Interview with the 2000 Nobel Laureate in Physiology or Medicine, Paul Greengard, 13 June 2008. The interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.

Paul Greengard, welcome to Stockholm and to this interview with Nobelprize.org.

Paul Greengard: Thank you.

It’s been almost eight years since you came to receive your Nobel Prize in the year 2000 and your work on unravelling the pathways of signalling in the nervous system continues, but your first introduction to experimental work was not in biology but in electronics because you were drafted by the army to work on radar.

Paul Greengard: I volunteered in the Navy.

That was during the second World War and that was straight from school. How did you find your first exposure to research work?

Paul Greengard: I really didn’t do much research in the field of electronics. I was not quite sure, I spend a period of time during the war up at the Massachusetts Institute of Technology in what is called the Radiation Laboratory working on the development of a microwave radar. At that time, one of the big problems for the United States was these kamikaze, these low flying Japanese aircraft that would just fly 20 feet above the water and due to the curvature of the Earth, these aircraft could not be detected until they were about 20 miles out. They had these antennae on the tops of the ships but that’s still not very high and so the curvature of the Earth is such that you can only see about 20 miles. This was in the days of very primitive television so the concept was you’d put a radar screen in a plane and then had the image projected down to the aircraft carrier. I’d been sent to an electronic school in the Navy and then they took two of us from that class to go up and work with these physicists who were, I thought at the time, old men, they were probably in their late twenties but I was like 17, 18. It was an amazing place, there were several of them went onto win Nobel Prizes in Physics and so on so I learned a lot. I wouldn’t say I did research, I was like a technician doing things for them.

But a wonderful environment.

Paul Greengard: It was an amazing place. It amazes me, the highest security level in the United States is top secret and the next one is secret and not many people get to see that but our project, we were all given clearance to look at all sorts of secret information and it’s just amazing. We shouldn’t have been, I mean we had no need to know that but for example, we knew that the English … At that time the Germans were trying to bomb London and they had these two beams that intersected over London and what the British did was they had two beams that deflected them so they were crossed in some place, I don’t know, 30 miles north east of London in empty fields. I knew about that, and there were dozens of people who know it with no need at all to know about it and these days you’d say that was a really bad security lapse but people weren’t so ultra-concerned about security then.

Yes, but how extraordinarily exciting.

Paul Greengard: It was amazing for a kid to be exposed to all that was going on.

Would you say that switched you on to doing science or was it just a nice episode?

Paul Greengard: I think it never occurred to me that I wouldn’t do science or mathematics or engineering, that was that spectrum that I was interested in.

But maths and physics was what you went on to study at university and then you made the decision to move towards the study of biological systems. What switched you from a physical sciences track?

Paul Greengard: When I went to college, I wanted to study physics and maths because that’s what I was good at and that’s what I’d majored in, mathematics and physics, when I went to college. When I was going to go to graduate school, then it had been not that long after the dropping of the atom bombs and the only support you could get to go to graduate school was from the Atomic Energy Commission and it just seemed to me, I wanted to do things with my life at whatever chance I might have other than finding better ways to kill people. I had learned from my roommate in college about this emerging field of biophysics or medical physics which is applying physics and mathematics to a biological and medical question, so I applied to study biophysics. At that time there were only two departments in the country that were doing that, and one was at the University of Pennsylvania where they were using electrical approaches to studying signalling in the brain and I applied there and that’s where I went.

Did the interest that you subsequently developed in biochemistry come at that point?

Paul Greengard: No, I learned a lot about the electrical properties and neuro cells and various interesting properties of neuro cells. At that time, just about the time I was going to start my thesis, at that time you had to do basically all the qualifying courses in physics and in biology to get your degree and then you went onto your thesis. During that period while I was still taking courses, Alan Hodgkin came to a lecture in our department and he and Huxley talked about the work for which they won the Nobel Prize on the ionic basis of the nerve impulse. I felt that, it’s going to be a long time before any more advances are going to be made in understanding the property of nerve cells by purely electrical means and I felt that one’s got to get at the biochemistry underneath the electricity. Then I started taking courses in biochemistry and so on and this didn’t exactly go with the main flow of the department, they were purely biophysicists measuring electro properties of nerve cells and membranes and so on.

