Research as an Art Form
S ol Snyder started the Department of Neuroscience at Johns Hopkins University School of Medicine in 1980—the same year he served as President of the Society for Neuroscience (SFN)—with a total staff of three, including himself. For fifteen years prior to that, he had been on staff at Johns Hopkins in the departments of pharmacology and psychiatry. Today, the Department of Neuroscience, still under the direction of Snyder, has solidly distinguished itself as a leading center for research, with twenty-five primary faculty members and over fifty additional researchers with primary appointments in other departments. As one of the founding fathers of modern neuroscience, Snyder has mentored dozens of students and postdocs, and counts his role as mentor among his most important achievements, which are many: countless prizes, five honorary degrees, membership in numerous honorary societies (including the National Academy of Sciences and the American Philosophical Society), six books, about nine hundred citations in PubMed, and board service to diverse scientific and artistic institutions. Under Snyder’s Presidency of SFN, he countered tendencies among the Society’s total of ∼7000 members that would have resulted in division of the “wets” (biochemists) from the “dries” (neurophysiologists). With a membership today of around 29,000, the SFN can thank Snyder, on a wide variety of fronts, for being a driving force in the emergence of neuroscience as one of the most prolific areas of biomedicine in our time.
MI: In addition to being a neuroscientist, you have a reputation as a musician. Did you come from a family that was particularly musical or science-oriented?
SS: The musical side comes from both my mother and my father’s side, but especially my father’s side. My grandparents from both sides came from Russia, during the largest Jewish immigration after the pogroms of the turn of the century, but my mother and father were born in the United States. My mother’s father, to whom I was very close—because he lived with us—played the balalaika in Russia, but in the United States he mostly played the mandolin. He showed me how to play it, and I picked it up very quickly.
MI: So at what age were you playing the mandolin?
SS: I started at maybe nine or ten. When I was five years old I had started playing the piano and I was already playing on an amateur radio show when I was five or six, in Washington DC. But within a couple of years I had an argument with my mother and she sold the piano. My father was also a semiprofessional musician, and he thought that would be very nice if I had some mandolin lessons. Although the mandolin isn’t widely played, there was one teacher in Washington who played the mandolin, a man named Sophocles Papas. He was also the leading teacher of the classical guitar in America. So I took mandolin lessons for two or three years, and because playing the mandolin is like studying Latin, he encouraged me to switch to another string instrument. I secretly wanted to learn the guitar anyhow, so I started to play the guitar and just couldn’t stop. I would spend hours every day on the guitar, and by the time I was a senior in high school, I was giving concerts. I played for Andrés Segovia, the father of the classical guitar, who was my teacher’s best friend. I’ve never stopped playing the guitar. Johns Hopkins has a cultural affairs program in which I perform from time to time.
MI: And your siblings—are they also musical?
SS: I’m the second of five children. My older sister is an artist. She’s a very talented, outstanding painter and illustrator. When she was three years old she could draw perfect likenesses of people—so amazing that my father had affidavits to verify that she did these various pieces of work. She became one of the leading natural science illustrators in the country. Her name is Elaine Hodges.
MI: And your other siblings—artists or scientists or both?
SS: My younger sister, Carolyn, was very beautiful. She was in the Miss America contest, as a finalist in Washington DC. She’s now a psychiatric nurse. I have a brother who’s a psychiatric social worker. My youngest brother got into theater when he was six years old and never got out of it. He’s spent most of his career with the National Endowment for the Arts, and continues to perform.
MI: So where did the science come from, not only for you, but also for your sisters and your brother?
SS: Basically, there was no science in my family, although my father greatly admired science, and he went to college at night school during the Depression, after my older sister and I were born. He got his college degree in chemistry, but he spent most of his career at the National Security Agency, code breaking. So there was no particular history of science in my family. In high school, I liked philosophy, but that wasn’t a fit job for a nice Jewish boy, and the other guys were going into engineering or premed. I naively thought that maybe I’d become a psychiatrist and in that way pursue philosophy.
