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VO LU M E 6 N U M B E R 3 | FA L L 2 0 0 9 From Research,The Power to Cure InsIde > D iA B E t E s RE s EARc h >B URNh AM N Ews >Phi L ANth ROPy the Quest to Cure Diabetes BUrnham REPORt iN this issUE Founders Trustees, continued wi LLiAM h . Fish MAN, Ph.D. Alan Gleicher BURNhAM REsEARch LiLLiAN Fish MAN W.D. Grant honorary trustees David Hale The Quest to Cure Diabetes 1 Jeanne Herberger, Ph.D. JOE LEwis Diabetes and its Consequences 3 Brent Jacobs c ONRAD t. P REBys James E. Jardon II (Florida) A National Quest 5 t. D ENNy sANFORD Daniel P. Kelly, M.D. trustees and Officers Robert J. Lauer BURNhAM NEws MALi N B URN hAM Sheila B. Lipinsky Chairman Gregory T. Lucier The View from Lake Nona 7 JO h N c. R EED , M.D., Ph.D. Papa Doug Manchester President & Chief Executive Officer Robert A. Mandell (Florida) Science News 8 Professor and Donald Bren Nicolas C. Nierenberg New Faculty 11 Presidential Chair Douglas H. Obenshain G ARy F. R Ais L, E D.D. Peter Preuss Collaborations 13 Chief Administrative Officer John C. Reed, M.D., Ph.D. Treasurer Stuart Tanz PhiL ANthROPy MARG ARE t M. D UNBAR Jan Tuttleman, Ph.D., MBA Secretary Andrew J. Viterbi, Ph.D. Burnham Welcomes Julie Johnson 14 Kristiina Vuori, M.D., Ph.D. trustees Bobbi Warren Lake Nona Events 15 Linden S. Blue Allen R. Weiss (Florida) La Jolla Events 16 Mary Bradley Judy White Brigitte Bren Gayle E. Wilson Arthur Brody Diane Winokur AROUND BURNhAM Malin Burnham Kenneth J. Woolcott Howard I. Cohen President’s Message 17 Ex-Officio Shehan Dissanayake, Ph.D. Partners in Science 18 M. Wainwright Fishburn, Jr. Raymond L. White, Ph.D. Jeannie M. Fontana, M.D., Ph.D. Chairman, Science Advisory Committee ON thE cOVER B L Ai R B LUM JO sh BA xt Drs. Timothy Osborne, Senior Vice President Editor, Burnham Report Stephen Gardell External Relations G AVi N & G AViN and Daniel Kelly are ELiz ABEth Gi AN iNi ADVERtisi NG committed to finding Vice President Design External Relations new ways to treat type Mic h AEL cAiRNs 2 diabetes and related EDG AR Gi LLENwAt ERs MAR k DAst RUP Vice President NAD i A BOROwski sc Ott diseases. As director of External Relations Photography the Metabolic Signaling c hR is L EE kEN G. c OVENE y, Esq. and Disease Program, Vice President FAB iAN V. Fi L iPP, Ph.D. Dr. Osborne wants to External Relations Contributors illuminate the normal signaling mechanisms that control ANDREA M Os ER Please address inquiries to: metabolism and how those signals differ in diseased tissue. Vice President firstname.lastname@example.org Dr. Steve Gardell directs Translational Research Resources, Communications www.burnham.org which seeks to move basic research findings from the labo- Burnham Institute for Medical Research ratory to the clinic. Scientific Director Dr. Daniel Kelly 10901 North Torrey Pines Road, La Jolla, CA 92037 • 858.646.3100 investigates cardiovascular disease and wants to expose its Burnham Institute for Medical Research at Lake Nona different causes and discover new treatments. 6400 Sanger Road, Orlando, FL 32827 • 407.745.2000 BUrnham DiABEtEs REsEARch the Quest to Cure Diabetes Pancreatic beta cells – photo by Ifat Geron, Levine and Itkin-Ansari laboratories In 1922, insulin was first reduces lifespan, on average, Though treatments for autoimmune disorder, in which administered to treat by seven to 10 years. both forms of diabetes have the body’s immune system type 1 diabetes, trans- Type 2 diabetes—a quite advanced, cures remain attacks and destroys beta cells, forming a deadly disease different disease—is associ- elusive. At Burnham, signifi- which monitor blood glucose into a chronic one. But ated with obesity and is fast cant work is being done on and release insulin. In type 2 insulin is not a cure. becoming an epidemic in the both coasts to understand diabetes, high levels of fatty United States. While type 1 these conditions and find new acids attack beta cells. As beta results from a lack of insulin, treatments. cells die, glucose accumulates Periodic blood sugar moni- type 2 appears when cells in the blood, leading to deadly toring and insulin injections lose the ability to respond MAkiNG N Ew iN sULi N- complications. However, if cannot match the 24/7 effi- PRODUciNG cELL s to insulin (See box, page 3). we could transplant or renew ciency of insulin-producing Both type I and type II According to the American beta cells, the body could once beta cells. According to the diabetes are caused by a Diabetes Association, more again produce its own insulin. Juvenile Diabetes Research deficiency of the cells that than 23 million people have Currently, beta cells are Foundation, type 1 diabetes produce insulin. Type 1 is an diabetes, mostly type 2. transplanted from cadavers w w w. b u rn h a m . o rg | T h e BU r n h a m r e p o r T 1 BUrnham DiABEtEs REsEARch biology, we may find thera- peutic targets where you add a drug or apply gene therapy to encourage the body to regen- erate the cells.” The Dong laboratory, which uses zebrafish as a research model, is also trying to encourage pancreatic exocrine cells, which produce digestive enzymes, to become beta cells. “They come from the same precursors,” says Dr. Dong. “We found that a particular gene helps decide the fate of these precursors. We hope that, by manipulating this gene, we can help make more beta cells.” Dr. Fred Levine chats with postdoctoral fellow Dr. Seung-Hee Lee Taking a different but quantities are very low. we made turned out to be ideal screening, Dr. Levine’s labora- approach, Alex Strongin, Fred Levine, M.D., Ph.D., for high-throughput screening tory is also pursuing other Ph.D., is interested in what directs the Sanford Children’s to search for drugs that affect avenues. What if adult stem happens if the immune Health Research Center beta cells. This project, done cells, or mature endocrine system can be selectively and is trying to solve the in collaboration with Burnham cells, could be transformed blocked. Dr. Strongin studies problem of making new beta investigators Drs. Mark into beta cells? Dr. Levine is an enzyme that helps inva- cells—either outside the body Mercola, Pamela Itkin-Ansari collaborating with Burnham sive cancer cells migrate to for transplantation or by acti- and Jeff Price, as well as the stem cell scientists, such as Dr. other parts of the body. The vating adult stem cells within Conrad Prebys Center for Alexey Terskikh, to understand enzyme, called MT1-MMP, the pancreas. Chemical Genomics, has the genes that induce adult is a proteinase, a protein “Our initial intent was to been a long road but has stem cells in the pancreas to that cuts up other proteins. make a cell line that would recently borne fruit, with become functioning beta cells. MT1-MMP interacts with a mimic beta cells so well they a number of compounds cell surface receptor called could be transplanted,” says Dr. entering preclinical trials.” POssiBi Liti Es iN CD44, which plays a number REGENERAtiON of roles in cancer cells and Levine. “While that goal