Yes, because these were very different time. This was the 1950s and chemical neuro transmission in the brain, for instance, still wasn’t accepted …

Paul Greengard: Correct.

… which I think is interesting in itself because peripheral chemical transmission had been known for decades and indeed Dale and Loewi got the Nobel Prize in 1936 for that and yet somehow it was impossible to accept for decades in the brain. Do you have a feeling why that was, why it took so long?

Paul Greengard: It was the background of the scientists working in the field. There were two types of people studying the brain, one was electrophysiologists who measured ion currents and action potentials and were not interested in the biochemistry underlying it. I guess you could formulate their thinking as, well, we need energy to keep these cells alive, we don’t even know why we need energy but we do, so they really were not interested at all in the underlying biochemical basis. The other group were biochemists who would take a brain and homogenize it to measure an enzyme because the brain’s a remarkably active place metabolically and for a huge percentage of enzymes. There’s much more activity in the brain than in the liver, the pancreas or the muscle, so you just take your brain out and homogenize it and use it to study an enzyme reaction.

Yes, mush it up.

Paul Greengard: Yes, and the two groups didn’t really talk to each other. At that time there wasn’t even a field of neuroscience, it was electrophysiology which was studying the electrical properties of nerve cells and then there was biochemistry where you’d use whatever organ provided the best source of an enzyme.

Nowadays there’s a great fondness for saying that people that are going into disciplinary research are trying to unite disciplines. Did you feel you were doing that back then, were you crusading to bring them together?

Paul Greengard: I was not crusading to persuade other people to do it, I did it and it was considered a very eccentric approach, I guess, but in fairness to the faculty of my department, they did not oppose my doing it. I actually did a thesis under the joint supervision of an electro physiologist in our department and a biochemist who was in a place called the Moccollum Pratt Institute which was a biochemistry department basically, as a subsidiary of the biology department but that’s where they did lots of enzymology and so. It was one of the more prominent places in the country at that time, doing enzymological kinds of work, so I did my thesis in the interface between electrophysiology and biochemistry and was interested in selling the biochemical basis for the nerve impulse.

As I continued, then I went on to do post-graduate work. I spent five years in England and continued to work in this boundary between the two disciplines and virtually nobody was doing that at that time, trying to understand the biochemical basis for neurobiological phenomenon. Then I was offered a position as head of biochemistry department at what at the time was Geigy Pharmaceuticals, today it’s part of Novartis. I was interested in the difference in salary between what I would have got in the university and truly it was like 10% or something, but I was quite idealistic and I wanted to use scientific approaches to new drug development, so I went into this company and I was there for eight years. It was a rather exciting period for me but I left because everything was done by committees and to a large extent it still is. Some of the things that I felt were avant garde, the other people would not agree to them and unless the committee would agree, it wasn’t done. I got frustrated and I thought I could do more in terms of understanding the basic biology and how you could use that information to study the action of drugs and develop new drugs. I felt I could do that better going back to university so that’s what I did.

You went back. That interlude must have given you an interesting perspective on what followed and it must have been quite productive if you stayed eight years, you must have really loved it.

Paul Greengard: It was very educational because as the head of the biochemistry division I was obliged to learn lots of stuff that I didn’t know anything about. In those days people were doing biomedical research, didn’t go into medicine, there was so little known about the basis of diseases and so on that it was more like laying on of hands and comforting patients, there was very, very little available, very little scientific knowledge. The situation is quite different now and I would advise young people wanting to do biomedical research to go through medical school now, at least through the first part of the curriculum, so you get a much broader education. I was educated in graduate school in a very narrow area and one of the functions that this being a pharmaceutical company did for me was to give me a much broader education in many different areas of medicine and diseases and I think that’s helped me in the ensuing decades.

When you left Geigy, you did return basically to the same research questions that you’d had before?

Paul Greengard: Pretty much, nobody picked it up in the meanwhile and when I started working again, the projects were somewhat different but the basic philosophy was the same. Earl Sutherland had shown that cyclic AMP mediated the actions of hormones and I’ve been following that work ever since I was in graduate school, it always interested me. Then Ed Krebs together with Fischer showed that the cyclic AMP activated a protein kinase and broke down glycogen.

