Eric R. Kandel during the interview.

Transcript from an interview with Eric R. Kandel, 2000 Nobel Laureate in Physiology or Medicine, on 13 June 2008. Interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.

So, Eric Kandel, welcome to this interview with Nobelprize.org.

Eric Kandel: Well thank you Adam, I’m very pleased to be here.

You were one of the co recipients of the 2000 Nobel Prize in Physiology or Medicine for your work, which was generally described as discoveries concerning signal transduction in the brain and we’ll come back to those discoveries in a little while, but I wanted to start with your childhood. In your Nobel autobiography, which is fascinating and also I think has the distinction of being perhaps the longest Nobel Laureate autobiography on our website.

Eric Kandel: That’s interesting, I didn’t realise that.

You speak very vividly about your childhood in pre-war Vienna and I wondered what abiding memories you had of that time?

Eric Kandel: Well, my abiding memories is that my family and I were expelled from Vienna and had to emigrate because of Hitler’s annexation of Austria and the Austrian enthusiastic welcoming of Hitler. So we were in a very awkward and frightening situation for a year until we had a chance to get visas to come to the United States. So my early years were really concerned with overcoming the traumata of that early experience and America has just been a wonderful place to mature and to really enjoy life.

You were nine when you moved to America?

Eric Kandel: Yes.

What was the first impression of arriving there?

… even in Vienna, before the Hitler era, one felt sort of constrained …

Eric Kandel: I had an immense sense of freedom almost from the beginning because even in Vienna, before the Hitler era, one felt sort of constrained, a very bourgeois sort of existence while in America I felt much freer. I enjoyed my schooling more here and I just have had a wonderful experience in the United States.

How did your family establish themselves though? It must have been hard.

Eric Kandel: It was extremely hard. I mean, my father deserves an enormous amount of credit. He’s a person of limited education but enormous energy. He ran a small toy store in Vienna and when he came to America he first worked in a toothbrush factory, this was in 1939 and he was very energetic and he was making more toothbrushes than other people, and the union foreman told him that he should slow down and he was uncomfortable about that and he went into business by himself. He sold undershirts and very simple women’s garments and things like that, sort of a haberdasher and first he carried it from door to door, as a pedlar, and then he had enough money to open up a store and he opened up a dry goods store haberdashery in Brooklyn at 411 Church Avenue, and he ran that until he died and he ultimately bought the house in which he was in and we had an apartment over the store.

So through hard work it became a big success story?

Eric Kandel: Yes. Well, he wasn’t a financial success but he was able to support me through college and medical school and my brother as well, so he was just a marvellous, generous person to all of us.

So college was history at Harvard?

Eric Kandel: Yes. I had a remarkable experience. I went to a very good public school called Erasmus Hall High School and then when I was close to graduating, one of the history teachers in the school, John Campagna, asked me where I was to apply to college and I said I was going to Brooklyn College, that’s where my brother was going. And he said “Have you ever thought of Harvard?” and I said “No” and he said “Well, why don’t you think of applying to Harvard?” and I went and discussed this with my parents and my parents, you know, did not have great means and they didn’t realise, neither did I, that Harvard was really a very interesting place and so my father said “Look, Lewis is going to Brooklyn College, we’ve already spent the money for your application, this is fine”. And so I told that to Mr Campagna and he gave me the money to apply to Harvard.

I was accepted to Harvard on a scholarship and I majored in history and literature there. I tried to do intellectual history and I wrote my honors dissertation at Harvard on three different German writers who had different positions on the political spectrum, vis à vis, national socialism and while I was working on this problem, tried to understand how the Austrians could, you know, listen to, you know, Handel, Mozart and Beethoven one day and beat up on Jews the next, I got interested in psychoanalysis through a friend who said “If you want to understand motivation of people you’ve got to understand the human mind”, and psychoanalysis was a good way of getting into that. I started to read Freud and I got very interested in that and then at very short notice I decided I would like to become an analyst, and in order to become an analyst you had to go to medical school.

