Eric Kandel: the Future of Memory
Watching ice floes glide by on the Hudson River from Eric Kandel’s office, one gets a sense of placid reflection tempered by constant action—an apt analogy for Kandel’s ability to calmly manage several ongoing projects and commitments at once. In addition to his well-lauded, ongoing research at Columbia University Medical Center’s New York State Psychiatric Institute, Kandel has written several books on neurobiology, behavior, and memory. In addition to being a Nobel Laureate Scientist, he is well-known as an editor of the seminal textbook Principles of Neural Science. He and his colleagues are in the midst of working on a new edition of Principles, and he is working on a scientific autobiography. MI sat down with Dr. Kandel and discussed with him a range of topics including childhood and early career influences, intramural research at the NIH, the HHMI, ethical considerations of altering memory and, of course, Aplysia.
MI: The autobiographical essay you have written, which accompanies several other documents at the Nobel Prize Web site (www.nobel.se), makes for very interesting reading and really offers a deep view into how your young life and world views affected your later development.
EK: I put that essay and the other one on the history of my research [a transcript of the Nobel lecture] together and have been working on a new book for about two years now that will hopefully be published by Norton in 2006, tentatively entitled: In Search of Memory: Emergence of a New Science of Mind.
MI: You grew up in Vienna. Were you aware of its rich cultural history and the socially brutal elements that afflicted the country when you were a child?
EK: No. Of course, I remember 1938 when Hitler came in, and I was aware of the implications of that. I was aware the country was politically unstable. I remember even earlier, in 1934, when I was three or four years old, there was a bit of a civil unrest in Vienna, so I remember the barricades, but I didn’t realize the significance of it. I also was not aware of Vienna’s cultural strength, nor, as a matter of fact, were my parents aware of it. It was my brother, who was quite precocious, who made me aware of Vienna’s intellectual history. He was already attending the Gymnasium [academic preparatory school] and was interested in such things.
MI: Speaking of your brother Lewis, can you describe him and his influence on you? I get the impression you were a bit awed by him.
EK: My brother was extraordinary and very helpful to me—very much of a role model. When my family arrived in America, money for the family was a concern, and so he felt he had to get a job. Rather than going to an academic high school, he attended a school for specialty trades and became a printer. It was tragic, because I felt, despite my wife’s attempts to disabuse me of the opinion, that he was really more talented than I. He really had to be self-supporting, whereas, by the time I was ready for college and medical school, my parents had a small store and were beginning to make a little money. I did some work in my spare time, and I had scholarships to college, so I didn’t cost my parents very much, but I did cost them some, and they had the resources by that time to help me. But they hadn’t had the resources to help my brother. I had the much easier life.
MI: Richard Feynman described that his father tried to explain the principle of inertia using a child’s wagon and a ball inside of it. I remember the first time I learned that the stars in the sky were always there, but couldn’t be seen because of the sun’s luminosity. In your childhood, did you have such a moment that sparked your scientific curiosity?
EK: No, I was not from a family that had a scientific background. I took no additional science courses in high school beyond those required and only did so in college when I decided to go to medical school. I had been training to go to graduate school to study the history of literature. It was really an interest in psychoanalysis that got me interested in medical school, and medical school got me interested in neuroscience. It wasn’t until I entered Grundfest’s lab here at Columbia in 1955 that I had any inkling that research was so enjoyable. I took a six-month elective in Grundfest’s laboratory because I thought a psychoanalyst should know something about the brain. I was astonished to find that doing science was fun! But the timing was also good: I entered medical school at NYU in 1952, just around the time that the structure of DNA was being understood. Mark Adams and Colin MacLeod were in the microbiology department then, and I really enjoyed that course. It was the first time I felt that I was not being taught something that was fifty years old, but rather I was encountering material at the frontier. And then in Grundfest’s lab, people would show up for work every day, in a relaxed atmosphere—no ties—and talking about science. I never had had that experience, and it made an enormous impact on me. I came into the field at a marvelous time, in which neuroscience was just becoming a cellular discipline. I realized that a cellular approach would open up new techniques to address complicated problems, and I think my good fortune was to apply this to learning and memory at a time when no one was thinking in those terms.
MI: When you began, others looked askance at your decision to study learning and memory, and to use an invertebrate to study it.