Showing protein phosphorylation in the liver, yes.

Paul Greengard: Yes, that was phosphorylation in the liver and muscle and since hormones are released by one cell and work on another, it possibly occurred to me that maybe neurotransmitters worked that way, they release from one neuro cell and act on another. I thought, maybe this system is present in the brain and we found that it was. We found that neuro transmitters could raise the levels of cyclic AMP, we found these cyclic AMP activated protein kinase activity and not only was it in the brain in enormously higher concentration than elsewhere, but it was in the synapse, the junction between two nerve cells. It was so high there that I knew this had to be right, that this basic principle that Sutherland and Krebs had elucidated in terms of a hormone making a second messenger go up and then that second messenger regulating protein phosphorylation was going to be important in the brain and I haven’t left since, that was 40 years ago.

If it was unusual to go down a middle path between biophysics and biochemistry earlier, it was positively heretical to work on second messenger systems newly discovered by Earl Sutherland in the brain, in the 1960s. How did it feel to move into an area where you were really …

Paul Greengard: It was interesting. It means I present our data and once a very well-known person got up and said, This is heretical, this is ridiculous, why are you talking such nonsense? It hurt my feelings but it’s interesting, I never doubted that I was right. I don’t know why but with lots of negative reactions, I never doubted I was right and it turned out that this was right and it had advantages and disadvantages. The disadvantage was it’s nice to have people appreciate your work which was not done very much then. The one exception was Earl Sutherland who said, Even if you’re only 90% right, it still meant that it’s been extremely important what you’ve done. He had that vision, he appreciated what I was doing, but most people did not. That was the disadvantage that people didn’t show any appreciation or very, very few did for the work. The advantage was that I had the field pretty much to myself, the signal transduction for almost 15 years and that was nice and by the time that people began to realise it was right, I’d laid out a large part of the foundation for signal transduction in the brain.

Right. How did funding work in that time, because nowadays, to do something that people disagreed with for 15 years would be presumably impossible.

Paul Greengard: That’s an excellent question. The fact is that today you could not get funding for this. At that time, funding was fairly liberal and people said, Well, he’s a smart chap, he’s on the wrong track but let’s fund him until he comes to his senses, it was that sort of thing. I did get good funding even though there was not much belief in that I was on the right track.

Nowadays people describe how they do their real passion on the side and they have pot boiler experiments that keep the reviewers and the grant awarding bodies happy and they do the two in parallel. But you weren’t doing that, you were just going wholeheartedly.

Paul Greengard: At that time, yes. But then, as the competition for money got tougher, I mean virtually everyone now is forced to put in experiments where you’ve already done some of the work because you know how this comes out and you give a more logical presentation. There’s a big difference in the philosophy in terms of support of research in Europe vs the United States. In Europe, if you have a good track record, they pretty much automatically give you money for the next five or ten years and when they evaluate people, they look back, what did they do in that previous period? In the United States it’s a very different philosophy. They say: Well, he did that but what has he done since he discovered fire, what’s he going to do now? They look at your grant application and it’s got to be good. I’ve seen, because I’ve served on committees as well as applying to committees, I’ve seen both kinds by some people saying this guy’s really good or this woman’s really good and let’s fund them another five years although the grant application is written so well, but in other cases, I’ve even seen almost inverse discrimination. They say: This person thinks they’re so hot, and it’s my impression from committees I’ve sat on that they have a higher bar for the more accomplished people, they can do better and that kind of thing.

I’ve seen the bias both ways but in my own case, the first grant I applied for after the Nobel Prize, I got turned down on. That was really amazing, we had a grant deadline in for November 1, and with the Nobel Prize given like October 10 or something like that. I wrote and I actually called somebody at the institute I was applying to, to ask if they could make an exception, so instead of being November 1, could I have an extra two weeks because life is really hectic right after the Nobel Prize and this woman actually said, We can’t do that, what if everybody who won a Nobel Prize wanted to have that exception? It’s really kind of amazing, watching the bureaucracy.

