We need some uniform endpoints. In fact, the ASLD just
18   had a conference on endpoints in hepatocellular cancer to try and get at
19   this need for uniformity of endpoints for a variety of clinical trials.
20   This was particularly in liver cancer. And we need the people that work
21   on these patients, the interventional radiologists, the hepatologists,
22   the oncologists, the surgeons and the transplant surgeons to all be at
23   the table. And consortia of interested multidisciplinary teams need to
24   be developed to implement therapeutic trials. I think we now - all of
25   our institutions have individualized approaches to how we handle
26   hepatocellular cancer and cholangio-carcinoma. There's no uniform way.
27   Many of us come up with the same way as other people do just by trial
28   and error, but it would be better if these things were coordinated.
29          Lack of a national registry for rare childhood liver diseases
30   from the pediatric liver disease vantage-point. The need for small
31   animal models for Hepatitis C and Hepatitis B and HIV co-infection. This
32   obviously constrains our understanding of viral and host interactions
33   and therapeutic events. Again, a need for public health networks, and
34   we've heard this theme echoed with many of the other topics that we've
35   discussed today. Deficiencies in the public health system and societal
36   factors limit the effectiveness of new discoveries since currently the
37   majority of patients who have or are at risk for chronic hepatitis do
38   not currently receive the standard of care. So even though we may
39   improve the quality of care that we give for these various problems
40   which make up the bulk of what we see in hepatology, we need to know how

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   to deliver this care.
 2          The need for integration of relevant knowledge produced by such
 3   disparate fields as cell biology, physiology, inflammation, immunity,
 4   virology, oxidative, nitrosive, hypoxemic and ischemic hepatobiliary
 5   injury. Again, networking and collaborations amongst investigators,
 6   industry and agencies such as the NIH. Forging scientific and business
 7   relationships between academia and pharma, biopharma and biotechnology.
 8   This all sounds great to say this. It's very difficult to pull this off,
 9   but I think if there was enough incentive to do this with maybe some
10   appropriate financial attractiveness that some of these groups could
11   come together.
12          Then the last one is related to fatty liver disease. It was
13   stated by some that the epidemic of obesity and diabetes and
14   hyperlipidemia may well overwhelm the pharmacologic approaches that we
15   have to control fatty liver disease. And I think all of us are aware of
16   how large, literally and figuratively, this problem of fatty liver
17   disease and obesity is in our society. That's all. Open for questions.
19   Discussion
21                DR. JAMES: Very good. David?
22                DR. LIEBERMAN: Bruce, I may have missed it, but it seems to me it
23   would be very attractive to have a non-invasive tool for both diagnosis
24   and prognosis of liver disease. I know hepatologists like sticking
25   needles in livers, but I don't. What do you think about that and should
26   that be a priority?
27          DR. BACON: Well, there's actually quite a bit of work with
28   serologic markers. Most people are looking for fibrosis there in the
29   liver and there are a number of serological tests that have been
30   proposed. There's a gadget called the FibroScan that's being used. My
31   problem with the biomarkers, the non-invasive tests are that they're
32   good for groups of people, but they're not necessarily good for an
33   individual person. There's a lot of overlap. That work is already going
34   on and I think we'll - well, I don't know if we'll have that solved in
35   10 years or not, but -
36          DR. LIEBERMAN: I guess my question was whether you think or your
37   group would feel that that's an important enough priority that it ought
38   to be -
39          DR. BACON: We could certainly put that in.
40          DR. LIEBERMAN: - be you know, listed in here.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. JAMES: Yes, I think if you look at the components of an Ishak
 2   score you want to know very sensitive measures of fibrosis and
 3   inflammation. If you could do it without a biopsy that would be
 4   fabulous. I think the practical issue is can you measure very small
 5   changes that might occur, say, if you're doing an interventional trial
 6   and you're looking for something that might change in one year which
 7   might be a very small amount, could you do this in a very robust way
 8   with any of these technologies so that you - or in individual patients
 9   as you're trying to make -
10          DR. BACON: The other interesting component of that is we compare
11   all of these things to liver biopsy, yet we know that there's lots of -
12          DR. LIEBERMAN: Variation.
13                DR. BACON: - there's variation in what you get with liver
14   biopsies. So it's not really a gold - it's a tarnished gold standard.
15          DR. LIEBERMAN: Exactly. I mean I feel that way about colonoscopy
16   too.
17          DR. BACON: Exactly.
18          DR. LIEBERMAN: That's why I think it would be attractive if we
19   did have a tool that we could use to measure the progress or the non-
20   progress of liver disease.
21          DR. BACON: That's - what's being proposed now for some of these
22   things is that you'll do a liver biopsy, determine the stage of the
23   disease activity at that point, or the stage of the fibrosis and do a
24   fiber scan, and then subsequently you'll do fiber scans to see if there
25   are differences in the measurements. You won't do subsequent liver
26   biopsies, but you'll do subsequent fiber scans.
27          DR. JAMES: John?
28          DR. CARETHERS: I notice you mentioned about small molecules for
29   hepatopulmonary syndrome, but you didn't mention one of the leading
30   causes of death for people waiting for liver transplant which is
31   hepatorenal syndrome. I was wondering if that was an obvious omission?
32                DR. BACON: I can't remember if that was one of the original 65
33   things or not. I don't think it was. But we can easily put that in.
34          DR. CARETHERS: I was just wondering because a lot of people are
35   just dying waiting for liver transplant. If there was a way - if we
36   understood that better to prolong life.
37          DR. BACON: Sure. Good question.
38          DR. JAMES: Maurice, you were?
39          DR. CERULLI: Just one thing is that we get a lot of sophisticated
40   knowledge from a liver biopsy. We'd have to get similar knowledge that

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   we could rely on from a test, but certainly the patients would prefer it
 2   and it would be a lot easier to serially measure something from a blood
 3   test or a fibrosis test rather than actually doing another biopsy with
 4   its risks.
 5          DR. JAMES: Barbara.
 6          DR. BASS: As more patients are receiving neoadjuvant chemotherapy
 7   prior to liver resection for metastatic disease in particular, the
 8   chemotherapy-induced steatohepatitis, is that - does that reach the bar
 9   of significance as an area of investigation for the group?
10          DR. BACON: It didn't. It didn't. So I mean, I don't - I think
11   it's not going to reach the bar compared to some of the other things
12   that we're seeing here I don't think. I'll write it down. I'll ask them.
13                DR. JAMES: Sam.
14          DR. ZAKHARI: Sam Zakhari from NIAAA. I very much appreciate the
15   inclusiveness you have, Dr. Bacon, in your presentation, especially
16   including the alcohol effects. We know that alcohol is responsible for
17   50 percent of liver cirrhosis effects, HCV therapy or lack of it, lack
18   of response. And also there are a lot of similarities between ASH and
19   NASH and so on, but there are some differences too. So this is a very
20   important area and I appreciate that you highlighted that. The area of
21   liver regeneration probably would need some attention because alcohol
22   decreases that. And I'm also grateful for Dr. Pasricha for highlighting
23   the chronic pancreatitis issue.
24          I have a few comments that are quite general and I don't know if
25   this is the time to say them or not. But I think in the area of cancer,
26   the colorectal cancer and liver cancer and esophageal cancer this is an
27   area that's impacted by alcohol. And I don't see some information there.
28   Alcohol also affects intestinal permeability and intestinal flora and
29   that can cause different diseases and so on, so this needs some
30   attention. Alcohol affects the - some nutritional aspects. I'm talking
31   about chronic alcohol consumption here, not a happy hour Thursday
32   evening or so. But alcohol affects nutritional aspects. It affects the
33   folate and methionine cycles, and that causes the epigenetic effects
34   that Dr. Bacon was talking about. Metabolism of alcohol affects
35   different things including fatty acid metabolism and that causes liver
36   damage and so on. This needs attention. And importantly, the interaction
37   between alcohol and other medications like alcohol and acetaminophen,
38   alcohol induces CIP-21 and that causes some problems not only with
39   acetaminophen, but also with the metabolism of pro-carcinogens to
40   carcinogen and that can impact on the cancer problem. So as you see

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   alcohol is quite ubiquitous. Compounded it can cause a lot of havoc on
 2   the digestive system and I appreciate that's given to it. Thank you.
 3          DR. JAMES: Thanks Sam. Dan?
 4          DR. PODOLSKY: Bruce, I realize you had a daunting task, such a
 5   broad area. One of the things I was interested to know in terms of what
 6   the thinking of the group was, in sort of challenges is around support
 7   for the failed liver, you know tying into organ fabrication, artificial
 8   liver concepts.
 9          DR. BACON: Yes. You know, that's kind of been - that was on the
10   liver transplantation, you know support as bridge to transplant. But it
11   didn't reach high enough priority to get carried through into the final
12   steps. I think a lot of that's done by industry as well. Is that? I
13   don't think - is there stuff supported by that?
14          DR. JAMES: Yes. I think the number of people who actually
15   seriously are interested in biosupport devices for example is small, but
16   it's a topic that doesn't go away. You don't have that in your chapter,
17   do you?
18          DR. BASS: We have a bit of regenerative tissue engineering work
19   in our group, but we didn't specifically address livers. But I think
20   it's a very important area to address.
21          DR. BACON: That's a good point.
22          DR. PODOLSKY: And they're related. You could make it a more
23   general point around also xenotransplantation. One of the hard realities
24   is that there's only so many livers out there.
25          DR. BACON: Six thousand to 7,000 a year for 17,000 people.
26          DR. PODOLSKY: So between - there will be some time before you get
27   to the point of actually curing or preventing all this liver disease.
28          DR. BACON: Right.
29          DR. JAMES: Well, the issue of - I would actually tend to think
30   what the tremendous advances in stem cell research that there might be a
31   rejuvenation of understanding of support devices before we'll overcome
32   the barriers to xenotransplantation which are formidable. Especially if
33   you love pigs. But no really, I think the rate of progress in stem cell
34   technology and research is just amazing, and I think that there may be
35   opportunities there for a resurgence of that very old field.
36          DR. PODOLSKY: Some kind of organ replacement - knowing which is
37   the right strategy to get there.
38          DR. BACON: I really think - I think maybe anti-fibrotic therapies
39   are - I mean a lot of energy is going into developing anti-fibrotic
40   therapies. None of them have been productive yet, have resulted in

                           NEAL R. GROSS
                           1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433        WASHINGTON, D.C. 20005-3701

 1   anything good, but I fully envision many, many years from now people
 2   will say geez, remember back in 2000 they used to wait for someone to
 3   die and then they'd take their liver out of them and put it in. Now we
 4   just give them a pill and their fibrosis goes away. I think that'll
 5   happen. Maybe not in 10 years though.
 6                DR. JAMES: Bob?
 7                DR. SANDLER: Dan asked my question, but I had a more general
 8   point about stem cells because it's touched all the other chapters and
 9   it really wasn't here. And there's a role perhaps for stem cells beyond
10   liver assist devices, like shooting them into the person.
11          DR. JAMES: Yes. I think we're going to hear certainly the topic
12   of regenerative medicine and so forth. And certainly in the basic
13   chapter there's considerable interest.
14          DR. BACON: It did leak into one topic in treatment of metabolic
15   liver diseases. It was in there. But I think there are many other places
16   where it could be utilized as well.
17          DR. CARETHERS: Since we didn't touch the liver cancer, I was
18   going to bring up two points. One is - I mean, you did mention about the
19   oval cells and the stem cells, but I was wondering, is there any thought
20   about looking at the local environment for regeneration? I mean, I guess
21   that's going to come up in the other, so maybe you partly answered that
22   question.
23          The other thing is we didn't touch base, but I didn't know if you
24   guys would on metastases to the liver which is a very common form of
25   quote unquote liver cancer if you will.
26          DR. BACON: Yes, in fact it's the most I think statistically it is
27   the most common.
28          DR. CARETHERS: It's the most common, right.
29          DR. BACON: Yes. We didn't talk about that. I'm not sure where
30   that belongs.
31          DR. CARETHERS: Because that has - well, I mean we can - we didn't
32   touch base on it, but I guess maybe we can address it.
33                DR. BACON: The problem is there isn't -
34                DR. JAMES: Yes. Whose home does that belong to.
35                DR. BACON: Yes.
36          DR. JAMES: Jay, did the Liver Action Plan include anything on
37   metastatic liver disease? I don't think so. Who - should we take some
38   ownership of that?
39          DR. CARETHERS: Maybe we should address it because all the -
40   essentially all the cancers that we address go there. And then also -

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. BACON: As a preterminal event. I think that's why there's not
 2   - there isn't a lot -
 3          DR. CARETHERS: But there is some knowledge on surgical treatment
 4   for limited size things and stuff like that. Okay.
 5          DR. JAMES: You've got something to work on tonight, John.
 6                DR. CARETHERS: Sam is going to help me.
 7                DR. JAMES: I had one other, just a practical question. That is
 8   given the large number of goals, whether they could be consolidated a
 9   little bit just with headers along the lines of the slides. So the
10   slides have them grouped and just to make them a little more workable in
11   terms of -
12          DR. BACON: You should have seen them when there were 65 though.
13                DR. JAMES: Well, that would be only half the Liver Action Plan.
14   So I think maybe it might just make the writing exercise easier if they
15   were somewhat more grouped than 35 goals. But that should be easy I
16   think.
17          DR. BACON: Yes, that's just a formatting. Yes.
18          DR. JAMES: Okay. Any other comments? Jay, did you have any
19   comments? No. Do you want to take a break now? Ten minute break, okay.
20   Is that all right or do you want to do another one? Five minute break.
21   Okay. Thanks. Five minutes.
22          (Whereupon, the foregoing matter went off the record at 3:36 p.m.
23   and went back on the record at 3:56 p.m.)
25   Diseases of the Stomach and Small Bowel (WG 8), Maurice A. Cerulli, MD,
26   Vice Chair for Eugene B. Chang, MD, Chair
28          DR. JAMES: Maurice Cerulli is going to present the section on
29   stomach and small bowel. Thanks very much.
30          DR. CERULLI: Good afternoon everyone. I always was wondering what
31   it would be like to give a talk with somebody else's slides. You know,
32   that's sort of - that's to keep you awake. But you never know, sometimes
33   you get what you wish for and then what you wonder what you were wishing
34   for. But this should be interesting. I mean, I've seen these slides
35   before. I went over them a bit, so it's going to be fun.
36          Okay, so Working Group Number 8. Okay, so this is the members of
37   our work group who worked actually very hard. I really have to commend
38   all the members of the work group. As you can see there's a lot of data
39   and we had difficulty as with most of the work groups. When you start
40   looking into it, there's a large volume of information and there's a lot

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   of data that you'd really like to get. This is sort of - everyone has
 2   presented their wish list of what they think is really important in
 3   their area and I'll be doing that here. And we set it up very much into
 4   short-, medium- and long-term goals, sort of you know 1 to 3, 4 to 6 and
 5   7 to 10.
 6          And so our list of short-term goals starts with defining the
 7   genetic, microbiological, pharmacological and host factors that
 8   determine gastric and enteric mucosal injury development and other
 9   disease-causing processes. Again we get back to the microbiome. We
10   wanted to develop animal and experimental models to better understand
11   integrative physiology and causes, pathophysiology, long-term
12   consequences of human gastric and enteric diseases. These models will be
13   useful for the therapeutic screening and testing of patients for these
14   diseases and for therapies. This we say is a short-term goal because
15   there's a significant amount of work that has been done, but we still -
16   it's not clear how short-term this really is. We also wanted to define
17   patterns in intestinal microbiome relevant to bacterial overgrowth,
18   Crohn's disease, necrotizing enterocolitis, microscopic colitis,
19   eosinophilic enteritis, celiac disease and other malabsorptive diseases,
20   lactase deficiency and obesity.
21          We also want to identify and characterize the additional
22   proteins, signaling pathways and proteinome of intestinal water,
23   electrolyte nutrient transport, particularly proteinome of BB and BL
24   membrane to better understand what abnormalities occur in diarrhea and
25   malabsorption. So our focuses are on the microbiome and then a number of
26   goals in diarrheal diseases such as developing high throughput screening
27   of antidiarrheal drugs that inhibit chloride secretion and/or stimulate
28   sodium absorption. Since diarrhea is a major problem around the world as
29   well as a significant problem in our aging population and at the other
30   spectrum in the pediatric population. We want to determine epidemiology
31   of acute diarrhea in the elderly including mortality, identify causes
32   and genetic bases of chronic diarrhea including maldigestion and
33   malabsorptive states. We wish to determine the role of non-hydrolyzable
34   starch-based oral solutions in the treatment of acute diarrhea in adults
35   and children in developing countries especially and in the United
36   States.
37          We also want to profile - this is now moving on to acid-peptic
38   diseases - the microbial, molecular, cellular and epidemiological
39   features of H. pylori-induced gastric carcinogenesis and peptic ulcer
40   disease to identify diagnostic, prognostic, predictive, preventive and

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   therapeutic targets. Also we'd like to define better the relationship
 2   between H. pylori and GERD complications, and sometimes a lack of H.
 3   pylori and assess prolonged proton pump inhibitor use. We think this is
 4   a short-term goal because we already are now developing at least
 5   somewhat reports of different possible complications of prolonged PPI
 6   use.
 7                We'd like to characterize and identify transport and adaptive
 8   proteins involved in regulation and mediation of nutrient and
 9   electrolyte absorption. We'd also like to determine the contribution of
10   paracellular transport of luminal materials to the intestine in
11   intestinal disease and characterize how tight junctions limit specific
12   molecule movement. Develop non-invasive methods to study in vivo the
13   intestinal absorptive and digestive functions such as using capsule
14   probes. Although being an endoscopist, I really don't feel too bad about
15   invasive things as Jay was saying about looking in the esophagus, but
16   most - there have been a number of points made this morning about
17   looking for non-invasive methods and we agree with that as well. Define
18   mechanisms, events that link the generation of large gluten peptides and
19   the ultimate development of pathogenic T-cell populations. Define the
20   relative roles and interplay of innate and adaptive immunity in celiac
21   disease. Again, among short-term goals. Refine genomic and proteinomic
22   techniques to identify biomarkers for NEC development using human
23   intestinal samples. We'd like to complete Phase I and Phase II trials in
24   the U.S. to assess tolerability and dosing strategy for probiotics in
25   pre-term infants, again getting back to the theme of necrotizing
26   enterocolitis.
27          Determine clinical phenotypes, establish diagnostic criteria and
28   identify non-invasive biomarkers and tests for eosinophilic
29   gastrointestinal diseases. That obviously would pair with the
30   eosinophilic esophagitis problem. Develop animal models to establish the
31   role of intestinal permeability in the pathogenesis of autoimmune
32   diseases and educate patients and physicians regarding risk factors and
33   improve adherence to appropriate strategies for the decreasing NSAID-
34   associated GI complications. I felt this was a good short-term goal
35   since again there's a significant literature on the complications of
36   NSAID-associated GI complications as well as some of the possible
37   remedies for this. However, further work needs to be done.
38          Intermediate goals that we felt were important were to utilize
39   the genomic and proteinomic approaches to study physiological and
40   disease mechanisms. That is, how alterations in intestinal epithelial

