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In Search of Memory: An Interview with Nobel Laureate Eric Kandel

In this episode, the guest is Eric Kandel, recipient of the 2000 Nobel Prize in physiology or medicine. Kandel discusses his research, his personal background and their intersection. He talks about what kinds of scientific investigation he finds most interesting and worthwhile and where he would concentrate if he were beginning his research career today. These and other subjects are also themes of his new book, In Search of Memory, and his article in the current issue (April/May) of Scientific American Mind, called The New Science of Mind. After the interview, we'll also test your knowledge about some recent science in the news.

Male voice: Novartis—committed to making innovative medicines for a world of patients and their families, online at novartis.com Novartis…. Think what's possible.

Steve: Welcome to Science Talk, the podcast of Scientific American for the seven days starting May 24th. I am Steve Mirsky. This week on our special edition of the podcast we will talk with Eric Kandel, winner of the Nobel Prize in Physiology or Medicine. Kandel shared the Nobel in the year 2000 with Arvid Carlsson and Paul Greengard officially for "their discoveries concerning signal transduction in the nervous system." But it's easier than that to remember what Kandel did because his work concerns memory, how learning and memory happen at the cellular and molecular level. Kandel's newly published autobiography is called In Search of Memory and a brief adaptation from the book appears in the current issue the April/May issue of Scientific American Mind magazine. The complexity of mammals led Kandel to try to find a simpler organism to use in his studies. The marine snail, Aplysia, fit the bill, having only about 20,000 nerve cells compared with about a 100 billion in the human brain. The snail has a simple reflex by which it protects its gills and Kandel used that reflex to study how the snail learnt and remembered stimuli. He showed that short-term memory involves increased levels of neurotransmitters at the synapses, the communication sites between nerve cells and long-term memory requires changes in the levels of proteins in the synapse. This understanding is crucial for attempts to develop medications to battle memory loss. Kandel is a senior investigator at the Howard Hughes Medical Institute. He is university professor at Columbia University and he is the director of the Kavli Institute for Brain Sciences at Columbia. We spoke at his office with a memorable view of the Hudson River on the west side of upper Manhattan.

Dr. Kandel, great to talk to you today.

Kandel: Steve it's wonderful to talk to you.

Steve: And I want you to begin with your background. You went from an interest in being a psychoanalyst to a molecular biologist of mind—not the mind, we'll get to that. I realize I'm asking you to give me your life history, but briefly can you trace that trajectory?

Kandel: Actually the more I think about it, the more routine that trajectory seems to me. I was interested in the nature of human mental processes, which is what got me interested in psychoanalysis. And it became clear to me after a while that mental processes come from the brain and in order to understand them, you need to be a biologist of the brain. And once I got into brain biology, it became clear you needed to study the brain on the cellular level, and once you began to understand aspects of behavior in the cellular level, you wanted to understand the molecular level. And this didn't occur overnight, this occurred over a period of decades. So I was already a fairly mature cellular neurobiologist when molecular biology came of age and began to have an impact in the nervous system; and I was fortunate to have Richard Axel as a friend and colleague and I got him interested in nervous system and he taught me some molecular biology.

Steve: And you both won Nobel Prizes, (laughs) so that went pretty well.

Kandel: It was a very nice friendship in collaboration.

Steve: I was at the recent symposium in the honor of Don Purpura.

Kandel: That was a wonderful symposium.

Steve: You both told a story—which I would like you to tell—about when you first went to his lab and what your intent was?

Kandel: I went to Don's lab when I was a senior medical student and we had a six-month elective period.

Steve: This is 1955?