EK: I began with a cellular approach to study the hippocampus. People thought it couldn’t be done, because it would be too technically difficult. Well, it was difficult, but we were young and we were willing to take on difficult experiments and we had enormous help at the NIH. When I was there from 1957 to 1960, some of the greatest research in biology, in the whole country, was being done at the NIH. They had wonderful people and the best equipment. Neuroscience, at that time, was just a fragmentary field. The person working next door to me at the NIH, Karl Frank, was an extremely decent human being, technically very gifted, curious, and very generous. He worked on the spinal cord. My colleague Alden Spencer and I could discuss things with him and apply them to our work in the brain. I had a lot of help from people who didn’t claim any credit, because they didn’t participate in the experiments. But they were extremely generous with their support. My peers at the NIH were the best and the brightest. It was the time of the Korean War after all, and Bethesda was wonderful!
MI: Talk also about the impact of becoming an HHMI senior investigator.
EK: One cannot overemphasize what HHMI did for me, for Richard Axel, Linda Buck, and many others. My career had been going fine, and I was in the National Academy of Science. But I knew nothing about molecular biology when I met Richard Axel. He in turn knew nothing about the brain. We began to talk. I didn’t have the resources to set up a molecular biology lab—to restructure my lab physically—and he didn’t have the resources to do anything in neurobiology. The HHMI asked Columbia to develop a group of seven people in neuroscience, all of whom would be independent to bring molecular approaches to neuronal function. I was appointed Senior Investigator. HHMI thus fostered my movement into long-term memory and transcription factors and into the molecular underpinnings of memory in genetically modified mice. It’s conceivable that I would have gotten there some day with RO1s, but becoming an HHMI Senior Investigator facilitated my movements in that direction greatly. The HHMI encourages you to start fresh, to think about what you want to do, to be bold and ambitious. The NIH made a professional scientist out of me, and the HHMI took a differentiated scientist and gave him the opportunity to do things he might have never done.
MI: Talk about the beginnings of neuroscience at Columbia.
EK: When I came to Columbia, I started a completely new neuroscience program from scratch and I took it very, very seriously. I think we developed a course of about fifty lectures, of which I gave ten. I sat through every single lecture of those fifty for years, researching the lectures, going over the transcripts and summaries and, ultimately, developing the textbook on neuroscience based on these lectures. I organized review groups and met weekly with students to see how the material could be improved. This process continues to this day, although I haven’t been involved in running it for about twenty years now. In my lab, however, I still love to interact with my people and teach them about the brain. The majority of postdocs that come to me know very little about neurobiology, and so I teach them neurobiology, and I learn an enormous amount from them, because they come with different expertise and points of view.
MI: Do you feel that having several points of view to study a problem is important?
EK: This is very much my feeling. Let me give you an example. Wally Gilbert is now one of my good friends. We started Memory Pharmaceuticals together, but we started an earlier company, Synaptic Pharmaceuticals, as well. I didn’t know how to run a company, and he had plenty of experience doing so. He was getting interested in neurobiology, and he’s a perfect example of a guy who was outside the field. I feel that’s how some of the most interesting experiments get done. And look at Richard (Axel), first knowing nothing about neurobiology, then opening up the study of the sense of smell.
MI: Your laboratory is studying learning and memory in mice and in Aplysia. You’ve plundered Aplysia so successfully for so much of your scientific career; do you foresee a time when you’ll devote your attention solely to mice?
EK: That’s a fantastic question. I periodically think about abandoning Aplysia, and every time my wife [Denise Bystryn Kandel, a Professor in the Columbia University School of Public Health] will say that I’m crazy—that I can’t give it up. She is right. I continue to find such interesting things in that animal! For example, our recent work in Aplysia suggests that a prion-like protein may be essential in maintaining long-term memory. To look at growth of synaptic connections, there is no other model system in all of biology that comes close to Aplysia for studying the movement of substances from the cell body to the synapse and the flux of signals from the synapse to the cell body. So, I can envision a time when Aplysia as a model will be exhausted because, perhaps, investigators will have become exhausted with the system! More than half my lab works on mice, but Aplysia work is wonderful even today for gaining insights that you can’t get in other systems.
MI: What other aspects of research are you pursuing?
EK: I’ve recently gotten interested in models of disease. I think molecular biology is poised to make major inroads on psychiatry.
MI: Your work then is coming full circle!
EK: Indeed. The American Psychiatric Association has asked me to put together a collection of essays for a book entitled Psychiatry, Psychoanalysis, and the New Biology of Mind. I’m including a new essay that describes, over the course of my career, where psychiatry was, and where it is going. I’ve been very much interested in psychiatry, since the beginning of my training, and it’s nice to think that one can now use mice to model aspects of mental illness.
MI: Some have described the brain as the machine and the mind as the product it makes. Is that a valid analogy? What other product feeds back to affect the architecture of the machine that produces it?