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   proteinomes relate to acute and chronic diarrhea, developmental
 2   abnormalities, malabsorption, maldigestion, malignancy, inflammation and
 3   metabolic diseases such as in obesity. Establish robust preclinical,
 4   such as animal and novel organotypic models to understand gastric and
 5   enteric physiology and diseases development. Using these models study
 6   mechanisms of integration, development and organization of intestinal
 7   processes that allow coordination of motility, absorption and secretion.
 8   Establish multi-center, again trying to set up networks. I guess Steve,
 9   you're not paying for these networks, but anyway. Establishing networks,
10   systems biology-based consortiums to integrate patient information,
11   experimental databases and biospecimens to better understand causality,
12   natural history, susceptibility and pathophysiology of gastric and
13   enteric diseases, and to develop better diagnostic treatment, disease
14   prevention strategies.
15          Also for intermediate goals, develop imaging techniques to
16   examine activation of signaling and regulatory molecules and transport
17   proteins in intact animals and man. Test new antichloride secretory and
18   pro-sodium absorptive drugs in animal models of acute diarrheal diseases
19   and begin trials in humans with acute diarrhea. Develop large-scale
20   biology approaches to identification of protein interactions of
21   intestinal sodium absorptive cells, chloride secretory cells and
22   enteroendocrine cells, including identification of all proteins involved
23   in pH homeostasis, calcium homeostasis and endocytosis/exocytosis
24   functions. Develop and test novel therapeutics and optimize existing
25   treatments for H. pylori based on identification and understanding of
26   molecular pathways involved in pathogenesis. Develop clinical profiles
27   and pharmacogenomic approaches for identification of individuals at risk
28   for NSAID-induced peptic ulcer disease as a basis for subsequent
29   intervention.
30          Other intermediate goals. Enable investigators by developing
31   optimizing gene delivery mechanisms for intestinal epithelial cells and
32   as part of future treatment strategies. Define cellular and molecular
33   pathways that regulate eosinophil-dependent tissue remodeling. Identify
34   novel agents for treatment of eosinophilic gastrointestinal diseases
35   such as anti-IL5 antibody, anti-CCR3 receptor antibody and imatimib.
36   Elucidate the role of TTG in celiac disease pathophysiology both as an
37   autoantigen and as a modifier of toxin gluten peptides. Identify
38   mechanisms responsible for probiotic effects on acute gut injury in pre-
39   term infants, getting onto NEC again. Elucidate mechanisms for small
40   bowel injury and bleeding due to NSAIDs and aspirin as a guide to

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   preventive therapies.
 2          Long-term goals, research goals. Develop clinical, useful non-
 3   invasive technologies to assess digestive and transport function,
 4   functions in abnormalities, H. pylori-induced premalignant and malignant
 5   lesions, gastronomas and metastases and inflammation. Develop preventive
 6   strategies based on the mechanisms of H. pylori-host interactions that
 7   lead to cancer precursors, lesions and neoplasia of the stomach.
 8   Evaluate their effectiveness in at-risk populations. Develop population-
 9   based screening to identify patients at high risk for NSAID-induced
10   complications. Develop cost-effective preventive strategies for reducing
11   morbidity of NSAID-induced gastric injury. Design anti-inflammatory
12   agents of comparable or higher efficacy to traditional NSAIDs but which
13   lack traditional side effects such as ulceration, bleeding, perforation,
14   obstruction, dyspepsia and also cardiovascular toxicity. Determine more
15   precisely the causes and mechanisms of dyspepsia which may be somewhat
16   related to our functional bowel process as well here. Develop gene
17   therapy for genetic abnormalities discovered to cause chronic diarrheal
18   and malabsorptive digestive diseases. Develop pharmacologic agents
19   capable of blocking or augmenting pathways that control intestinal gene
20   expression. Crystallize transport proteins and their regulators to
21   understand their function in normal states and in disease both genetic
22   and acquired, including how they cause diarrheal malabsorption disease.
23          Understand integration of cellular and paracellular movement and
24   regulation of movement and how these are affected by diseases including
25   as targets in host-pathogen interactions. Establish the link between
26   celiac disease and the development of other autoimmune diseases and the
27   ability of the gluten-free diet to prevent or delay the development of
28   other autoimmune diseases in patients with celiac disease. Define
29   mechanisms by which other host genes contribute to celiac disease and
30   develop therapeutic strategies in place of a gluten-free diet. Establish
31   a standard of care for probiotics for NEC prevention in premature
32   infants.
33                So we feel thus from these short-, intermediate- and long-term
34   goals that these would be our major challenges. In general, and some of
35   this has been said before by other speakers, paucity of robust animal
36   and cell models for investigating gastric and small intestinal
37   physiology in diseases. So we need to develop animal models for GI and
38   liver disease. For less common diseases such as gastronomas, genetic
39   diarrheal disorders, or complex disorders such as dyspepsia, celiac
40   disease, inflammatory bowel disease and NEC single institutions lack

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   sufficient numbers of cases, biospecimens, research resources, or
 2   therapeutic capabilities. Again, a common theme of this meeting. So we
 3   should develop multi-center systems, biology-based consortia to share
 4   materials and information and increase statistical power. We have lack
 5   of interactions between adult and pediatric clinicians to define the
 6   natural history of diseases. We perhaps need small conference grants to
 7   support clinical and scientific interactions. Again, another theme of a
 8   paucity of young doctor MD and PhD investigators in GI and inadequate
 9   support to help them transition to R awards. So perhaps we need special
10   programs and funding. Insufficient investment in infrastructure or
11   approaches to develop proteinomics, genomic, metabalomic, bolomic and
12   bioinformatic approaches to the study of GI disease to develop ways to
13   genetically target epithelial cells and to study basic cellular
14   processes. So we need to develop such programs and earmarks - that's a
15   Washington word, isn't it? Earmarks? - to enable research investigators
16   and advance technologies.
17          In acid-peptic diseases, we felt that the major challenges were a
18   lack of information of cost-effective prevention of H. pylori or NSAID-
19   induced injury. So we need to establish multi-center studies to develop
20   screening, early detection, intervention in social and behavioral
21   dietary, microbiological or genetic predictors. We have a poor
22   understanding and definition of dyspepsia so we need to establish a
23   broad network via large multi-center studies. Poor adherence to
24   guidelines or best practices. The problem of bench to bedside.
25   Protective strategies in high-risk NSAID users. So we need to establish
26   programs that determine cause, make appropriate recommendations and
27   develop mechanisms to disseminate recommendations. Assess whether
28   recommendations are being followed and assess alterations in outcomes
29   such as looking at the quality of care.
30          There are unknown risks of long-term use of proton pump
31   inhibitors. We're starting to see some reports now so we should perform
32   an observational study with large numbers of patients and a long period
33   of observation. So again, transport malabsorption and maldigestion. We
34   have a poor understanding of most chronic diarrheal diseases. We have
35   insufficient experimental tools and models. Again, going back to
36   problems with paucity of animal models. We have no effective good
37   antidiarrheal drugs. In celiac disease, we do not again have a suitable
38   animal model for studies of celiac disease. For necrotizing
39   enterocolitis we have limited ability to study patients, obtain
40   biospecimens and perform analyses, so again we call for multi-center

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   systems. Lack of any specific treatments or prevention. We need to
 2   develop new therapies such as specific microbes, probiotics, or
 3   microbiological products. In eosinophilic gastroenteritis and autoimmune
 4   diseases we have lack of understanding of these diseases and inadequate
 5   treatment so we need to establish a centralized network or some type of
 6   database for healthcare professionals, including primary care physicians
 7   to acquire information on these diseases. And I still have 37 seconds.
 8   I'm ready for questions and whatever now. Thank you.
10   Discussion
12                DR. JAMES: Thanks very much, Maurice. Comments? Questions? David.
13                DR. LIEBERMAN: I have just a quick comment. It struck me as I
14   thought about this section that the most common thing that we see in
15   clinical practice is probably non-ulcer dyspepsia. And it's certainly
16   mentioned in here, but I didn't get the sense that your group felt that
17   this was an especially high priority for either considering you know
18   definitions, you know phenotype which we've talked about earlier,
19   diagnostic tests. And then as we've talked about in other groups,
20   particularly the motility group, underlying pathophysiology and then
21   ultimately therapy. And it seems to me, given the high burden of disease
22   - or the high burden of this problem, whether it's a disease or not, I
23   don't know, this should be a pretty high priority. What do you think,
24   Maurice?
25          DR. CERULLI: Well certainly more than half of the patients with
26   dyspepsia will have non-ulcer dyspepsia. We like to push it over there
27   on those motility people, but we don't really know. It probably isn't
28   the microbiome in this specific case, but it could be. Could be a
29   motility problem. It could be some type of perception problem or a
30   neurologic problem. I think we need to have a better quantitative
31   definition based on some type of pathology that we don't see right now.
32   I mean, people take biopsies all over most of which come back with
33   chronic gastritis or some other nondescript thing that is almost of no
34   help. I think we could emphasize that more since that's a major cost
35   burden.
36          DR. LIEBERMAN: Given the burden of disease it just seemed like
37   this would be an area that would bear emphasis.
38          DR. JAMES: Yes, I think our original thinking was that HP and
39   NSAID-induced or related diseases would fall in this group and that the
40   dyspepsia as a symptom complex without - non-ulcerative especially would

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   fall in the other. Obviously a very artificial division of the research
 2   that's needed, so certainly this is an area that we could -
 3          DR. CERULLI: Should we own non-ulcer dyspepsia, or is it a
 4   motility issue? I mean it's a specific GI issue, but.
 5          DR. JAMES: I think where to put it depends on - I think there's
 6   still some issues to be resolved with how to further polish the clinical
 7   issues for the functional GI group. But I think as part of that it could
 8   also be moved. I think some of the issues such as fundamentally pain
 9   issues do belong in the functional chapter, and a lot of the brain-gut
10   stuff probably belongs there, but certainly needs to be tied to the
11   other kinds of - because the mechanisms are going to overlap. And people
12   who have other definable etiologies such as HP or NSAIDs.
13                DR. CERULLI: There's been some fundal discussion, some fundal
14   dysfunction and fundal dysmotility so we didn't really think it was more
15   in our purview, but it certainly is the purview of the group, of the
16   commission.
17          DR. JAMES: Barbara?
18          DR. BASS: I similarly wondered where - maybe I just missed you
19   say it, but in terms of gastroparesis and electrical pacing and all
20   those kind of. I wish someone would, given the proliferation of that
21   technology, put a rest or put it in its proper place. Is that a priority
22   area for your group?
23          DR. CERULLI: I don't think gastroparesis was ours.
24          DR. JAMES: I think it does belong in the functional.
25          DR. BASS: Did you all address that, then?
26          DR. SANDERS: Well, I didn't address it by name. But certainly
27   it's in the group and some of the goals that we have obviously are to
28   get at mechanisms of gastroparesis. And this also could be a central
29   perception kind of thing as well, some of the negative symptoms of
30   gastroparesis.
31          DR. BASS: I think specifically - yes.
32                DR. SANDERS: - I didn't list, again, all 20 political entities
33   that I tried to summarize.
34          DR. BASS: I think that specific technology which is sort of
35   proliferating and being applied to a variety of poor gut disorders needs
36   to fall in somebody's bucket because -
37          DR. SANDERS: Gastric pacing and also electrical stimulation in a
38   way that's not going to pace the stomach, in a way that's going to
39   stimulate afferent neurons probably is in one of our steps. I didn't go
40   through all those, but it's there.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. PASRICHA: This is a practical question as to organization
 2   because in our esophageal section we did take a bite out of the motility
 3   disorders as you saw.
 4          DR. JAMES: Yes, that was a conscious decision that it seemed that
 5   the people who focus on GERD view that in a very much already an
 6   integrated way and that the motility aspects of that sort of seem to
 7   have a good home there. Again, it was a totally arbitrary decision about
 8   how to dice and splice these things together, but I think - pretty sure
 9   that we addressed where would motility go, motility basic science and it
10   seemed in your group, so.
11          DR. PASRICHA: So one suggestion is if you're looking for ways to
12   replace the chapter that you dropped is to split. I mean, it seems
13   there's really enough in motility and functional to warrant two
14   chapters. One could be the old view of that and populate it with
15   sections from the esophagus, stomach, intestine and specific disease
16   entities. That's just an idea.
17          DR. JAMES: A comment I had in general was going through all this
18   is that you have like 43 goals and many of them are interspersed on the
19   same thematic areas. So you have goals related to celiac disease and
20   goals related to transport. And I would tend to want to consolidate them
21   all together in the same thematic areas which would probably make it
22   much easier to understand and write about these rather than the
23   artificial way of starting with short-, medium- and long-term. It wasn't
24   clear to me how to - I'm sure it's all there, but I think it can be
25   done.
26          DR. CERULLI: I like the presentation of the GI cancer group with
27   those sort of like spreadsheet slides with the short-, intermediate- and
28   long-term and the discoveries on the side. If I could figure out how to
29   make that chart I think I would do that.
30          DR. JAMES: Yes. Although admittedly some of the short-term ones
31   seem very long-term. So I think - that's again, I think too much of the
32   focus was on try to have an integrated pathway of short, intermediate
33   and long where it was not clear at all that that would be the sequence
34   of discovery. And maybe it's better just to focus on the goals.
35          DR. CERULLI: And I thought the IBD presentation was good also
36   because it was very focused in specific areas and I think we would try
37   and borrow from those two templates if you will.
38          DR. JAMES: Yes. So I think actually, I started to go through this
39   a little, just picked the theme areas such as NSAIDs. Very, very
40   important area and just go through and pick out the ones, and you could

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   have something about the importance of NSAIDs and these separate bullet
 2   items that go with it as hanging together. Something that would be
 3   easily understandable. But the way, the current organization which was
 4   kind of dictated by us does not make it easy. But I think certainly the
 5   information there looks quite good.
 6          There are you know controversial things about - yes, are you
 7   going to talk about NEC? So the issue of coming up with a standard of
 8   care for probiotics when we don't know whether they work. I think it's a
 9   little premature to talk about standards of care.
10          DR. GRAVE: That's a long-term goal, 10 years.
11          DR. JAMES: Well, I think what we'd like to know is is there a
12   role for probiotics in any disease and this is obviously an important
13   target.
14          DR. GRAVE: It's actually under active investigation now and there
15   was that study from Taiwan that showed quite a difference in the kids
16   that had been exposed to probiotics and the ones that hadn't in terms of
17   the attack rate of NEC and even the morbidity.
18          DR. CERULLI: Yes, that was Dr. Walker's point. He was on the
19   subgroup that thought that was very important because of the emerging
20   data. We don't know that it's a standard of care now.
21          DR. JAMES: Yes, I just am quibbling about - I guess I shouldn't
22   be doing wordsmithing, but. Mitch?
23          DR. COHEN: I think the point is well taken. I agree with you that
24   if asked today to come up with the highest priority clinical trial it
25   might be to replicate that data. However, since this isn't going to be
26   published for two years or whatever and it's got to be enduring for five
27   to ten after that, it may be helpful not specifically commenting on - or
28   giving as an example, but being more generic I think in the approach.
29   You know, novel therapies or whatever, and you know, examples such as
30   probiotics. Because you really don't want to be - I don't think we want
31   to be that constrained five years from now when somebody's done the
32   study on probiotics, not confirmed it and then that aim is no longer as
33   vibrant, or that goal is no longer as vibrant as it might have appeared
34   in 2007.
35          DR. JAMES: Right, so my guess would be that we're likely to
36   conclude that the whole theme of microbiome will have tremendous weight
37   and opportunity that manipulating the microbiome with probiotics or
38   prebiotics or chemicals or nutrients will all be on the horizon in terms
39   of addressing specific disease conditions either as treatments or
40   preventions. So there's so much there I don't think we'll be wrong in

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   pointing out the research opportunities there. I might wonder about
 2   specifying a specific clinical trial unless it's so clear that, well I'm
 3   sure the NEC community - well, I'm not sure. Are they really ready to
 4   go?
 5          DR. GRAVE: Well, they're pretty excited about commensal organisms
 6   and reaction of the -
 7          DR. JAMES: I think everybody is excited about the
 8   pathophysiology. The issue of whether we're ready to do a clinical trial
 9   in the very high-risk infants makes people, even pediatricians I think
10   squeamish about are we ready. With the state of our knowledge of the
11   microbiome and probiotics, are we really ready to subject this very - I
12   mean, what's the death rate, 30 percent? Already the death rate is so
13   high.
14          DR. GRAVE: The death rate is about 30 percent of the ones that
15   get it and about 10 to 12 percent get it.
16          DR. JAMES: So I mean this does make people pause as to I'm not so
17   sure we want this. That's your option, but if you want to specify that
18   that kind of clinical trial should be done go right ahead. But I would
19   wonder if we want to get that level of detail in recommending -
20          DR. COHEN: Steve, just so I understand. You are reacting to the
21   exact phraseology of establish standard of care for probiotics for NEC-
22   prevention in premature infants. It sounds like it's a fait accompli
23   that the science backs up the approach.
24          DR. JAMES: Of course, yes.
25          DR. COHEN: And I think you're simply being -
26          DR. JAMES: I'm simply saying the science hasn't been done.
27          DR. COHEN: So I don't think anybody would object, I don't think
28   any of the pediatricians would object to a randomized double-blind - a
29   well-designed double-blind placebo-controlled trial. I suspect that's
30   what that's hinting at.
31          DR. JAMES: Yes, and that sounds fine to me -
32                DR. COHEN: It's just a wordsmithing.
33                DR. JAMES: - if you can get through all the hurdles including
34   recruiting patients into the study and doing it, by all means. But.
35          DR. GRAVE: So I just had a brief announcement if that's okay with
36   you.
37                DR. JAMES: You just funded the trial, right?
38          DR. GRAVE: Well, no. But we do have an RFA on the street. It came
39   out in mid-April and it doesn't close until the fifteenth of November.
40   So tell your friends and family and colleagues to apply. There's a fair

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   amount of money behind it. We got some money from our institute, the
 2   Child Health Institute, also from NIDDKD and AID interestingly enough.
 3   So we're looking forward to some good grant applications and appreciate
 4   all your help.
 5          DR. JAMES: Back to the issue at hand. Other questions or
 6   comments? Now, the issue is I think from a practical point of view do
 7   you want to try to do some reorganizing of this tonight?
 8                DR. CERULLI: No. I started doing some of it earlier, putting some
 9   titles and moving things around a bit, but it needs some more.
10          DR. JAMES: But I think maybe tomorrow, again the time would be
11   short, but just to give us a general glimpse of how you think these
12   might sort out would be helpful.
13                DR. CERULLI: Yes, I'll try and pare it down.
14          DR. JAMES: I think the issue of functional GI disorders and how
15   to dice and splice simply requires that the two are linked because
16   there's overlap, but I'm not sure we necessarily need to change the
17   original plan of having functional dyspepsia primarily represented in
18   the functional chapter, but the diseases for which we think we
19   understand pathology in this chapter too.
20          DR. LIEBERMAN: But as long as one or the other covers some of the
21   clinical aspects of it as well.
22          DR. JAMES: Yes. Sure.
23          DR. SANDLER: One of these overarching issues, and there's some
24   wording here that's really subtle but interesting where you talk about
25   the unknown risks of long-term use of PPI inhibitors and doing an
26   observational study. And doing the observational study doesn't imply
27   doing it prospectively, or doing it other than using existing records.
28   And maybe whoever's writing the overarching - I mean, we talk a lot
29   about molecular biology and the proteomics, but we don't talk about
30   bioinformatic methods to do epidemiologic studies. And you could do this
31   with an administrative database. Several people have called for a
32   consortia to study rare diseases. Bruce wanted to do it for autoimmune
33   hepatitis and various people, but if you had the right database you
34   could get 10,000 Crohn's patients and get a bead on the issue using that
35   technology rather than spending a whole boatload of money trying to do
36   it prospectively.
37          DR. JAMES: Well, certainly when we - two years ago Jay Everhart
38   and I had a long discussion about the burden of disease report to go
39   with this and epidemiological research. He of course burned my ears that
40   I didn't know what the difference between research and just reporting