proved In addition to the studies Like Dr. Levine, Duc Dong, autoimmune T cells—the overly ambitious, the cells that with high-throughput Ph.D., is trying to regenerate culprits in beta cell destruc- beta cells from cells that tion. Dr. Strongin has found Dr. Levine is collaborating with already exist in our bodies. that inhibiting MT1-MMP Burnham stem cell scientists, such as Dr. Alexey “Usually in diabetes there keeps T cells out of the are a few beta cells left,” pancreas. Terskikh, to understand the genes says Dr. Dong. “How can “We found that if you stop that induce adult stem cells in the pancreas to we replenish them? If we the killer cells from getting become functioning beta cells. understand the developmental into the pancreas, it gives beta 2 T h e B Urnham repor T | www.burnham.org BUrnham DiABEtEs REsEARch cells the opportunity to regen- system must be controlled. erate,” says Dr. Strongin. Current transplant recipients The tricky part is finding must take immunosuppres- the right inhibitor. Dr. Strongin sive drugs to prevent their T notes that an MT1-MMP cells from attacking replace- inhibitor has failed in clinical ment beta cells, presenting a trials for late-stage cancer. To stark choice between diabetes be useful, the compound must and a suppressed immune be minimally toxic. system. “We would have to develop Recently, Burnham a less toxic inhibitor because adjunct professor Pamela patients would be taking it for Itkin-Ansari, Ph.D., placed the rest of their lives,” says pancreatic precursor cells Dr. Strongin. “It’s one thing in an immunoprotective to have a toxic treatment for device and transplanted them cancer and another entirely into mice. She was testing for diabetes, where insulin whether precursor cells would is an effective treatment. So, mature into productive beta there’s still a great deal of cells in the body and whether Dr. Duc Dong in the zebrafish facility work to be done.” the protective device, made from a material akin to the immune system rather glucose and produced insulin P ROt Ec t iNG c E L L s Gore-Tex, could prevent than suppressing the immune and the immunoprotective F RO M t hE i M M U N E system,” says Dr. Itkin-Ansari. device kept the immune the immune system from systE M attacking transplanted cells. Early studies have been system at bay. For transplantation to be a “We wanted to see if we very positive, as the trans- “We are excited to see viable treatment, the immune could protect the cells from planted cells responded to how well they did,” says Dr. Diabetes and its foreign and destroy them, reducing or eliminating cells, which ultimately fail and die. Consequences insulin production. High circulating glucose In type 2 diabetes, the levels damage cells. Because problem is with the insulin glucose moves primarily receptor—the lock that through blood, the cells Insulin is produced in the cells and telling them to let allows glucose to enter. For lining blood vessels are the pancreas by beta cells, which glucose inside. reasons that are not clear, most severely hurt. These measure glucose (the main In type 1 diabetes, beta the receptor mechanism consequences extend to source of energy from food) cells are destroyed by the does not work properly, virtually every organ in the in the blood and secrete body’s own immune system. even when insulin is body. Diabetes is a leading insulin to control glucose White blood cells that present. The body responds cause of blindness, kidney concentrations. Insulin acts ordinarily protect us from by producing more insulin. disease, amputation, heart as a key, binding to recep- bacteria and viruses mistak- While that works for a disease and many other tors (locks) expressed by all enly recognize beta cells as time, it overworks the beta conditions. w w w. b u rn h a m . o rg | T h e BU r n h a m r e p o r T 3 BUrnham DiABEtEs REsEARch play a role in insulin resis- fat is linked to higher blood tance and fatty liver disease,” pressure and triglycerides says Dr. Wood. and makes that person a Given that recent statis- candidate for heart attack, tics show a third of Americans diabetes, or both,” says Dr. are obese, the research being Wood. “Visceral fat tissue done by Dr. Wood and others leaks fatty acids, which go could have a profound impact to the liver and cause fatty on the nation’s health. One liver disease, enter the key focus is the underlying blood as triglycerides and genetics that make certain also cause inflammation. people susceptible to disease. The most disturbing part is “We’re not likely to find that today’s children may be specific genes that cause the first in history to have a type 2 diabetes,” says Dr. shorter lifespan than their Wood. “Perhaps they exist in parents because of obesity- rare cases, but not enough related diseases.” for a genetic risk assess- While Dr. Wood is ment. We’re not looking for focused on what goes the cause of the disease; wrong for people with type we’re looking at the genetic 2 diabetes, Tim Osborne, and environmental determi- Ph.D., wants to understand Dr. Philip Wood nants of the body’s response the processes that make the to this burden of excess fat. metabolism run normally. Itkin-Ansari. “We could mechanisms behind type 2 Why do some people have “There’s a lot of synergy see evidence of beta cells diabetes, in which insulin a predisposition towards between Dr. Wood’s forming and replicating. That levels are normal (or elevated) means the environment in but cells do not respond to the device was conducive its signals. Scientists want to The most disturbing part is that to beta cells continuing know why insulin resistance today’s children may be the first in to develop and survive. happens in the first place, history to have a shorter lifespan Also, we thought that T how diabetes affects the cells, although unable to heart and the role fat plays in than their parents because of penetrate the device, would diabetes, metabolic syndrome obesity-related diseases. cluster around it. But we and other conditions. found no evidence of an Philip A. Wood, D.V.M., insulin resistance in the face research and mine,” says active immune response, Ph.D., is interested in fat: fat of obesity? So we’re looking at Dr. Osborne. “He comes suggesting that the cells in metabolism, fatty acids, fat the genetics of response, not at it from the disease side, the device were invisible to signaling, fatty liver disease. the genetics of cause.” and we’re interested in the immune system.” Dr. Wood is trying to unravel the On a practical level, Dr. identifying the pathways consequences of too much fat. Wood is particularly concerned that occur normally. If we th E PRO B L E M w ith FAt “I’m interested in how the with visceral fat, the extra can understand the normal At Burnham’s Orlando, body reacts to excess fat and baggage we may have hanging processes and how they go Florida campus, researchers how fat metabolism and the over our belts in front. awry, it will help us find are focused on the underlying genetics of fat metabolism “Excessive