In college, I gave guitar lessons and ran the guitar store for my teacher on the weekends. One of my students, Dan Brown, was a Research Associate at the NIH; he needed a technician in the summer before I started medical school. I worked in his lab, and found research wasn’t like science in school. It was creative; it was an art form; it was a lot of fun. And everybody at NIH was just nice. It was a great institution in those days, late 50s early 60s. I still wanted to be a psychiatrist, but in those days, every male graduate of medical school went into the military doctors’ draft. One way to avoid going to Berlin or wherever they were going to send you in those days was to be accepted in the NIH, which was part of the Public Health Service—a military service equivalent. There was a program called the Research Associate Program, which was very competitive, considering that thousands of graduates of medical schools wanted to get in. But because I had been hanging around at the NIH, I knew people. Still, I never would have gotten a position. But then I went around looking for positions, and Julius Axelrod, whose lab was across the hall from where I was working, said, “Well you know Sol, all the people we take are valedictorians from Harvard or Yale and such. But I have a vacancy and nobody to match; it’s already too late. You can have it.”
MI: Is that the ceremony with which he presented it to you?
SS: Yes. And then he of course was a very, very great scientist and a wonderful mentor. The percentage of his students who did well is extremely high. It was an incredible two years that I spent in his lab. I just found that it was really fantastic. That’s where I really learned…that was actually the only research training I had. After that, I still wanted to be a psychiatrist, and so I came to Johns Hopkins for a psychiatry residency. And I’ve never left.
MI: You came to Johns Hopkins still planning to be a clinical psychiatrist?
SS: Right. I wasn’t sure of the balance that I’d pursue between clinical work and research. I wanted some sort of arrangement for my residency so that I could be paid more than the 240 dollars per month that residents got. My wife and I wanted to have children, and we’d been married already four years—we got married when I graduated from medical school. I was fortunate to work out an arrangement where after my first year of residency, I was to become Assistant Professor of Pharmacology and to be paid like a full-time assistant professor. It worked out great; we had a baby.
MI: And how long did it take you to find your balance between research and clinical work? And do you still have any clinical duties?
SS: Until recently I would see some patients in consultation, but not any more. After I finished residency I continued seeing some patients, supervising residents, but it was clear—I was on the faculty and the research was going great, and I had NIH grants and so most of my time was in research even right after residency.
MI: And what was going so great in your research at that time?
SS: The very first person to work in my lab was a medical student named Joe Coyle, who subsequently did very well and went on to become Chairman of Psychiatry at Harvard. As a medical student, he developed a means of studying catecholamine uptake and found that this process was affected very interestingly by amphetamines. That work led to a lot of thinking about how amphetamines cause behavioral stimulation and psychosis, which was exciting because of its psychiatric relevance.
By 1969, using the techniques for studying neurotransmitter uptake that Joe Coyle had developed for catecholamines, people were doing a lot of thinking about amino acids as neurotransmitters. It was very hard to provide evidence that endogenous amino acids really were neurotransmitters. The neurophysiologists found that by adding an amino acid the firing of neurons could be affected, and that was helpful and interesting. But we felt that if amino acids were neurotransmitters, then for those that are the best candidates, like glutamate, aspartate, and glycine, there should be a separate neurotransmitter pool distinguishable from the larger metabolic pool. If uptake were a mechanism of inactivating a neurotransmitter, we should observe high-affinity sodium-requiring uptake for the specific neurotransmitter amino acids, which should be discriminated from the low-affinity general amino acid uptake. And so using the same techniques that had worked for catecholamines, that’s just what we discovered—that glutamate, aspartate, and glycine had such uptake systems. We could even separate synaptosomes—pinched-off nerve endings—that selectively accumulated amino acid neurotransmitters from the general bulk of nerve endings. Things were going well and Johns Hopkins was really nice to me; they appointed me to Associate Professor and then in 1970 I was promoted to Full Professor, largely based on job offers from elsewhere.
MI: You came into the department of pharmacology. What was it like coming to Hopkins at that time in terms of neuroscience.
SS: There were very few neuroscience departments in the whole country at that time. The word neuroscience was only coined in the mid 1960s and only in the late 1960s did the disciplines of neurophysiology, neuroanatomy, neurochemistry, and neuropharmacology mesh. It wasn’t until the late 1960s that techniques were sufficiently advanced so that you could finally visualize a neuron based on its neurotransmitter content, and record form that neuron, and give a drug to it.
MI: So when did the Department of Neuroscience form here at Johns Hopkins?
SS: Neuroscience as a department formed in 1980. What happened was that Joshua Lederberg became President of Rockefeller University, and he recruited me, along with my colleagues Joe Coyle and Michael Kuhar, to go to Rockefeller as a group, and there was very attractive, substantial funding. I was going to leave, when the dean at Johns Hopkins said to me, “I can’t match in dollars what Rockefeller can do for a professor, but if you and your two colleagues would stay to form a department of neuroscience at Johns Hopkins, I’d more than match what they do at Rockefeller in terms of institutional focus on neuroscience.