So there just wasn’t time to do it and it got turned down?

Paul Greengard: I don’t remember, did we actually get it? Yes, we got it in on time and then it got turned down. I’ve had other Nobel Laureates tell me that they’ve had grants turned down right after they … I don’t know, they just raised the bar for what they expect or something, but it’s a psychological thing.

Yes, they’ve had their reward, they better do …

Paul Greengard: Yes. But anyhow, to go back to your earlier question, I’ve been very fortunate at getting funding both in the earlier days and now that it’s somewhat more difficult or it’s a lot more difficult now.

Just to return to the sort of inner confidence that people for 15 years in the main were just not believing you and occasionally you were getting criticised by the great and good, so going down the wrong track. You say you never doubted, I think that’d probably strike people as quite an extraordinary degree of self-belief.

Paul Greengard: That’s true and there are people who are ultra, ultra confident, they must have had very happy childhoods. I’m one who often has doubts about different things but I was so convinced that this was the way cells had to work, it all made so much sense. There was loose ends and apparent contradiction, I just tried to figure out why that experiment came out the way it did. Sometimes you’d find interesting unanticipated answers but the basic picture held up, but I’ve talked to other Nobel Laureates who have said that, I think it’s much more the rule and the exception that most Nobel Laureates, I guess you could say we’re all paranoid, feel that their work wasn’t appreciated and everybody was criticising them and finally they prevail. I think, as I said, it’s much more the rule than the exception that people go against the main thought and if you think about it, it makes perfect sense. If you’re just adding a marginal advance onto what’s already known, you shouldn’t get a Nobel Prize, there were prizes given for major discoveries and major discoveries almost by definition go against the prevailing thought that preceded them.

It’s interesting that going against the preceding thought also means encountering opposition in those who believe in the way that things are perceived to be. People don’t necessarily welcome new ideas, they actually positively push them away. I think it’s probably an impossible question to answer but, as you say, many Nobel Laureates have stories about being isolated in their research.

Paul Greengard: You’ve had that experience in interviewing people.

Absolutely.

Paul Greengard: Nobody believed me.

Exactly. Everybody else was burdened by dogma and they somehow saw a way through that and it was self-belief, not trying to prove other people wrong or anything but simply believe what the experiments were telling them.

Paul Greengard: This is the way the system has to work. It’s almost like beyond yourself, I just know this is right. I’m positive I left my keys in that room and if you’re positive, usually they’re there, not always.

Yes, and the experiments are telling you …

Paul Greengard: My ego wasn’t even involved in it, I just felt, this is the way it has to be. It made so much sense, so much could be explained by this way of thinking.

The question I was going to ask is, whether it’s possible to get any sense of the number of people who are doing this sort of thing who aren’t right?

Paul Greengard: Who are not right?

Who are not right, because Nobel Laureates are by definition in the end right, at least on that, but there must be lots of people who are dedicated to what their experiments are telling them, that are going down tracks that never actually get accepted and I wonder how many, what the balance is.

Paul Greengard: It’s easy because it’s because they’re wrong, because if they’re right it is accepted. The only way you could say they were right but their fellow scientists didn’t believe them and so they stopped funding them and then it takes years until somebody else goes back and picks that idea up. I mean that happens in science. Gregor Mendel was not believed in his time, it was only like decades later that support came for his ideas about genetics.

One can’t approach the question of how many good ideas are just being lost by lack of funding or lack of ability to continue.

Paul Greengard: I think the nature side is such that, I think very few ideas are lost because science tends to be such that there’s a next obvious problem to solve and you solve that, then there’s a next obvious problem. I think it’s quite common that different groups make the same discovery at the same time because that’s the body of knowledge that provides the foundation for those discoveries. I don’t think there are too many great ideas that don’t eventually get proven to be correct for lack of funding because I don’t get the funding for it but if that’s idea’s right, you’re going to come along ten years later with the same idea and prove it’s right.

The truth will out, sort of thing.

Paul Greengard: Yes, I believe so.