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   out data. And I challenged him to this should be a venue to really push
 2   the importance of epidemiological research. And if you can put it into
 3   words clearly it's a different part of the foundation necessary for
 4   clinical and translational research. Any time you want to do a trial and
 5   you have to power it you have to know how many people are out there and
 6   where are they and what are their manifestations and all sorts of things
 7   beyond the issues of discovering new testable hypotheses through
 8   epidemiological methods. So I think there again the topic of
 9   epidemiology has come up a little bit and I would be very - encourage
10   the group to come up with very strongly worded rationales and goals
11   related to application of epidemiological research. Of course, when I
12   invite guys like you to talk about what I understand as epidemiology
13   they immediately tell me that I don't know what I'm thinking about.
14          DR. SANDLER: But Jay left and he would argue it's not just - it's
15   more than just counting.
16          DR. JAMES: Oh yes.
17          DR. SANDLER: So that isn't very interesting anymore, knowing the
18   incidence and prevalence. It's somewhat important, but we need to ask
19   critical questions and use databases and advanced methods to answer a
20   specific question.
21          DR. CERULLI: Well, we have a second PPI that's going to become
22   over-the-counter in two years and if we look back at what's happened
23   with the NSAIDs that are now over the counter. And perhaps, I don't know
24   what the real number is, but the number quoted is 15,000 to 16,000
25   people dying from using them, perhaps it would be good for us to look
26   at, at least in our neck of the woods, what these drugs are doing. Is
27   that within our purview?
28          DR. JAMES: Absolutely. This is perfectly legitimate and very
29   important research questions that need research to answer.
30          DR. CERULLI: But we need a good method. We can't just you know,
31   that osteoporosis thing was a little difficult.
32                DR. JAMES: Okay.
33                DR. CERULLI: Thank you.
35   Diseases of the Colon and Rectum (WG 9) Joanne A. P. Wilson, MD, Chair
37                DR. JAMES: Thanks very much. Now we're back to Joanne.
38          DR. WILSON: Good afternoon. This is Work Group 9 colon and
39   rectum. Nancy was the vice chair and kept us focused on our patient
40   issues. I have a somewhat eclectic group in our work group because we

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   wanted to encompass both basic science researchers, clinicians,
 2   gastroenterologists and surgeons to cover the areas that we wanted to
 3   focus on in the colon and rectum. Most of the typical areas that you
 4   think of in the colon and rectum had been taken from us, so we created
 5   our own.
 6          One of the things we wanted to look at was colon injury and
 7   repair, mucosal absorption and vasculature. And we talked about this in
 8   the November meeting. And gut flora and then some of the disease
 9   entities. Actually, I kept forgetting about appendicitis so I had to
10   assign that to myself. We then reviewed and came up with a series of
11   research goals and I've categorized them in the subgroups that I spoke
12   of, and then also within short-term, intermediate- and long-term. And we
13   focused primarily on recent advances in identifying ways that we might
14   take work forward in looking at colon injury.
15          The first - and I won't read these verbatim here - would be to
16   identify major signaling pathways involving Ntf3 and growth mediated
17   epithelial migration and other specific receptors. And we felt that we
18   would use this as a jump-off point but then point to further information
19   that might be coming in these areas. Further determination as to the
20   efficacy of these peptides in protection of the bowel and prevention of
21   injury as well as looking at the interaction of enteric microbiota and
22   toll-like receptors that promote a macrophage-dependent proliferation of
23   progenitor cells. Again, this is not areas that I work in. I'm a
24   clinician and look to basic colleagues to really dig into this area
25   further and look at the advances that we are coming up with. To define
26   which of many mediators released by macrophages may be - are required
27   for this further cell repair. Further, looking at the other area in
28   colonic mucosal absorption in vasculature, one of the short-term goals
29   would be a comprehensive survey of sodium chloride, protein fatty acids
30   and other transport expression in the human colon in comparison with
31   animal models. To define segmental alterations which to date we really
32   have not using animal models in very defined diets and protein-rich
33   diets. To establish a complimentary cultured colonocyte in native
34   tissue. In other words, in vivo ways of looking at the expression of
35   sodium transporters and other key proteins to elucidate the basis for
36   redundancy of transport mechanisms within the colon.
37          I turn to Tom Lamont as he surveyed the literature and colleagues
38   to look at the role of gut flora. We talked about the microflora in
39   great detail and in further sequencing organisms within that, and one of
40   our major recommendations was a multidisciplinary NIH topic conference

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   with researchers and microbiology, pediatrics and so forth to elucidate
 2   the intestinal flora in health and in disease. And we've already talked
 3   about that. To establish and validate functional parameters, biomarkers
 4   of gut flora further than those that we have used to date which are only
 5   surrogate markers. And to establish rapid throughput chip-based
 6   technology which I think is a major part of our new ability to sequence
 7   these organisms and to look very critically at the gut flora.
 8                In the second sector of our concerns were to look at some of the
 9   more common gastrointestinal disorders affecting the colon and to look
10   toward what is needed in further evaluation of research or to take
11   forward research in time. We overlap a little bit with the gut motility
12   group when we talk about diverticular disease, or at least we think we
13   do. But one of the concepts here was to study the factors involved in
14   the pathogenesis of diverticular disease, including altered wall
15   expression of matrix, metalloproteinase and tissue inhibitors of these
16   proteins and look at why there are reduced numbers of interstitial cells
17   and so forth, and to look at levels of pro-inflammatory mediators and
18   other changes within the colon. On the clinical side we felt that we
19   needed to identify risk factors for symptomatic diverticular disease,
20   specifically diverticulitis and bleeding aside from the known
21   precipitators such as NSAIDs.
22          The next area that we looked at was colonic ischemia and
23   antrictasias and felt that we need to devise means of diagnosing colonic
24   ischemia early before infarction ensues and differentiating it from
25   other processes within the bowel, in particular inflammatory bowel
26   disease, perhaps with other markers other than those that we use today.
27   We also looked at anal-rectal disorders and in short-term goals felt we
28   needed to understand the epidemiology, cost and quality of life impact
29   of fecal incontinence, to develop educational tools for providers and
30   the public that would raise awareness of the impact of this disorder,
31   and then to identify preventive strategies. Again, this focuses on
32   quality of life and patient care. Further, to understand the
33   epidemiology of other anal-rectal disorders, fistulas and hemorrhoidal
34   disease and these entities with and without association with
35   inflammatory bowel disease, and to develop educational tools for primary
36   providers to have them identify these properly.
37          Radiation proctitis was another interest. One of our short-term
38   goals was to determine the prognostic factors, genetic, comorbidities
39   and the like, that lead to the development of chronic radiation injury.
40   Regarding appendicitis the literature really does not clearly define why

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   certain children get appendicitis and others don't. Most of our
 2   literature is focused primarily on early diagnosis, differential
 3   diagnosis and the like, and so to study the effect of dietary factors,
 4   especially fiber content and bowel function. There's some studies from
 5   Greece and Brazil that focused on constipation as a precipitating
 6   factor. Study the role of prebiotics and probiotics on the instance of
 7   appendicitis. There had been some data suggesting that this might be
 8   important. And then finally, some early data has suggested that
 9   patients' immune response to certain organisms may precipitate or
10   modulate the course of appendicitis. It would be important from either
11   past samples or from prospective studies to determine whether or not
12   this is indeed the case.
13                Moving on to intermediate research goals regarding colon injury
14   and repair we're taking forward the TFF3 and other growth factors to
15   identify the molecular basis of the cell-specific expression of these
16   entities to determine whether one or more of the different entities, and
17   again I think we could probably consolidate this some, are dependent on
18   T- or B-cell dependent, how they function in the T- or B-cell dependent
19   models of chronic colitis. Determine whether enteric bacteria
20   macrophages can be exploited to treat chronic colitis and then to define
21   the molecular determinants used by monocytes and macrophages to migrate
22   into the colon to help with colonic mucosal repair and determine the
23   interrelationship of these various factors.
24          Regarding colonic mucosal absorption and vasculature, to develop
25   a comprehensive understanding of the coordinate regulation of sodium
26   absorption and chloride secretion, and to identify targets for potential
27   therapy and diarrheal diseases, particularly focusing on both
28   immunosuppressed and non-immunosuppressed patients. To examine injury
29   and repair responses of transporter knockout mice in standard models of
30   ischemia and inflammatory colitis. And this again may overlap with the
31   IBD group and perhaps we might eliminate this as one of our goals,
32   focusing on it in their group. Develop functional imaging techniques
33   that define dynamics of transporter surface expression and local pH
34   micro-domains in vivo. Again, an area that has not been focused on to
35   date.
36          Looking at the role of gut microflora, one of our intermediate
37   goals would be to establish tissue banks of mucosal biopsies to allow
38   large-scale chip-based comparison of adhered bacteria to the surface
39   epithelium. To compare bacterial flora in active and inactive IBD, and
40   again this may crossover with the IBD group, and in obese and lean

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   humans using molecular fingerprinting and the like. To compare
 2   microflora before and after antibiotics in patients with and without C.
 3   diff. Again, this crosses over a little bit with the infectious group so
 4   this might be one of the ones that we could eliminate. To define the
 5   difference between the normal flora in feces and the adherent - and bad
 6   adherent to the epithelium, the so-called bio film. And this is an
 7   important concept both in the bowel and the biliary tree when we're
 8   looking at infection and to date we don't really have good ways of doing
 9   that.
10                Regarding diverticular disease, and actually Larry Friedman did a
11   lot of this work and called people so actually he ended up getting asked
12   to do a couple of talks on diverticular disease because he was calling
13   people asking them about it. Determine whether treatment with certain
14   agents including pro- and prebiotic agent reduces the risk of
15   diverticulitis and whether this is cost-effective. Again, this would be
16   one of our intermediate goals. To conduct randomized studies to
17   determine the indications for surgery and the optimal surgical approach
18   to complicated diverticular disease, and establish whether a one-step
19   surgical procedure reduces the rates of postoperative peritonitis and
20   emergency surgery. Again, as we delved into the literature and so forth
21   we thought, most people thought that these kinds of issues were long
22   since resolved, but appear not to be. Determine whether genetic factors
23   contribute to a risk of diverticulosis. And again, it's so common in
24   this country we assume that it is, that it's diet and that there are no
25   genetic predispositions, but maybe we're more genetically homogenous
26   than we thought.
27          Regarding colonic ischemia, understand why colonic ischemia is
28   associated with IBS. This is in face of new recent data looking at IBS
29   and ischemia. Determine the underlying proximate cause of chronic
30   ischemia, especially with regard to behavior of the colonic arteriolar
31   and venular microstructure and the serotonergic agents. And this again
32   has come from our recent sort of epidemiologic studies associating IBS
33   and colonic ischemia, and we don't really have clear-cut reasons why
34   those two should be associated.
35          Regarding anal-rectal disorders, intermediate goals would be to
36   understand contributing factors for fecal incontinence, and again the
37   natural history of obstetrical sphincter injury and other forms of anal
38   sphincter dysfunction. Again, pointing to our lack of an understanding
39   of natural history of many of the diseases. We have snapshots, but not
40   really looking at the long-term course. Initiate studies comparing

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   outcome and cost of treatment alternatives for mild fecal incontinence
 2   and incontinence associated with sphincter defects. Again, a lot of
 3   technology has been developed, some on the market, off the market,
 4   without clearly defining the roles of these various interventions. And
 5   furthermore, develop better understanding of risk factors and mechanisms
 6   for perianal fistulas with and without IBD and looking at long-term
 7   collaborative studies on the effectiveness of both medical and surgical
 8   therapy. Again, major causes of morbidity in people, not so much
 9   mortality but certainly morbidity that may be lifelong.
10          Again, our anal-rectal crew, and we were all very excited because
11   there's so little data about anal-rectal disorders. Further intermediate
12   goals would be to understand the pathophysiology and risk of symptomatic
13   hemorrhoids. Sounds kind of mundane, but is a source of a lot of
14   morbidity for women in particular. Initiate long-term studies of
15   effectiveness, outcome and medical management of some of the new
16   modalities as well as traditional hemorrhoidectomy processes. And to
17   look again at effective pain control in these processes with
18   hemorrhoidectomy.
19          Radiation proctitis. Determine efficacy of agents of the
20   prevention of radiation injury via multi-center trials with
21   collaboration between gastroenterology, oncology and radiation oncology.
22   Again, a multidisciplinary approach if we are to have any further
23   valuable information in this area. Regarding appendicitis or appendiceal
24   disorders, intermediate: study the effect of dietary modification,
25   prebiotics, probiotics on the intestinal flora and the incidence of
26   appendicitis. Identify high-risk patients from immune standpoint with a
27   modification of responses.
28          And finally, long-term research goals were fewer with colonic
29   injury to determine the bioavailability, safety and efficacy of orally
30   administered TFF3's and other epithelial growth factors in models of
31   mucosal injury. Develop strategies for mimicking enteric antigen toll-
32   like receptor interactions to promote gut healing. So again, long-term
33   ways which we might be able to intervene in promoting gut healing.
34   Colonic mucosal absorption and vasculature. Develop and test small
35   molecule inhibitors of chloride transport and agents that enhance sodium
36   absorptive pathways. Probably somewhat similar to luborcoston which is a
37   chloride activator in the small bowel. Develop comprehensive
38   understanding of the effect of diet-derived luminal fermentation process
39   on colon absorption. And then screen - and this is a much more ambitious
40   goal - screen pediatric and adult U.S. population for altered

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   transporter complex expression and/or gene mutations to look for at the
 2   congenital and acquired constipation and diarrheal disorders. Again, the
 3   - a form of personal medicine in identifying specific abnormalities.
 4          Role of gut flora. Again, organize a double-blind controlled
 5   trial to manipulate the colonic microflora in IBD patients in the form
 6   of primary treatment and in obesity as a possible adjunct therapy based
 7   on some of our most recent data. And then to organize randomized
 8   controlled trials of bacteria therapy to prevent C. diff. And some of
 9   this may actually be ongoing. And to treat chronic and recurrent
10   infections.
11          Regarding diverticular disease, much along the same line as with
12   the anal-rectal diseases, to look at lifestyle changes, diet and so
13   forth to see if we can change the rates at which people develop
14   diverticular disease. It was kind of interesting to see that from Boston
15   there was one study on popcorn and diverticular disease at DDW from one
16   of the physician databases. Determine why people with diverticular - why
17   some people with diverticulosis develop symptoms and others don't, and
18   then further looking at the wall proteins and proteinases and so forth
19   to determine efficacy.
20          Again, looking at colonic ischemia. Evaluate the role of
21   vasculature as a cause for Crohn's disease. This may overlap with IBD
22   and it's probably not appropriate here. Anal-rectal disorders. Again,
23   developing algorithms based on our earlier studies as to what are
24   effective ways of treating patients with perianal fistulas and fecal
25   incontinence. And along that same line, the same kinds of approaches for
26   hemorrhoids and other - identification of other high-risk conditions.
27   And regarding radiation proctitis, again to develop the evidence-based
28   algorithm for prevention and treatment of radiation proctitis. We do not
29   have that to date. Most of the algorithms have focused on modifications
30   of the way the radiation is delivered.
31          There are a series of major challenges. How much time? Are we
32   over time? Why don't we - these are really pretty much self-evident and
33   really go along the same lines as we have with the other areas where it
34   is difficult to - we may have difficulty identifying the specific
35   factors, developing the specific molecules and so forth. Some of the
36   challenges will be again having a comprehensive database or tissue banks
37   or databases. Again, all of the sort of organizational problems that are
38   difficult. And then others in regarding colon transport in developing
39   appropriate models. And I think I won't go through these in any further
40   detail because they're really all pretty self-evident based on what

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   we've reviewed with all the other presentations.
 3   Discussion
 5                DR. JAMES: Thank you. Great. Questions? Comments? John.
 6          DR. CARETHERS: Just a couple of brief ones. I'm just wondering in
 7   setting priority for goals I noticed you had a lot of stuff on
 8   diverticular disease and the - I'm just wondering what the I guess
 9   impact of that would be. Because as you mentioned diverticular disease
10   is very, very common and I mean, understanding I guess the
11   pathophysiology of diverticular disease in you know half the population
12   over age 60, I mean without - I guess a small percent do get bleeding
13   and some percent get diverticulitis, but I'm just wondering.
14          DR. WILSON: Yes. It's a major burden for the healthcare system,
15   particularly when you look at a huge percentage of your population being
16   over the age of 65 by the year blah blah. I mean, we're going to all be
17   hanging around and we're going to have diverticulitis. Right now even if
18   you decided that your surgical approach would be different, that it was
19   a one-stage versus a blah blah or that you could do this to diminish the
20   rate of bleeding and so forth you could have a significant impact on the
21   healthcare system.
22          DR. CARETHERS: So are you suggesting maybe targeting a population
23   within the diverticular disease, or the whole diverticular population?
24          DR. WILSON: Well, it's hard to really target - yes. Well, part of
25   what we said was identifying the people at greatest risk for so that you
26   - that would be - because we don't know now. The assumption is if you've
27   got one diverticulum you're at risk for diverticulitis and bleeding,
28   whether that's true or not. We now know that if you take NSAIDs and so
29   forth that that can increase your likelihood of bleeding from
30   diverticuli. But we don't know of a lot of other things. And it's kind
31   of weird that we don't because so many people have this. You figure,
32   well you've this huge population, you'd be able to figure it out in a
33   heartbeat, but we haven't really because we haven't approached it in
34   that way. We've waited for something to happen and then we respond as
35   opposed to all the other sorts of approaches that we typically have for
36   disease.
37          DR. CARETHERS: Okay, so that helps. And also you mentioned about
38   studying genetic factors risk for diverticular disease. How?
39          DR. WILSON: Well, the query is that you always have these
40   patients that tell you, well you know, Granny so and so had bleeding and

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   10 people out of my family had bleeding, and you see, you know if you do
 2   colonoscopies you see diverticuli and you see diverticuli. And so the
 3   query is is there any difference. I don't know. And I don't think
 4   anybody does because it's so common and you don't quantify it or you
 5   don't describe it. I mean, people tell me they've got diverticuli and
 6   they have one and then you have others that have got it everywhere. I
 7   mean, why do some people have diverticuli in their entire colon. Some
 8   people think it's a manifestation of irritable bowel and so forth and so
 9   on, but I don't know that.
10          DR. CARETHERS: So I guess my point with that is, which is fine,
11   is you know usually if you screen for something there's a - you do an
12   intervention to prevent whatever. So like for instance in someone who
13   has a colon cancer predisposition gene you'd take their colon out or
14   whatever. So I was just wondering where -
15          DR. WILSON: Well, I guess the query would be is there some, you
16   know because in the long-term it would be to look at lifestyle
17   modifications. I mean again, you have to look at the data that we have
18   to data have come from some of the physician studies and other long-term
19   studies.
20          DR. CARETHERS: A long time ago.
21          DR. WILSON: Yes, because it's a number of years. So we're
22   talking, if you're talking about making some changes it would be to
23   someone younger. But if you wanted to prevent bleeding and prevent
24   infection it might be something more acute. I don't know. Like we tell
25   them don't take NSAIDs, but that's pretty simple.
26          DR. JAMES: Barbara?
27          DR. BASS: I was just going to say in terms of your surgical trial
28   that you propose that, I think - I'm not sure where that came from, but
29   it's -
30                DR. WILSON: Two surgeons told me that.
31                DR. BASS: It's a little off track I think in the sense that it's
32   really - I mean by and large those decisions are - first of all you try
33   to avoid operating in an acute setting anyway. Secondly, those decisions
34   are virtually always dictated by all of those other comorbidities
35   besides the disease itself, and so in some respects it's almost one of
36   those impossible to do studies. And I'm not sure that that central
37   question is really the most important one in diverticular disease.
38          DR. WILSON: It was one of several. So it was down on the list.
39   Because they're more or less prioritized, so that's one that was sort of
40   - but there were two surgeons.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. BASS: Yes. And I think - I mean, it's an interesting - you
 2   can always debate or not, but the fact is it's dictated by something
 3   else.
 4          DR. JAMES: I think the question is important, but the way to get
 5   the answer isn't always through an RCT. It might be possible to do a
 6   long-term observational study and without doing a randomized
 7   intervention and still make progress in really learning more. I think
 8   the burden is unquestionably very high and I don't think we know much of
 9   anything. I mean, maybe I'm stupid, but I don't think we know anything
10   more than what I learned when I was a medical student and that wasn't
11   very much about diverticular disease. It's all very much an empiric - I
12   mean, the other great area with a huge burden about which we do very
13   little research is gallbladder disease and we know a lot more there than
14   we do about diverticular disease. So I actually have encouraged the
15   group to really try to put this on the map because the burden is very
16   high and we're not learning much.
17          DR. BASS: Well, I agree with the studying of the disease. I think
18   the phenomenon, the progression of the disease and identifying high-risk
19   patients for complications is very important. I was just challenging the
20   particular surgical trial you proposed.
21          DR. WILSON: Well that, I think we may have honed down to too much
22   detail, but that could be much more general because, you know because
23   technology changes. So I think that some of the - when I was looking at
24   our recommendations. So what I charged our group initially with doing
25   because we were so diverse was to go back and then they re-stratified
26   their recommendations and you know, sort of tailored them more to the
27   format that we were given, and then to try to come up with very clear
28   recommendations, and that was one.
29          DR. BASS: And the other area that actually, again, a huge burden
30   of disease although people do very well with it now is appendicitis. And
31   there's more and more in the literature to suggest that there are
32   actually sort of two different phenotypes of appendicitis. There's a
33   group that is going to present with aggressive progressive disease and
34   perforation no matter what you do and there's another group that you can
35   probably get by with even medical management. I think -
36                DR. WILSON: That's what I was trying to get at.
37                DR. BASS: - characterizing that would be a very useful study.
38          DR. WILSON: Right. And the question is whether that's immune-
39   mediated, is it determined by your gut flora and so forth. But there's
40   so little in the literature. I mean, the papers are mostly from like