Kandel: 1955, 1955-56. And I had, up to that point, never entertained an alternative possibility besides becoming a psychoanalyst. But I thought a psychoanalyst, even a Park Avenue psychoanalyst, should know something about the brain, and since I had a 6-month elective period, I thought I would do that in brain science. And I looked around and the best laboratory in New York City was one that was run by Harry Grundfest. And I went to see Harry Grundfest, and he asked me, what do you want to do? And I said I wanted to localize the ego, the id and the superego; and he thought I was out of my blooming mind, but he was very gracious and patient. And he told me, you know, those problems are beyond the reach of neuroscience at the moment; but that I should speak to Don Purpura, who was interested in higher mental function and see whether I could work out some kind of research project with him, so that's how I was let do Don. Harry Grundfest also felt very strongly that the way to study the brain is one cell at a time, and he got me interested into [a] reductionist approach to behavior, which is really the approach that I've taken since then.

Steve: Let's talk for a moment about the virtues and the pitfalls of a reductionist approach.

Kandel: Right! And you put it very well. The virtues are when you have a complex problem; it's often best to study it in the simple system. To look at the most elementary representation of that process, and since learning and memory are extremely conserved in phylogeny, you need to know what's good and what's bad, what's dangerous and what's safe, what's edible and what's toxic, so you need to learn how to discriminate between alternatives and to remember that decision; and that is such a conserved process that almost all animals with nervous systems can learn and remember. So I thought that rather than continue, as I had started working on the hippocampus of a very complex structure, involving complex memory, I might go to a simple reflex act that can be modified by learning and see how learning occurs and how memories are stored. And that proved for me very useful. I went to the marine snail, Aplysia, I worked out a simple reflex, the neurocircuitry that reflex could be modified and so how it be learnt. What's the weakness of that approach? You can't study attention. You can't study complex representation of space and of objects in the brain. For that you need a more complex organism. But I would say that even in a complex organism we need to take broader approaches; you need both [a] bottom-up reductionist and [a] pump-down approach, you need both in order really solve these more complicated problems. So certainly reductionism has great strengths—it's sort of the super highway of biology but it also has limitations in the sense that you need to combine it with synthesis with an approach that looks at the whole organism, that looks at complex behavior and that looks at complex neurocircuitry.

Steve: You talk in the book in the article in Scientific American Mind about the importance of asking the right question and picking the right system to examine that question with, and it seems like an obvious thing, but it's not.

Kandel: Well! The principle is obvious, the selection is difficult. And I think I was very fortunate with Aplysia; I mean, I had no way of knowing that it and I would fit so well and because I think that's where the emphasize[emphasis] is. Obviously there are a number of systems that have absolute merit and Aplysia has lots of absolute merits. But there are also certain things that if an investigator like[s] to do, and I came from cellular neurobiology having learnt from Grundfest and from Wade Marshall and from my period at the NIH how to study nerve cells in the brain; and I was until that point studying complex organisms—a cat; Aplysia fitted me to a tee. I could see the cellular interconnections with a clarity that you couldn't possibly see in the mammalian brain. In the mammalian brain, a single cell receives input from hundreds of other cells; each produces a tiny effect. In Aplysia, the interconnections between two cells are extremely effective. One cell can drive another cell the [to] fire or if the connection is inhibitory can shut up the fire itself. So to see [that] this powerful action [occurred] as result of the interaction took [of just] a few cells was quite dramatic and I just loved it.

Steve: You talk about the resistance that you encountered with that choice of a model organism. Why did you have faith that your results will be applicable in a more widespread way?

Kandel: I have a philosophy that has guided me throughout all of my scientific career and that is, I think of myself as a fairly thoughtful person. I don't go into projects impetuously and I try to select important problems. And once I decide, a problem is important, I really trust my judgment and you're not going to talk me out of it. It's essentially what I feel, because I see things in it that you might not see because I have thought a lot about it. That puts it in a more arrogant way. I don't feel arrogant about that, I just feel I just have thought a lot about it and most people probably haven't thought that much about it, so I can justify in detail if you want to hear it. As I argued before, I thought that learning and memory are likely to be conserved. And if that's so the solution to any problem, no matter how simple the animal or the task, any problem of learning or memory is going to be instructive; since we don't know anything about any form of learning and memory to see how any of it works is going to be good.

