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Home , Alan Hodgkin, Paul Greengard

A conversation with

Ushma S. Neill

J Clin Invest. 2013;123(3):937-938. https://doi.org/10.1172/JCI68877.

Conversations with Giants in Medicine

If you, or someone you know, has Parkinson’s disease, mental health issues, or other neurological disorders, medication can often help. The bulk of these medications have been established based on the work of Paul Greengard (Figure 1) from the , who worked out just how the responds to — the chemicals that help the brain signal. The bulk of what most know today about neurotransmission, and specifically the dynamics of slow synaptic transmission, is predicated on the work of Paul Greengard. The full interview, with many more stories about his seminal research discoveries and his competitive streak in potato sack races, can be seen on the JCI website, http://www.jci.org/kiosk/cgm. JCI: Can you tell us a little bit about your path towards becoming a scientist? Greengard: I grew up in . My mother died giving birth to me, and then my father remarried when I was one year old. He was a businessman; she was a housewife. They were both very anti-intellectual, and so I did not get the bug for doing scientific research at home. It was a very anti-intellectual atmosphere at home and to a certain extent, possibly a rebellion against that, was what made me very committed to science. They did not want me to go to college, but fortunately I […]

Find the latest version: https://jci.me/68877/pdf Conversations with giants in medicine A conversation with Paul Greengard

If you, or someone you know, has Parkin- to start a new department of . He ceutical company. I was very young, and son’s disease, mental health issues, or other took a few of us with him, and I ended up they offered me this very senior position. neurological disorders, medication can often doing a PhD degree there at Hopkins. Kef- I thought it might be exciting to take my help. The bulk of these medications have been fer Hartline was the first scientist I worked knowledge of basic science and apply it to established based on the work of neuroscien- with. He was a vision person who went on new drug discovery. And so, I worked for tist Paul Greengard (Figure 1) from the Rock- to win a . At the time, everybody nine years in a pharmaceutical company efeller University, who worked out just how in the department was studying the electri- which was called Geigy at the time, then the brain responds to neurotransmitters — cal properties of nerve cells. merged with Ciba and became Ciba-Geigy, the chemicals that help the brain signal. The came and gave a beautiful lecture about and then merged with Sandoz to become bulk of what most neuroscientists know understanding the ionic basis of the nerve what’s today known as Novartis. today about neurotransmission, and specifi- impulse, and I thought it might be a long JCI: How did that time at Geigy shape the cally the dynamics of slow synaptic transmis- time between that discovery and the next way that you did your research or how you sion, is predicated on the work of Paul Green- major advance in biophysics of the nervous thought about targets? gard. The full interview, with many more system. So, I decided it would be interesting Greengard: I think it did a couple of things stories about his seminal research discover- to understand more about the underlying for me. It gave me an education of the sort ies and his competitive streak in potato sack molecular properties of nerve cells. one might have gotten in medical school. At races, can be seen on the JCI website, http:// JCI: In the autobiography that accom- the time, when I was ready to do advanced www.jci.org/kiosk/cgm. panied your Nobel lecture, you remarked studies, I decided not to go to medical school JCI: Can you tell us a little bit about your that the lecture by Alan Hodgkin was one because it was very much a hands-on profes- path towards becoming a scientist? of your first Aha moments that helped you sion where the physicians really couldn’t do Greengard: I grew up in New York City. My to shape the direction of your career. very much for their patients. There were bril- mother died giving birth to me, and then my Greengard: Yes, that’s true. He was a mar- liant clinicians, but there was a very limited father remarried when I was one year old. He velous lecturer and a marvelous human repertoire of tools they had. Instead, I decided was a businessman; she was a housewife. They being, and it was very inspiring, but it to do a PhD. But, I got a kind of education were both very anti-intellectual, and so I did inspired me in sort of a negative way. I said, while I was in the pharmaceutical industry not get the bug for doing scientific research “I don’t want to be in this research area any- similar to that which I would have gotten at home. It was a very anti-intellectual atmo- more.” Hodgkin had solved the biophysical in medical school, as I learned much more sphere at home and to a certain extent, pos- problems that were solvable at that time. about the biology of the body, particularly of sibly a rebellion against that, was what made So, I turned to studying the biochemistry the brain, and what the major issues were, and me very committed to science. They did not of nerve cells and their function. began to think about ways of studying them. want me to go to college, but fortunately JCI: After you finished your PhD at At the end of that nine-year period, I I had served in the Second World War, and Hopkins, you then spent several years abroad did one semester as a Visiting Professor at was able to get through college on the GI Bill. in England and in Holland. How did that with a brilliant scien- JCI: What did you study? time shape your path and your discoveries? tist named Earl Sutherland who discovered Greengard: In college I studied mathemat- Greengard: I spent a lot of time thinking cyclic AMP. That was an excellent experience. ics and . After that, I was going to go about how the rapidly increasing knowl- At the time I was a graduate student at Johns to graduate school, and I had been planning edge of biochemistry could be applied to Hopkins, Sutherland was publishing some to work in theoretical physics. But this was an understanding of nerve function. It amazing papers on how hormones were pro- almost immediately after the dropping of was a difficult period in the sense that bio- ducing their effects and showing that they the atomic bombs on Hiroshima and Naga- chemists were only interested in the brain as acted through cyclic AMP. In another line of saki, and I felt that was not an area I wanted a source of enzymes. There are thousands of study, Edwin Krebs and his colleagues had to be really involved in because I thought enzymes that are much more active in the been studying protein phosphorylation and there were better ways of spending my life brain than any place else. The neurophysi- discovered cyclic AMP regulation of protein than trying to destroy mankind. I had heard ologists were not really interested in the phosphorylation. After nine years of devel- about the nascent field of medical physics or underlying molecular mechanisms. oping CNS drugs, I returned to my interest biophysics. And at that time, there were two I went to a pharmacology department in the biochemical basis of nerve cell func- biophysics departments in the country. One for three of the five years that I was doing tion and leaned very heavily on the discover- was at the Lawrence Laboratory in Berkeley, my postdoctoral studies because they had ies of the Sutherland lab and the Krebs lab which was involved in doing radioisotope both biochemical and electrophysiological to try to determine what was going on in the studies in biology and the other one was the equipment that one could use. While I was brain. One key to progress was my consider- Department of Biophysics at Penn which there in the laboratory of a very distin- ing the possibility that what Sutherland had was involved in studying the electrical prop- guished scientist named Wilhelm Feldberg, been studying, namely how hormones work erties of nerve cells. I was able to gain a lot more experience in in the endocrine system, might be applicable I started at Penn but then the chairman both biochemistry and . to nerve cells — that a of the department, Detlev Bronk, moved to While in the Feldberg laboratory, I was released from a presynaptic terminal and Johns Hopkins to become the president and approached about a position in a pharma- activating post-synaptic receptors might