MI: By then your name with was linked to the discovery of endogenous opioids, right? How did that happen?
SS: In the early 1970s, President Nixon had declared war on heroin, and he appointed Dr. Jerome Jaffe as the czar of drug abuse, who had control over immense resources in the Department of Defense and Health and Human Services—and also had enormous pressure. Jerry Jaffe was a psychiatrist and a friend of mine. He was arguing that something ought to be done about all the soldiers in Vietnam on heroin—that there was the potential for a big, big problem. And I convinced him that one efficient way he could do something quickly was to establish drug abuse research centers to focus on this kind of issue. He set them up and we applied for a grant. The first thing I wanted to work on was the possible existence of a receptor specific for opiates. Interestingly, at the time we wrote the application to the NIH the publications from our lab that were relevant to drug abuse pertained to amphetamines and catecholamines. The opiate receptor was just an idea—no data at all. When the site visitors came to review us, they decided that we had some good solid work on amphetamines, but labeled the opiate receptor stuff as pie-in-the-sky, and they deleted it from our grant proposal. But of course if you get a grant, you do what you want to do. And in the meantime, I wanted to pursue the idea of an opiate receptor, independent of the funding anyhow—there were already vast amounts of studies on opiates, where you gave rats morphine and you measured this and you measured that. But that type of work didn’t tell us, fundamentally, how opiates act. But if you knew the initial precise molecular target where they act, that would be terrific!
People had tried to find neurotransmitter receptors by ligand binding techniques over the years, but were generally unsuccessful for various technological reasons. There were published estimates, for example, that opiate receptors might be one millionth by weight of the brain. So, if you take a radioactive drug or neurotransmitter and look at its binding, there would be so much nonspecific binding based on ionic attractions that you never could see signal above noise. To approach that problem, I drew on experience we had had with a colleague in the next laboratory, a faculty member named Pedro Cuatrecasas, who had been studying the insulin receptor by binding radioactive insulin. He had overcome similar challenges by having high specific–radioactivity insulin and trapping bound ligand in a vacuum filter system where he could trap bound ligand in a small fraction of a second by quickly washing away nonspecific binding. Pedro Cuatrecasas had collaborated with us to detect the receptor for nerve growth factor, and so we had learned to do this ligand binding technique.
MI: And so then you turned to the opiate receptor…
SS: Right. I had a graduate student apply named Candace Pert, who had been working on choline uptake in intestinal smooth muscle, which has attached nerves so we could study the relationship of choline uptake to the firing of the cholinergic neurons. As that project was getting finished, I said, “Why don’t we try to look for opiate receptors.” The key thing to starting that work was to have a radiolabeled drug of sufficiently high specific radioactivity. We got New England Nuclear (NEN) to custom prepare naloxone—an opiate antagonist—in tritiated form, which we then tried out on our intestinal preparations. The very first or second experiment worked with the naloxone. We started those experiments in the fall of 1972, and by late 1972 we had completed the initial study and had submitted it to Science . Once we characterized the opiate receptor, the binding properties were telling us that it was behaving like a neurotransmitter receptor.
We subsequently used that technique to study all the major neurotransmitters of the brain. The only trick was to get the right tritiated drug. We scrounged around for whatever high-affinity drugs we could find. We were able to find such agents for most receptors, and again, because NEN had been so successful in developing ligands for the opiate receptor, they were eager, at their own expense, to supply any drug that I requested.
MI: Because you were creating markets for them with follow-up work?
SS: They earned many millions of dollars off of this work. We were successful in finding receptors for the major neurotransmitters in the brain. Because opiate receptors acted like neurotransmitter receptors, and man is not born with morphine in him, the next step was to look for naturally occurring morphine-like substances in the brain. An MD-PhD student of mine, Gavril Pasternak, looked for endogenous morphine-like substances in brain extracts by competitive radioligand binding assays using naloxone. He found such activity, and the distribution of this morphine-like substance in the brain paralleled that of the opiate receptor, so we knew we were dealing with something biologically relevant. Independently, in Scotland, Hans Kosterlitz and John Hughes were looking for endogenous opioid substances utilizing the well-known ability of morphine to affect electrically induced contractions of smooth musle. They found such activity in brain extracts, and to prove that it was biologically relevant, they showed that the ability of this substance to affect electrically induced contractions was blocked by naloxone. They identified the chemical structure of the morphine-like substance first—the structure of the enkephalin peptides. Four weeks after their publication, we obtained the structure of the same two enkephalin peptides.