Your research has explained the intracellular signalling mechanisms behind slow synaptic transmission, which is basically the way that neurotransmitters modulate the responsiveness of the neurons that they’re talking to. Do you feel that you have a complete picture of how intracellular signalling is working or a very incomplete picture? Where are we now?

Paul Greengard: A very incomplete picture. The picture today is the following: these fast-acting neurotransmitters where the signalling goes on in less than a millisecond, that analogies the hardware of the brain and then the slow signalling pathways that we have worked on, you can consider that the software of the brain, what they do is modulate the fast signalling. This modulation is incomparably more complex than the signalling itself and I think we just know a very small percentage of what is to be known. There are so many of these intracellular signalling pathways and I believe we’ve just discovered a very small number of them. Take this region, I mean the Nobel Prize, last year on the ds RNA. This is a major, major regulatory system and nobody knew about it, it’s amazing in retrospect. I’ve heard other scientists say the same thing, how can such a prominent phenomenon not have been found earlier, but it wasn’t and you wonder how many more things are. I’m certain that in terms of these signalling pathways, there are going to be dozens more known. I think we probably know a very small percentage of them.

Bearing that in mind, I’d be interested to talk about the disease implications of your work because, your work’s primarily on the dopamine system which is implicated in lots of diseases of the brain. You’ve identified a couple of key molecules as DARPP-32 which is like a master switch for a synapse and also more recently this P11 which just seems to be a depression associated protein. Those represent good drug targets, that’s the received wisdom, and I know that you and others are trying to target them. Given that they are only a small part of the puzzle and there are lots of pieces that we’re missing, do you think it’s nevertheless a sound idea to pursue those as drug targets, given a very partial understanding of their role?

Paul Greengard: We don’t have an option. We can’t wait until we know the whole story, because we’ll never know the whole story, so there’d never be another drug developed for a disease if you take that attitude. Let’s not start working on this yet because maybe part of the puzzle is missing. In fact this sort of knowledge is already paying off big time. We know enough that some of these signalling pathways that our group and others have studied have become major targets in the pharmaceutical industry. By far the major drug target right now are these receptors for neurotransmitters and a couple for these G-protein-coupled receptors or GPCRs. GPCRs are by far the major target now. These GPCRs are all part of this software or this slow synaptic signalling that I was talking about and I’d say today, the information about slow synaptic transmission has transformed the pharmaceutical industry so that the major targets come from these slow synaptic signalling pathways.

In general, would you say that the drug industry is taking the right approach to pursuing those targets?

Paul Greengard: Yes, I do. The drug industry is sufficiently more sophisticated than it was when I worked in it and I do some consulting for them and I can see it. When I was in the pharmaceutical industry, it was dominated by organic chemists, synthetic chemists and by and large what they would do is say would just modify molecules. Company A would see Company B has such and such a drug and they say, let me see how we can modify that drug to get around Company B’s pattern. There was very little thinking about the biological systems. Just as all the drug companies or almost all the drug companies were dominated by synthetic chemists thinking about how to get around their competitor’s patterns, nowadays the drug companies, their heads of research are almost all biologists who think in these sorts of terms about what are the best targets for developing a new drug, should it be this enzyme or this receptor and so on.

There’s been a dramatic change in the approach and by and large, they’re pretty open, people in the pharmaceutical industry are in general more conversant with the literature than my colleagues in academia and myself because they’re continuously combing the literature to find out what look like interesting new ways to develop drugs. The problem is the momentum or inertia, depending on your point of view of programmes. If some academic person publishes an interesting new story with an interesting target for drug development, the drug companies could say, oh sure we’d like to do that, but they’ve got seven people working on the finishing of this drug and four people on this one and you can’t just keep pulling them off every time something gets published. There’s an understandable resistance to picking these things up too quickly, but the attitude is that the appreciation is there, I guess for the better companies you’d say their attitude would be. I really would like to do this new programme based on that study that /- – -/ just completed but we don’t have the manpower for it right now, we have to wait until this programme is completed and then we go onto it.

Obviously there’s a tremendous amount of effort in this but I guess that the answer is partly finding translational programmes that will take research out of academic environments into drug company environments in a sort of staged way, so that some of that initial testing can still be done within academic environments.