abdominal ways to reverse or alleviate 4 T he B Urnham repor T | www.burnham.org BUrnham DiABEtEs REsEARch A National Quest Burnham is committed to uncovering the underlying is more focused on the translational aspects of diabetes. mechanisms behind diabetes and finding new ways to treat Together, we cover the space from the gene, to novel drug it. But the Institute is not alone. Burnham has numerous targets, screens and clinical candidate molecules, followed collaborations, large and small, with organizations around by proof of concept studies in animals and humans. These the country that share our desire to beat diabetes. In partic- are all aimed at delivering innovative cures for diabetes to ular, Sanford Health and the Juvenile Diabetes Research the patient.” Foundation (JDRF) are working with Burnham to cure type 1 Both the Sanford Project and Burnham partner with diabetes. JDRF to accelerate the research. Alan Lewis, Ph.D., is Paul Burn, Ph.D., is professor of Pediatrics at the President and CEO of JDRF, which has funded diabetes Sanford School of Medicine of the University of South research at Burnham for many years. JDRF supports research Dakota and the Broin Chair and director of the Sanford into new treatments, as well as new devices. Project, a venture sponsored by Sanford Health that seeks JDRF is also working to help talented researchers, such to develop new therapies for type 1 diabetes as quickly as as Drs. Fred Levine and Pam Itkin-Ansari, and recruit possible. Dr. Burn notes that the collaboration between young scientists. Burnham and the Sanford Project bridges the gap between “We need to encourage researchers to go into the field basic and clinical research. by giving them seed funding, as well as a sense they can “The capabilities of Burnham and Sanford nicely partner with JDRF,” says Dr. Lewis. “This research takes complement each other,” says Dr. Burn. “Burnham’s time, and we want researchers to know they will have the strengths lie in the early phases of discovery, while Sanford support they need.” the complications of the Osborne. “All these pathways disease itself.” have common nodes. We The collaboration between want to bring this knowledge Drs. Wood and Osborne together to understand how is typical of the Institute’s these mechanisms function.” approach to research— different labs investigate pieces t h E L ANGUAGE OF FAt of the larger puzzle and pool Traditionally, people have their knowledge. As director thought of fat as being a of the Metabolic Signaling relatively passive part of the and Disease Program at Lake body. But fat is no innocent Nona, Dr. Osborne is eager to bystander. Researchers are recruit new scientists who will learning more about how fat carry on that tradition. signals other areas of the “Right now, we are body, including the brain. working to integrate people Devanjan Sikder, Ph.D., is who study various cellular looking at how these signals signaling pathways,” says Dr. can affect both biological Dr. Devanjan Sikder w w w. b u rn h a m . o rg | T h e BU r n h a m r e p o r T 5 BUrnham DiABEtEs REsEARch processes and perceptions incentive to stop eating. This of food. may be one reason why it Dr. Sikder studies the can be so difficult for obese hormone orexin, which people to lose weight.” controls hunger and sleep/ M OV i N G D i s c OV E R i E s wake cycles. High glucose F O R wA R D after a meal reduces orexin Steve Gardell, Ph.D., levels and the activity of director of Translational orexin-producing neurons, Research Resources, came making us feel sluggish. to Burnham Lake Nona to Plunging glucose levels, help move basic science following overnight fasting, discoveries from the labora- elevate orexin, which wakes us tory to the clinic. With more to find food. than 20 years experience in The cyclic waxing and the pharmaceutical industry, waning of orexin appears Dr. Gardell understands the to be perturbed in type 2 challenges of translating diabetes, obesity and even basic scientific knowl- cancer. “Several epidemio- edge into new medicines. logical studies have reported However, he sees many a correlation between lower opportunities in the work Dr. Layton Smith orexin levels and a higher being done at Burnham. burgeoning young discipline provide great clinical benefit incidence of obesity and type “My job is to help shep- to create new diagnostics. with few side effects. 2 diabetes,” says Dr. Sikder. herd some of these incredible “Metabolomics is a “Medicine has done powerful way to identify all the easy things,” says “Metabolomics is a powerful way to disease markers that could Layton Smith, Ph.D. “It’s lead to new tests and early not that difficult to knock identify disease markers that could detection,” says Dr. Gardell. out a protein. Vioxx (an anti- lead to new tests and early detection,” Dr. Gardell will also inflammatory drug that was says Dr. Gardell. be working closely with pulled from the market due Drs. Gregory Roth and to increased risk of heart Layton Smith to screen for attack) is a good example. It Dr. Sikder is also inter- discoveries and check them compounds in the Conrad worked too well because it ested in how leptin affects for clinical effectiveness,” says Prebys Center for Chemical completely knocked out the the brain. Leptin is a hormone Dr. Gardell. Genomics. This pain- Cox2 enzyme. Vioxx created that controls appetite, telling One area where Dr. staking process could lead Cox2-deficient people. So we us to stop eating. Mice Gardell hopes to have a big to new chemical probes to need to create compounds without leptin become peril- impact is metabolomics. illuminate the underlying that work more subtly. We’ve ously obese. Biochemical reactions mechanisms behind disease done the chainsaw; it’s time “Fat tissue produces produce small molecules, and possibly new medicines. for a scalpel.” leptin, which tells us to stop or metabolites, which can One of the targets they eating,” says Dr. Sikder. “But be measured. Dr. Gardell aim for is specificity: finding if you lose weight, the body and others at Burnham are the right chemicals that produces less leptin and hoping to capitalize on this influence the exact protein to you have lost a physiological 6 T h e B Urnham repor T | www.burnham.org BUrnham florIda NEws The View from Lake Nona The landscape outside Burnham has an incredible Dr. Daniel Kelly’s office track record of breaking down at Burnham’s new Lake disciplinary barriers and we plan Nona campus is a work in to continue that tradition.” progress. There is a sandy One area Dr. Kelly wants plain, a few puddles from a to explore is diabetic heart recent rainstorm, trees in disease. He notes that heart the distance. But Dr. Kelly failure is not a single condition sees beyond this temporary that will respond to one-size- sparseness to what Lake fits-all medicines. Researchers Nona will become as new and clinicians need to hospitals, research facilities understand the underlying and a university building distinctions between different spring up around Burnham. types