I had no science at all. I’d finished my third year of college and I went to summer school between my third year and my fourth year. I took one science course and planned to take the other three required courses, but based on that one course and my earlier record I was accepted in medical school and I went to medical school with the only idea of becoming psychoanalyst and then just like I had a fluke in getting interested in psychoanalyses, while in medical school I had a fluke that I thought even a psychoanalyst should know something about the brain.

I liked doing the experiments, working with my hands, thinking about things …

So I took an elective with a very good guy, Harry Grundfest at Columbia on brain sciences and to my astonishment, because I had no deep interest in science whatsoever, I just absolutely loved it. I liked doing the experiments, working with my hands, thinking about things. I found that in a laboratory one had a completely different attitude toward science than one has when one reads books. Text books on science often are quite boring but doing science in a laboratory is unendingly fascinating. You talk about things and you mull them over and you discuss the data and you plan experiments. It’s an ongoing dialogue, it’s a very social interaction, it’s not, you know, little persons sitting in a dark room with the lights out looking at a microscope.

And I just thought this was a wonderful way to lead one’s life and I discussed this with the woman I was about to marry, Denise Bystryn, and she strongly encouraged me to think of science as a career if it gave me such pleasure and as I was finishing my elective, Grundfest asked me whether he should nominate me for a position at the National Institutes of Health, which had the best place in brain sciences, best training in brain sciences at the time and I accepted his gracious invitation and I was accepted at the NIH and between internship and residency, I took a residency in psychiatry, I spent three years at the NIH and that turned me into a scientist, from an incompetent medical student into a reasonably competent scientist.

It’s an unusual beginning in the lab, because most people come to the lab with some theory behind them but I imagine you arrived fairly fresh?

Eric Kandel: I had very few ideas about what to do. When I first went to Grundfest I thought I would look at psychoanalytic processes. He asked me “What do you want to study?” and I said I wanted to study the ego and the super ego and he thought I was just crazy and he told me you have to study the brain one cell at a time and that was really the sort of the motto of my scientific career. When I came to the NIH, Wade Marshall, who was my chief, said what do you want to work on and I really wasn’t sure. I thought about it for a while and I thought the central issue in psychoanalyses is memory; how is memory stored, how is it recalled, because most of psychoanalyses is dealing with ones earlier experiences and working them through in a trusting environment and about six months before I came to the NIH Brenda Milner described that the hippocampus of humans is essential for the storage of long term memory. She had studied a patient HM, a very famous case, who had …

Who’d had his hippocampus removed?

Eric Kandel: Both sides, the hippocampus removed because he had chronic epilepsy and the epilepsy was cured but he was, you know, he had this permanent loss of the capability of converting short term to long term memory. And I thought well, why don’t I study the hippocampus one cell at a time and soon after I got started another person who’d been recruited to the NIH joined me and we talked about it and he also thought this was a wonderful problem, Alden Spencer, and he and I had a wonderful collaboration on this and within a short period of time we succeeded in obtaining the first intercellular recordings ever obtained from neurons in the hippocampus and we were ecstatic and other people were ecstatic. Here were these two incompetent people had done something quite nice, but after the enthusiasm subsided and we looked to see, you know, what had we learned about memory storage by looking at just the single cell in isolation we realised very little and we needed to think through what one needs to explore in order to understand memory and that is how information is altered in the nervous system as a result of experience and we needed to see how does information come into the brain, how does information come into the hippocampus? So we tried to figure out how that happens and we used light stimuli and sounds and touch stimuli.

It was very feeble responses and we realised this is a very complicated problem. It actually took more than a decade to solve that problem and we needed a different approach and I personally felt we needed a radical reductionist approach rather than going to the most complicated system available, the hippocampus, it stores complicated memories, that maybe to use a very simple, maybe a simple animal or a very simple reflex learning that could be modified like Pavlov or Thorndyke had studied, classical conditioning and operant conditioning and so I began to look around for very simple, animal with very simple nervous system, with very simple behaviour that could be modified by learning and, again, not having a strong background in comparative biology I went to seminars and I read and I looked at flies and worms and crayfish and lobsters and settled in on a snail, a marine snail called Aplysia, which I’ve studied for the rest of my career and it’s been a wonderful collaboration.