MI: And the enkaphalins were the first class of what we now call the endorphins.
SS: There’s an interesting story about the names of the opiate-like peptides. By 1975, many people were getting interested in the possibility of endogenous morphine-like substances. At a meeting on opiate research in Airlie House near Washington, a group of us discussed, “What should we call this stuff?” The consensus was to call them endorphines —note the e on the end of endorphine . Then Avram Goldstein circulated a letter to participants at the meeting and he said he’d like to make a modification. He said, “You know, if these substances are neurotransmitters, like serotonin, maybe their name shouldn’t have an e at the end, so why don’t we call them endorphins . Of course, he forgot that other transmitters like dopamine, norepinephrine, and acetylcholine do have e ’s at the end. But since nobody cared, everybody said fine. Kosterwitz and Hughes used the word enkephalin ,which means “in the head.” Subsequently when other opioid peptides were discovered, people started using the words endorphin as a generic name for any opiate-like substance.
MI: And what was the progression of your work after discovery of the opiate receptor and endorphins?
SS: The enkephalins, being peptides, heightened interest generally in peptides as neurotransmitters, and we started studying a variety of peptides as neurotransmitters. Subsequently, we turned our attention to signaling inside the cell—second messengers. In the early 1980s, inositol trisphosphate (IP3 ) was appreciated as a second messenger system, just as important as cyclic AMP, that releases internal stores of calcium. We were interested in finding the protein to which IP3 binds to release calcium—the IP3 receptor. Other labs had found a little binding of IP3 to lymphocytes and neutrophils, but you couldn’t do much with that binding because the signal was low. We found that the cerebellum has about one thousand–times more IP3 receptors than peripheral white blood cells, which allowed us to characterize them, solubilize them, and purify them to homogeneity. One of the big questions about the IP3 receptor was whether ligand binding elicited some interaction with a separate calcium ion channel protein, or whether one protein had both the IP3 binding site and the calcium channel. In collaboration with Rick Huganir, one of our faculty members who had just joined our department—and an expert at reconstituting proteins into lipid vesicles—we could show that that the pure IP3 receptor protein contained the calcium ion channel.
Now a big focus of our lab is identifying novel neurotransmitters. The enkephalins were pretty novel in their day. For the last ten years, we’ve been working on nitric oxide, beginning when David Bredt, a very talented MD-PhD student of mine, and I read about nitric oxide in the regulation of blood vessel function. We began to investigate a role for nitric oxide in the brain, and discovered indeed that it mediated major actions of the excitatory neurotransmitter glutamate. In this case, in order to understand the function of nitric oxide, we searched for the enzyme that makes nitric oxide. Many people had looked, but nobody could purify it—it had been presumed to be very labile. David thought that the lability might reflect the loss during the purification effort of a critical cofactor. He discovered calmodulin to be that cofactor, which permitted the purification and cloning of nitric oxide synthase.
MI: You’ve spoken to young scientists about your success, and one of your tips to them is, “Get a life.” What does that mean?
SS: Being a successful human being is the most important thing. You’ll be a better scientist if you’re a better human being. In general, scientists are much more constricted in their life than other professionals, and that’s unfortunate. For example, you rarely see scientists on civic boards.
MI: A stereotype of PhD advisers is that they look on their students merely as pairs of hands. Why would you care whether your students “get a life” or not?
SS: How you work with students is critical. Fortunately, I have good students. But lots of people have good students that end up doing nothing. So the issue isn’t just having people who are smart, but rather, whether they are creative and discover things. One thing that is important is to encourage creativity. My mentor, Julius Axelrod, was very good in structuring things for his students in a way such that experiments would work—there would be a positive reward. You’d feel good, and then you’d get a feel for how to design experimental strategies of your own. You must learn how to ask an important question and then develop a simple experiment to answer the question. A mentor should set his students up for success, then independence, and then give positive reinforcement so that they will be bold and have ideas.
If you treat your students as pairs of hands, then you’ve got to have all of the ideas. That means nothing will come out of your lab other than something in your own head. And here, if I have fifteen to twenty students in the lab and only one brain working, well, that’s inefficient. I think in terms of developing people. Being a mentor is like being a parent. As with my children and grandchildren, I look to see what’s in them, to help them develop into outstanding people.
- © American Society for Pharmacology and Experimental Theraputics 2002