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   Europe and - yes. There was nothing from this country. Everything here
 2   is about you know, early CTs and ultrasounds and white counts and you
 3   know, so forth and so on.
 4          DR. JAMES: Jay.
 5          DR. PASRICHA: One of the things I don't know, just wasn't
 6   emphasize enough or certainly want to - maybe I missed it, was colonic
 7   AVMs, intestinal AVMs.
 8                DR. WILSON: That was with vascular and then with colonic ischemia
 9   -
10                DR. PASRICHA: I saw it lumped together with ischemia, but in the
11   context more of that rather than as a standalone. I think you know it's
12   probably the commonest cause of GI bleeding, lower GI bleeding and
13   occult GI bleeding and a lot of resources are spent investigating it.
14          DR. WILSON: Yes. Well, the person who I charged with sort of
15   thinking about that most was Larry Brandt. And I mean initially he had a
16   lot of recommendations and he thought that it paled in comparison and
17   importance in comparison to a lot of the other things that we don't
18   know. And that perhaps it was a part of the whole ischemia sort of
19   picture in looking at the effects on vasculature and so forth and so on.
20          DR. PASRICHA: Well, I don't know if there's any evidence to
21   suggest that. It doesn't certainly come out in your presentation as a
22   standalone important entity which I think it really is from a clinical
23   perspective. It's an important cause of morbidities, consumes a lot of
24   resources and certainly is conspicuous by its absence I think in a
25   discussion of colonic diseases.
26          DR. WILSON: Yes, well I called colonic ischemia and antrictasias,
27   but they could be separated out certainly.
28          DR. PASRICHA: Right, I saw that category. Just not really - it's
29   in the context of ischemia.
30          DR. WILSON: Well, I mean I guess the query was you know I guess
31   what was new. I mean, I guess just like diverticular disease there's
32   probably much more to learn.
33                DR. PASRICHA: Exactly.
34                DR. WILSON: Than we know.
35                DR. PASRICHA: We don't know the cause of TCAVMs. We presume it's
36   ischemia, but that's - there's a big step between saying it's ischemia
37   and it develops AVM. We need to understand all the pathways and all. We
38   don't - I think there's just one paper that even has looked at
39   androgenic factors in the development of AVM, so I think it's a big
40   problem.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. WILSON: When I said look at serotonergic factors and other
 2   factors, it was for both of those, both ischemia and antrictasias, but
 3   maybe I should say that more clearly. Because that's really what - that
 4   was what we basically decided, those two things would be looked at in
 5   much the same way.
 6                DR. JAMES: Maurice?
 7                DR. CERULLI: Two comments. One is that for diverticular disease
 8   we're still talking about popcorn and seeds and so we really haven't
 9   gone very far and don't seem to know very much at all. I tell my
10   patients eat everything, drink a lot of water, but I don't know that I
11   have any evidence for that either. And the second thing is in radiation
12   proctitis we have more and more men with radium seed implants and some
13   of them develop significant bleeding and radiation proctopathy so maybe
14   we should just mention about prostate cancer therapy. I guess that's
15   done by radiation oncologists, but since it's a growing number of people
16   maybe we should just mention something about prostate cancer therapy.
17          DR. WILSON: Almost all the radiation now is radiation - is
18   prostate. So in our discussions that's what we talk about is prostate.
19   Is prostate almost specifically, because many fewer of the women are
20   getting it cervical. So that was the only major other one.
21          DR. JAMES: Dan?
22          DR. PODOLSKY: It may be probably just a failure of imagination,
23   but on the diverticular diseases, it seems like if there's any going to
24   be traction it's going to be through one or both of a combination of
25   general approaches. One being some kind of epidemiologic way to get an
26   idea, a better hypothesis as to what you know may make a difference, and
27   the other which is mentioned as a challenge, but I think you should
28   consider as really a short-term goal is an animal model, something you
29   can start to study. I mean, the challenge here is that there's, as
30   you've already pointed out, that it's so prevalent in terms of
31   diverticulosis and the events that happen to only a small fraction,
32   albeit it adds up to a significant morbidity, are so infrequent that you
33   know, without some tractable model sort of hard to see how you're going
34   to start to get some mechanistic - opportunity to really look at
35   mechanistic factors. Like you mentioned MMPs and so forth. So it seems
36   to me that ought to sort of come up on the list of priorities here.
37          DR. WILSON: Okay.
38                DR. JAMES: Did you want to comment on TLR and defense things
39   here?
40                DR. PODOLSKY: I thought you were going to - talk about TFFs.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   Well, the TLRs in some ways are an embedded issue in IBD. I think you
 2   know the connection with the defensins in relationship to IBD is you
 3   know, if I had to guess on the basis of available evidence a factor,
 4   although I don't think - and only a factor that eventually shows the
 5   mechanistic connection to IBD. But I think just, you asked a question
 6   that begs the broader comment - issue that you've touched on a few times
 7   Joanne, which is which of what you have in here does still remain in
 8   here, how much of it you know does get deferred to others, or whether
 9   this is an area like the anal-rectal complications of IBD you know being
10   redundant or covered in two places is a question.
11                DR. WILSON: I think we covered -
12                DR. PODOLSKY: Well, we didn't specifically mention that at all.
13   It would have been -
14          DR. JAMES: I think you actually didn't mention this at all.
15          DR. PODOLSKY: No, no, we didn't. It would have been sort of
16   caught up in the overarching priority, developing treatments and so
17   forth, but we did not make any specific attention. That's why I raise it
18   as a question.
19          DR. JAMES: I think it better remains here because there are
20   multiple etiologies and problems and it fits together there. John I
21   think was next.
22          DR. CARETHERS: You know, one of the things you mentioned was
23   colonic ischemia which I think you know is like some aspects of
24   diverticular disease is going to be a huge burden as we age. And I
25   assume, it wasn't clear to me. I mean, this is going to - the
26   presumption is to look at just natural old age ischemia I assume through
27   you know vasculopathy as well as anti-hypertensives and that kind of
28   stuff, but also inter-op. I get consulted probably once a week on
29   someone doing a AAA and some kind of ischemia going on. I mean because
30   you were talking about predictive factors. So I don't know if that was
31   included in that aspect.
32                DR. WILSON: More of the people who present without specific
33   vascular compromise. I mean, because that's what you're seeing an
34   incredible number of I mean that you can't explain it by having you know
35   two out of three major vessels gone. I mean, so it's just not - it's not
36   easily explained so it has to be something to do with regulation of
37   rates of flow and so forth, and possibly hormonal.
38          DR. CARETHERS: And you know there's a lot of anti-hypertensives
39   out there too.
40          DR. WILSON: Right.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. CARETHERS: Maybe there's some you know non-selectivity
 2   between the peripheral versus the mesentery beds. I don't know. So I
 3   think that's a good area.
 4          DR. JAMES: And just we'll have two more quick questions because
 5   we do have to move along.
 6          DR. SANDERS: So I was wondering also, I mean this Point 7 here is
 7   interesting and I'm wondering whether you've considered whether the
 8   microflora within diverticuli is different than the general gut
 9   microflora.
10          DR. WILSON: We don't know. I mean that's the whole query about -
11          DR. SANDERS: That's a completely different microenvironment and -
12   I mean actually it's sort of an interesting question from the standpoint
13   that maybe that complement of microflora in diverticuli is what causes
14   part of the problem. It should be tested on normal mucosa.
15          DR. WILSON: Yes, you know, again it's a very intriguing but
16   mundane and simplistic disorder. I mean we just whack it out if it
17   causes trouble which I don't think we can continue to do.
18          DR. PASRICHA: So just on the diverticulosis issue. I never
19   thought I'd sit through eight hours of a digestive disease conference
20   and not hear the word "fiber." So -
21          DR. WILSON: I had it in there. I said dietary manipulations.
22          DR. PASRICHA: Well, I think the thing about nutrition and GI
23   health, apart from I know Barbara is going to cover nutritional support,
24   but normal nutrition, prebiotic stuff, maybe it's not emphasized enough
25   and particularly I think from the public's perspective. One of the
26   things that - if this report goes public, one of the things they're
27   going to look at is you know what's the take-home message as far as
28   nutrition.
29          DR. JAMES: Well again, just to - we started at - the very
30   beginning of this discussion was how far to go with general nutrition
31   research and the answer was not very far primarily as it relates to
32   digestive diseases, understanding them and treating them, but not
33   general nutritional research overall. I admit I don't think I ever have
34   seen a patient who didn't ask what should I eat for my problem.
35          DR. PASRICHA: But isn't this, diverticulosis, isn't this like the
36   whole fiber hypothesis was pretty much built around this disease. So I'm
37   just wondering where it is in our scheme.
38                DR. WILSON: Well, prebiotics are fiber vitamins and all the other
39   stuff.
40                DR. JAMES: I think we better move on. One other comment. I think

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   this chapter, like the last, would be better organized across -
 2   longitudinally across the topics rather than by timeframe. Which is just
 3   re-sorting. It's just a re-sort. Yes. I know, you followed the
 4   directions.
 6   Intestinal Failure and Regeneration, Nutritional Disorders and Support,
 7   Surgically Modified Gut, and Transplantation (WG 6), Barbara L. Bass,
 8   MD, Chair
10                DR. BASS: Okay. Thank you. We'll go ahead and get started on this
11   one. I want to thank Margaret also as well for helping us, the vice
12   chair on this. Somewhere in here we have our members. We were assigned
13   the topic of intestinal failure, intestinal transplantation, a variety
14   of entities and had the help of this distinguished group that included
15   pediatricians, pediatric surgeons, transplant surgeons,
16   gastroenterologists with expertise in short gut and management of
17   patients with intestinal failure. And we did our work on a series of
18   conference calls like everyone else. In our preliminary discussions we
19   came up with these five areas of those that kind of fit into the bucket
20   we thought we were dealing with. And one nice thing about going towards
21   the end here is we realized that there's a whole lot of this that's been
22   covered on many different fronts already and even more so I'm sure with
23   what we're going to hear certainly from Richard's group.
24          The first area of course is that of the basic mechanisms,
25   processes of intestinal growth and differentiation. The first disease
26   entity that we wanted to talk about was that of short bowel syndrome and
27   that process of post-intestinal resection adaptation, repair and
28   regeneration, both in the setting of resection as well as other injury
29   to the bowel. Obviously focusing exclusively on the small bowel in this
30   particular group. We talked about intestinal transplantation as a
31   treatment and a process that needs a lot of work before it's ready for
32   prime time. We focused on the metabolic and nutritional consequences of
33   the surgically modified gut, including things such as bariatric
34   modification, blind loops, other kinds of restructuring of the bowel
35   that leads to need for enhanced nutritional support and leads to other
36   metabolic sequelae in other organs. And last we talked specifically
37   about nutritional support of patients with a variety of gastrointestinal
38   disorders. And this is where most of our pediatric discussion came in.
39          We tried to come up with a group of - for each of these five
40   areas a brief group of research goals. Many of them as you'll hear,

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   especially in this first group we've touched on already. But obviously
 2   if you want to study intestinal growth and differentiation, one of the
 3   mos important things you have to do is define the molecular mechanisms
 4   that govern the selection of the cell phenotypes from the intestinal
 5   stem cell populations, assuming you can find those intestinal stem cell
 6   populations to study. Secondly, you need to define those factors which
 7   via luminal or systemic or other parameters can lead to enhanced post-
 8   resectional adaptation. Growth factors, luminal nutrients and fiber
 9   matrix of the epithelial matrix interactions and the whole milieu of
10   that adaptive environment. We wanted to look at - wanted to figure out
11   how we could develop better in vitro systems for isolation and expansion
12   of intestinal stem cells. We've sort of put a lot of stock in those
13   particular cells as being key to subsequent tissue engineering
14   regenerative medicine approaches.
15          We had a fair amount of discussion about the business of
16   enterodistraction as a tool to enhance intestinal growth, that if you
17   can actually - and this is a new concept, but the idea that actually if
18   you enhance the muscular, enteric muscular component you will also
19   thereby expand the area available for intestinal mucosal - and actually
20   lead to augmented adaptation. So we thought that was an area that would
21   be interesting to pursue. Not a front burner item, but something that
22   rose up from several of our discussants.
23          The intermediate goal here was to - so that was primarily to kind
24   of define whether or not that's a phenomena or not that needs more work.
25   And intermediate goals, we thought how better to determine the impact of
26   specific growth factors, other proteins, other luminal items on
27   intestinal stem cell growth and differentiation and specifically looking
28   at enterocyte function in terms of absorptive, secretory function of the
29   differentiated enterocyte.
30          In regards to making more intestine we thought we needed a lot
31   more work on the optimal definition of the bioartificial scaffold to
32   support intestinal mucosal growth. That's uncharted territory for the
33   gut unlike other areas of tissue and regenerative medicine elsewhere
34   outside of the GI tract. We wanted to characterize the molecular
35   features of intestinal adaptation in human patients. As you'll see, one
36   of the major challenges in this is that we obviously don't have ready
37   access to intestinal tissue over a series of - over a longitudinal
38   period in patients who have intestinal resection and subsequently have
39   repair and regenerating adapting intestine. But we thought it was very
40   important to be able to characterize that process at the molecular basis

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   in human patients who were recovering with this phenomenon. We wanted to
 2   look at gene expression enterocytes and the smooth muscle cells during
 3   this process of enterodistraction to see if in fact there are changes
 4   consistent with enhanced proliferation and adaptation.
 5          The long-term goals in this particular area of intestinal growth
 6   and differentiation is to, 8 to 10 years from now be prepared with the
 7   knowledge that we've gained in terms of optimal factors to augment these
 8   processes to do human trials of exogenous factors, whatever that might
 9   be, luminal, nutrient, systemic, whatever, to optimize this process of
10   post-resectional adaptation in patients. We hope that 8 to 10 years from
11   now we will have defined the optimal scaffolding for support of
12   neointestinal or neomucosal growth such that we can actually consider
13   constructing replaced segments of small bowel, and that we'd also be
14   able to better isolate, characterize and manipulate human stem cells.
15          The second area that we looked at was that of the short bowel
16   syndrome. Patients with intestinal failure, patients who are in the
17   active process of intestinal adaptation post-resection after massive
18   resection. Here we had some more specific clinically testable kind of
19   goals. First we wanted to look at the specific effects of micronutrients
20   and diet on this process. Although that's been done in many, many ways
21   and many different times we still don't have the right cocktail defined
22   to optimally enhance this process. Part of that limitation is that we
23   really don't have good non-invasive measures to really assess the
24   success of our treatments to actually look to see is the intestine - is
25   intestinal mucosa actually growing more. Are we actually enhancing
26   secretory function. We have very crude markers of success and success or
27   failure of the therapies offered. So we thought one of the key things we
28   need is a better marker, non-invasive marker of that parameter of
29   success, or at least consensus on what successful treatment or
30   successful measures are in terms of augmenting intestinal growth.
31          Like everyone else here we thought since this is a rare
32   phenomena, rare but deadly and expensive phenomena that we needed a
33   national registry at least of patients that we can follow if not in a
34   randomized - not necessarily to enroll in trials, but at least to
35   effectively follow their outcomes and the treatments they received in a
36   registry sort of fashion so that we might learn something about this
37   process even though it's not well - there's few centers with a lot of
38   experience in this. We thought that an animal model of bacterial
39   overgrowth with partial obstruction would be a very valuable tool to
40   look at some of the interventions for treating that condition. Right now

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   we have no good animal models of bacterial overgrowth which is a
 2   limitation. Again, getting back to the quality, we thought we needed
 3   better quality of life. Again, almost one of the outcome measures for
 4   effective therapy of patients with intestinal failure.
 5          We think we need to identify tools, clinical parameters, clinical
 6   measurables that are predictive of patients who are at higher risk for
 7   developing parenteral nutrition-induced liver disease and of those who
 8   are at higher risk for sepsis or other adverse outcomes including
 9   mortality. Right now it's just sort of bad luck if you happen to be one
10   of those people. We don't have good predictors about that.
11          In terms of the intermediate goals here, here they are. Develop
12   more effective techniques and strategies to reduce the complications of
13   parenteral nutrition. Obviously many of these people spend many years on
14   parenteral nutrition and we really thought that we have limited tools to
15   minimize sepsis, minimize the liver dysfunction and other metabolic
16   sequelae of long-term parenteral nutrition. It's slightly off the track
17   for a GI focus, but given that we are often the people that manage these
18   patients we sort of thought it falls in our domain. It's also obviously
19   relevant to many other types of disease, including pancreatitis and
20   other patients with chronic dysmotility or other forms of effective
21   short gut or chronic abdominal conditions.
22          Again, we really think we need to have some non-invasive measures
23   to accurately measure intestinal growth and adaptation in patients since
24   - one that does not require repeat endoscopies or surgeries to assess
25   the success. We wanted again, sort of in the same way to identify
26   molecular markers for adaptation and for the development of
27   complications. What are those markers that tell us that a patient is
28   getting ready to have venous thrombosis, sepsis or hepatic failure. We
29   thought we better study on the role of nutrient delivery route in
30   patients on parenteral nutrition in regards to the development of liver
31   disease.
32                Long-term goals. We've heard a little bit of talk about radiation
33   enteritis and radiation proctitis, but the molecular basis of that
34   disease remains totally undefined, at least in a satisfying way and we
35   thought we need better molecular basis for that, understanding of that
36   disease. We wanted to see if there were alternative surgical techniques
37   that could be used to enhance digestion absorption. I don't want to
38   reinvent the wheel as we did years ago in terms of the tools to change
39   transit times and other parameters, but could we perhaps modify the
40   intestinal tract surgically to enhance the absorptive process. We would

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   like to see by the end of this time a human trial of the best soup,
 2   cocktail, whatever you want to be to enhance the process of intestinal
 3   adaptation aftermath of resection. We think this is something that
 4   deserves more than an observational study, but really one that would
 5   require a clinical trial to optimally define those components. And
 6   finally, if we actually can figure out what these pathways are in
 7   adaptation and absorption, develop specific targeted therapies to
 8   augment those particular processes that are otherwise compromised in
 9   these patients.
10          In terms of intestinal transplantation, we have - there was
11   uniform agreement that we do need a better national registry and
12   research consortium for patients with intestinal failure, end stage
13   intestinal failure who are anticipating or receive intestinal
14   allografts. We thought that one of the big limitations in this
15   particular area is that the public is almost unaware of this as a
16   disease entity and we thought that, and again this falls almost more in
17   the quality than the research thing, how best to get the word out there,
18   but how might we actually make it - inform the public of the
19   significance of this disease as well as enhance the referral of patients
20   for treatment effectively at the time that would benefit them.
21          There are no good means to identify rejection in intestinal
22   transplantations at this time. All require invasive approaches,
23   biopsies, investigation of stomas, and so there was a groundswell of
24   support for the development of serum markers or some other type of non-
25   invasive marker that would allow us to follow and detect early
26   intestinal transplantation. And there's also enthusiasm for determining
27   what nutritional growth factor, other micronutrients would be best
28   suited to enhance the process of - or support the transplanted gut and
29   enhance its function.
30          For the intermediate goals, again more of an expansion of the
31   first, but to deliver proteomic signatures for monitoring
32   immunosuppression and rejection. These patients unlike many other
33   transplant patients are at higher risk of complications of
34   immunosuppression than other solid organs and at higher risk for
35   rejection. We needed better means to detect those patients who are at
36   high risk for developing those complications. We need better methods to
37   preserve the bowel than we have right now and we also need better
38   immunosuppressive therapies. In the long term, the goal would be to
39   apply these things we've learned to effectively optimize
40   immunosuppression and avoid complications for the individual patient

