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					Clinical Chemistry 56:2
321–326 (2010)                                                                                      Interview
                                                                                                    By Misia Landau

                  A Conversation with Dennis Hochstrasser
In the mid 1980s, as the race to sequence genes was
heating up, Dennis Hochstrasser left his full time med-
ical practice and set off on a less trendy scientific pur-
suit. Convinced that the secret to human disease would
lie in understanding how, when, and where individual
genes and their proteins are expressed, he began refin-
ing a method to separate and analyze proteins. In this
approach, called two-dimensional (2-D) gel electro-
phoresis, proteins are sorted along a gel by charge and
mass. Hochstrasser’s technical efforts, and his work
using computers to analyze the 2-D gels, have brought
him to the center of two of the hottest fields in biomed-
ical research, bioinformatics, and proteomics. Hoch-
strasser spoke with me from his office at Geneva Uni-
versity Hospital, where he is chair of the department of
genetics and laboratory medicine and director of the
laboratory medicine service—and where he still sees
                                                              Do you have siblings?
Reading your C.V., I noticed that you were born in            I have a sister who is a pharmacist and a brother who is
Collonge-Bellerive outside of Geneva. You still live          an engineer and CEO of a company. He deals with
there.                                                        transportation and helps figure out things like how you
I live in the house where I was born.                         carry a very heavy transformer from one place to an-
                                                              other, or how to transport bridge materials.
Really? What has kept you there?
It’s a beautiful place. I’m about a thousand feet from        Sometimes children go in the opposite direction of
the lake where I have my sailboat. It’s about 15 or 20        their parents’ interests but it sounds like that was not
minutes by car from the first snow resorts where I can        the case with your family.
ski.                                                          There were no physicians. My father was not a physi-
                                                              cian, my mother was not a physician, nor were my
You’ve stayed close to home in your personal life but         grandparents.
you’re anything but provincial in your work. You’re
an extremely adventurous scientist, crossing interdis-        How did you become interested in medicine?
ciplinary boundaries right and left. Were you intel-          Since I was a child, I always felt I would be a physician—I
lectually curious as a boy? Did you have a wide-              don’t know why. I was also interested by basic sciences
ranging imagination?                                          and technology, and from the beginning I felt I would
It’s a difficult question to answer. Clearly I always liked   do medicine with a flavor, an orientation, to technol-
to build things. But I grew up in an environment of           ogy. When I was in college, I learned computer sciences
research. My father is a physicist and mathematician          and physics and chemistry and when I started medi-
and he was working for Battelle Institute—it’s an             cine, I continued to study physics for a while. I always,
American institute and there was a Battelle in Geneva.        through my studies, did some work in computer sci-
With my parents, when we traveled, we would look at,          ences. For example, I did a year as a visiting medical
say, the electric power line. We would stop and have a        student at Duke University in North Carolina and to
discussion about high voltage, why it’s interesting to        pay my tuition and fees, I programmed for Duke Med-
save electricity. Or, if we would come to a dam, how we       ical School.
would use the water to make energy. Or the railroads,
how they work. As a child I always grew up discussing         So your interest in computers goes back very early.
science, any kind of science—physics, mathematics,            When I was 16 and 17, there were optional lectures
biology.                                                      during lunch time on programming. I learned how to
                                                              program at that time. I learned how to perforate cards
Was your mother also a scientist?                             and it was in Fortran 77—that was the early program-
No, she was not.                                              ming language.


In this country we have a word for young people, or          expected that. I had the feeling I was getting into a
even older people, who like technical sciences, com-         shower. That was the first time I was in the US and in
puters in general. They’re called geeks. Have you            the South and I never experienced that before. I must
heard that word?                                             say I really enjoyed tremendously being in the
No.                                                          Southeast.

They wear pen protectors in their shirt pockets.             Did you like the weather? Or did you enjoy the
They’re just very focused on technology and comput-          Southeast despite the weather?
ers. Did you have other interests?                           I really enjoyed the weather. The lightning bugs, Ocra-
(Laughs.) I had many, many interests. I was playing          coke on the outer banks, the dogwoods—it was really
music. Also I liked to build things. I built cars. I had a   spectacular. But also the people. As a student I was
sailboat since I was 12 years old and I was rebuilding       living with a family, a typical family, in North Carolina.
boats. And I was sailing. I did many things.                 I enjoyed so much being at Duke that I organized my
                                                             internship and residency at UNC Chapel Hill to be
                                                             back in the area.
Did you do sports?
I did a lot of skiing. I don’t want to promote myself but
                                                             As a young internist you must have seen a wide array
I’m a very good skier and I was when I was a kid.
                                                             of patients.
                                                             For me, the teaching and practicing experience at UNC
How would your brother and sister have described             Chapel Hill was absolutely spectacular and fantastic. I
your personality?                                            have seen there pathologies of disease I have never seen
Probably they would say very entrepreneurial.                here.