of heart disease, so that Daniel Kelly, M.D., Scientific Director, Burnham at Lake Nona the best treatments can be He sees multiple collabora- prescribed based on a clear can help regulate proteins clinic. As researchers learn more tions leading to new insights understanding of what is going implicated in disease. In about the metabolome (the list into human biology and new wrong in the heart. addition, the Cardiovascular of all metabolites), they can treatments for heart disease, “Diabetic heart disease is Pathobiology program at Lake develop better diagnostic tools. diabetes, cancer and other more aggressive and different Nona will enhance the study of “There are different kinds of conditions. He sees Burnham’s from other forms of heart fat metabolism, type 2 diabetes, cancer, and we are very sophis- basic science and transla- disease,” says Dr. Kelly. “If we heart disease and other condi- ticated in describing them,” says tional research expertise as a follow diabetics after a heart tions. This will be supported by Dr. Kelly. “But in heart failure, critical piece of Lake Nona’s attack and give them the usual the emerging Cardiometabolic we lack the sophistication to burgeoning medical city. therapies—cholesterol lowering Phenotyping Core, which will distinguish between different “This is the perfect environ- drugs, ACE inhibitors—we’ve diagnose cardiovascular disease disease types and causes. We ment to create a truly innovative found that those treatments and metabolic disturbances in just call it heart failure. In our style of research,” says Dr. Kelly. don’t work as well. We’re only small animal models. research, we are trying to reca- “We are already breaking down beginning to understand that Dr. Kelly is particularly pitulate different types of heart the silos that separate physi- heart and vascular disease in excited about the collabora- failure to find the metabolic or cians and basic researchers. The diabetics may have a completely tion with Duke University’s genomic signatures that will Florida Hospital – Burnham different basis.” Stedman Center to establish help us individualize treatment Clinical Research Institute (see a metabolomics core facility. for each patient based on the article, page 13), along with LEVERAG i NG Every chemical reaction in the precise nature of their disease. tE c h NOLOGy our emerging collaborations body produces compounds If we can recognize these signa- One of Burnham’s trade- with the University of Central called metabolites, which can tures, or markers, we will be marks is the strategic use of Florida, M. D. Anderson be measured and catalogued. able to tell whether a person’s sophisticated technologies. For Cancer Center-Orlando, the These markers can help heart failure is more related to example, Lake Nona’s Conrad Stedman Center at Duke physicians detect diseases or diabetes or high blood pressure Prebys Center for Chemical University, the University of metabolic defects and test or heart attack. Physicians will Genomics, like the facility in Florida and others will advance treatments for effectiveness. know the exact condition they La Jolla, will identify small science and bring new treat- Metabolomics provides a link are seeing and that will lead to molecule compounds that ments to patients—faster. between the laboratory and the innovative treatments.” w w w. b u rn h a m . o rg | T h e BU r n h a m r e p o r T 7 BUrnham sciENcE NEws Embryology Study Offers Clues to Birth Defects Gregg Duester, Ph.D., limbs. This research corrects professor in the Develop- longstanding misconceptions ment and Aging Program about limb development and at Burnham, Xianling Zhao, provides new insights into Ph.D., and colleagues congenital limb defects. The have clarified the role that study was published online in Dr. Gregg Duester retinoic acid plays in limb the journal Current Biology on development. May 21. limb patterning but rather is therapeutic or preventative “For decades, it was thought necessary to initiate the limb measures to combat congenital The study showed that that retinoic acid controlled limb budding process.” limb defects, such as Holt-Oram retinoic acid controls the patterning, such as defining By providing a more syndrome, a birth defect charac- development (or budding) of the thumb as being different complete understanding of the terized by upper limb and heart forelimbs, but not hindlimbs, from the little finger,” says Dr. molecular mechanisms involved defects. and that retinoic acid is not Duester. “However, we have in normal limb development, responsible for patterning (or demonstrated in mice that reti- these findings may lead to new differentiation of the parts) of noic acid is not required for ally” disrupted in mice. This showed that transgenic mice, is the first time a conditional in which Has2 was inactivated Has2 knockout mouse has in the limb bud mesoderm, been created, a breakthrough had shortened limbs, abnormal that opens vast possibilities for growth plates and duplicated future research. The paper was bones in the fingers and toes. published online in the journal “Because hyaluronic acid is Development on July 24. so prevalent in the body, it has Drs. Kazu Matsumoto and Yu Yamaguchi HA is a large sugar been difficult to study,” said Dr. molecule that is produced by Yamaguchi. “Systemic Has2 New Insights into Limb Formation every cell in the body and has been thought to play a role in knockout mice died mid-gesta- tion and could not be used to Investigators at Burnham Significantly, these discov- joint disease, heart disease and study the role of hyaluronan in and the University of Connec- eries were made using a novel invasive cancers. Yu Yamaguchi, adults. By inactivating Has2 ticut Health Center (U.C.H.C.) mouse model in which the M.D., Ph.D., a professor in in specific tissues, we give have gained new under- production of hyaluronan is the Sanford Children’s Health ourselves the opportunity to standing of the role hyaluronan blocked in specific tissues. The Research Center at Burnham study the many roles hyal- (also known as hyaluronic acid Yamaguchi laboratory geneti- and Robert Kosher, Ph.D., uronan plays in biology. This or HA) plays in skeletal growth, cally modified the Has2 gene, a professor in the Center mouse model will be useful to cartilage maturation and joint which is a critical enzyme for for Regenerative Medicine study the role of hyaluronan in formation in developing limbs. hyaluronan synthesis, so that and Skeletal Development arthritis and skin aging, as well the gene can be “condition- at U.C.H.C. and colleagues as cancer.” 