Paul Greengard: One big shift has been that the big pharmaceutical companies are relying more and more on biotech companies. Somebody who is an expert in this area was telling me that, something like 80 or 90% of the research money for new drugs is spent by a big pharma and 80 or 90% of the new drugs came out of biotech. These big pharmaceuticals has almost a necessity of changing their strategy and they’re becoming clinical trial companies, the exciting new leads tend to come out biotech companies. Biotech companies can attract scientists who are very creative and like do something really exciting and don’t have the inertial associated with gigantic pharmaceutical companies where there’s several layers of approval that have to be gotten. They are coming up with these targets and then they’re being either partnering with or being bought by the big pharmaceutical companies who then take these compounds and do toxicity studies on them and then put them into clinical trials. The course goes from the basic research kind of thing which is in the order of millions or tens of millions /- – -/ to these clinical trials when you get into phase three, you’re talking 100s of millions of dollars. With very few exceptions such as Genentech and Amgen, these biotech companies are dependent entirely on partnering with the pharmaceutical companies.

Still on the theme of drugs a bit, I want to talk about pharmacology as a discipline. You moved in 1983 to Rockefeller, to a neuroscience department, and I wondered whether you felt it mattered what the departments you worked in were called and what they were, especially with reference really to the perceived decline in pharmacology these days.

Paul Greengard: At Rockefeller there are no departments, their laboratories are headed by individuals and if there’s anything exciting, then the university will recruit somebody in that area but it will be the ‘Adam Smith Laboratory of Immunology’ or say the Morphology or whatever. Historically I was happy to be in the pharmacology department. The reason we were talking about earlier, that the electrophysiology departments only had electrical equipment and the biochemistry departments only had homogenizers to homogenize stuff. Pharmacology departments had both because they tended to be more biochemically or in pharmacology, more electro-physiologically units. When I was young, that was an attractive thing to do, to work in a pharmacology type of department. When I was in England, I spent several years in the laboratory of man named Wilhelm Feldberg who was one of the people who was involved in this demonstration of chemical transmission in the brain and they had both types of equipment there and so that’s why I chose to go there rather than to a biochemistry department or a physiology department. Today I don’t think I know enough about the structure of various pharmacology departments but I would say most of the cutting edge research now is done in departments other than pharmacology, with a few exceptions.

Yes, I suppose the question is whether that is a problem, whether the lack of pharmacology departments as a draw to students who want to go to places where cutting edge things are happening, might be inhibiting the next generation of pharmacologists from ever appearing, if you see what I mean. It’s just not a very popular discipline these days and is that a problem?

Paul Greengard: It is a problem that pharmacology is no longer considered an attractive science but there are people doing very interesting research which is basically at the molecular pharmacology level, but they do it in all sorts of departments now. These departments make more sense now in terms of teaching responsibilities. Pharmacology departments teach pharmacology and biochemistry departments teach biochemistry and molecular biology and the research that used to be done in pharmacology departments now can be done in any department where there’s somebody interested in the molecular basis for a disease or the molecular basis by which a particular therapeutic drug works.

Turning to teaching, it’s interesting that in your Nobel Lecture you illustrated with pictures of many of your co-workers. Obviously, you have very close and productive relationships with lots of people who come into the lab. What do you look for in a co-worker, how do you choose your co-workers and the post-docs and students who come into the lab?

Paul Greengard: There are several things that one looks for and mostly you just go by your gut reaction. I was reading an interview with Jobs, head of Apple.

Steve Jobs.

Paul Greengard: Steve Jobs, I think it was him, but it might have been one of the other big shots in the field, who said that before he talks to somebody, as they walk in the door to come up to his desk, he knows, he has this gut reaction, yes or no. I think most of us do that. I think if you think about it, you see someone, you sort of like them or don’t like them before there’s a word exchanged, there’s something. I have no idea what it is but there’s body language or whatever, I’m arrogant, you’re modest. That’s a major part just instinct, but before I ever interview the person, in my case I’m fortunate because I’ve had a large number of applicants each year and so I can pick who I think are the best people. Even so one makes mistakes, not infrequently, but you see what kind of laboratory they trained in, what kind of letters of recommendation they have, which journals they’ve published in. Sometimes one will take a student who didn’t publish anything yet, if the letters explained why they didn’t and why this young person’s very promising and so on.