That would entail good people skills.                        For example?
That’s really one of the things I’m doing a lot, putting     Tuberculosis of the pericardium—tuberculus pericar-
people together to realize or establish a new thing or to    ditis. I’ve never seen any here. I could see it once a week
build a new institute or new companies.                      at the university. There were also diseases like Rocky
                                                             Mountain spotted fever. There were diseases I’ve never
Did you like medical school—was it expansive, open-          seen before, diseases I’ve not seen since.
ing your eyes to new things or overly narrow and
focused?                                                     Were you tempted to stay?
I enjoyed tremendously going through medical school.         My first two girls were born in Chapel Hill—they have
One of the first things you learn in medical school is       American passports, and Swiss. We had some discus-
about yourself, how you function, how you work. It           sion. But at the same time when you live in the house
was eye opening.                                             where you were born, you have roots there.

                                                             When did you get married?
Was there an organ system or some area of study—
                                                             We were engaged when I came as a visiting student at
immunology, endocrinology—that captured your
                                                             Duke but we were married just after that, in 1977.
It was more a holistic view and helping patients. That’s     Where did you meet?
why I have kept seeing patients until now because I like     We were together in college.
really taking care of patients.
                                                             You had two stints working at the National Insti-
Were there some patients that even to this day you           tutes of Health during the 1980s. I heard that your
remember?                                                    wife, Anne-Catherine, worked with you there.
Yes, always. There are typically some patients that you      She’s a biologist and also a naturopath—she does re-
will never forget.                                           flexology and so on. She did some medical research and
                                                             we were together at the NIH.
When you came to Duke as a visiting medical stu-
dent, you were focusing on internal medicine. How            After your internship and residency in Chapel Hill,
did you like the States?                                     you went back to Switzerland.
When I came out of the airplane in Raleigh-Durham            I was invited back to finish my board of internal med-
airport, I thought I was not outside of the airplane be-     icine and to become an attending physician of internal
cause it was so hot and humid in the summer. I never         medicine at Geneva University Hospital. At some