Steve: You bring up, I think, such an important point. Many people—obviously we're living in a time where evolution is under fire and a lot of people, even people who accept evolution, don't necessarily see why it's so important that it's studied, but when you are talking about …

Kandel: It's so fundamental, absolutely—[it's] the driving force of all of biology. Biology does not work—as Francois Jacob pointed out—it doesn't work by designing the nervous system, it works as a tinkerer. It uses the tools of the trade that are there in and modifies these slightly. So if you have something that works in a primitive organism, that's going to be maintained. I mean cyclic ANP—the molecule that I found to be important in learning and memory—is used as a scape in bacteria, it's used as a hunger signal in bacteria. So I mean it's amazing how conserved these processes are. So I felt quite confident. And I think being a psychiatrist gave me even more confidence because I knew that psychiatry is a field filled with aspirations, tremendous goal[s], but very little fundamental knowledge. And if you can contribute any bit of solid knowledge it would be useful for psychiatry, useful for psychoanalysis. This is not to say that this is going to explain the ego, the id and the superego, but you know, you need to start at ground zero and this was providing the ground zero.

Steve: I mentioned earlier the difference between biology of the mind and biology of mind, and it's a point you make in the article.

Kandel: Yes, yes, yes, yes.

Steve: Why did you make that point?

Kandel: It's a pedantic point and that is the biology of the mind suggests that there is a limited set of functions that's localized at a particular point in the brain; while mind refers to the whole family of mental processes, every thought that you have, every feeling that you express, every dream that you aspire to, and it works on the assumption that these are going to be localized in a variety of each one of these functions, it's going to be localized in a variety of different areas in the brain.

Steve: More with Erick Kandel right after this.

Robotic Voice: Greetings human. When there are some thoughts about the podcast, let us know what you think by participating in our survey at www.sciam.com/research.

Steve: Back to the interview.

You talk in the Scientific American Mind piece about what you would be thinking about in terms of how you would make a choice about what to study if you were starting now. Not so much just specifics about what you will study, but about what you'd have to consider when deciding; and I know that a lot of students listen to this podcast, so it'll be just useful for them.

Kandel: Right! I like problems at the borders of disciplines. One of the reasons that neurobiology of learning and memory appeal to me so much was that I liked the idea of bringing biology and psychology together. How was that? The first one I'm not, the last one—this is something that has been going on for long time—but you know, with my self biological perspective, I was there before most people on that particular perspective and similarly with the molecular biology. So it put me in a position to see relationships between things that, you know, other people were not just aware of as I was, and I think this is generally true. One area like—now again, all of these areas, you know, have been discovered by others—is molecular-associated biology identifying genes that are important [in] social behavior. Carl Bergmann has made some marvelous progress in worms, Tom Insel in voles. I think there is lots of work to be done there. I think it's a fantastic area.

Steve: Why is that important?

Kandel: Well because we like to know what are the biological determinants of how you and I interact. See, you know we're having a perfectly pleasant conversation, we don't have any angry feelings toward each other—you know how does one form an acquaintance, begin the initiation of a friendship, what is it?

Steve: On a molecular level?

Kandel: On systems and a molecular level, yes. There are probably genes that code for being a nice guy, being a son-of-a-bitch; it's not a one-to-one relationship, but there are probably things that enhance aggressivity—well, things that enhance sociability—so that's interesting to know. The other thing that fascinates me, being Jewish and having been exposed to anti-Semitism is, what is the origin of anti-Semitism? To some degree it is probably not specific to Jews; it's probably [a] reflection of an attitude that may be gulped into the genome about strangers, about foreigners, about eccentrics. They may very well have some early evolutionary origins, once people begin to bond together, to form groups in order to develop a social structure; the bonding to one another may carry with it the consequence of excluding people that don't belong to the group. And that exclusion may have aggressive components to it. You don't simply say, we would prefer that you don't join, but you know, we'll kill you if you try to get into this group.