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   based on their individual signature. And in the long term we obviously
 2   would move forward with our bioscaffolds and artificial intestinal
 3   conduits to avoid the need for allotransplantation altogether using
 4   native residual host stem cells.
 5          In terms of the metabolic consequences of these modifications to
 6   the gut, bariatric surgery patients, there is a whole network out there
 7   that is looking at obesity management and bariatric surgery, and it
 8   wasn't clear how we interfaced with them. We clearly pulled out most of
 9   the obesity work, but one of the things that we thought could fall in
10   the domain of this group was to characterize the neuroendocrine, the
11   hormonal proteomic response to bariatric procedures in patients and
12   animal models to try and get a signature as to what those changes would
13   be that would subsequently be mimic-able in therapeutic modalities. We
14   thought to do that we really needed a tissue bank, a national tissue
15   bank to accrue, to you know take those samples, the serum, the tissues,
16   whatever we have in both interoperative, ideally pre-op, but certainly
17   interoperative and then longitudinally in these patients so that we can
18   have a source for subsequent study. In patients having bariatric surgery
19   we wanted to characterize the anorexogenic hormones to see if we can
20   determine predictors of success. We wanted to see if we could better
21   identify preoperative biomarkers that would be predictive of weight loss
22   or success and metabolic correction in patients undergoing bariatric
23   procedures.
24          We wanted to look at - and switching now to necrotizing
25   enterocolitis we wanted to look to see if we could optimize the dietary
26   management of those patients to minimize the development of that
27   disease. And to look at the - to compare as we've discussed already the
28   role of a variety of agents to optimize the management of patients with
29   short gut syndrome. Based on what we learned in the short term section
30   we wanted to look to see if we could develop some neurohumoral
31   treatments that would mimic that of bariatric procedures. We wanted to
32   look at some of the long-term sequelae of the bariatric procedures.
33   There's more and more evidence that vitamin metabolism, mineral
34   metabolism, a variety of things are in fact substantially altered in
35   these patients and we will be having a wave of these patients in the
36   very near future to study, to deal with. And lastly, to look at if we
37   had more effective ways to augment nutrition and digestion.
38          The last one is nutritional support of patients with these
39   disorders. We thought that we really have inadequate quality of life
40   measures relative to a variety of gastrointestinal disorders, patients

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   with a variety of complaints from pancreatitis to intestinal failure to
 2   short gut and we needed a better tool to assess that. So we need new
 3   quality of life agreement on what those measures are.
 4          We wanted to look at the role of cycling or other intervention
 5   strategies on parenteral nutrition patients to see if we might minimize
 6   the morbidity of that support in long-term patients and we wanted to
 7   look at the role of specific dietary formulation in babies at risk for
 8   feeding intolerance and necrotizing enterocolitis.
 9          Again, getting back to the intestinal microbiome, whatever it is
10   we're talking about. I've said it so many times that I can't remember.
11   Looking again at the role of the variety of organisms in the gut to see
12   if they contribute both to gut failure as well as this necrotizing
13   enterocolitis - I'm not sure where that came from - and catheter-related
14   sepsis. Again, strategies to look at that.
15          Challenges we came up with. There were a bunch and that is that
16   access to human intestinal tissue is very, very tough. I mean it's
17   really sequentially, longitudinally it's just very hard to do without
18   causing significant morbidity to patients. We're limited by the small
19   number of patients at any institution. We're limited by the lack of a
20   national registry and a collaborative network of hospitals. Each of
21   these can be phrased in a positive for you, Dr. James. And we also are
22   compromised we think by the lack of awareness of the clinical problems.
23   I don't think I need to go on further here. They sort of state basically
24   why we chose those other things as our goals because these sort of point
25   to the fact that we don't have the tools right now available to fix
26   these things.
28   Discussion
30                DR. JAMES: Comments? Very clear. No comments?
31                DR. BASS: Let's move on.
32                DR. JAMES: Yes, there's a - we have a comment.
33                DR. SY: Thank you for an excellent presentation and this is not a
34   question, but this is a testimony. I had bariatric surgery two years ago
35   at George Washington University and lost 140 pounds. And I'm very happy
36   to see all these cautions that you raise because my surgeon never - they
37   never had done any neuroendocrine, hormonal, none of these were done in
38   my follow-up. Like every time I would go for follow-up it was just
39   they'd weigh me and see how much I'd lost since the surgery, and you
40   know that's it. But there were nutritional counseling pre-op and then a

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   few months afterward, but after that there was really nothing. So after
 2   a year I stopped going to my surgeon, but I'm glad to see that you're
 3   doing all this longitudinal follow-up study. Thank you.
 4          DR. BASS: Yes, thank you. I know it's very important and I think
 5   that's a uniform problem we have. You need to go get a bone density test
 6   among other things. So and you need to take your vitamins, that's for
 7   sure. Okay. Let me move on. Should I go on to the next one?
 8                DR. JAMES: Any other comments? Good. Oh, Dan.
 9          DR. PODOLSKY: Don't let people think too long, they'll take it
10   up. Just on the bariatric, and I realize in some ways this gets to be a
11   little bit of a gray zone here in terms of what is properly in our
12   domain. But given where things are moving to in what will I guess be an
13   intermediate term which is not - necessarily non-surgical approaches,
14   devices that will be GI devices that accomplish some of the same
15   physiology. I didn't sort of see where that was covered, that that would
16   be you know promoting endoscopic or you know -
17          DR. BASS: Yes, you're right, they're not on there. We're going to
18   talk about some of those technologies in this next section, but you're
19   right, in terms of defining the - we can say bariatric procedures. I
20   mean, whether it's electrical pacing, plication, balloons in your belly
21   again like 20 years ago or whatever. All those things.
22          DR. PODOLSKY: Or sleeves and all these things.
23          DR. BASS: Sleeves, yes. Bands, whatever it happens to be. But if
24   we could define the neurohumoral and endocrine consequences of those
25   things they may well be a unifying thing which would lead to a non-
26   procedural intervention in the future.
27          DR. PODOLSKY: Right and that's why I said there would be a
28   transitional -
29          DR. BASS: So it's really - we really should be defining bariatric
30   procedures or procedures designed to lose weight.
31          DR. PODOLSKY: Physiological -
32                DR. BASS: I think that's true. You're right.
33                DR. JAMES: And certainly for our institute as you know, some
34   patients with some procedures have dramatic and rapid resolution of Type
35   II diabetes, but we don't really know why and that's a wonderful
36   research opportunity - probably somehow related to GI hormones and
37   physiology - to understand that and hopefully replicate that somehow
38   without having to do the surgery.
39          DR. BASS: So that's the idea. And the non-obese Type II diabetics
40   who have a - gastric bypass, 80 percent of them have their diabetes

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   gone.
 2                DR. PODOLSKY: It would fall into a natural paradigm of if we stay
 3   within intermediate goals you know versus long-term goals.
 4          DR. BASS: Yes?
 5          DR. SANDERS: We had quite a bit about stem cells and transplant
 6   as well, and it seems to me that we should probably you know give that
 7   over to your section. It fits better there. But I also wonder about
 8   would you also be interested in taking our long-term goal or whatever on
 9   gastric pacing and stimulation because it seems to fit into
10   biotechnology and may be applicable to more than just our chapter as
11   well.
12                DR. BASS: We can.
13                DR. SANDERS: You don't have to do any more work and I'll send
14   what we have on it.
15          DR. JAMES: I think it's crosscutting because I think part of the
16   problem with pacing and stimulation is we don't know what you're trying
17   to achieve. It's not really just an engineering issue.
18          DR. SANDERS: In the case of where you're actually pacing the
19   pacemaker then you know what you're trying to achieve. I'm not sure that
20   the short pulse stimulation is quite clear what that's trying to
21   achieve, but.
22          DR. BASS: I mean, pacing is also being used as a bariatric
23   procedure.
24          DR. SANDERS: Exactly. Exactly. That's a really good point. I mean
25   there's several companies working on that I know about.
26          DR. JAMES: Quick. Yes.
27          DR. PASRICHA: So what is - the thing you were asking at one time
28   with enterodistraction, is that these intestinoplasty? Is that what
29   you're talking about?
30          DR. BASS: No, it's actually - I mean it's in an animal model. I
31   actually wasn't even aware of this, but I mean there's an animal model
32   where if you stretch - you know, you mechanically distract the small
33   bowel. You actually increase the available surface area and you augment
34   the intestinal mucosa.
35          DR. JAMES: It's remarkably simple. If you want a longer gut, all
36   you have to do is stretch it and keep it that way for awhile.
37          DR. BASS: Yes. It's not the longitudinal - it's not the
38   intestinal lengthening procedures that are conventionally done for the
39   big dilated gut.
40          DR. PASRICHA: Yes.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. BASS: It's not that. It's not that. This is just stretching
 2   and you get more, they say. So we think it's worth studying. I think
 3   it's actually worth looking at. And it's only in animal models
 4   obviously. It hasn't been done in people. But - it's sort of akin to
 5   Marc Basson's - I think Mark Basson may be the guy that's been doing
 6   this for the most part. And apparently it substantially augments the
 7   available surface area. The small bowel mucosa just, boom, fills it up.
 8   As you might expect it would. So we've got to look at that. I think it's
 9   worth looking at. So it's on the short-term list. It didn't make it to
10   the long-term list because it may be a flash in the pan.
12   Bioengineering, Biotechnology, and Imaging (WG 13), Barbara L. Bass,
13   Chair
15          DR. JAMES: Okay, next chapter.
16          DR. BASS: Okay. This next -
17          DR. JAMES: Changing gears.
18          DR. BASS: Yes. This next one, again we had - this was one of
19   those you know crosscutting, where do all these different pieces fit.
20   And I want to thank David for his insights on all of this. And I want to
21   reassure you I have replaced the thing, the sort of stream-of-
22   consciousness thing that was in your book has been trimmed down
23   substantially, not as much as it needs to be, but it has been trimmed
24   back a bit. We had some wonderful people on this panel that really were
25   - just gave us great ideas. Everything from the people that are the
26   endoluminal, you know, enhanced observation techniques. Steve Badylak is
27   really one of the premier leaders in the field of regenerative medicine
28   tissue engineering. Yuman Fong is a hepatobiliary surgeon at Sloane
29   Kettering who has done some very fascinating, doing some really
30   fascinating work with image guidance and image detection, optical
31   detection. So we had a really - and Lee Swanstrom is sort of one of our
32   techiest of high-tech surgeons. So we had a great group to work on this.
33                The things that we looked at, and again, although these are the
34   things we all considered I'm not going to give you 10 goals for each of
35   these, I promise. But we did think that these were the things that sort
36   of fell into our general domain, and areas where there are new
37   technologies evolving all the time that may or may not be of value, but
38   they certainly are proliferating like weeds. The things where we think
39   there are really valid needs for these new tools are in the following
40   areas. In luminal structures we think we need new technologies to help

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   us better survey and detect pathology, whether that's in your esophagus,
 2   your stomach, your small bowel or your colon. We think we need new
 3   tools, better tools, better toys, better devices to allow us to attack
 4   those, to ablate resection size, those luminal abnormalities than we
 5   have right now. We think we need new imaging devices to allow us to
 6   optimally in a most - least invasive way to biopsy and treat, define
 7   whatever these luminal pathologies are. And I'll get to some of what
 8   those might be in just a minute. We tried to keep it generic. We really
 9   did not want to get to individual diseases obviously. I think you all
10   know within each of your disease entities which of these diseases fall
11   into these categories, whether it's Barrett's or colonic dysplasia and
12   you see. I think we all know what they are, but we need better tools for
13   what we do and right now we go and we pluck biopsies of them and hope
14   for the best.
15          In solid organ structures we focused a lot on procedural
16   planning. So using imaging to allow us to direct our procedures for
17   guidance as well as for optimal planning, for optimal surgical
18   approaches, optimal interventional ablation approaches, and for
19   detection and for targeting. In imaging we thought these were in our
20   domain, both the value of how do we better image the GI tract, what's
21   the role of molecular imaging in specific diseases in the GI tract,
22   hepatobiliary and GI tract. How can we enhance our ability to do remote
23   endoscopy and virtual endoscopy? So what's the next step in capsule
24   endoscopy or in virtual imaging, virtual endoscopy for visualizing the
25   GI tract. And then we talked some about emerging technologies, the two
26   most front burner ones right now being notes and the robotics. Robotics
27   meaning remote control devices as opposed to true robotic devices. And
28   tissue engineering and regenerative medicine that also fell in our
29   domain and we'll talk a little bit about that. We were thinking more in
30   terms of luminal structures, but obviously with our discussion this
31   morning about liver it also applies to restructuring the liver and even
32   perhaps the pancreas. And lastly we got a little bit into the role of
33   simulation in maintaining the competency of our workforce out there, and
34   can we - should we be players in that dynamic.
35          Well, as we've heard we're not going to have any more of these,
36   but we thought right off the bat one of the things we need is really a
37   better registry and a consortium of really the sites that are using
38   these - of experts who are really introducing, testing, developing these
39   advanced new technologies. And really if we could sort of focus it on
40   disease-based that would be great. I mean, here are all these many

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   different diseases that these might be relevant to. And you can read
 2   them there. I'm not going to go through all of them. But all of these
 3   are obviously luminal disorders for which we - if we could see them
 4   better and get to them better and treat them luminally we would be in
 5   much better shape than if we didn't have to do it with an operation. Or
 6   if we could even look at them and see them and repair them or treat them
 7   in some other way. So there they are. And we thought that we need -
 8   there are lots of devices out there, and we thought we needed really a
 9   high-end group of people that will honestly and fairly participate in
10   such an observational set of studies and share what they learn about
11   these things in a good way.
12          One of the things that was very clear in our group too is
13   obviously that we kind of have the clinical ideas, we know what the
14   problems are, but the people who know how to build the toys and make the
15   toys and do the imaging are not us. I mean they're not physicians.
16   They're not even you know people that work in medical schools. They work
17   in universities and computational biology labs, or computational science
18   labs, or in engineering labs, or places like that and we really have to
19   figure out some way to get us talking to them in a more effective way.
20   And we thought that was both a very important short-term, actually it's
21   a durable goal, as well as probably one of our greatest obstacles
22   because it's not a natural for us.
23          The other big overwhelming issue we had was the fact that this is
24   really expensive stuff and the primary driver for a lot of this of
25   course is making a new toy that will sell well that will make somebody a
26   lot of money and it therefore lends to this tendency for scientists to -
27   if you get a good idea you're afraid to share it. If you share it you
28   worry more about - you end up being labeled - when you share and you
29   partner with industry you get labeled as you know having sold out to
30   industry and therefore you can't really advance your ideas. So we
31   thought that really we need to have some better process, a much more
32   clear process to allow funding of scientists who will in fact partner
33   with the tech industries that have the drive and the resources to push
34   this forward to allow us to better manage our conflict of interest and
35   IP issues that we have in this whole field. I think that really it's a
36   major obstacle and something we really have to figure out how we're
37   going to get past that. I don't know how we're going to do that, but I
38   think we need to comment on that somehow or the other.
39          Those are kind of the big overarching things. In addition to
40   that, some of the more specific things we wanted to look at were in the

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   field of endoscopy versus minimal access surgery. I mean, there's lots
 2   of things that can be done with an endoscope that can also be done with
 3   a minimal access surgical approach via the abdominal wall for example.
 4   And the question really is which one's really better. And we have to
 5   define more better. We need to define better outcome measures in terms
 6   of short- and long-term morbidity, short- and long-term efficacy, cost
 7   and quality of life and all those kind of things, and that's going to
 8   require some honest you know accrual and reporting. I think we need some
 9   good trials on some of these things. We thought that one way to
10   jumpstart this would be to convene an NIH-sponsored session early on
11   that would kind of do a survey assessment of our current technologies
12   that are out there and get some key experts in here to discuss it. At
13   least put on the table these different areas that are there and then
14   follow that up with an RFA to do this in a more rigorous scientific
15   fashion.
16          We thought we needed better studies on minimal access surgery to
17   determine - right now we focus exclusively on getting out of the
18   hospital earlier and how much pain medicine you use, but to look more
19   closely at whether there are biological advantages in terms of immune
20   response to these procedures, particularly in patients having treatment
21   say for malignancy. Are we in fact compromising their - do old
22   conventional procedures actually compromise their immune response in a
23   way that is bad?
24          We thought, getting now to the tissue engineering, again back to
25   the stem cell things. We thought we needed to very early on really get
26   to the heart of the matter with intestinal stem cells or - and really
27   start looking closely at tissue engineering applications. Again, we
28   thought - you know if you go to any tissue and engineering - I mean, the
29   bones and joints and tendons. I mean, they're routinely done now. I mean
30   we are so far behind when it comes to tissue replacement in the GI tract
31   it's almost astonishing. And yes, we're sort of more complicated, but
32   muscle, bone, tendon, all those kind of things are - you can buy them
33   off the shelf now. So we really have a long way to go in getting back
34   into that area.
35          And we thought early on we needed to do a validation study on the
36   use of simulation training for endoscopy, for minimal access surgery to
37   see whether this is in fact a translatable product that would in fact
38   enhance the competency of the workforce out there. So take a step into
39   simulation.
40          Intermediate goals. This again gets to the idea of doing

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   molecular biopsies of luminal abnormalities. We think we need better
 2   ways to do biopsies than our current techniques, and if we could do a
 3   realtime molecular biopsy that would allow us to deliver the
 4   intervention at the same time or take care of the problem at the same
 5   time that's highly desirable. We need obviously improved endoscopic
 6   instrumentation. We need triangulation. We need larger lumens. We need
 7   more tools that can play with things. And we need better access
 8   certainly to the small bowel, small intestine in particular. We thought
 9   one fundamental scientific underlying theme which we've heard about here
10   before is that of scar formation fibrosis, that that's really a theme
11   that we need to address in terms of tissue engineering and regenerative
12   medicine as well, focusing particularly on the esophagus and small
13   intestine in our discussion, but obviously in other areas as well.
14          In regards to the imaging work we thought we need better PET
15   tracers to look at our patients with cancer, looking at better markers
16   for proliferation, tumor-specific antigens so that we can then therefore
17   use more directed image-guided interventions with our technologies. We
18   need better interoperative gamma and beta detectors that allow us to be
19   more specific for interoperative localizations. We need better
20   navigation and control devices for single-port laparoscopic device,
21   laparoscopic procedures, NOTES procedures. They actually use very much
22   the same kind of tools and that it's - if we get to a single port kind
23   of technologies.
24          We need better stents. We need better stent technology and the
25   materials that they're in. We need a better understanding of biofilms,
26   getting them in and out, all those kind of things. We thought it would
27   be very important to start spending a lot more time on scaffolds. In the
28   tissue engineering regenerative medicine field the scaffold is in fact
29   more important than the stem cells if you talk to most of the
30   engineering types out there, the bioengineers that do this work. And
31   there are specific requirements in scaffolding that we need to address
32   more thoroughly.
33                For more on the image-guided therapeutics, let me see. So
34   continue to again refine our sources of energy, get better at delivering
35   the energy for tissue ablation as opposed to resectional procedures. We
36   need to enhance our virtual reality or virtual endoscopy procedures. We
37   need techniques that allow for realtime stereotaxis so that we can do
38   our remote interventions, whether it's ablation, resection or whatever
39   with realtime stereotactic guidance. Which as we can do in the gut we're
40   just beginning to be able to do that in the liver and we need to be able