322 Clinical Chemistry 56:2 (2010)

point, I was called by the chairman of the department          same number of genes and yet there was an extraordi-
of internal medicine. He said I should do an academic          nary difference in the proteins. And I did not at the
career and asked me, “What do you want to work on?”            beginning have the explanation, though now we have
It was 1983. I said I wanted to work on two things—            the explanation. What makes the difference between
protein separation and computer sciences. He said,             them is the posttranslational modifications. Suddenly
“You should work on DNA.” It was the time when the             when you’re looking at a 2-D gel you were capturing
genome program was starting. I said that in Geneva we          visually the complexity of going from a simple organ-
would not be competitive in genome and genome se-              ism like a bacteria to a human sample. That was ex-
quencing because we did not have the time [to get up to        traordinary and fantastic.
speed]. You know the story of La Fontaine, the story of
the turtle and the hare? The turtle starts early to race       How did the complexity manifest itself?
and eventually he wins. I felt that if we were to be com-      Many more spots, trains of spots. In a 2-D gel with
petitive it would be by immediately starting work in the       colored stain, you could see, with the colors, that the
area of protein separation and analysis of data.               protein reaction would be very different from one train
                                                               of protein to the other. If you tried to purify the pro-
How did you first become interested in proteins and            teins, you would get more spots, and new spots. And so
protein separation? I read that it was your facility           from the 1980s I knew that proteomics, though we did
with computers that opened the door.                           not call it that at the time, would be tremendously
I was doing a clerkship in endocrinology as a medical          complex.
student. One of my professors knew that I was working
with computers so he asked me if I could help him to           What might have been causing this increase in post-
connect a video camera to his computer to analyze his          translational modification? Back then it was a big
2-D gels. I had no idea what the 2-D gel was. I went and       puzzle, right?
found the publication of Norman Leigh Anderson and             Back then I had no idea. I knew that some might be
read what they had done at Argonne National Labora-            caused by phosphorylation, some were deamidation,
tories. They were calling it, at that point, the human         some were glycosylation. We were starting to see that.
protein index. And I said, “Oh, that’s something that          But we did not at the time have the power of mass spec,
will be very critical eventually.” I had that in the back of   which came later. As soon as I realized that mass spec
my mind—when you go through life there are things              was really the way to go, we started working on mass
you do not forget but you keep it in one corner of your        spec.
brain. Immediately, when my boss said, “You should
do an academic career, what do you want to do?” I              You invited two then-students, Ron Appel and Amos
remembered the 2-D gels and I remembered the idea of           Bairoch, to help you tackle the problem of analyzing
a human protein index. And I said, “Aha, now is the            the 2-D images, right?
time to do that.”                                              The software to do 2-D analysis, to look at proteins on
                                                               an image, was developed by Ron Appel. Amos Bairoch
Do you have a visual imagination— do you visualize             was developing the protein sequence database,
proteins?                                                      SwissProt. I thought I should put those two together.
Yes, yes. I’m visual, I’m not auditory. I’m entirely
visual.                                                        A lot was going on in the early 1990s. It was then
                                                               that you became certified in clinical chemistry.
Do you think there was an aesthetic component to               I liked to work on proteins, protein separation, and
your attraction to proteins and to the technology?             bioinformatics and I felt the place where I could do that
I don’t know. But clearly the image of the 2-D gels            best would be in laboratory medicine. In 1994, I got the
attracted me.                                                  position of head of clinical medicine, which gave me
                                                               the space to increase our wet laboratory. By the late
Did you dream about them?                                      1990s, the medical imaging unit was too small for the
Yes.                                                           computer scientists who wanted to build up their pro-
                                                               tein data bases so with Ron, Amos, and Robin Offord,
You would spend years perfecting the 2-D gel tech-             we founded the Swiss Institute of Bioinformatics. We
nology and developing computer software to analyze             created a nonprofit foundation that would really sup-
the images. What were some of the big mysteries, the           port the establishment of the best protein database in
intellectual puzzles, that emerged from the images?            the world, which is SwissProt (now part of UniProt).
From the beginning what struck me was the difference                Meanwhile, back in 1993 I learned that we had
between a bacteria and a human. They have nearly the           invented the world wide web in CERN (the European

                                                                                    Clinical Chemistry 56:2 (2010) 323

Organization for Nuclear Research). I learned about           Switzerland, how do people feel about the relation-
that and I said to my colleagues that we should build         ship between science and religion?
one of the first web servers in the life sciences. This was   In Switzerland, religion is well protected but people
ExPASy (www.expasy.org). It was the hundredth web             also like to have their religion separated from the gov-
server on the planet and the first for the life sciences.     ernment because it took centuries to have a govern-
We had a few hundred hits the first month, a few thou-        ment that was not directed by religion. Now, some peo-
sand the second month, about ten thousand the third           ple believe science is in opposition to religion but I
month. It was exponential. We now have about 20 mil-          don’t believe so. Science gives a different explanation
lion hits a month.                                            from what has been written in religious books. The
                                                              Bible was written when people could only explain that
Was it almost closed down due to lack of funding?             way. Because science has progressed does not mean
The Swiss government, seeing the success of ExPASy,           that the message from the Bible has changed. Religious
said they would stop funding. Amos Bairoch did what I         books have a message and it depends on how you look
call a cyberspace earthquake. He sent an email to all         at them—literally or for meaning, the interpretation. I
people using it to say, “Well, if we don’t get any funding    think many of mankind’s problems have been due to
in a few months, we’ll close down.” There were thou-          the interpretation of the books.
sands of letters of support. Twelve Nobel Prize winners
and so on. It created tremendous pressure. It was at          Did you grow up reading the Bible? Was your family
that point that we decided to have a Swiss Institute of       religious in that respect?
Bioinformatics and we created the foundation. We              Yes, I think so. I was not reading it all the time. I’m not
decided to have a commercial arm, GeneBio. That               that religious but I am Christian.
went very well. We have about 250 people in Swit-
zerland working on bioinformatics together in the             Does it play a role in your life? Do you and your
institute now.                                                family go to church?
                                                              I do not go to church that often, although my wife
Is GeneBio producing products used by companies?              decided to do a master’s degree in theology. But I
GeneBio has pushed the Melanie software. It’s free for        would say that the Christian education—I’m con-
academic institutions and companies can buy it.               vinced by that. And I use it all the time in my work.