Steve: Right!

Kandel: So to understand what the social and biological and genetic factors that predispose to cohesiveness and anti-cohesiveness if you are quite fascinating; even I was years away from them, but ….

Steve: And hope would be that an awareness of that would stop our reflexive attitudes.

Kandel: Might very well; might very well.

Steve: You bring up your personal background, which you go into in the book. And when I was reading it, I was thinking about, I had heard an astronaut interviewed once, who had done a space walk, and he was asked, what did you think of when you were on the space walk, outside the capsule, looking at the planet and universe? And he said, what I thought of was, what did I do to deserve this unbelievable experience? And I thought of that when I was reading your background, because you seem to be so grateful for everything that's happened, and you are kind of the (laughs) American dream.

Kandel: I find it unbelievable that a little kid from Vienna, coming from a poor family, coming to America without any money, [to] have had this fantastic life that I have had in the United States, that brings tears to my eyes. Really I find it, I would say, unendingly grateful. I don't spend my days say[ing] thank you. You know I'm not incompetent; I've contributed something to my success. But nonetheless I feel so fortunate at the opportunities that I have received here. I'll give you one example. I was so grateful to the United States for so long that it was a long time after we had entered the Vietnam war that I realized it was a wrong war for us to be in. I was reluctant to be critical of the United States because I thought the United States could do no wrong; that the government could not lie to its people. I had not realized you know, any government can at sometimes, you know, because [go] out of its way to not tell people the truth for variety of political reasons. But I was such a romantic youth that I closed my eyes to lots of things that I should've had my eyes open to; and I described it in my book, how, you know, a high school teacher pushed me to Harvard. How Harry Grundfest gave me a chance to work in his lab despite the fact that I showed up myself to be [a] bozo on the first interview. That because of Harry Grundfest I was able to go to the NIH; that I have had wonderful colleagues and collaborative experiences from which I gained an enormous amount.This guy who walked in before, Steve Siegelbaum, I gave a lecture—I'm making it up; I don't remember exactly, 1978 in Paris. I was a visiting professor at the College de France and he spent the year at College de France. I didn't know him. And he came to my lecture and he said, you know, what you're doing is pretty interesting, and I've got a new method, a biophysical method that I think would help your studies. I'm not much of a biophysicist; it was a fantastic opportunity. We had a fantastically productive collaboration. We, you know, both are matured scientists and now his tenure as a professor is going to be in two years to now the chairman of [the] neuroscience facility at Columbia, a big effort. We still collaborate periodically. I've learned an enormous amount from him. I mentioned Richard Axel, what I learnt from him. When I moved into the biochemistry of the nervous system, I collaborated with Jimmy Schwartz. I knew no biochemistry.

Steve: You had taken almost no science as an undergraduate.

Kandel: A very poor background. In fact I had no background. Even after I finished medical school, I didn't have much of a background in science. So I learned most of what I know in the course of my scientific career. And the way one learns in science, you obviously read—that's fundamental—and I did take courses later on, but I would say the vast majority of what I know is from talking to people and learning from them. This is the wonderful thing about the university experience. There is nothing like it.

Steve: You also benefited from the advice from a man you never met, your wife's father.

Kandel: Yes. He said that she should marry a poor intellectual because he would be ambitious enough to work hard and do something interesting.

Steve: Actually [a] not-rich intellectual, not a bad intellectual.

Kandel: That's right, that's right, that's right!

Steve: Well what were you going to say? You actually were …

Kandel: I often tell Denise that the one thing I am certain of, I am the sort of guy her father would have liked her to marry, (laughs) which makes me feel very good.

Steve: Thank you very much. It was such a pleasure talking to you.

Kandel: Nice talking to you.