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   to do it more thoroughly in the abdomen, the retroperitoneum. And we
 2   need better optical kind of labeling things, such as fluorescent
 3   antibodies, other kinds of optical imaging materials that will allow us
 4   interoperatively to see disease and more effectively use minimal access
 5   procedures and be more thorough in our resection or ablative
 6   technologies.
 7          Here's just a long list of things that we thought would be
 8   important toys to develop. Not so much toys, but important things to
 9   develop. Microbiotic-driven endoscopes. You know, the real truly robotic
10   endoscopes that would be little bitsy that we could put in and drive
11   around. We need better high-definition virtual reality simulation
12   training for skills acquisition and mastery such that really we can set
13   measurable thresholds for performance that are translatable to actual
14   clinical care. We need a lot more investment in that technology to make
15   it valuable. We need to expand capsule endoscopy technologies that will
16   allow not only diagnostic therapeutic interventions and there in the
17   NOTES technology or the obstacles to making that a more usable tool than
18   it is right now. It's sort of at the point where laparoscopic surgery
19   was almost 20 years ago or 15 years ago and it's a lot easier to do it
20   now because we have much, much better tools.
21          In terms of the long-term goals, we think that some epidemiologic
22   validation of the use of simulation in preparing the workforce,
23   interventional workforce would be desirable. We need 3D robotic flexible
24   operating systems. And again, I already mentioned the robotic things.
25   Some of the challenges we have. I mean, here's a bunch. This is where we
26   really got into the stream of consciousness. I mean, if you read your
27   thing it's everything from like nobody wants to be a scientist to we pay
28   endoscopists too much money. So we've tried to hone it down a little
29   bit. But basically the idea that the mechanisms for translational
30   clinicians, translational science has not been a high priority for the
31   NIH in the past. That randomized clinical trials outside of cancer have
32   not been at the forefoot of NIH funding in the past. We thought that
33   very clearly as we get into training that training in line specifically
34   focused on these - preparing these surgeons, endoscopists, whoever in
35   technology development and working with industry and having the
36   scientific tools to do that would be very important. We thought we could
37   use some change in the makeup of the NIH study section. And I think one
38   of the really central themes was this notion that we have to figure out
39   how we're going to partner with industry to do these things because this
40   is really extraordinarily expensive work and we really have to figure

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   out how to do that.
 2          We similarly really need to figure out how to build
 3   collaborations between those groups that don't typically collaborate,
 4   the hard scientists, the computer scientists, the modelers, the cartoon
 5   people to figure out how best to do this. We thought that industry has
 6   to step on this as well and that really, obviously the driving force
 7   between most industry development isn't the science, it's the marketing
 8   and the developing a product that will serve the next - be the next big
 9   seller. And I think we really have to figure out a way to tilt that a
10   bit, or at least work with that, recognize that and work with it to
11   allow us to achieve our aims. There was even some discussion in our
12   group that you know, gastroenterologists aren't going to want to know
13   about these things because then they won't get to do as many procedures.
14   It was really, we really went way out on a lot of these things.
15          We thought that it would be valuable to have the NIH hold INDs
16   for promising new agents. I mean, each time you go through one of these
17   it's a huge deal and if we could have a central function that would meet
18   this it would really perhaps step up the rate at which clinical grade
19   agents are made available for testing. We thought that a national
20   reference preclinical toxicology lab would be valuable to look at some
21   of - as we go to developing the molecular imaging reagents. And the last
22   one. And then talking about the idea that sometimes some of the people
23   with the best ideas just don't have the capital and the resources to do
24   it, and how do we extract the good idea groups and the good idea
25   materials and partner with a small industrial partner to do the
26   important translational work, unlike the big gorillas who have the
27   money, but don't necessarily have the creative ideas.
28          Here again are a long list of things. I'm not going to go through
29   all of these, but everything from the malpractice environment to HIPAA.
30   I think we're all familiar with these things. The NIH salary cap is
31   insufficient, driving people to be clinicians as opposed to scientists.
32                But I think more centrally that is very relevant here is that
33   IRBS really are very reluctant to allow new - technologies are tough to
34   get through IRBs if they present risk, and by definition virtually all
35   interventional technologies present a very measurable risk that's often
36   viewed as being more hostile than the risk of a medication. So I think
37   we have to figure out some way to persuade our national IRB group that
38   these are important things to do. But with that comes the imperative to
39   deal with the ethical implications that new technologies are sometimes
40   incremental as opposed to revolutionary in their impact and not every

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   one of those is worth pursuing if we put patients at risk.
 2          From the regenerative medicine side, Steve Badylak who was on our
 3   group said you know, nobody's done anything in the GI tract. You just
 4   take a little stab at this, you're going to have more results from this
 5   in two or three years than other organs would take in 20 years because
 6   you haven't done anything yet basically is kind of what he said. So I
 7   think that some early support in this particular area would be called
 8   for to address what is perceived to be a wide open gap.
 9          In terms of the last piece, the simulation and workforce
10   preparation, you know the cost of developing simulation is substantial
11   and therefore - and yet the market return is really quite small. I mean,
12   nobody pays much for education or training. So how do you balance that
13   to offset patient quality and safety versus the investment required for
14   simulation? Again, outside of our usual collaborator network. And
15   finally, the infrastructure just isn't - how do we develop that whole
16   infrastructure in the country to support these simulation centers, these
17   training centers, these tools so that we don't end up with an
18   increasingly dated workforce that's always 5, 10, 20, 30 years behind in
19   terms of their technical skills. That's it.
21   Discussion
23          DR. JAMES: Terrific. Questions? Jay.
24          DR. PASRICHA: Very nice job, Barbara. So a couple of questions or
25   comments actually. One is about the challenges regarding the - you
26   mentioned having centralized INDs for these new molecules. The NCI
27   actually has that. They have the image-guided intervention initiative
28   where they are actually holding INDs and actually assisting in
29   developing and producing GNP-grade small molecules for use in trials. So
30   you may want to factor that in.
31          And the other mechanism which Steve can probably comment more is
32   for the smallest startups which are not capitalized there is the SPIR
33   and STR mechanism to fund some of those studies early on. But actually I
34   think you touched on all the major technologies that we are all
35   interested in, but from the perspective of this commission, from the
36   perspective of the NIH I think this chapter really highlights you know
37   what the distinction between development is and research. You know, you
38   talk about them almost in one breath, research and development. But I
39   mean I think when laparoscopic surgery came out there wasn't enough done
40   from a true research perspective to validate its or establish its value.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   Even today if you look at about half a dozen prospective trials,
 2   randomized trials that have been done between laparoscopic and open
 3   surgery, the evidence is equivocal at best which one is better in the
 4   long term. Of course patients, it's a done deal. Nobody's ever going to
 5   go back to open surgery. So I think one of the perhaps missions we
 6   should have is not so much assisting the actual development of this. I
 7   mean that would be nice if you had the resources to do all that, but
 8   there are actually mechanisms for that, but more to emphasize a rigorous
 9   research agenda for the validation of these technologies rather than
10   their development. That's just my own bias.
11          DR. BASS: Yes, I tried to get at that, the idea of really
12   rigorously comparing minimal access surgery, endoscopic techniques.
13   Really being honest I think about the value, the incremental and
14   substantial value of these technologies and rigorously comparing them. I
15   think we absolutely have to do that.
16          DR. PASRICHA: And we haven't done that though.
17          DR. BASS: We have not done that.
18          DR. PASRICHA: And the result is that we've been preempted by
19   industry. A good example is what's happening with Barrett's esophagus.
20   People out there are already having basically road shows right now and
21   telling people, and it's relatively easy to get these approved by the
22   FDA because the FDA doesn't usually use a very strict efficacy criteria.
23   They're basically looking at safety. There's almost no new device that
24   has ever required a full you know approval. Everybody gets into a 510(k)
25   and it's on the market.
26          DR. BASS: Well, that's part of what we thought about establishing
27   this linked group of high-end new technology users to see if we could
28   get them to be the leaders in this in all honesty. Because they're in
29   some respects both the drivers of this problem, but they also are in the
30   best position to - if they choose to honestly appraise it and do this
31   work for us. But I think we need to make a fundamental kind of judgment
32   call in that regard that that's a valuable thing to do, recognizing that
33   it's going to potentially alienate some industrial partners.
34          DR. JAMES: Yes, the industry of course fortunately marches ahead
35   very fast when there are - and part of the problems with doing NIH
36   trials, by the time we figure out even what the trial is the technology
37   has already been revised three or four times. Or vanished in some cases.
38   So that's progress. Some things just go fast. But certainly there are
39   other areas when a technology seems to be established and then how
40   should it be used. So I guess two weeks ago there were papers in the New

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   England Journal on surgery for back pain. And difficult to conduct
 2   trials that -
 3          DR. BASS: For the fourth time.
 4          DR. JAMES: Yes, so showing the results. So those are examples
 5   where clearly - and the partner is there. The driving factor will be who
 6   pays for it. So carriers and CMS will be very much interested, in fact
 7   are very interested in having NIH partner to help validate the
 8   risk/benefits of various things that have become established but we
 9   still aren't sure whether they're the right things to do. So I think
10   there are opportunities there. It's very hard to define them.
11                DR. BASS: David, do you want to make comments? I know you were.
12                DR. LIEBERMAN: I think you covered it really well. I mean, you
13   could tell our group was clearly thinking outside the box in terms of
14   new technologies and I think that was productive. How much of that
15   should end up being NIH priorities, you know, I think is a subject that
16   we'll all have to debate a little bit.
17          DR. JAMES: I think it's critical. It's so - imaging and endoscopy
18   technologies are so fundamental to what do we actually - what has
19   revolutionized GI in the last 20 years? These are the things. And to not
20   address them or grapple with them I think would be a big mistake. So.
21   John?
22          DR. CARETHERS: Just like in your previous section on nutrition,
23   are you going to address any potential complications? For instance,
24   we're marching ahead with Notes. Do we study stomach function after
25   poking holes in stomachs? I don't know. Stuff like that.
26          DR. BASS: We've done that for a long time and it still seems to
27   work. We actually hadn't talked about that, but yes. I think the notion
28   of long-term sequelae of any of our interventions obviously is an
29   important thing to add.
30          DR. LIEBERMAN: We did talk a little bit about looking at various
31   aspects of Notes versus other things, including like immunologic
32   effects. I mean, one of the potential advantages of not going from the
33   outside is that there might be some immunologic advantages and that was
34   one of the things I think that we did discuss.
35          DR. JAMES: Nancy?
36          MS. NORTON: This may be way outside the scope of what we're
37   talking about, but just thinking from a patient perspective and new
38   technologies and how much of this is market-driven, but it gets very
39   quickly adopted by the clinicians. And so you know, sometimes we end up
40   with extreme morbidity associated with some of these things before it

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   even gets to the point of being stopped. So I don't know if there's any
 2   way to sort of figure this into how we move forward.
 3          DR. BASS: Yes, it's an interesting thing you know. It depends on
 4   where you live you know. So if you live in Boston, or you live in
 5   Houston you're at risk for being harmed by new technologies. You live in
 6   West Texas, you'll be lucky if you get the right operation that was
 7   offered 10 years ago. So it's really a very heterogenous kind of, you
 8   know so part of it is like how do we get the whole workforce up to snuff
 9   so they use the right tool at the right time and are capable of doing
10   that versus that sort of leading edge that maybe is offering things that
11   have no proven benefit. I don't know that that's really the kind of
12   thing we can get to in our report, but I think it's a really important
13   issue and I think nationally, I can tell you in surgery there's a great
14   move afoot to try and make sure that we have a surgical workforce that
15   is appropriately trained. We're trying to build the infrastructure
16   across the country in simulation centers where you can actually go and
17   you know, show me on a box you know how to do what you're doing when
18   you're doing it. But again, we're aiming not so much as the cutting
19   edge, it's just sort of the basic 95th percentile of the common diseases
20   that are out there.
21          DR. JAMES: Well, the FAA has used this to train your pilots who
22   brought you here for a long time, so hopefully it'll work for digestive
23   diseases. Dan.
24          DR. PODOLSKY: This last exchange actually brings to mind an issue
25   that maybe we should consider where it goes in here which is variation
26   in practice. And you know, wherein some of the health services research
27   as it applies to the care of digestive diseases should be incorporated.
28   So your point about you know whether you get a new technique or not is
29   against the backdrop of you know, huge variations in practices. One of
30   the key, I think we all know one of the key controversies the healthcare
31   treatment community is going to be dealing with along with safety as
32   well. So somehow maybe this is a point at which we can try to
33   incorporate that as an element of a total vision of what digestive you
34   know sciences ought to be considering.
35          DR. BASS: Yes. I really think we need to add at least one
36   quality-related piece into this. We really do. Yes.
37          DR. JAMES: So noted. Right. Margaret.
38          DR. HEITKEMPER: I was just going to make a similar comment that I
39   think in that overview chapter the issue of health disparities and
40   access to care, and that weaving in the technology piece. And then one

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   other very small comment is that I think simulation provides a wonderful
 2   opportunity for multiple disciplines to train and work together and that
 3   is a nice way to launch some of the things that we hope to see actually
 4   in practice.
 6   Overview of the Digestive System (WG 1), Richard S. Blumberg, Chair
 8                DR. JAMES: Thank you very much. And last but most important we're
 9   actually going to talk about what NIH traditionally does the most of,
10   basic science. So you thought it would be easy.
11          DR. BLUMBERG: Last slide, please. I figured you'd appreciate
12   that. Okay. So this is Working Group 1, overview of the digestive
13   system. This is deja-vu all over again, Steve. Thank you. I'm going to
14   try to do this as quickly as possible because I know everybody wants to
15   leave and I'm also going to try to, to the best of my ability highlight
16   some overlaps that came to my attention. I was trying to keep some
17   careful notes today.
18          So this group involved a number of very talented individuals.
19   Gene who unfortunately is not here helped out enormously. Ramesh
20   Shivdasani. These individual members were broken up along party line
21   with respect to discipline. Ramesh Shivdasani provided support with
22   respect to development. Hannah Carey, the section that we decided upon
23   called integrative physiology. Nick Davidson on digestion. Chip Montrose
24   on membrane transport. Chung Ouyang for neurophysiology. Abigail Salyers
25   for the microbiome and finally, Warren Strober for mucosal immunology.
26          So I'm just going to right into this. We took the charge from
27   Steve and Bob and divided it up along short-, intermediate- and long-
28   term. And I'm going to present each of these from the deliberations of
29   the individual working subgroup chairs. And I'm going to start with
30   Ramesh and with his deliberations on development. Short-term goals are a
31   research aim to understand how particular cell tissue niches are
32   generated and maintain embryonic digestive disease organs. Just
33   parenthetically this will require a great deal of tools which I'll come
34   back to in the challenges. In addition, the second major short-term goal
35   is to exploit the wonderful advances that we've generated in the field
36   on ABC beta-catenin signaling which is obviously of enormous importance
37   to development, but downstream needless to say to cancer.
38          Intermediate goals in development of the GI tract is to try to
39   bring this all together in a systems-like fashion. To develop a
40   reasonably complete understanding of the specific signaling pathways,

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   transcriptional profiles, regulation, interactions that ultimately
 2   mediate the critical pattern events that lead to the various endodermal
 3   and subsequent organismal development that is a part of the generation
 4   and maintenance of the distinctive major derivatives of the
 5   gastrointestinal tract. So bring essentially the first part together
 6   into more of a reasoned systems understanding to how the organs develop.
 7          And the longer term goals from Ramesh are ultimately, and this is
 8   where the overlap starts to come with John and many others, to begin to
 9   try to translate this to - these discoveries in GI development to
10   diseases and try to fast-forward and to forward think the possible ways
11   in which these various fundamental mechanisms contribute to a variety of
12   GI disorders, not least of which could be even diverticular disease for
13   that matter. We just don't know. The challenge there will be to be able
14   to achieve that. And a prior long-term goal is to integrate molecular
15   databases that are being generated in many different types of manners
16   and forms. Gene expression profile databases, chromatin precipitation
17   databases and so forth and so on and try to integrate those or at least
18   to do some physiologic genomics if you wish in terms of functionally
19   define exactly where they actually fit into these pathways and hopefully
20   to then ultimately appreciate the underlying regulatory circuits of this
21   entire process.
22          Digestion. Moving on to the digestion, and again this was Nick
23   Davidson's group. Nick's short-term goals were to encourage research
24   programs aimed at generating and characterizing new intractable models
25   of digestion and absorptive functions. That is, taking defined genetic -
26   rather, elements that are associated with digestion and beginning to
27   develop models that are gain of function, loss of function in vivo. And
28   with conditionality. That's a critical thing and that will be a very
29   important challenge when I talk about the challenges. Conditionality is
30   a big challenge for us as a community. That's an overarching theme of
31   all these groups and I'll come back to that later. What's that?
32   Conditionality means it's a conditionality of deletions of genes, or
33   knocking out of genes so that you can not only control them in a cell
34   type fashion, but also control them temporally. So you can induce them
35   on or off at particular points of time during adult life. That's how we
36   define conditionality.
37          And then second major goal is to identify cell membrane topology
38   and the biochemical mechanisms of known transporter functions that have
39   been defined to date, including their substrate recognition, trafficking
40   and regulation. Identify mechanisms that control metabolic

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   compartmentalization of substrates. Where do they move inside the cell
 2   and where do they traffic and within the secretory pathways. And
 3   finally, to encourage work that will identify and characterize novel
 4   genes that participate in absorption of luminal substrates and
 5   xenobiotics.
 6          Intermediate goals within digestion are to extend the studies of
 7   candidate genes to examining selective absorptive and metabolic
 8   pathways. And he gives - there's several examples here. Cholesterol,
 9   bile acid, micronutrients. And begin to try to generate humanized models
10   of these particular genetic permutations that have been defined as being
11   important in the human population by making human knock-ins. To begin to
12   develop targeted approaches that can begin to again fast-forward these
13   or forward - make these forward moving into obesity, hyperlipidemia and
14   diabetes through testing candidate small molecule inhibitors of gene
15   function, a number of which already exist in mouse models. To begin to
16   integrate advances in developmental biology to understanding the
17   regional differentiation of intestinal absorption, and to begin to
18   define the plasticity of these. And finally, to encourage the
19   development of selective inhibitory methods, siRNAs and other tractable
20   knockdown methodologies for widespread use in deconvoluting and
21   interrogating digestive absorptive pathways.
22          The long-term goals of digestion are finally in all these to have
23   a common theme of trying to in the latter years of these recommendations
24   to begin to try to translate them, or begin the process of translation
25   which will again be overlapping with a number of the groups. Identify
26   targeted therapeutics based on the informative pathways from the
27   aforementioned discussion to predict how obesity, hyperlipidemia and
28   diabetes developed, which in many respects are either related to or
29   downstream of digestive diseases, and to figure out ways to actually
30   intervene in these. To identify serum and tissue biomarkers that predict
31   alterations in the pathways that are associated with the development to
32   these diseases, and finally to recognize the specific molecular defects
33   that are associated with nutrimalabsorption and defective or
34   inappropriately increased intestinal nutrient delivery. Obviously of
35   great implication for the fundamental biologic basis for the development
36   of obesity.
37          The growth in integrated physiology. This was Hannah Carey and
38   Hannah, we decided that Hannah would take more of a systems view and try
39   to take a systems view. We encouraged her to do as such. And these are
40   the recommendations from Hannah's subgroup. To generate databases that