8 T h e B Urnham repor T | www.burnham.org BUrnham sciENcE NEws In particular, miR29 plays a infectivity. The scientists further key role in controlling the HIV demonstrated that strains of life cycle. The study suggests HIV-1 with mutations in the that HIV may have co-opted region of the genome that this cellular defense mechanism interact with miR29 are not to help the virus hide from inhibited by miR29. the immune system and anti- “We think the virus may viral drugs. The research was use this mechanism to modu- published on June 26 in the late its own lifecycle, and we journal Molecular Cell. may be able to use this to our The team found that the advantage in developing new microRNA miR29 suppresses drugs for HIV,” says Dr. Rana. Dr. Tariq Rana translation of the HIV-1 genome “Retroviral therapies greatly by transporting the HIV reduce viral load but cannot MicroRNAs and HIV mRNA to processing bodies (P- entirely eliminate it. This bodies), where they are stored interaction between HIV and Tariq Rana, Ph.D., director of RNAs that interfere with or destroyed. This results in a miR29 may contribute to that the Program for RNA Biology gene expression) reduce HIV reduction of viral replication inability. Perhaps, by targeting at Burnham, and colleagues replication and infectivity in and infectivity. The study also miR29, we can force HIV into have discovered that specific human T cells. showed that inhibition of miR29 a more active state and improve microRNAs (non-coding enhances viral replication and our ability to eliminate it.” Carbohydrate Acts as the amount of the glycans, leading to greater move- Tumor Suppressor ment by invasive cancer cells. However, when the the enzyme that produces researchers forced aggres- Minoru Fukuda, Ph.D., and these glycans, β3GnT1, sive cancer cells to express colleagues have discovered results in a significant reduc- β3GnT1, the laminin- that specialized complex tion in tumor activity. The binding glycans were sugar molecules (glycans) research was published July restored and tumor forma- that anchor cells into place 6 in the journal Proceedings tion decreased. act as tumor suppressors in of the National Academy of These results indicate breast and prostate cancers. Sciences. that certain carbohydrates Dr. Minoru Fukuda The specialized glycans on normal cells and enzymes These glycans play a are capable of binding to that synthesize those critical role in cell adhe- from migrating. The team glycans, such as β3GnT1, sion in normal cells, and laminin and are attached demonstrated that β3GnT1 to the α-dystroglycan cell function as tumor suppres- their decrease or loss leads controls the synthesis of surface protein. This binding sors,” says Dr. Fukuda. “Up to increased cell migra- laminin-binding glycans facilitates adhesion between regulation of β3GnT1 may tion by invasive cancer in concert with the genes the epithelium and basement become a novel way to treat cells and metastasis. An LARGE/LARGE2. Down- cancer.” increase in expression of membrane and prevents cells regulating β3GnT1 reduces w w w. b u rn h a m . o rg | T h e BU r n h a m r e p o r T 9 BUrnham sciENcE NEws Caspase 8 toma cancer cells to proliferate and migrate. For the first time, migrate and invade neighboring tissues—a critical process in and Invasive Caspase-8 was shown to play a cancer metastasis. key role in relaying the growth “Caspase-8 has a well Cancer signals from epidermal growth defined role in promoting factor (EGF) that cause cell apoptosis, especially in response Cancer Center director division and invasion. The to activation of the so-called Kristiina Vuori, M.D., Ph.D., and researchers also identified an death receptors on the outside colleagues have found that RXDLL amino acid motif that of cells,” says Darren Finlay, the Caspase-8 protein, long controls the signaling from Ph.D., first author on the Dr. Kristiina Vuori the EGF receptor through paper. “Although Caspase-8 is known to play a major role in promoting programmed cell the protein kinase Src to involved in apoptosis, it is rarely The study was published in death (apoptosis), helps relay the master cell proliferation deleted or silenced in tumors, the journal Cancer Research on signals that can cause cancer regulator protein MAPK. This suggesting that it was giving June 15. cells to proliferate, migrate and same signaling pathway stimu- cancer cells a leg up in some The team showed that invade surrounding tissues. lates neuroblastoma cells to other way.” Caspase-8 caused neuroblas- What Makes Stem Cells Tick Investigators at Burnham to looking at changes in genes, and The Scripps Research we have come to realize that Institute (TSRI) have made proteins are the real work horses the first comparative, large- and ultimately determine cell scale phosphoproteomic behavior,” says Evan Snyder, analysis of human embryonic M.D., Ph.D., professor and stem cells (hESCs) and their director of Burnham’s Stem differentiated derivatives. Cell and Regenerative Biology Drs. Evan Snyder and Laurence Brill program. “This study represents The data may help stem the first comprehensive study Burnham’s Proteomics Facility, mechanisms that influence self- cell researchers understand the of genes being activated during Dr. Synder and Sheng Ding, renewal and differentiation. mechanisms that determine differentiation and offers predic- Ph.D., associate professor “This research will be a big whether stem cells divide or tions on cell behavior.” at TSRI, catalogued 2,546 boost for stem cell scientists,” differentiate, what types of cells Protein phosphorylation, phosphorylation sites on 1,602 said Dr. Brill. “The protein they become and how to control the biochemical process phosphoproteins. Prior to this phosphorylation sites identified those complex mechanisms that modifies protein activi- research, protein phosphoryla- in this study are freely avail- to facilitate development of ties by adding a phosphate tion in hESCs was poorly able to the broader research new therapies. The study was molecule, is central to cell understood. Identification of community, and researchers can published in the August 6 issue signaling. Using sophisticated these phosphorylation sites use these data to study the cells of the journal Cell Stem Cell. phosphoproteomic analyses, provides insights into known in greater depth and determine “While the field of stem cell the team of Laurence Brill, and novel hESC signaling path- how phosphorylation events biology has become accustomed Ph.D., senior scientist at ways and highlights signaling determine a cell’s fate.” 10 The B Urnham repor T | www.burnham.org BUrnham sciENcE NEws Cells Respond Unraveling How to Low Oxygen Gary Chiang, Ph.D., and expressed in cells under low colleagues have elucidated oxygen conditions (hypoxia). how the stability of the The Burnham scientists showed REDD1 protein is regulated. that the REDD1 protein rapidly undergoes degradation by the The REDD1 protein is a ubiquitin-proteasome system, critical inhibitor of the mTOR which allowed for the recovery signaling pathway, which of mTOR signaling once oxygen Drs. Enbo Liu and Gary Chiang and Christine Knutzen controls cell growth and prolifer- levels were restored to normal. ation. The study was published “Cells initially shut down the expressing REDD1, which REDD1 protein turns over so in the August 2009 issue of most energy-costly processes, inhibits the mTOR pathway. But rapidly, it allows the pathway EMBO Reports. such