Steve: Erick Kandel's new book is called In Search of Memory, his essay titled "The New Science of Mind"is in the April/May issue of Scientific American Mind magazine currently for sale at newsstands and available at www.sciammind.com. Also, in the late '90s, Kandel wrote a couple of articles about where he saw psychiatry going in the future, thanks to advances in neuroscience; and I wrote a brief article about him in that work in the year 2000. It came out just before he won the Nobel Prize and when I reread it the other day I was reminded about how interesting his thinking is on that subject. The article is available online for free, it's the first thing that comes up if you Google his name—K-a-n-d-e-l—with my name—M-i-r-s-k-y.

We'll be right back.

Male voice: Novartis—committed to making innovative medicines for a world of patients and their families, online at novartis.com. Novartis…. Think what's possible.

Steve: Okay, let's get in a quick round of TOTALL…….Y BOGUS. Here are four science stories; only three are true. See if you know which story is TOTALL…….Y BOGUS.

Story number 1: Wiggly, wobbly jellyfish need to break into their crustacean prey's hard shells to get a decent meal. To accomplish it, they accelerate their stinging cells to one hundred times the acceleration we all feel due to gravity at the earth's surface.

Story number 2: Dolphins have the equivalent of names by which they may address each other and even talk about other dolphins behind their fins.

Story number 3: The number of twin births in the U.S. has tripled in the last 30 years and a new study implicates the presence of bovine growth hormone in the food supply as a factor.

And story number 4: Since taking office, President Bush has issued so-called signing statements on more than 750 new laws which basically say, my fingers were crossed when I signed this, so it doesn't count. One such signing statement dealt with stopping scientists from sharing their findings with congress.

And, time is up.

Story number 3 is true. The presence of Bovine growth hormone in the food supply may be a factor in the increased rate of twins over the last three decades—that's according to a new study in the Journal of Reproductive Medicine. Women who ate meat and milk products were five times more likely to have twins than were vegans. You can read more in David Biello's article on our Web site, www.sciam.com.

Story number 2 is true. A new study published online by the proceedings of the National Academy of Sciences indicates that each dolphin has a so-called signature whistle that identifies it. The special whistle could be the equivalent of a name and the marine mammals may even refer to third-party dolphins as in, "Hey get a load of (whistling sounds)."

Story number 4 is true. The Boston Globe reported on the president's signing statements, which the administration believes allows the president to basically ignore the law he just signed in to effect. One such law noted that when congress requested scientific information "prepared by government researchers and scientists shall be transmitted uncensored to congress and without delay," but the president's signing statement read "the President can tell researchers to withhold any information from congress if he decides its disclosure could impair foreign relations, national security, or the workings of the executive branch." Not to worry though, because what chance is there that our scientific study results could even be related to foreign relations, other than, you know, research on global warming or acid rain or fish populations or avian-flu transmission or mad-cow-disease transmission, or ozone depletion or …. Anyway all of that means that the story about jellyfish shooting their stinging cells at prey at one-hundred times the acceleration equivalent to that of normal gravity is TOTALL…….Y BOGUS. Because according to a report in the May issue of Current Biology, the jellyfish can accelerate their stinging cells to over five million g—it might be the fastest cell movement in nature. Now remember that force equals mass times acceleration and there is a whole lot of mass to go along with the acceleration, so the overall force isn't going to smash open the planet, but it's enough to smash through a crustacean's armor to inject some poison. The resultant force is actually up there with some fired bullets; and we know that because the jellyfish information either was generated at the University of Frankfurt or was judged not to threaten foreign relations.

We'll be right back.

Rennie: I am John Rennie, the editor in chief of Scientific American magazine. If you'd like a free preview issue of Scientific American as well as a gift, visit www.sciam.com today.

Steve: Well that's it for this edition of the Scientific American podcast. Our e-mail address is podcast@sciam.com; and also remember science news is updated daily on the Scientific American Web site, www.sciam.com. For Science Talk, the podcast of Scientific American, I am Steve Mirsky. Thanks for clicking on us.

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