Your entrepreneurial nature must have been an ad-             What lessons in particular?
vantage in this foray into business.                          How you help people. I’m head of a department of 600
Yes. Then I also founded GeneProt. I pushed the idea to       people and there are precepts, or teaching aspects, that
have a proteomics company with a large number of              I got as a child that I use every day.
mass spectrometers. We raised several hundred million
dollars. It died eventually—after September 11th and          The Golden Rule— do for others as you would have
the crash that happened in the biotech industry. But it       them do for you?
was a fantastic adventure.                                    More than that. The way I respect everyone. I have total
                                                              respect for everyone. I look at the hierarchy as reflect-
What made it fantastic?                                       ing the way you help people. As chairman of the depart-
That’s when I met Craig Venter. I asked Craig whether         ment I’m here to help the people, support them, and
we could do this together. I wanted to call it Elegans        not the other way around. They are not working for
because he was developing a company called Celera             me. I’m working for them.
[focused on genomics] and that would make it C.
Elegans. Eventually, Craig did Celera and we did Ge-          That’s something you have drawn from your medical
neva Proteomics, or GeneProt. Both of them kind of            education and experience as a doctor. As a doctor,
disappeared. But it was a fantastic time. By the way,         you’re meant to serve your patients.
my chief resident at UNC Chapel Hill was Francis              Exactly.
Collins, who headed the human genome project on
the public side. It’s a very small world, a very small        How much time do you spend with patients now?
world.                                                        I generally do attending rounds on the wards two
                                                              months a year.
Francis Collins was recently appointed head of the
NIH. He is also a self-avowed Bible-believing Chris-          And you’re not doing research during that time?
tian, which has earned him some criticism here. In            I keep it in the background, on the back burner.

324 Clinical Chemistry 56:2 (2010)

How about time for your family. You have now three             opposite— clinicians try to exclude patients. They try
children?                                                      to say you do not need to stay in the hospital, you do
I have three girls and two, soon to be four,                   not have this disease. If you have normal D-dimer lev-
grandchildren.                                                 els you know the patient does not have pulmonary em-
                                                               bolism. You measure proBNP because you know that if
What were some of the main lessons learned raising             proBNP is low, the patient does not have heart insuffi-
three girls?                                                   ciency. Often that’s what we need in making a decision
It was fantastic. The first one is an internist. She just      for the patient. What is difficult is to find a biomarker
finished her board in internal medicine. The second is a       to include, to confirm, a diagnosis. That’s why the ef-
mountain guide, because they grew up in the moun-              fort to find biomarkers of cancer is the most difficult
tains. We have a Swiss chalet in the alps and they like to     because you need to have specificity to confirm it, and
ski—they are all excellent skiers. The third one is be-        it’s very difficult to do that. I don’t know even if it’s
coming a journalist.                                           possible for some of the early cancers. At least it’s not
                                                               really possible to start with the blood. Many of the mis-
You mentioned that your wife decided to do a degree            takes that have been made—people did not know this
in theology.                                                   at that time—is that the blood is extremely complex.
Well, she also likes to take care of people and she likes to   It’s very difficult to start with the blood, to find the
understand. She has done biology and some medical              needle in the haystack.
research. Now she feels that she can help more, even,
from the spiritual point of view. She is a member of the       Because so much is happening there?
ethics committee of the hospital. The well-being of            So much is happening and there is so great a dynamic
people is also part of her interest and it’s why she de-       range between a very evident protein like albumin and
cided to do that.                                              the very least evident protein like TNF, tumor necrosis
                                                               factor. The other thing is, people in many studies have
Returning to your work, one of the great goals of              compared disease with control and control with
clinical chemistry is to identify proteins and mole-           healthy. If you’re healthy you do not go to see your
cules that can predict whether a person is going to            physician. You go when you have a disease. So the
become ill, or to detect disease at very early stages. In      problem is to differentiate between one disease and an-
a recent article you talk about the lack of success in         other. The trouble is, in any disease—pneumonia, can-
finding such biomarkers and attribute it, in part, to          cer, autoimmune disease—some of the effects will be
nature’s complexity. Could you say more?                       the same: you will have inflammation, you will have
I strongly believe that. Diseases can be entirely de-          coagulation problems, you will have complement sys-
scribed by three elements—the genes, on the one hand;          tem problems. If you compare a cancer with a normal,
and the environment, which can be divided into two             and pneumonia with a normal, or any infectious dis-
elements, microbes and toxicants. The environment              ease with a normal, you will find a difference but the
plays a critical role in determining whether your genes        difference will be unrelated to that disease. It will be the
are expressed or not. For many diseases, say high blood        fact that you are sick. Having a biomarker to tell you
pressure, you may have a genetic predisposition, but           that you are sick, we don’t need that.
often you are overweight, having too much salt, stress,
whatever. Tuberculosis—it’s a microbe but you may              How do you address this problem?
have a genetic predisposition or you may be alcoholic          I believe that at least for now until we have more precise
and that gives you more chance to be infected. Cancer,         tools that can go much deeper, we need to separate the
it could be a genetic predisposition but it’s often also       discovery phase from the clinical validation phase. In
exposure to some toxins from food additives, what you          other words, if you have a disease in an organ like the
breathe, exposure to chemicals. For some rare, unique          brain, the heart, the pancreas, and you want to find
diseases like Huntington’s chorea or retinoblastoma,           biomarkers of that disease, you should do the study on
you know the disease from the gene but in these other          the tissue itself. And when you have found the differ-
diseases, the gene will only give you a predisposition         ences to build an assay, like an immunoassay or a mass
and you will need to look at the effects of the environ-       spec assay, then you go to the blood because now you
ment. And the effects of the environment most of the           have a magnet to find the needle.
time will be metabolomic or proteomic—that’s what
we have measured in clinical chemistry for many years.         You have recently developed an interest in environ-
     Now in clinical practice there are two approaches.        mental toxicology.
The first is to look at ways to confirm a diagnosis, to        It’s not so new. If you think diseases are due, as a big
include a patient into a box. But often it’s the               vision, to genes and the environment and the environ-