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   include RNA and protein measurements of circulating tissue
 2   concentrations in intestine trafficked hormones. Obviously of great
 3   implication for some of the things that Barbara was talking about with
 4   growth failure, in normal health and compromised states such as gut
 5   injury, bowel resections and so forth. To begin to develop systems
 6   biology approaches to define the downstream mediators of the growth
 7   factor signaling that is important to tissue regeneration and metabolic
 8   pathways - as well as metabolic pathways to define biomarkers and
 9   factors which affect epithelial proliferation. Obviously very important
10   for tissue regeneration. To integrate physiology with peptidomic,
11   proteomic, metabolic and other technologies to identify adipokines that
12   influence gut function and how these signals originate from the gut and
13   affect adipose tissue biology and metabolism and again, implications for
14   tissue failure and energy utilization and so forth.
15          Intermediate-term goals for the growth in integrative physiology.
16   Again, to - this is some overlap. A number of groups discussed this.
17   Identifying stem cell populations that are lured by the local mediators.
18   And I should mention that there's a paper putatively in press and cell
19   where the gene that's associated with regulating the intestinal stem
20   cell that has been identified by Hans Clever's group is apparently in
21   press, so we'll have that information very soon. So we'll begin to, as a
22   community begin to interrogate that. Understand the cross-talk and
23   synergism among the intestinotrophic peptides, neural pathways, growth
24   factors, nutrients. A systems biology approach to adipokines and try to
25   pull it all together in the gut-brain axis. This is also touched upon in
26   Chung's discussion. And I don't have it here, but also in terms of
27   intestinal growth.
28          Characterize the molecular basis of stromal epithelial
29   interactions in gut injury and repair to identify potential therapeutic
30   agents. This is very interesting and obviously overlapping with Barbara,
31   but if we could understand the mechanisms by which bariatric surgery
32   actually caused weight loss we could reductionistically apply it without
33   actually doing the surgery in the first instance. And so taking
34   advantage, this is a good translational proposal. Identifying the neural
35   circuitry involved in pro- and anti-inflammatory pathways, the cause and
36   effect relationships between inflammation, ultra-neural function and the
37   role of nutrition in manipulating neural immediate anti-inflammatory
38   pathways. And the appreciation of the vagal nerve stimulation in
39   particular is a good example, has particularly important anti-
40   inflammatory properties. And can we develop therapeutics based upon this

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   understanding, how vagal nerve for example stimulation actually does
 2   this.
 3          And then longer term is to demonstrate the efficacy of
 4   intestinotrophic mediators in clinical trials. And again, this is the
 5   translational aspect. This is where the overlap begins to occur. And
 6   I'll just jump through this because of the overlap. Novel methods of
 7   tissue engineering, overlap. Therapeutic interventions to mimic the
 8   effects of bariatric surgery, overlap. And develop an effective
 9   peripherally active substances for control of food intake in satiety.
10   And again, overlap.
11          Now moving on to the intestinal microbiota which is an
12   overarching theme for essentially everybody. And this was done by
13   Abigail Salyers who is at University of Illinois who's a really
14   outstanding molecular microbiologist. This is her roadmap if you wish
15   for getting at this problem. It's just her editorialized roadmap. And
16   there's going to be many other ways to probably go after this. But this
17   is her short-term and then intermediate-term and long-term approach to
18   the intestinal microbiota with all of its ramifications.
19          Collect and organize a curated database to accommodate the mass
20   of 16S ribosomal DNA and metagenomic sequence data and develop advanced
21   bioinformatic methods for analyzing these data. Develop microarrays that
22   contain these ribosomal DNA sequences from all the major human colonic
23   species for rapid characterization of the species composition of the
24   colonic population. Undertake a metagenomic analysis of the microbiota -
25   and for those of you who don't know what metagenomics is, it's where you
26   actually do sort of shotgun cloning, put it into another bacteria and
27   see what the metabolic activity of that particular gene is. But to
28   interrogate that you need to have sequence data so you know where it
29   actually fits in the context of the genetic information contained in the
30   500-plus species in the intestine. So undertake a meta - and this came
31   actually out of the environmental microbiology literature and is now
32   being applied hopefully to our community. So undertake a metagenomic
33   analysis of the microbiota of healthy people and determine the extent of
34   person to person variation. Determine whether members of the major
35   bacterial populations can transfer DNA to mammalian cells. Develop a
36   humanized mouse model. This was overlap. I think it was overlapped with
37   Mitch when he gave his presentation - in which germ-free mice are
38   colonized with human fecal material. And then determine whether
39   bacterial enzymes, toxins, or hormone-like compounds which would come
40   out of the metagenomic analysis have effects in colonic cells.

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1          Intermediate-term would be to obtain genome sequences, the grand
 2   - of anaerobic bacteria that account for over two-thirds of colonic
 3   microbiota, but virtually nothing is known about them. And again,
 4   utilizing this information in with metagenomic data. Developing
 5   microarrays based upon metagenomic data from healthy individuals and
 6   using these to analyze various disease states. This is where the
 7   translation starts to occur. Take a census of the methanogenic archaea
 8   and sulfate-reducing bacteria found in the colons of health people and
 9   people with intestinal disease about which almost nothing is known. And
10   examine the genome sequences from colonic bacteria to identify possible
11   gene transfer events using advanced computational methods.
12          And then finally, long-term is using this technology to begin to
13   translate. And this is where all the overlap occurs and I'm not going to
14   get into this. And again, hopefully there will be something that will
15   come out of this out of the metagenomic analysis in particular that will
16   be able to be able to be related to diseases. And with respect to
17   probiotics and prebiotics, Abigail focused on the possibility of
18   engineering these in the future to actually be smart and targeted.
19          Okay. Mucosal immunity. This was Warren Strober. This will have
20   significant overlap with Dan in particular, but I think it's
21   sufficiently discrete with adequate tissue plans that I think it will be
22   okay. Focusing number one on essentially the immunobiology of the
23   epithelial cell. Number two, focusing on the immunobiology of the
24   dendritic cell. Focusing, three, on the immunobiology of mucosal
25   trafficking. Four, on regulatory environment of the gut and five, on
26   immunoglobulin regulation and the way in which these act as effector
27   molecules both IGA as well as IGG in the intestines.
28          Intermediate goals. The mucosal immunity is to begin to - again
29   this is the idea of conditionality - begin to develop animal models that
30   can begin to model those aforementioned molecular targets or molecular
31   pathways in the short-term goals using conditional models. To study mice
32   that again have abnormalities, targeted abnormalities and gut homing
33   mechanisms to try to deconvolute the biology. To focus on the biology of
34   regulatory T-cells and the intracellular factors that control regulatory
35   cell function. The mechanisms by which these affect regulation. And to -
36   this is again overlap, significant overlap and we can probably delete
37   this which is - but that's Warren's focus is to look at the final common
38   pathways that are associated with inflammation which overlaps obviously
39   with IBD. And with respect to vaccines, I think this overlaps nicely
40   with Mitch's, that rather than developing vaccines to try to develop new

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   adjuvants that can adjuvate for the development of mucosal immune
 2   responses for the development of vaccines for rotavirus and so forth and
 3   so on.
 4          And then finally, a longer-term mucosal immunobiology is to again
 5   look at the embryonic and adult stem cell differentiation, epithelial
 6   cells, how that is - how that can be manipulated to attain all the
 7   properties that one would ascribe to the various elements of the
 8   gastrointestinal tract. And now knowing that we have some data that's
 9   coming out that might be actually more of a short-term goal or
10   intermediate-term goal. Generation of mouse models that are
11   characterized by dendritic cell dysfunction. Begin to take some of these
12   notions to a more systems approach to try to think about how these
13   various factors work together to regulate homing in inflammation. Begin
14   to think about gene therapy actually for a number of these diseases,
15   especially when the IBD folks will be coming, helping us to define a
16   number of the genetic factors associated with these diseases. And I know
17   there's some animal model data that actually suggests gene therapy is
18   not completely a pipe dream. And again, this is overlap with Dan's
19   group. Establishing treatment of patients with Crohn's disease. This
20   will probably be deleted in retrospect, having heard Dan today. And to
21   try to apply some of these observations to the development of effective
22   mucosal vaccines, especially HIV which was not mentioned in Mitch's
23   presentation.
24          Nutrient fluid absorption, secretion. This was Chip's program.
25   Defining pathways that mediate the regulation of barrier function versus
26   transport function and the various aspects of the fundamental cell
27   biology of the epithelial cell and pursuing these functions.
28   Identification of the membrane transport proteins and chaperones that
29   are involved in the micronutrient and metal ion absorption. And to begin
30   to try to expand the use of non-mammalian models to interrogating
31   absorptive functions, zebrafish, elegans, drosophila.
32                Then, intermediate-term goals is begin to develop more advanced
33   mutant mouse models for studying human proteins. Applying, developing
34   mouse models that allow fine genetic mapping of cuticles to begin to
35   look for relationships between human essentially absorptive - try to
36   bring mouse models into - describing human absorptive and secretory
37   problems of unknown function. Translating what the diversity of
38   epithelial cell absorptive and secretory functions are at the
39   proteinomics level as we really don't know, and defining the molecular
40   pathways that lead to finally the differentiated absorptive epithelial

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   cell type. We have some information on some of the genes that regulate
 2   that such as the Winn signal pathway, APC, not APC but Math-1, Hess-1,
 3   Notch and so forth and so on, but we really don't know the proteins that
 4   are actually driving these things in the last instance. What's that?
 5   Cutile quantitative trait locus.
 6          Goals, long-term. Nutrient fluid absorption. Begin to integrate
 7   this information in a systems-like approach. Developing understanding of
 8   epithelial development and remodeling. Response to injury. This came out
 9   of a number of presentations, both Barbara and Dan and others.
10   Understanding the molecular functional adaptation of individual
11   epithelial cells in the intestine and response to challenges. And again,
12   this is where the translation begins to see overlap with some of these
13   other groups in creating interdisciplinary teams to begin to look at a
14   number of the aspects of things that Chip was focused on.
15          Now this particular section is very much overlapping with Ken and
16   frankly I could not do it nearly as good as Ken in a million years. So
17   if because of time if you allow me just to jump through the
18   neurophysiology and endocrinology? Okay. I think it's - if you agree,
19   it's okay for the significant overlap. There would be significant
20   overlap.
21          And just to finish up now with challenges. I'm just going to talk
22   about the challenges. I'm not going to talk about the steps, but I put
23   them there for your reading pleasure if you really want to fall asleep
24   tonight. If you're not tired yet, then I don't know what your problem
25   is. You better be tired because I'm tired. Challenge. One of the big
26   challenges is, and we've heard this over and over again, is the current
27   range of animal models is inadequate and we really need to develop tools
28   that will permit accurately targeted genetic studies in a variety of
29   animal models, not just in mice, but zebrafish, xenopus and so forth and
30   so on, that are not only tissue-specific, but cell-specific and
31   inducible. So you can actually turn things on and off in vivo. So that
32   was an overarching goal for everything I've just talked about and
33   probably everything everybody has talked about at a fundamental level
34   here.
35                A second overarching challenge is to - and again, what I've done
36   is I tried to look at the challenges rather than by individual theme. I
37   tried, when we worked together we tried to think about the challenges as
38   an overarching group. So I'm going to talk about them more in brush
39   strokes. To evaluate the extent to which molecules that mediate
40   development of the GI tract are also active in adult gut and therefore

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   may be the targets for specific disorders, cancer and God knows what
 2   other diseases they will end up being involved in. But this will come
 3   I'm sure.
 4          One of the overarching problems for all of us is inadequacy of
 5   current genomics and proteomics approaches and bioinformatics databases
 6   and GI research. That's I think fundamental to all the things that we're
 7   doing. This was something that Hannah brought in particular. The high
 8   risk of applying population-based screening approaches and biomarkers in
 9   disorders of heterogenous origin such as obesity, diabetes and other
10   disorders of nutrimalabsorption and neural signaling and functional
11   bowel disorders and intestinal inflammation given the high cost and the
12   possibility that you might fail. And that gets to high risk/high return
13   types of decisions the NIH will have to make, and how industry should be
14   or not be involved. And the resources that will be needed to do these
15   types of things.
16          The incredible need for germ-free facilities. Given the fact that
17   not only IBD, but we heard just about everybody in the room had some
18   aspect of the microbe-host interaction, and to interrogate that all of
19   us are going to need germ-free facilities. So the need for germ-free
20   facilities and how do we do that.
21          Challenge. Cells derived from animal models with defined
22   attributes are really needed and really one would say that cells define
23   - really carefully and well-defined cells from human origin are really
24   needed that are well standardized and well controlled that can - such as
25   an epithelial cell which we just don't have for example. Another
26   challenge is many studies in mucosal immunity, particularly those
27   focusing on vaccine development before they get into humans ultimately
28   often require the vetting in primates. There are no adequate primate
29   facilities.
30          The increased success of translational research that will come
31   out of these types of studies requires experimental approaches in animal
32   models that can be more directly compared with human outcomes to enhance
33   bench to bedside approaches. This was something that was pointed out by
34   Chip. This also I think even has implications for even some of the
35   technological things that Barbara was suggesting that we need probes and
36   other kinds of modalities that we can actually apply to a mouse and then
37   apply with knowledge this will be translatable to a human.
38          And then in interrogating the microbiome we're going to need to
39   have much more - and this was brought up by a number of individuals.
40   Mitch brought this up, Dan brought this up, others, that in order to

                          NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   interrogate the microbiome we need more sophisticated analyses and
 2   ability to analyze huge quantities of sequence data, especially
 3   metagenomic sequence data, to deduce known and undiscovered activities
 4   in the intestinal microbiome. So we need much better advanced
 5   methodologies for informatics and individuals will understand this and
 6   can develop new tools for doing the things that we need to do.
 7          And I'm just going to jump through this because I largely went
 8   through this. I broke it down. I think because of time it's really not I
 9   think going to be that instructive. So with that I want to finish up and
10   take some questions.
12   Discussion
14          DR. JAMES: So thanks. A true tour de force of basic science. Any
15   comments? Questions? At the risk of being difficult I would point out
16   for mucosal immunology it really has an immunology focus as opposed to
17   inflammation and I would wonder with some trepidation whether that
18   should be expanded a little bit to include inflammation because of the -
19          DR. BLUMBERG: Well, we tried to avoid it.
20          DR. JAMES: You tried to avoid it. Well, as you heard this morning
21   or may have inferred from Betsy Wilder, that was a hot topic for a
22   future Roadmap, but the problem was it was so big the large group of
23   people working on it couldn't their hands around what of all the huge
24   number of things people might want to do, what would they actually do.
25   That doesn't mean it's not important. In fact, it's just the converse.
26   It's so big and so involved in everything the question would be the
27   immunology part is pretty clear, but the information biology really is
28   somewhat different and maybe because there's so much opportunity for
29   translation and therapeutics whether that needs a little buffing. I
30   mean, very tough, admittedly a tough subject and that's why it's often
31   left out.
32                DR. BLUMBERG: We tried to avoid that because of the IB section by
33   Dan, but we can do that.
34          DR. JAMES: Well, is it - I'm not sure. Is it there, Dan? Yes, per
35   se. I just wondered if there was enough there to -
36          DR. PODOLSKY: It gets to sort of one of the thematic questions
37   we've had through the day, you know, what needs to be added up and is a
38   cross - an issue versus in this case inflammation disorders, IBD being
39   one of those disorders. Every organ really having - inflammation is one
40   of the key -

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. JAMES: Yes, so maybe it's just inferred that because it
 2   touches almost everything that there really is a lot there, it's just
 3   not all captured in one bucket called inflammation.
 4          DR. PODOLSKY: - one or two highly concise ways in which we
 5   reference the inflammatory, not just the immune aspect.
 6                DR. BLUMBERG: I can do that. That's no problem.
 7                DR. JAMES: Should just add inflammation whenever there's
 8   immunity.
 9          DR. PASRICHA: It's a very difficult task, Rick. Congratulations
10   on doing it so well. Some specific questions and some general comments.
11   First, we talked about the enteric microbiota. We talked about the role
12   in pathogenesis and we talked about probiotics treatment, but there's
13   also literature on actually genetically manipulating them for
14   therapeutic purposes. I want to - when we started this commission Steve
15   gave us the charge go wild, think beyond and maybe that's something that
16   is a very smart point.
17          DR. JAMES: I didn't say that. I'm very conservative. It was Dr.
18   Zerhouni who said don't let there be any barriers to your thinking. He
19   doesn't have to write this report.
20          DR. PASRICHA: The other thing that I think today we missed, and I
21   think the chapter was deleted, but we really haven't perhaps emphasized
22   something like diabetes in the GI tract. It didn't come out.
23          DR. JAMES: Well, I guess the issue of how diabetes affects, it
24   overlaps and relates.
25          DR. PASRICHA: It is many themes there, but it is a disease big
26   enough to warrant some special discussion.
27          DR. LIEBERMAN: I'll make a comment on that because I was involved
28   with the decision to do away with the other. We felt that the principal
29   manifestations of diabetes are going to be motility issues in the gut
30   that would be handled by the other group and so I guess my suggestion
31   would be that as we think through the motility issues that we make
32   certain that diabetes is included in that. I mean, that was my sense.
33                DR. JAMES: Yes, and then there are others. For bariatric surgery
34   it's an obvious issue for therapy.
35          DR. LIEBERMAN: Obviously for bariatric surgery, but that's - yes.
36          DR. JAMES: The other is a little more subtle and that is because
37   weight gain and obesity are linked at the hip to the pathogenesis of
38   Type II diabetes that in fact there is a lot here that's highly relevant
39   to diabetes, we're just not calling it diabetes research. But in fact
40   that could be highlighted that a lot of the - in reverse, the issues

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   about transport and nutrition and so forth and digestion, feeding
 2   behavior, GI hormones, all this can relate to overweight and diabetes
 3   all the way through to potential therapies. So that could be built in.
 4   I'm not sure we want to carve out a separate chapter.
 5          DR. PASRICHA: Could I just add to that? There was a recent paper
 6   in Cell a few months ago that showed the role of nerves to the pancreas,
 7   pancreatic nerves, in particular Trip-B1 receptor bearing nerves. The
 8   role of pancreatic nerves in the pathogenesis of diabetes and that if
 9   you knock out the analyte receptor on the pancreatic nerves you can
10   actually prevent. So there's a lot there that I think -
11          DR. JAMES: It's pretty clear we decided not to include the
12   endocrine pancreas as part of our mission because -
13                DR. PASRICHA: I'll tell you why it's important. Because nobody is
14   studying pancreatic nerves in the pancreas, endocrine or exocrine,
15   period. And so it's something that falls in the gap, but it does
16   actually come into the purview of the enteric nerve system and spinal
17   nerves and so on. So it's something that I think is worth emphasizing.
18          DR. JAMES: I think you know, we could end up going too far
19   afield. If we include one really major disease such as diabetes, well
20   why not heart disease? Why not Alzheimer's? Why not, you know. Then the
21   list could grow of all the things that these important areas of science
22   might touch. I think you do have to put some kind of limits on how far
23   you want to go. I think for important ones like diabetes they can be
24   mentioned certainly as the important relevance.
25          DR. PASRICHA: And just to be provocative, another area that we
26   haven't touched and I don't know if it falls under, but I think it's
27   going to have a lot of importance in the future is visceral fat and its
28   relationship to GI organs. It's not something that we've talked about,
29   but at some point that's going to emerge as an important GI organ. I
30   know it's not viewed as that as such right now, but it might come out to
31   be that. It's a big source of a lot of things here, yes. And the neural-
32   hormonal connections to the gut are probably more intimate than anything
33   else.
34          DR. JAMES: Again, consciously, although we have clearly included
35   some obesity-related topics, preceding this commission there already is
36   a trans-NIH working group on obesity with its own plan and report. And
37   we sort of thought maybe we shouldn't go too far -
38          DR. PASRICHA: I think these things should be mentioned in your
39   chapter so that five years from now we don't all look back and say hey,
40   we should have put that in.