as growth, when they’re when the cell needs the mTOR to respond very dynamically As part of the cellular under hypoxic stress,” says pathway active, REDD1 has to to hypoxia and other environ- stress response, REDD1 is Dr. Chiang. “They do this by be eliminated first. Because the mental conditions.” New Faculty research has enumerated the building blocks of the four fundamental components of all cells and combined JA M Ey MA Rt h , P h . D. gineering to identify the them into a research plat- molecular and cellular origins form that has revealed Dr. Marth joins Burnham as of disease and develop new pathophysiologic origins of director of the U.C. Santa approaches to diagnosis, autoimmune disease, sepsis Barbara-Burnham Center prevention and cure. and dietary-induced type 2 for Nanomedicine. Dr. Marth’s laboratory diabetes. The Marth labora- is known for integrating tory previously developed Dr. Jamey Marth The center will focus molecular and cellular biology the Cre-loxP technology that Dr. Marth earned his on the emerging fields of as a means to discover is now used throughout the Ph.D. in pharmacology from nanotechnology and bioen- the origins of disease. His world as a mainstay technique the University of Washington, in biomedical research. Dr. where he worked under Dr. Marth’s discoveries have Dr. Marth’s discoveries have spanned spanned multiple fields Edwin G. Krebs, a 1992 Nobel laureate in medicine multiple fields including immunology, including immunology, hema- and Dr. Roger M. Perlmutter, hematology, metabolism, oncology, tology, metabolism, oncology, now executive vice president glycobiology, neurobiology glycobiology, neurobiology and infectious of Research and Development and infectious diseases and at Amgen. diseases and are unique in combined are unique in combined breadth and accomplishment. breadth and accomplishment. w w w. b u rn h a m . o rg | T h e BU r n h a m re p o r T 11 BUrnham sciENcE NEws New Faculty continued tiMOthy OsBORNE, Ph.D. emphasis on how this influences molecular mechanisms relevant to diabetes and obesity. Dr. Osborne joins Burnham Dr. Osborne received his doctorate in microbiology and at Lake Nona as professor molecular biology from the University of California, Los and director of the Angeles, conducted postdoctoral research at the University of Metabolic Signaling and Texas at Southwestern Medical School and was most recently Disease Program. chair of Molecular Biology and Biochemistry at the University of California, Irvine. He has received a Chancellor’s Award His research seeks to for mentoring undergraduate research, was recognized as an understand how the body Established Investigator of the American Heart Association senses dietary content to alter and received a Lucille P. Markey Scholar Award in Biomedical Dr. Timothy Osborne nutrient absorption with an Science. RA N JA N P E R E R A , Ph.D. He received his Ph.D. in Molecular Genetics from Moscow State University and the University of Ghent-Belgium. Dr. Perera Dr. Perera comes to completed his post-doctoral studies in gene targeting and DNA Burnham from Mercer recombination at Massachusetts Institute of Technology. He has University’s School of many years of industry experience and holds numerous patents Medicine, where he was related to gene regulation. an associate professor As an associate professor at Lake Nona, Dr. Perera seeks to and director of Genomics identify prognostic and diagnostic markers for melanoma and will and research and develop- lead Burnham’s analytical genomics lab and establish expertise in ment at Anderson Cancer RNA biology. His research is partly supported by a Department of Institute. Defense grant to study the link between obesity and cancer. Dr. Ranjan Perera J ULi O AyAL A , Ph.D. Dr. Ayala received his skeletal muscle. At Burnham, Ph.D. and conducted his post- he will focus on the control of An assistant professor doctoral work in molecular inter-organ fuel metabolism at Lake Nona, Dr. Ayala, physiology and biophysics at with emphasis on the regula- comes to Burnham from Vanderbilt. He has studied tion of glucose production and Vanderbilt University School factors that increase the utilization. He seeks to reveal of Medicine, where he was production and secretion how metabolic syndrome is a research faculty member of insulin. His research has influenced by errors in sugar and director of Technology shown that the hormone and fat metabolism and to use Transfer at the Vanderbilt- GLP-1 affects not only the those findings to pursue new NIH Mouse Metabolic secretion of insulin but also treatments for diabetes and Dr. Julio Ayala Phenotyping Center. insulin action on the liver and obesity. 12 12 The B Urnham repor TT || www.burnham.org The B Urnham repor www.burnham.org BUrnham NEws Burnham Chosen for novel drug candidates in high- risk, under-represented areas of National Chemical cancer biology. Biology Consortium “Burnham’s strategic focus for the past five years has been on building our capabilities Burnham has been selected The consortium will trans- in chemical genomics and as one of three compre- late knowledge from leading drug discovery,” says President hensive centers in a new academic institutions into new and CEO John Reed, M.D., National Cancer Institute drug treatments for cancer Ph.D. “The Chemical Biology (NCI) Chemical Biology patients. Burnham’s La Jolla Consortium gives Burnham an Consortium, an integrated and Lake Nona campuses will to expedite the development additional platform to use our network of chemical biolo- both participate. and distribution of new cancer advanced technologies, some gists, molecular oncologists The NCI seeks to coordi- treatments. The consortium of which are virtually unprec- and chemical screening nate their own drug discovery will expand current NCI edented in the not-for-profit centers. efforts with academic institu- programs in personalized medi- research world.” tions and private companies cine to identify and advance Clinical Research directing the new institute.” Florida Hospital will also Institute Moves Forward build a state-of-the-art, 35,000 square-foot facility to house the Clinical Research Institute. appointed execu- “Our vision was to recruit Groundbreaking is scheduled tive director of the a world-class physician and for early 2010. The Institute Florida Hospital – scientist to lead our mission,” will combine scientists and Burnham Clinical says Dr. Daniel Kelly, Scientific clinicians with sophisticated Steven R. Smith, M.D., an Research Institute, which Director of Burnham at Lake technology to enhance transla- internationally-renowned will investigate diabetes, Nona. “We have found the tional research and bring new diabetes and obesity obesity and cardiovascular very best and are delighted treatments to patients. researcher, has been disease. that Dr. Smith will be Burnham Collaborates with Center’s metabolomics expertise “Burnham and Stedman with Burnham’s complementary Center scientists will be able Duke University technologies. to exploit the