                                                                                     Clinical Chemistry 56:2 (2010) 325

ment is toxicants and microbes, then proteomics fits        Given your roots in the region, you should have
extremely well into toxicology. In fact, a way to push      friends that go way back.
proteomics into clinical practice is through human ap-      Yes, most of my friends are from the local region. I have
plied toxicology.                                           also scientist friends from around the world but many
                                                            of my friends are local friends. We were together in
Which environmental threats really preoccupy you?           primary school.
What are the greatest challenges?
The chemical diversity that we are building as human        That’s wonderful. It’s not typical, at least not in this
beings. And we have no way of knowing the toxicity of       country.
all the molecules we are creating.                          It’s not unheard of here.

What are the biggest culprits from your point of            Do you have time to read at night or listen to music?
view—are they coming from air, water, food?                 Generally at night I listen to a bit to music but I also do
Our greatest contact with the environment is through        my emails.
the digestive system because if you take your stomach
and all the digestive organs, it has the size of a tennis   At one point you mention that to do proteomics, you
court. Imagine that your skin has the size of a tennis      have to be a kind of Renaissance person, crossing
court—you would be scared. When you eat food you            interdisciplinary boundaries. Speaking of the Re-
have incredible contact with the environment. The           naissance I was wondering, if you could travel
other one is breathing, obviously.                          through time and space where would you land?
                                                            I would land today. Today is really spectacular with all
How about your diet? Does knowing what you know             the knowledge of the genomic sequence and the knowl-
affect the way you live your life?                          edge of many things. I’d like to come back now.
Well, we look at the label on the box when we go to
the grocery store. Too many chemicals, processed            Finally, talking of travel, if you had to describe your
food—we try to avoid that.                                  life as a kind of quest or journey, what would be the
Do you like to cook?                                        Better patient care.
                                                            That’s what drives you?
Do you work weekends?                                       Yes.
Generally I try to keep the weekend for my family. I
always did that.                                                              Sponsored by the Department of
                                                               Laboratory Medicine, Childrens’ Hospital Boston
What do you like to do? You love to ski, of course.
Mountain climbing. Hiking, not with ropes and so on,
just walking the trails.                                                                           Misia Landau
                                                                             e-mail misia_landau@hms.harvard.edu
Do your friends tend to be in science?
Most of my friends are outside of the working               Previously published online at DOI: 10.1373/clinchem.2009.127829

326 Clinical Chemistry 56:2 (2010)

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