The filtering goes on, first reading the letter, getting letters of recommendation, looking at grade point averages or publications, depending what level, whether it’s a graduate student or post-doc and then the chemistry when they come to the laboratory, if you invite them to the laboratory, what’s the chemistry between them? I also am very fortunate having some extremely talented young people with me and I let them pass the callipers over these potential applicants to. We usually agree pretty much on who we should offer a position, who we should not.

What do you think the people who come to the lab look for most from you? What’s the most important element in your mentorship of them?

Paul Greengard: I think over the years people have come to my laboratory who thought what we were doing is exciting. One of the best yardsticks of how well you’re doing is the kinds of students that apply to you. It goes back to this idea we were talking about before how, you’re a scientist and you have these ideas and you publish papers on these ideas and you want to go on longer with that and your colleagues say that’s not very interesting. The students who don’t have this bias that we all develop think what this person’s doing is really interesting, I want to go and study there. I’ve had that happen to me. This one very distinguished person who told me in high school he wanted to come and stay with me, he’d been reading my paper. He’s a very gifted guy and then he went to college and then when he wanted to go to graduate school, he applied to the department I was in, the pharmacology department, and they turned him down. I didn’t even know about him and then he did a graduate study in another very distinguished laboratory and applied to me at the end of that and he was so good that I took him and then he told me this whole story, I hadn’t met him before that. A lot of times, the more creative and talented young people know what they want to do way before other people do. It’s a funny thing now, there’s an increasing tendency in education to oblige students to rotate in several laboratories. Don’t make up your mind yet. In fact, there’s a strong correlation of my opinion between people deciding exactly what they want to do and then being successful later on.

That’s interesting.

Paul Greengard: What they do now, the best students, they have to go through the system notes and this happens in many schools now. They’ll say, Okay, I want to work with Adam Smith and then they’re told by the dean of students, Well, you’ve got to do three rotations, so he sits down with Adam Smith and finds out what rotations that I’d do would be most helpful to my work with you Sir? Okay.

They keep their focus, yes.

Paul Greengard: Yes, they do and as I said there’s a correlation between. Some of the most gifted people I know and have trained knew at a very early stage they want to go here or here or here. It’s a very interesting yardstick and one of the nice things about having students is we all tend to get into these ruts, like we were talking earlier about how most Nobel Prize winners in their paranoid fashion, feel that they were not appreciated, their work wasn’t appreciated earlier on and finally, having become so overwhelming say, Oh, he was right. The nice thing about having students around is I found myself continuously falling into that thing. There have been several examples in my own case where I thought this young person just published this but this can’t be right, it just doesn’t fit in with what I believe and it turns out they were right, so I really try to keep my mind open.

It’s one of the most important things as you get more structured in your thinking about how the brain works and students are wonderful for that because they’re always questioning whether you’re talking about publications from some other laboratory or your own work, they’re always looking at it with fresh approaches, so that I think is extremely helpful to have graduated students, post-docs but especially graduate students because they are really still, you know, wide eyed and bushy tailed and they haven’t set up a structure of how the system works and I really try to listen to them if they think something’s wrong and often they’re not right but often they are.

You need brave graduate students who are willing to put forward their ideas.

Paul Greengard: That is a problem and it became an increasingly big problem the more recognised I got because the students tend to be very respectful. I’ve talked about this with a number of colleagues and it’s to try to get the students to say what they really think. Criticise me if you don’t like my idea, don’t just sit there and think, Gee, the professor’s wrong. I really want to know about it and I try to draw them out but it’s a problem, for example at our lab seminars, one of the post-doctorate fellows might be giving a presentation and I will critique it and make comments and I’d like other people to, but often they will not do that. They’ll go and talk to the presenter afterwards because they didn’t want to embarrass themselves if they were wrong or embarrass the speaker if they were right. It’s a major task to get the students not to be inhibited.