power of these Metabolomics Center The Stedman Center is well known for its metabolic technologies to define disease signatures relevant to diabetes, research, particularly metabo- heart disease, cancer and other Burnham and the Sarah of disease and identify lomic profiling of biological diseases” says Dr. Daniel Kelly, W. Stedman Nutrition biomarkers for diagnosis samples using mass spectrom- Scientific Director, Burnham and Metabolism Center and treatment. etry-based technologies. The at Lake Nona. “Metabolomic (Stedman Center) at Duke Burnham-Stedman metabo- approaches show great promise University Medical Center The agreement will estab- lomics platform will create for identifying diagnostic have announced a new lish an extension of Duke’s collaborative opportunities and markers that will aid clini- collaboration to use meta- Stedman Center laboratory at expand the research capacity cians in distinguishing disease bolomic profiling to clarify Burnham’s Lake Nona campus of both Duke University and patterns and in developing the basic mechanisms and combines the Stedman Burnham. individualized treatment plans.” w w w. b u rn h a m . o rg | T h e BU r n h a m re p o r T 13 p h I l a n T h r o p y U P D At E Burnham Welcomes director of development for the College of Engineering Julie Johnson at the University of Florida, Gainesville. “I’m excited to be part Lake Nona’s new asso- Association (MDA) over the of Burnham at Lake Nona,” ciate director for external summer and that’s where the says Johnson. “My sister died relations Julie Johnson is love affair began.” from a heart attack at 47 a seasoned development Johnson graduated with as a result of uncontrolled professional with more a degree in journalism and type 2 diabetes. Obesity and than 26 years experience. continued with the MDA Julie Johnson diabetes are challenging health as an events coordinator. issues, and I am certain that “I became interested in Later, she served as assistant Florida; regional vice president researchers at Burnham will nonprofit work when I was executive director for the of the Arthritis Foundation of make significant discoveries a student at the University Leukemia and Lymphoma Northeast Florida; president that will advance our ability to of Florida,” says Johnson. Society; president and of Expedition Inspiration treat them.” “I had an internship with CEO of the Mental Health Fund for Breast Cancer the Muscular Dystrophy Association of Northeast Research and, most recently, to the buyer without gift tax cost. If the asset is depressed real Estate Planning In property selected with location in mind, it likely will come back Challenging Times eventually. Allow children to capture the recovery by selling it to them now. Outright gifts while values are depressed are even better than Ken G. Coveney, Esq. sales. If a parent sells to a child (or a trust for the child’s benefit), Burnham Planned Giving Advisory Council and if the sale price is less than the parent’s basis, the parent’s loss on sale will be disallowed, but the child (or trust) will be stuck Every cloud has a silver lining. We have been in difficult with lower basis. If the parent gives the property to the child (or economic times for awhile, but most people remain opti- trust), the recipient will take the donor’s higher income tax basis mistic about the future. Now is the time to take advantage for purposes of computing gain when they dispose of the property. of these circumstances. Consider transfers in trust with remainder interests to chil- dren or the Burnham Institute for Medical Research. If a donor Interest rates are near historic lows. Make loans to children transfers assets to a grantor retained annuity trust (GRAT), the and grandchildren or trusts for their benefit. A loan at the value of the retained annuity interest will be higher in this low applicable federal rate (AFR) for long-term loans (more than interest environment. nine years) is 4.33 percent. A loan at the AFR is not a gift. If Similarly, if a donor transfers assets to a charitable lead annuity the children/borrowers can obtain a higher return than the AFR, trust (CLAT), the value of the annuity interest given to the they will reap future value at no transfer tax cost to the parents/ Burnham will be higher in this low interest environment and the lenders. If the parents see a good investment opportunity, they value of the remainder interest gifted to the children will be lower. can allow the children to capture it by lending them the funds to Remember, in both a GRAT and a CLAT, the present value of the acquire the investment. remainder interest is what counts for gift tax purposes. Installment sales use the same interest rates as loans. A sale So don’t surrender!! The iron is hot; now is the time to strike. of an appreciating asset transfers the appreciation from the seller 14 The B Urnham repor T | www.burnham.org p h I l a n T h r o p y U P D At E The Chair-iot Society Just as the ancient state-of-the-art audi- For more information, chariot was critical to torium. Membership please call 407-745-2061. warfare, Burnham’s in the Chair-iot Chair-iot Society seeks to Society is $1,000 SPONSORS battle disease by raising and entitles you in Central Florida,” says Dr. funds and awareness of to annual briefings about Nicole Beedle. “And as a Burnham’s mission. Burnham’s cutting edge doctor, I am personally proud science at the Lake Nona of the research going on in Please consider being campus. Orlando.” an inaugural supporter of “As Florida natives, The Chair-iot Society Burnham at Lake Nona by my husband and I were will host an Unveiling Event placing your name on one excited to be able to put our October 9, 2009 at 7 p.m. of the 201 chairs in our name on the future of science Team Burnham professional training, race gear by Brooks, personal shoe fittings and discounts at Fleet Feet, all race weekend accommodations, local transportation, all meals, a one-day Disney pass and the only cour- wA Lt D i sN Ey wO R LD , O RL ANDO , F LOR i DA tesy RV at the finish line. JA N UA Ry 9 A N D 10 , 2010 To become a member of Team Burnham, please contact Kathy Team Burnham for Medical Research will be running Pierson at 407-595-8099 or log onto www.teamburnham.org. the Walt Disney World Half Marathon & Marathon to raise support for Burnham’s cutting-edge biomedical research. Regardless of age or experience, we welcome all runners to join us and run for discovery. Our coaches have put together a training program that can get anyone over the line for either the half (13.1 miles) or full (26.2 miles) marathons. Or, if you are feeling Goofy, you can do both — and there is still time to join. “I had never run a step in my life, and certainly never thought I could run a half marathon,” says Catlin Potter Valmont, who GOLD is returning for her second half marathon. “Training with Team SPONSORS Burnham was the inspiration I needed to get into shape and complete what I thought to be impossible.” Each team member raises $2,500 to fund Burnham research, with