Just to centre on that question of reductionism, just as you were brave in tackling questions that others may have felt were too difficult to tackle you were brave in choosing such a reductionist approach to studying learning and memory and I’m interested to know what it was that gave you the confidence?

Eric Kandel: That’s very interesting. I’ve asked myself that often because I didn’t feel it was such a courageous move. It was an extremely good decision on my part and it was against considerable opposition from my seniors, Jack Eccles for example, whom I’d befriended, who was sort of the senior neurobiologist in the field, who’d invited me to Australia to work with him on the hippocampus. Once he saw what we had done he himself wanted to work on the hippocampus and he invited me to initiate those studies. I decided not to go because I wanted to take this reductionist approach. He thought I was damaging my career. I didn’t for a moment think that and I guess it was for a couple of reasons. First I felt very confident that this was the right thing to do. In all of biology reductionism’s been a key approach. One studied genes first by looking in viruses and bacteria. In every situation, the way the action potential was studied was by using a giant axon of the squid, synoptic transmission was studied in elementary systems in which the synapse could be studied in isolation. So I thought, why shouldn’t learning and memory be studied this way.

I suppose only because the other things are biological and this is behaviour.

In those days young people were easily funded to do science if they had any track record whatsoever …

Eric Kandel: I assumed that all of behaviour’s biological and learning and memory must be stored in the brain and there were several other reasons which are social factors. So I made this decision in 1960 and I finished a very nice piece of work on the hippocampus.  So I had shown that I had some competence. While I was a resident; 60-62 I did another very simple piece of work in my spare time under endocrine cells of the hypothalamus. When I applied for a NIH grant to go abroad to work in a /- – -/ I had absolutely no difficulty. In those days young people were easily funded to do science if they had any track record whatsoever. It’s completely different than it is right now. I don’t think I would be supported for that. Well first of all there’s much less money available. The workforce is much larger, there are more people competing for it and the funding agencies, not the Howard Hughes private funding but the government is very conservative.

So to do something which was a little bit out of the way, to work on a system that you’ve never worked on, that no-one had looked at from a behavioural point of view and to try to do a cellular analysis of learning memory, which seemed very straightforward in 1960, would have seemed radical today. And so I was fortunate to come along at a time in which the funding was generous and people were encouraged to try new ideas. I’d in fact received a small grant to do the research that I was doing as resident part time. So the funding picture was completely different in those days, and particularly in psychiatry where there was a desperate need for research.  People like myself who were psychiatrists interested in science were tremendously supported.

Do you think that the different funding environment these days is perhaps inhibiting base research?

Eric Kandel: Oh, it’s enormously inhibitory. It’s a disaster in the United States at the moment, yes. The young people are really struggling in order to start their careers and I’m privileged and I’m a Howard Hughes Medical Institute investigator but otherwise I would be struggling.

And it’s causing people to ask safer questions presumably?

Eric Kandel: Safer questions. Some are leaving science. Fewer people are going into science. No, it’s a very serious situation in the United States.

And is there any foreseeable fix at hand?

Eric Kandel: Hopefully a change in administration would fix that, yes. A bit more positive attitude towards science, yes.

So back to the reductionist approach, could you just speak a little bit about how learning and memory in the sea snail is related to learning and memory in high mammals.

Eric Kandel: Right. Well my argument was, and I think this has proven to be, you know, largely right, is that learning must be conserved in evolution. It’s absolutely essential for an animal’s survival. An animal has to know where is the source of food, how to get nutrition. It has to know how to avoid things that are dangerous and to approach things that are desirable. This is essential for any animal. So I thought that any animal, with any nervous system would have some capability for learning and since so many things in biology are conserved I saw no reason for a process like this, which was so important for survival, not to have elements that are conserved.