The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 3 March 2013 937 conversations with giants in medicine

my daughter saying, “But he’s sound asleep. You really want me to wake him up?” And then the reply, “Well, my name is Hans Jörn- vall and I am the Secretary of the Nobel Prize Committee.” I said, “It’s okay. I’m awake.” So, that was how I first learned about it. JCI: You used your share of the winnings to endow a prize in the name of your moth- er, The Pearl Meister Greengard Award for . Why did you decide to use your honorarium in that way? Greengard: When I grew up it was pretty much universally accepted, by both men and women, that women were inferior. It’s hard to believe now but almost everybody I knew thought men were smarter than women. It took a long time, and a lot of fighting by a lot of courageous women and some sup- portive men, to put that idea to rest. Having seen all this discrimination, I thought it’d Figure 1 be nice to do something to help champion Paul Greengard on January 10, 2013, in New York City. Image credit: Semyon Maltsev. these women who were struggling and still are today. The situation today is incompara- bly better than what it was but there’s still a work through an analogous pathway. We friends and radical by my non-friends, it was lot of discrimination. found neurotransmitter-sensitive adenylyl a very friendly atmosphere. I mean the col- JCI: How do you approach mentoring of cyclases in the and showed leagues at Yale were all wonderful and had young trainees? that they are present in the plasma mem- an open mind to a large extent, and funding Greengard: I don’t have a formula. A num- brane. It became clear that the nervous sys- was much more ample then than it is now. ber of former students have said they learned tem responded to neurotransmitters the There was more support for people with a lot, but I’ve also been told by a number of way the endocrine system responded to hor- unconventional ideas at that time. students that the most unpleasant experi- mones even though there’s a million-fold The first part of my career at Yale had to ence of their life was writing a manuscript difference in the distances traversed. do with elucidating the signaling pathways with me. They thought it was sheer hell, and JCI: That must have been a rather hereti- by which nerve cells responded to neu- then they would tell me 15 years later, “I had cal proposal to have at the time. rotransmitters and how nerve cells receiving no idea how much I learned.” Greengard: It was. People said a lot of signals from several different places could This mentoring thing, I think one can get unkind things. The interesting thing about integrate that information, and explain a more credit than one deserves. For example, it was that because it was considered so lot of the electrophysiological responses. In I’ve had the pleasure of observing many of unlikely to be true, I had basically 15 years, the last 15 years or so, and since I’ve been at my former students and post-docs become from about 1968 to 1983, to develop the Rockefeller, I became increasingly interested leaders in . I don’t think that story. And by the time people accepted it, my in studying the molecular basis for various I was brilliant in teaching them how to be research group had laid a lot of the founda- diseases because we now know more about such good scientists. I think that the young- tion of the molecular basis for neurotrans- the pathways involved. And so today, much er generation tends to have an instinct mission. So, we didn’t have this ultra heavy of the work of our research group is dedi- about what the important new directions competition. I’ve talked to other people who cated to studies of depression, Alzheimer’s are. Since they were brilliant to begin with, have had the fortune of being recognized as disease, Parkinson’s disease, and schizo- they went on to very successful careers. Nobel Prize winners and, in many instanc- phrenia. These diseases seem very different JCI: If you were to have considered an es, it has been the same thing. They’ve but the signaling pathways have a lot in alternate career, what would you have done? done something very unconventional, and common and the techniques to study them Greengard: Recently, my granddaughter, nobody believed them for a while, and then have even more in common. who is an attorney, was trying to search out it was shown to be true. JCI: In the year 2000 you were awarded what exactly she would like to do in the long JCI: After short stints at both Vanderbilt and the Nobel Prize in or Medicine. run. She asked me what I would do. I told Einstein, where you had the germinal seeds of Greengard: Each year, I had been told her that I thought I would like to be a con- some of these ideas, you spent 15 years at Yale that I was going to win the Nobel Prize that stitutional lawyer. And, in my wilder dreams, working on some of the early bases for what year. On a Monday morning in 2000, the either a professor in constitutional law; or in you would later be lauded with the Nobel announcement came. Our daughter was my even wilder dreams, a Supreme Court Prize. What was that time like — when you staying with us in our apartment and some- Justice; and in my wildest dreams, I would were first building an independent lab? body called at 5:15 in the morning. We had be the Chief Justice of the Supreme Court. Greengard: Even though my thinking was gotten to bed very late the night before. By considered extremely unconventional by my the time I picked up the telephone, I heard Ushma S. Neill

938 The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 3 March 2013