the overall goal of raising more than $150,000. The top fundraiser will receive two free tickets anywhere AirTran flies. All SILVER participants will have their own fundraising page and will receive SPONSORS w w w. b u rn h a m . o rg | T h e BU r n h a m re p o r T 15 p h I l a n T h r o p y U P D At E The Power to Cure Gala 2009 Saturday, November 14, 2009 Hyatt Regency La Jolla Aventine 6:00 pm Cocktail Reception 7:00 pm Dinner, Auction, Dancing This award-winning image of Osteoclasts was produced by Dr. Melanie Hoefer in the Rickert laboratory. The basic biomedical inspiring images taken directly and inflammatory, neurode- and lead sponsors include research at Burnham produces from the research bench. generative and childhood Jeanne and Gary Herberger, knowledge, treatments and diseases. The live auction will Roberta and Malin Burnham sNEA k P EE k even art. Co-chaired by feature a jet trip and dinner and Peggy and Peter Preuss. The Fund-A-Need will Caroline Nierenberg and in Napa Valley, a dinner party The Burnham Gala sells support talented young Kathryn Stephens, this year’s at Pamplemousse Grille and out every year, so be sure scientists and help purchase gala celebrates the art of an internship with John C. to reserve your seats today. essential technology to science, as the ballroom will Reed, M.D., Ph.D, Burnham Tickets and sponsorship enhance Burnham research on be transformed into a gallery of President and CEO, opportunities are still avail- cancer, as well as infectious Professor and Donald Bren able. For more information, Presidential Chair. please contact Chelsea Jones “The art and science of asking questions is the This year’s presenting at 858-795-5239 or cjones@ source of all knowledge.” —Thomas Berger sponsor is Life Technologies burnham.org. Each year, the Fishman Fund Award, established in honor of Dr. William and Lillian Fishman, recognizes a group of outstanding postdoctoral fellows for their hard work and scientific vision. Burnham and the Fishman Fund cordially invite you to this year’s reception to recognize the 2009 Thursday, October 15, 2009 Award recipients. 5:30 pm Please RSVP by October 12 to Wendy Sunday at wendys@ at Burnham Institute for Medical Research burnham.org or 858-646-3100, 10901 North Torrey Pines Road, La Jolla extension 3420. hELPiNG yOUNG REsEARch sciENtists sO thEy cAN hELP thE wORLD 16 The B Urnham repor T | www.burnham.org presIdenT’s MEssAGE Scientific Excellence Fuels Strong Growth In our 33rd year, Burnham has surpassed significant milestones in scientific achievement, research staffing and infrastructure development. As of July 1, the Institute exceeded 1,000 employees, including 74 full-time faculty and 800 scientific staff. With the opening of Burnham’s Lake Nona campus in Orlando, Florida, the acquisition of an additional research building in La Jolla, California and the creation of the joint Center for Nanomedicine with the University of California, Santa Barbara, we have increased our space from 382,000 square feet in January 2009 to more than 671,000 square feet today. This continued growth is creating many opportunities to expand the boundaries of scientific knowledge and John C. Reed, M.D., Ph.D. increase employment opportunities during these challenging times. President and CEO Although we are growing rapidly, we have also maintained strong attention to quality, as Professor and Donald Bren evidenced by Burnham’s number one ranking for the past decade in scientific journal citations per Presidential Chair publication in the fields of biology and biochemistry among all organizations worldwide. In the past two years alone, the Institute has published more than 600 research papers in scientific journals. These papers advanced understanding of the mechanisms underlying cancer, Alzheimer’s, HIV, diabetes and many other conditions. Among many recent advances, Burnham researchers have helped discover monoclonal antibodies that attack a variety of flu strains, illumi- nated how HIV co-opts cellular mechanisms to create persistent infections, devised novel chemicals In the past two years that attack anti-death proteins responsible for sustaining malignant cells and thus providing a means to kill chemoresistant cancer cells, elucidated how protein misfolding and protein oxidation alone, the Institute 15. John Reed essay has published more contribute to the demise of brain cells in Parkinson’s, Alzheimer’s and other neurodegenerative diseases and generated replacement heart cells from synthetically-produced stem cells as a new than 600 research approach to treating heart attack and heart failure. papers in scientific We have also increased our overall grants and contract revenue. We are the only organization journals. These in the nation to achieve more than five consecutive years of growth in funding from the National Institutes of Health (NIH), averaging 11.5 percent annual growth for the past 8 years. Last year, papers advanced Burnham received a $98 million contract from the NIH to support a national network in chemical understanding of genomics, as well as an $8 million NIH grant to establish a national Parkinson’s disease research the mechanisms center. While covering more than 90 percent of costs from competitive grants, we have also underlying cancer, secured important philanthropic gifts to help accelerate our research programs. South Dakota Alzheimer’s, HIV, banker T. Denny Sanford donated $20 million to create the Sanford Children’s Health Research diabetes and many Center, San Diego developer Conrad Prebys gave $10 million to name the Conrad Prebys Center for Chemical Genomics and Irvine Companies owner Donald Bren contributed $2.5 million to other conditions. create the Donald Bren Presidential Chair at Burnham. At Burnham, our motto is From Research, the Power to Cure. By adding more scientists to our team and providing them with additional laboratory space, we hope to accelerate our efforts to trans- late basic science discoveries into better treatments that reduce human suffering around the world. w w w. b u rn h a m . o rg | T h e BU r n h a m re p o r T 17 Nonprofit Organization U.s. Postage PAiD 6400 Sanger Road the Burnham institute Orlando, FL 32827 phIlanThropy Partners in Science: Denny Sanford and Dr. Fred Levine Denny Sanford wants to help medical scientists cure type 1 diabetes in his lifetime. He has created the Sanford Project to achieve this goal. Fred Levine, M.D., Ph.D., director of Burnham’s Sanford Children’s Health Research Center, is also working to find a cure. Both a research scientist and a practicing physician, Dr. Levine knows well the suffering type 1 diabetes can cause. His laboratory “Injected insulin does not cure type 1 diabetes,” is investigating new ways to replace insulin-producing beta cells, either says Denny Sanford. “But by gathering the through transplants or regeneration. best scientific minds to investigate the immune system and beta cell regeneration, we will find a cure.” Printed on recycled paper
"the Quest to Cure Diabetes"