Now obviously they’re going to be variations of the basic themes in different context and the mammalian brain, the human brain, would have, you know, add ons that would enrich the learning process and it’s absolutely so but I was interested in the most elementary components; what happens in a neural circuit when learning occurs? One had no idea. I mean, we had ideas but one didn’t have the evidence to support one or another idea. So I thought I would define a very simple reflex and I defined a reflex which was a simple withdrawal from a hot object and I showed that this could be modified by a variety of different learning processes.

The reflex could be enhanced, it could be diminished, it could be pared so it would be specifically enhanced in relationship to a condition stimulus and I could now see that a simple behaviour could be modified by different kinds of learning and I could ask what happens in the nervous system when that learning occurs. So I worked out the neural circuitry of this very simple reflex, worked out the sensory neurons, the motor neurons, the inter neurons and saw how they interconnected with each other and I found there was amazing precision. The same sensory neurons always connected to the same motor neurons, always connected to the same inter neurons and that of course raised a paradox; how do you reconcile the capability of learning with this predetermined neural circuit for behaviour and we looked what happens in the neural circuit when the animal learns and we found that even though the wiring is specified by genetic and developmental processes, what is not specified, what is not preordained, if you will, is the strength of synaptic connections and learning produces alterations in the strength of synaptic connections.

So when the reflex is weakened by a form of learning called habituation the connections become weaker, the cells talk less effectively with one another. When they’re enhanced by learn fear for example the connection become much more powerful and then we took one process and we tried to drive it into the ground, to really understand it. We found that as with complex forms of learning there’s a short term memory and a long term memory. So if you give a single training trial the animal learns it and remembers it for minutes but if you repeat that, practice makes perfect, in snails as in people, the learning can last for days or weeks and we saw what happens in the nervous system. We saw that with short term memory the connection’s strengthened for a short period of time and that involves a signal transduction pathway, very similar to the kind that Paul Greengard and Arvid Carlsson had been studying, with whom I had the privilege of sharing the Nobel Prize. With long term memory that signal process goes into the nucleus, it activates genes and gives rise to anatomical growth. So, as I like to say, in so far as you and I remember anything of this encounter tomorrow is because actual anatomical changes will have occurred in our brain that allows us to recall this discussion.

And the neuron selects which parts of its connectivity it’s going to change?

Eric Kandel: Exactly right.

You established that and then you went on to investigate, in detail, the molecular mechanisms that align those changes?

Eric Kandel: That’s right.

If one takes our current understand of learning and memory in the model systems that are studied, which I suppose are things like the sea snail and also in the mouse heavily, how far are we now away from understanding the sort of thing like memories of Vienna that we hold and what remains to be answered?

Eric Kandel: An enormous amount. Memory is a deep problem in brain science and brain science is, you know, an enormous mountain that we have to climb. We now understand some of the molecular details of a very simple reflex response that can be modified by learning. The neural circuitry that is involved in remembering my Vienna experiences involves, for example, my visual perception of the apartment, of being kicked out of the apartment. Those kinds of things involve complex circuits in the brain whose functioning we do not as yet understand. So in isolated instances we can see, we can trap elementary components of learning and memory in the mammalian brain, like the mouse, and we can see that even though there are variations, the basic themes are the same.

… that’s the challenge of the next century if you will, to understand in greater detail the neural architecture of the mammalian brain …

There is in the cellular level a representation of short term and long term memory. Many of these memory processes involve a signal transaction path with a cyclic A and P pathway. All long term memory involves alterations of gene expression and a growth of new synaptic connections but the systems that have recruited are much more elaborate and in most cases we do not have a complete understanding of that and that’s the challenge of the next century if you will, to understand in greater detail the neural architecture of the mammalian brain, of the human brain.  How it perceives the world, how it uses that perception to act on the world and how experience modifies it. So we have a beginning. The field has become much more powerful. There are many more people in it. There are many techniques available to study it. Imaging techniques that allow you to look at the human brain in action while the person learns something, so I’m confident we can make excellent progress but there’s a lot of work to be done.