Yes. In fact, we’re seeing exactly the same thing going on right now in Stockholm, with this Nobel Symposium that you’re at, that Torsten Wiesel, who’s going to sum it up has invited some of the students who are listening to give their comments at the end and of course it’s too frightening to deliver their comments.

Paul Greengard: They don’t want to do that.

It’s too inhibiting.

Paul Greengard: Yes.

They’ll write them down but they won’t…

Paul Greengard: Are they saying they’re going to hand them and he’ll read them?

I think that’s the compromise we’ve reached.

Paul Greengard: That’s a pretty clever way to do it.

I wanted to finish by asking you about the Pearl Meister Greengard Award which you started by donating your share of the Nobel Prize money to endow. It’s an award for women working in science. I think it’s been going for four years now?

Paul Greengard: Yes. It was going to start right afterwards, but the then the president of the university and I had a difference of opinion about how this should be done. Then he left and nothing happened for several years until … I mean I just kept to my position and then when Paul Nurse came in, he was very enthusiastic about it. The idea of the prize was to recognise the most outstanding woman in biomedical research from anywhere in the world each year and a lot of people were very excited about it. I announced that on the day of the Nobel Prize with all the cameras and all that. I had hundreds of emails from women. There was not a single exception to them saying how much this meant to them. Some of these letters, they felt so much discriminated, they said they cried when they heard this, it was just unbelievable, the response. Anyhow, when Paul Nurse came in as president, he was very enthusiastic, we set up an award committee, I think it’s got something like seven Nobel Laureates on it, it’s a pretty prestigious committee. I had assumed the president would bestow the award each year and he had a very clever idea saying let’s have a very outstanding woman not in science present the award …

That’s a good idea.

Paul Greengard: … and so now we really have two prizes and the first one was Sandra Day O’Connor who was the first woman ever on the supreme court who’d been a victim of tremendous prejudice. She graduated third in her law school of Stanford and could not get a job in a law firm in the United States. Each year these people tell about these discriminations and these are very successful people. The scientists were much less well known than the presenters, it’s really funny. A woman named Helen Thomas who was the dean of the Washington Press Corp.

These people are also awarded or they’re just the presenter.

Paul Greengard: No, they present it, but by the very fact they were picked to present the award. They’re picked by another committee which is all women, who pick somebody from various fields each year and then they present it, so it’s not an award but it is an award …

I see.

Paul Greengard: … and they’ve been very prominent women so far so there’s now really like two prizes, which is very nice.

Is it a closed nomination process? Do you invite nominations or can anybody nominate?

Paul Greengard: No, so far the committees have done it themselves because if you start doing that, the costs escalate unbelievably.

Of course.

Paul Greengard: With both of these prizes enough fairly informed people, there’s no shortage of people. Sometimes somebody will say, Gee, you should think about so and so but there’s no letters of not saying, Now can you suggest women, because then the costs go up 100. I mean there’s basically no cost to this. I guess most of the people on the committee are from nearby but some are from distant lands, but the university pays the expenses for their travel, so basically it’s minimal costs for their part.

How nice that it’s up and running, it’s an amazing thing.

Paul Greengard: It’s been great for the university too, it’s like one of the highlights. People have said, this is the highlight of my year and some of the people on the awards committee are very busy people and they say they really love this and thank us profusely for having asked them to be on the committee. I didn’t want to have anything to do with it because I don’t think the people who give the money should, but they asked me if I would be, so we had a compromise right, I sit in on the deliberations but I don’t vote on the winner.

Yes, that’s a nice compromise, very interesting.

Paul Greengard: It seems to work well, yes.

Of course we haven’t mentioned that the award is named after your mother.

Paul Greengard: My mother died giving birth to me, so it’s not like I was a beloved mama’s boy. I didn’t know her, but I’ve seen so much discrimination against women in my own career that I felt it would be nice to do something of this sort and my wife was very supportive about that. She was quite enthusiastic about it, she’s a sculptor and there’s been discrimination against women in all fields. She’s been very successful but she has witnessed lots of discrimination.

With that I’d just like to thank you very much indeed for taking all this time to speak to us, it’s been fascinating.

Paul Greengard: Thank you.

Watch the interview

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