EK: Very good question. And this is what I find so fascinating about neuroscience. People who are not scientists think that genes are the ultimate controllers of behavior, but what they don’t realize is that environment can alter the expression of genes and thereby modify the anatomical structure of the brain—and of course, Aplysia was the first to reveal all that. Experiments in Aplysia showed that learning can turn on CREB-mediated gene expression that leads to anatomical changes in the brain.
MI: You’ve recently turned your attention—so to speak—to studying attention in the mouse. What have you found so far?
EK: We have found that unless the animal attends, it can’t remember a spatial task for the long term. There is a representation in the hippocampus—as has been known for decades from John O’Keefe’s work—in which individual cells in the hippocampus, the pyramidal cells, represent different sections of the space around the animal, such that when put together, a map of the space around the animal is created. Now, that map will form whether the animal attends or nor, but if you subject the animal, say ten hours later, to a previously learned environment, an animal that has attended will “play back” the same map, whereas an that has not attended will not. So, we’re studying how this occurs and what mediates it, which is turning into a very interesting story.
MI: Can you briefly give a history to the founding of Memory Pharmaceuticals?
EK: Memory Pharmaceuticals arose in large part from research conducted in my lab, whereas Synaptic Pharmaceutics [an earlier pharmaceutical company shaped by Kandel] was for me more of an abstract exercise in how neurobiology can make a contribution to the development of new drugs. The founding of Memory Pharmaceuticals was based upon assays that we had developed here at Columbia. I was involved in the selection of the venture capital people who came in, and I selected the chief scientific officer, so I had more of a role in establishing the company. I still have fruitful interactions with the leadership of the company, and I’m quite happy with how the company is moving along.
MI: The aim to create memory drugs is also fraught with considerable ethical quandaries. Have you had to deal with these?
EK: I think there are two issues involved. The first, which bothers the ethicists most, addresses the implications of the compounds that would erase memory. We do not work on those, but others do. There are drugs on the market that you can take ahead of time before, for example, going to battle or engaging in a potentially traumatic event, such as a firefighter entering a burning building. Such drugs may allow the person to experience the event, but they weaken the imprinting of the event later on because the long-term emotional impact is dampened. (It’s a little bit like attentional processes in which you can form a map perfectly well that can’t be remembered a day later.) There are such drugs on the market: propranolol is a perfectly good example. Ethicists are concerned about the possibility of mind control: is it possible to extinguish certain memories and keep others? Researchers currently in this area, of course, have no interest in controlling the minds of others, but the ethical issue nevertheless arises. Although Memory Pharmaceutics is not involved with this area or the ethical questions it poses, we are involved in the second of the two issues—that is, positively enhancing memory storage. The concern here is that perfectly healthy people could exploit memory-enhancing drugs to perform better in their jobs.
First of all, I think there are better ways of improving one’s mind than taking drugs; studying and learning are well-proven efficacious methods for improving one’s mind. But in addition, most drugs have side effects, short-term and long-term, and it’s unlikely that any of the drugs that we and others are developing will be free of them. So, if you have Alzheimer Disease you are likely to be willing to tolerate whatever the side effects are to improve debilitating memory loss. But if you’re young and healthy, there is no need to tolerate side effects, some of which may culminate in serious damage over the long lifespan ahead of you. So, I hope the FDA and others will put stringent safeguards on these therapeutics. There really is little that the developers can do to curtail non-therapeutic uses.
MI: One of the most provocative things to come from your lab lately is the idea that CPEB [cytoplasmic polyadenylation element binding protein]—an mRNA. binding protein—has prion-like properties.
EK: Klausik Si and I are now exploring the expression of CPEB in Aplysia sensory neurons in response to serotonin. I think the published evidence that CPEB “acts like” a prion in yeast is strong. The question we are addressing now is whether the active conformation state is required for the maintenance of memory storage systems.
MI: It’s not required for formation of memory?
EK: No. I think we’ve nailed that pretty well. Whereas we’re pretty convinced that CPEB is required for maintenance of memory, we have not, as yet, been able to show convincingly which form of the protein is necessary for maintenance. We’re in the process of trying to figure out definitively which form is active.
MI: What is your prediction of the next breakthrough in neuroscience?
EK: I think we know a modest amount about the storage mechanisms of memory: How at a particular site in the brain memory gets transformed and structures get transformed. But we don’t know how systems of memory work, how the hippocampus works as an organ having different points of information influx from the entorhinal cortex, going directly to CA1, going indirectly to the dentate gyrus to CA3 to CA1, coming out the subiculum to the entorhinal cortex. How does that whole system communicate to the prefrontal cortex, where working memory occurs? How does the processing of information in the hippocampus interact with the ultimate storage site in the neocortex? We are only at the beginning in the study of memory storage. It is a very deep problem.
- © American Society for Pharmacology and Experimental Theraputics 2005