Could we turn to teaching. You’ve put a lot of effort in your Principles of Neural Science textbook, which is now in its 4th or 5th edition.

Eric Kandel: 4th edition about hopefully to come out and a 5th edition within a year.

Teaching is obviously very important to you. What does it give you, do you think?

Eric Kandel: I’ve gotten an enormous amount out of teaching because, first of all, I like interacting with young people. I mean, when you run a lab you’re teaching all the time and it’s only when you really try to explain something to somebody else that you find out whether you’re in a standard or not and I think it’s essential for people to do that. Now you can spend a disproportionate amount of time teaching and you don’t want to have it interfere seriously with your science but you can work on the abdominal ganglion of Aplysia and think that’s the beginning and the end of the world and only by teaching a neural science course or getting involved in the text book do you see what the corpus of the field is about.

Becoming a scientist and evolving as a scientist because, you know, even at my age I feel I’m still learning is a question of developing taste. In science, as in all aspects of life, and you develop taste by seeing what other people do, what are the really important questions, what’s trivial and making important distinctions between them and I think only by teaching and writing in more general terms do you begin to develop that kind of taste. Of course talking to people which is implicit in all of that.

And as you survey the field there must be so many fascinating questions that occur to you and occur to you as ones that you yourself could perhaps address and yet you’ve maintained your focus on memory, that’s been the central question throughout your entire career. How do you do that? Is it an effort to stop going down other paths?

Eric Kandel: No. I mean it is an effort in part because learning and memory are so broad. I mean any single person just scratches the surface so I’m recently become interested in animal models of mental disorder. I’m a psychiatrist, the tools are now available to begin to study anxiety disorders. I studied anxiety disorders in a snail, right, but what about the mammalian brain? So I’ve studied anxiety disorders in the mouse, learn fear. I’ve been involved in a project looking at a component of schizophrenia because schizophrenia also has a memory deficit, it’s called working memory. It is the cognitive symptoms of schizophrenia are defects in a memory process.

So memory is involved in depression, it’s involved in age related memory loss, it’s involved in Alzheimer’s disease. So it’s not a very narrow problem, it’s an enormous problem that, if you will, encompasses much of mental function. So I need to restrict myself to some things I can do well and, you know, limited number of things I can do at all but restricting myself to the general area of memory is like saying, you know, is Sweden a large enough country to walk around in? Yes, there’s no problem.

When you recruit young people to come into your lab to work on the problem, what do you look for, what do you search for?

Eric Kandel: Creativity. Many people that come to work with me know nothing about the brain. They come to me to learn about the brain. They bring their own ideas and their own techniques. So they may come with a background in immunology, they may come with a background in molecular biology or yeast genetics or mouse genetics and we combine the post doctoral fellow skills and mine in order to tackle a problem and we both enjoy and it’s essential to select a problem that is gratifying, not only for you but for the person that you’re working with because otherwise they don’t feel this is their problem and they’re motivated to do it.

And what about for younger students or do you tend to concentrate on post docs?

… once you’ve sensed what it’s like to really solve something wonderful you become addicted …

Eric Kandel: I only take one graduate student at a time and even with graduate students I try to sense out. I’ve been very fortunate in the quality of graduate students I’ve had. Many of them have had wonderful ideas, where we talk together I would suggest something. I tell them first to just walk around the lab and to speak to people and see what projects really interest them. The one point I would make is I encourage students to tackle important problems because I think once you’ve sensed what it’s like to really solve something wonderful you become addicted. The satisfaction of doing something which is novel and which is important is very, very satisfying.

So how, as a young person, do you spot an important problem?

Eric Kandel: You discuss it with them and you help them. That’s how I can be useful. I can tell them, this is not interesting, this is. It’s a question of taste. You help them develop taste.

That sounds like perfect advice for a young person moving into science. Ok, well with that I’d like to say thank you very much indeed for taking the time to speak to us.

Eric Kandel: I’m delighted. Really enjoyed it. Thank you.

Thank you.

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