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1          DR. JAMES: Fair point. But you could also mention that the
 2   nervous integration in the pancreas in your chapter too. John.
 3          DR. CARETHERS: It's too bad the primate facility at the NIH is
 4   scheduled to close because you mentioned about primates.
 5          DR. JAMES: Actually, I had a question. I hate to ask, get into
 6   real science, but why primates? I'm not so sure if you had a robust
 7   biomarker of effective vaccine response in humans and you could do it
 8   with testing, why - it's so much easier to do research in humans than
 9   primates. Why not do it in humans?
10          DR. BLUMBERG: Safety issues. This came out of - this is Warren's
11   recommendation. I know that he's working on it cleverly with Dave
12   Margosky on an HIV vaccine right now.
13                DR. JAMES: Well, I think this gets into the international issues
14   of scientific research that certainly might be true I guess of vaccines
15   in the U.S. because of Alzheimer's and everything else. But most
16   countries of the world I think vaccines go into humans pretty quickly.
17          DR. CARETHERS: I was just going to finish my point.
18          DR. JAMES: Sorry.
19          DR. CARETHERS: Sorry. So just it will be very quick. So we talk a
20   lot about the microbiota and that infers bacteria. Is there any talk of
21   viral presence in the gut?
22          DR. JAMES: Yes. Actually people talk of - it's just shorthand
23   because clearly at the - we had a big internal workshop. It means all
24   living things that aren't you that might be in your flora. Yes.
25   Periodically people remind - Mary Estes reminds us of viruses.
26          DR. BLUMBERG: In her full report she put it in there.
27          DR. JAMES: Other issues? We should turn to - oh, okay. Raj.
28          DR. GOYAL: Maybe I dozed off, but you elegantly covered all the
29   cell types in the gut, but somehow I thought the discussion about
30   primary diseases of the smooth muscle in the gut was lacking, or at
31   least was very little. To be sure there have not been real major
32   advances in smooth muscle of the gut in the last five years, but the big
33   issues still persist like what are sphincters, how do they develop, what
34   are the phasic muscles, how do they develop, and also their
35   biochemistry. That is very well understood - or not understood, but
36   being investigated in vascular smooth muscle. But my point is that maybe
37   somehow we should cover it.
38          DR. BLUMBERG: That's a good point Raj and I'll make sure I get it
39   in there.
40          DR. JAMES: I think the smooth muscle certainly was mentioned and

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   of course the relevance to motility disorders. Yes.
 2          DR. SANDERS: I think that's a really good point and in the lung
 3   and in the vascular system both there's this enhancement of calcium
 4   sensitization that goes on in inflammatory responses and I think that's
 5   a really important topic.
 6          DR. BLUMBERG: But in your section when you talked about an
 7   opportunity - I'm sorry. So Ken, when you were - in your report when you
 8   talked about tunica propria, that presumably will deal with Raj's
 9   concern that we're not omitting that.
10          DR. SANDERS: Yes. I mean we had something about that, but I do
11   think something in the overview would be really good -
12          DR. BLUMBERG: Okay.
13                DR. SANDERS: - to talk about, the smooth muscle biology
14   specifically because we wouldn't be necessarily covering that in you
15   know in really great detail.
16          DR. BLUMBERG: I can make sure that it's in there. Yes.
17          DR. GOYAL: Big thing is about sphincters. For example, we really
18   know very little because there have been no studies done what is a tonic
19   muscle as opposed to a phasic muscle. And also, all the myopathies that
20   are responsible for intestine pseudo-obstruction syndrome, and there are
21   many of them. They are not common, but they are there and I think
22   probably we should try to cover.
23          DR. BLUMBERG: I'll make sure of that.
24          DR. JAMES: Good points. Some though belonging probably in the
25   functional.
26          DR. SANDERS: I mean even something as basic as calcium-handling
27   by smooth muscle. There's some shocking things in the recent literature
28   about how smooth muscle cells get calcium. And I mean it's amazing that
29   stuff like this still exists, but it does.
31   Preparation for Day 2 and Adjournment
33                DR. JAMES: Okay. Is that why calcium channel blockers cause
34   constipation for people with hypertension? Do we know? Okay. Is that it?
35   Thank you. Tomorrow. Tomorrow. So just to - we're going to start at 8
36   o'clock. I think we should, despite the pain, with coffee in the morning
37   and everything probably go through each chapter very briefly, what, five
38   minutes? Really just to see if - to list what you think are the most
39   important shall we say long-term goals I think, or categories of goals,
40   or in particular if there are things you want to put in or were left out

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   that belong there. Because again, I think what we want to take away from
 2   this is something that people can actually start to write text around
 3   and so we'd like to get as close to that as possible by the end of the
 4   day.
 5          Then there are some other issues. We want to talk about two other
 6   things that we agreed would go in the report. We talked about it today
 7   somewhat and that is training and career development, and also
 8   information transfer. And I'm not even sure we completely defined what
 9   we mean by that. And then the other are truly - how we'll handle the
10   truly overarching things that are so common to nearly every chapter.
11   Will we put that in an executive summary? Will we put that in a separate
12   chapter on overarching themes? Or both? And if so, who will put that
13   together? And that kind of issue. Were there other things we needed to
14   cover tomorrow? I think that's - hopefully this really will go on time.
15          The other thing we could attempt, not mandatory, is if anyone
16   wants to volunteer what they think really are the most important goals,
17   that we could see what the sense of the group is and whether that's even
18   achievable, I mean without duress, without twisting of arms. So I mean,
19   it may be clear that there's little to no agreement on hardly anything,
20   but typically when you do these exercises tell me three most important
21   goals, there will be - and everybody gets there, there are going to be
22   one or two that really seem crosscutting and recurrently come up.
23   Microbiome maybe, genetics, maybe a few other things. And these would be
24   - what that would tell us is it's very clear that in our final executive
25   summary and overarching themes that has to be included. And I'm not
26   sure, are there other administrative issue? We could talk a little bit
27   about then - we talked about challenges I think enough today that we
28   have some ideas about the things that will be recommended to actually
29   achieve these goals. We could talk about the next meeting, and what we
30   would like to do at the next meeting, and the timeline for what we plan
31   to do over the summer and would want to do at the next meeting. Yes,
32   Dan.
33                DR. PODOLSKY: Maybe it would be helpful if you could again get
34   back to what we really want to achieve or what do you want us to achieve
35   in the five minutes, you know, including self-referential. I think what
36   we learned today is that it takes us five minutes to clear our throat
37   you know one each one of these topics. And so the question is is it
38   really - I mean, what are we attempting in going back -
39          DR. JAMES: Well, maybe it's too hard. You're right, maybe that's
40   little time. Maybe -

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1                DR. HAMMOND: Well, we've got 10 minutes.
 2                DR. JAMES: Ten minutes? Maybe we could have people - can they -
 3   do you all have access to a laptop? Most of you? You have laptops here?
 4          DR. HAMMOND: Yes. We have five extra laptops you can check out.
 5   But the idea perhaps is within 10 minutes tomorrow you could list what
 6   you think are the most important goals that you heard yesterday in
 7   discussion, but also what has moved out of your group so you can see
 8   where it's going, what have you picked up, just so we can see that we
 9   have the essential goals which would then drive the challenges and so
10   forth for your writing. It doesn't mean you go through everything to
11   make sure -
12          DR. JAMES: I think if they're listed and we could see them and
13   maybe if we could even have handouts made?
14          DR. HAMMOND: I don't think we'll have time, but we'll load
15   everything back on.
16          DR. JAMES: You won't have to describe them, but they'll be there.
17          DR. PODOLSKY: So what would do is essentially highlight the
18   edits?
19          DR. JAMES: Yes.
20          DR. HAMMOND: That would be good. The edits. What has changed.
21   That's a good - what has changed since yesterday. You might show the
22   organization not in a timeline like, in terms of short-term, long-term,
23   but in topic and you might show basically what has been deleted, what
24   might be going to an overarching goal. But just the edits.
25          DR. PODOLSKY: If we manage the time enough to go beyond other
26   things and describe I think it might be helpful if we can get back to
27   this issue of you know, have some consensus around what's the level of
28   granularity that we really want to hit. Because I think - and they
29   weren't wildly, but there's a fair range here.
30          DR. JAMES: Yes, I think you raised the issue what do we want the
31   final report to really look like because I think most people would agree
32   we want it to have a sort of common look and feel so it doesn't look
33   like it was written by 40 people. We know what those things look like.
34          DR. PODOLSKY: I mean, I think we should all be generally at
35   30,000 feet or 5,000 feet you know. If that's - what's the right plane
36   that this report needs to be hitting to be an effective vehicle?
37          DR. JAMES: I think clearly one should be able to pick out of this
38   big goals. I think you had two big goals at the beginning which is take
39   care of diseases when you've got one and prevent one if you're at risk.
40   Now that sort of model is going to apply to most diseases. Maybe that's

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   too simplistic. But then you add sort of like six or eight thematic
 2   areas to try to reach that ultimate goal, and maybe that's the level of
 3   granularity. And beyond that I think that you can have a variable level
 4   of detail. You had, you know, six to ten bullets or so that went with
 5   each of those big themes, but I think that it has to be pared down from
 6   45 goals, those of you who have 45 goals, to pare it down to a much more
 7   workable sort of. It's not really - the sky high view would be I'm going
 8   to cure diseases and I'm going to prevent diseases in people at risk.
 9   That's probably too global. I think the much more detail about goals
10   that are relevant to the topic area at the level of six to eight to ten
11   probably sounds right. Does that make sense? We could discuss it now.
12   But you're right, I think we should settle that.
13                DR. PODOLSKY: - discussion about where in that, or you could make
14   a debate maybe there should be a lot more detail. And I think we should
15   all be somewhat in the same ballpark.
16          DR. JAMES: That's true.
17          DR. PASRICHA: I think - sorry. Relevant to this in terms of final
18   presentation within those chapters, are some chapters going to be
19   emphasized more, themes going to be emphasized more than others? I mean
20   you know, if somebody came up with 20 goals versus five goals, is that
21   going to get weight in the final presentation? I mean, it's something
22   that also needs to be factored in. I think that's a concern too. You
23   don't want your disease area to be neglected.
24          DR. JAMES: That's right. My view all along is that this exercise
25   should be all-encompassing. There's no particular reason to exclude
26   anything. But on the other hand for it to be workable it has to be at a
27   manageable level of detail. So I don't think this should be an exercise
28   about one area is competing against another for recognition or - I hate
29   to use the "funding" word, that kind of thing. I don't see it as that
30   kind of exercise. I think it should be casting a broad net to try to
31   capture as many areas that are highly relevant and will demonstrate how
32   robust digestive disease research is, how many areas of science we're
33   bringing to play, how many other areas we'd like to bring into digestive
34   disease research. I think it's a very positive exercise and I don't
35   think we want to be trying to exclude areas certainly in any kind of
36   arbitrary fashion. But still do it in a workable - my test of - you
37   should be somebody - there will be people who will be asked to give a
38   20-minute presentation of what did this thing say. Some people might
39   have the luxury of having 45 minutes to present it. Some people who -
40   many people who will read the executive summary only and others who will

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   read the area, the chapter that's only in their area and nothing else. I
 2   think a good report will be satisfactory to all of the different groups.
 3   Some people, we might have charts of interactions and overlaps. Some
 4   people love those things and go right to those. So I think that NIH
 5   administrators will be looking for, gee, what are areas that I need to
 6   work on in my institute and my program that seem fertile for
 7   development. So the better you can target the needs of all the different
 8   communities for what they would like to get out of it, that's a good
 9   report. But still within a workable number of pages.
10          DR. SANDERS: But you make a really good point there because some
11   people may only read one chapter that's relevant to their own thing so
12   that's why some of these overarching themes have to be reiterated
13   chapter to chapter.
14          DR. JAMES: Yes. I think - I thought it was pretty clear that
15   overlap is good, it's not bad and that because of this issue that
16   somebody studying functional bowel disease is probably going to want to
17   know what has this report got in it and they probably aren't, people
18   being very busy, aren't going to read the rest of it. So if it's not
19   there, they'll just say gee, how did they leave that out. No matter how
20   much you cross-reference in the little footnotes saying see Chapter 3
21   and see Chapter 5, it doesn't really happen that effectively.
22          DR. LIEBERMAN: Steve, can I make a suggestion for tomorrow?
23          DR. JAMES: Yes.
24          DR. LIEBERMAN: That I think would at least be useful for me. I'd
25   be interested to know what the others think, is if each working group
26   leader presented somewhere between six and ten goals, but then had to in
27   their own view list their top three plus one overarching theme and then
28   see if the group agrees with that. I think as long as we've got
29   everybody here that gives -
30          DR. JAMES: I think we'll do this as a - this is a typical thing
31   for strategic planning - exercises is to do this. It's very informal.
32   You're not - you won't - I guess we are recording it. It is a public
33   meeting, but because we've exhausted the public and but I think it is a
34   very useful exercise just to do a straw vote, you know sort of a test to
35   see are there - I think there will be clearly themes that will drop out
36   as being no-brainers for overarching things. Yes, Joanne.
37          DR. WILSON: I just had one question. I noted that for instance
38   Barbara did two presentations that were very different because the
39   topics were so different. Now, within those two organizations it would
40   be very hard for instance in the one that's outlined more like mine with

                           NEAL R. GROSS
                          1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433       WASHINGTON, D.C. 20005-3701

 1   the multiple different topics to pick six - I mean, there would be one
 2   goal per subsection.
 3          DR. JAMES: Yes. Well, just my own strategic way of looking at it
 4   is that those of you who dutifully followed our directions and had
 5   short-term, intermediate- and long-term carefully integrated is to look
 6   first at if they are integrated to look at the long-term goals. Because
 7   if you state very effectively a long-term goal you're not going to leave
 8   out the concepts of what would be needed, the incremental steps to reach
 9   that goal which are probably going to be short-term and intermediate
10   things. It's true it's a problem if you have an intermediate thing and
11   it only appears in the intermediate and nowhere else, but it's an
12   important goal, and you would have to look carefully. In looking at
13   these, many of them are structured that if you just look at the long-
14   term goals you're likely to capture the very important things.
15          DR. WILSON: Can I pin you down on that? Do you want a goal, or do
16   you want - you want goals. You don't care about the time horizon for the
17   goal.
18          DR. JAMES: Yes. That's right. In fact, the best goal of all is
19   one that we could do within a year.
20          DR. WILSON: Because some of the short-term goals seem to be the
21   most like immediate and doable and it's just like why haven't we done
22   this already.
23          DR. JAMES: Well I think, again to echo Dr. Zerhouni's charge,
24   that is to think long and hard and aim high, and that the test for an
25   important goal shouldn't mean that I'll be able to do this for sure this
26   year and put it in my progress report and it's a no-brainer. So that's
27   the way administrators think is I'm going to put down all the goals.
28   This is like doing my performance review plan. I only put in my
29   performance plan of what I'm going to do in the next year the things I
30   have actually already done. Well, we don't need to do that. I think we
31   can aim high and be somewhat ambitious. But it's clear, I mean we don't
32   want to miss the low-hanging fruit either.
33                DR. PASRICHA: So, I just wanted to clarify my question. I just
34   want to make sure that this report will not - or is it going to be used
35   by the NIH or the Congress to allocate resources or prioritize within
36   the digestive disease portfolio?
37          DR. JAMES: Yes, so that's a very good question and I can answer
38   to the extent that federal officials are allowed to which is that in
39   general the Congress, although we show pie charts of funding for
40   digestive diseases, the great bulk of that is - first of all, there are

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   not appropriations for digestive diseases. We talk about dollars that
 2   are awarded, we never talk about dollars that are appropriated because
 3   there are only appropriate dollars for certain types of diseases. Cancer
 4   I guess is one of them. There are appropriated dollars for Type I
 5   diabetes, but generally within the mission of most of the institutes
 6   such as NIDDK, the intermediate-sized ones we get a big chunk of money
 7   that is not appropriated in any kind of micro detail for specific
 8   diseases. And in general the research community supports that approach
 9   as being this is the way - that this supports investigator-initiated
10   research, largely RPG mechanisms and that everybody always gets
11   suspicious when you have targeted funding that's directed top down as to
12   whether that's going to get the most bang for your buck. So in general
13   the Congress has gone along with what the research community has
14   continually emphasized which is the great importance of investigator-
15   initiated research, and that's why we don't have. So the commission can,
16   or anybody can advocate for whatever they want and typically people
17   advocate for more research for their own disease, but in general that
18   does not get turned into an appropriation for specific diseases with
19   some exceptions. So I'm not sure. You'd have to think hard about whether
20   that's what you really want.
21          I think in general the biggest impact of these sorts of things on
22   Congress, what they look for is things that are new and things that
23   relate to improvement in health of the public. Those are the overarching
24   things. They don't like to see - I'm not sure I should say. They're not
25   quite as enamored for doing more of what we did. Well, we did the
26   doubling before, we should do it again. They want to see new, high-
27   profile things that will be achieved I think. That's my view. My
28   personal interpretation. I would envision a good report like this could
29   be used by many different groups for different purposes, including for
30   other independent organizations to see how it might complement their own
31   planning.
32                DR. PODOLSKY: It seems to me there's also an intermediate point
33   of view. We don't have a report which ends up being a series of the
34   proprietary - around varied areas, but in the aggregate it's for
35   digestive diseases as a major source of morbidity, some mortality and
36   poised for significant leaps, steps if not leaps forward you know along
37   a number of - that we've already identified. So I think that in the
38   balance between earmarks or you know mandates that go along with those,
39   being very important thing to be cautious of.
40          DR. JAMES: Yes. I think - I mean, the hope for a concept of

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   course is that you'll make such convincing and powerful arguments that
 2   you know the whole ship rises. Everybody comes out ahead. Probably not
 3   hope for approaches that we make such convincing arguments or a few are
 4   picked up for certain things saying - and they become mandates, but you
 5   don't get any more money to do them. And of course that doesn't
 6   necessarily help very many people. So again, I think to take the high
 7   road which is what I generally we think we're supposed to do with the
 8   Congress is to point out as scientists what we think are the most
 9   important things to do and let the politicians do the politics - that's
10   not our role - with how to sort out funding. In general, the support of
11   NIH from the Congress has been largely non-directed. The usual opinion
12   is that the professionals should be figuring out how to use the money.
13                DR. PASRICHA: So from our perspective it would be very helpful
14   for the digestive disease section rather than the NIDDK to get a bigger
15   overall budget so that you guys can decide how to.
16          DR. JAMES: That's very interesting. Our own particular institute,
17   like many, does not have divisional budgets. There's one budget for the
18   institute and that most of the funds are divided up according - by
19   competition directed by peer review. So you might say well, what we
20   really want to do is help our investigators to be more competitive in
21   the study sections where they're reviewed and that's -
22          DR. PASRICHA: I'm sorry I'm belaboring this point, but I just
23   want to understand in concrete terms. So is it a feasible goal that if
24   we put together a really good report, and this is where actually the -
25   disease probably becomes very important, becomes in terms of convincing
26   the Congress of the importance of this area as a whole. Is it feasible
27   that after receiving the report this - even if the overall NIH budget
28   stays the same there is a mechanism by which to divert more money to the
29   NIDDK?
30          DR. JAMES: Yes. So each institute gets a line-item budget. In
31   fact within the line are multiple lines, four or five categories of
32   things. So yes, there are minor tweaks, but largely if you look at how
33   the budgets come it's pretty much incremental changes across the board
34   with some small variations for specific things. A big example would be
35   biodefense caused a big jolt and a very specific change largely in one
36   institute. But in general that doesn't happen too much. But of course
37   more money is always better in terms of what to work with. These reports
38   are useful internally to all of the institutes for which they're
39   relevant for people who plan initiatives. I mean, when there is flexible
40   money that becomes available for planned things then this of course

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

 1   provides a lot of the groundwork for the things that people turn to for
 2   pointing to this as being important and that there is a momentum behind
 3   it and that there's interest in the scientific community to do these
 4   things. We have to have this kind of ammunition. As a program person we
 5   can't simply go to a director and say well, I think it's a good idea
 6   that we should study the microbiome. You have to have a big process
 7   behind that to show there's a momentum and community interest in
 8   actually doing it. So these reports have many uses. I wouldn't minimize
 9   how important they are. I think they're very important. Any other?
10          DR. HAMMOND: Just a quick point. You may want to take a look at
11   the flip charts for your group. Michelle tried to capture some of the
12   highlights of the discussion and Michelle is here to interpret it if you
13   have any questions about that. So that could be useful. So I think that
14   we - we'll use the strategy that Dr. Lieberman had suggested with the
15   top goals tomorrow.
16          DR. JAMES: Yes.
17          DR. HAMMOND: Okay. And we'll actually start at 8 o'clock
18   tomorrow. The room will be open at 7 o'clock though for refreshments and
19   registration.
20          DR. JAMES: And can we leave anything here or not?
21          DR. HAMMOND: I think we can leave things in the room. Is that
22   correct?
23                DR. JAMES: Like books and things?
24                DR. HAMMOND: Yes, I think the room will be locked.
25                (Whereupon, the foregoing matter went off the record at 7:04
26   p.m.)

                               NEAL R. GROSS
                           COURT REPORTERS AND TRANSCRIBERS
                               1323 RHODE ISLAND AVE., N.W.
     (202) 234-4433            WASHINGTON, D.C. 20005-3701

To top