Conversations with Laureates
Eric Kandel talks with Richard M. Cohen, former CBS News Senior Producer, about the formation of memory.
Eric Kandel: I should first tell you why I think memory storage was so interesting and important to study. I was born in Vienna, and I left Vienna one year after Hitler annexed Austria. I came to the United States in 1939.
I got my schooling in New York City and then went to Harvard and majored in history and literature, with an idea of trying to understand the forces that could lead civilized nations like the Austrians and the Germans to be transformed into barbarians, into mass murderers.
As I became more involved in the intellectual history of contemporary Europe, I wrote my honors dissertation and...I became fascinated with the psychology of the human mind.
I decided, based really on my interest in the mind, that I would go to medical school with the idea of becoming a psychoanalyst.
Richard Cohen: Did you reach conclusions about the questions you posed about society?
Kandel: I was beginning to think that...you mean, how societies can be transformed? I did reach a conclusion during my dissertation an initial conclusion that in both Germany and Austria, but particularly in Germany in the early days of the Hitler period, the intellectuals were not sufficiently assertive of their independence. They were too easily intimidated and they did not speak out enough.
If in fact there had been major intellectual opposition to Hitler, or even significant opposition to Hitler in the early days, when his hold on power was less secure, he might have been contained. He might have been weakened in a variety of ways.
Cohen: But there are inevitabilities in science, it seems to me. I wonder whether you can say that in matters of the state.
Kandel: It's uncertain. I mean you can't play history over again. You can't repeat the experiment as you can in biology. One of the most interesting processes to understand, central to human behavior, central to psychoanalysis, was the biology of memory.
That, after all, is the psychoanalytic experience—an attempt to relive earlier experiences in a more protected, trusting context and to work through those experiences in a more satisfactory way than they were the first time.
So the biology of memory struck me as a wonderful theme that would tie together my emerging interest in the biology of the brain and my long-standing interest in psychoanalysis.
I really became trained in neuroscience. I came there being incompetent, having some very simple, preliminary ideas of how to do experiments, and I learned how to become a scientist there. I learned how to approach questions in a systematic way, how to run controls, how to think about problems, how to discuss them with colleagues and use the environment to enrich one's understanding of problems, and I had a fantastic experience there.
It was there that I began to focus on memory storage. In 1956, Brenda Milner described a very famous patient who has been known in the literature ever since as H.M. He had been operated on by a surgeon called William Scoville for bilateral temporal lobe disease that he sustained as the result of concussion of his brain, which he incurred as being knocked over by a bicycle when he was 9 years old.
He developed seizures that became worse and worse. Scoville operated on him, removed on both sides large parts of the temporal lobes where these seizures came from, and a structure deeper in the brain called the hippocampus.
Brenda Milner found that as a result of this surgical removal, H.M. suffered a tremendous loss of memory. So even though his epilepsy was largely gone, dramatically improved, he sustained as a result of the operation a very severe memory loss.
That was the first evidence and there has been mounting evidence since then, that the hippocampus, a structure about the size of a thumb, deep in the brain—not only the human brain but the brain of all mammals—is critically involved in certain types of memory storage.
We were very pleased. This had not been done before and was considered a very nice scientific accomplishment. For a year or so, we were really thrilled with what we were learning and the excitement of doing something very novel.
But as we thought more and more deeply about it, we realized that boy, memory is a complicated problem, and memory in a complex brain...we were working on the cat, [a] mammalian brain that is very complicated. [We learned] that the hippocampus, which is critical for this complex memory—memory of associations of people, places and objects—involves a conscious recall. So it gets into the deepest mystery of human behavior, that maybe to understand that was premature, that we needed a simpler system, and a simpler form of memory.
There must be a system for studying memory storage, and I began to look for a very, very simple animal that had a very simple nervous system, that had elementary forms of behavior, that nevertheless could be modified by learning.
Since I wanted to use our biological techniques, I wanted an animal that not only had fewer nerve cells, but gigantic nerve cells. I looked around and I found this marine snail Aplysia that two French people had been working on that had the largest nerve cells in the animal kingdom.
I went to France because that's where the people were working on it and I played a little bit with this animal. I got familiar with it. I got familiar with the labs and I decided this is what I wanted to do.
Cohen: Was your assumption that whatever you learned from that could be applied?
Kandel: The assumption that I had is that learning and memory are conserved biological processes that one finds throughout evolution. If that's so, it is likely to have components that are fairly universal, or at least extremely general. That if one understood in detail the cellular underpinnings of any form of learning and any form of memory storage, one would have one's handle on the mechanism that might be of general importance. What we found is that genetic and developmental processes determine the architecture of the behavior, the ability to have a reflex response.
Cohen: But is the genetic component versus cellular behavior the great lesson of what you were doing?
Kandel: Not yet. The great lesson was of course the position of the behavior, that there is a genetic and developmental contribution to the position, which was emerging [in] a number systems. The interesting thing that I found was, if you look at that precisely interconnected set of neurons, while the animal learns something, we saw that the strength of synaptic connections could change—that even though connections were specified, their strength was not specified genetically.
What learning did was to alter the strength of synaptic connections and memory.
That was really an interesting finding. It was the first direct demonstration of an idea that Ramon y Cajal, the great anatomist, had at the beginning of the century, that learning involves alterations in synaptic strength.
Cohen: Can you translate that to tell me what that means for a human being?
Kandel: That means that when you and I talk to one another, insofar as you remember anything about this conversation, it is because specific nerve cells in your brain have been altered in strength—the communication between nerve cells has been altered.
Let me just elaborate a little bit more and think this will become clearer to you. As we began to study the process further, we began to realize that on the level of cells, you could make the same distinction that one can make on the level of behavior.
In behavior, we knew that memory had stages. There was a short-term memory, like looking up a telephone number. You look it up and you forget it soon thereafter. And a long-term memory, a memory after repetition, which can persist for long periods of time. We found that these alterations in synaptic strength had a short-term and a long-term phase. The long-term phase was accompanied, not simply by a functional strengthening, but by an anatomical strengthening. There was a growth of new synaptic connections in the brain. So insofar as you remember anything of this conversation to continue this metaphor, it is because anatomical changes are occurring in your brain. So you will walk out of this conversation, you will walk out of this room with a different brain that you walked into this room with.
Cohen: But aren't you almost saying that, it is like a testament to the value of the exercise? It sounds like the more you use your brain, the more brain activity there is.
Kandel: I think that's a part of it, because repetition is necessary for long-term memory, but I don't think it is just usage. It is usage in a motivated and disciplined way. But you are right that there is a bulking up of muscle with appropriate usage.
This is really quite profound if you think about it. In addition to the genetic makeup, which determines a lot of the basic wiring of the brain, there is another layer whereby the environment feeds back, social interaction feeds back, analytic experience feeds back, in order to produce structural rearrangements in the brain that contribute to the biological base of individuality.
So this is what we call an "epigenetic layer."
Cohen: But what do you say to the middle-aged person perhaps in his 50s who is beginning to feel, not just understand but feel the differences between long-term and short-term memory and changes in his own mind? How does this research relate to that?
Kandel: It relates to it in two ways. One is very much as you indicated. We have reason to believe that if you don't use it, you are likely to lose it. So intellectual activity is extremely beneficial to maintaining intellectual vigor in the long run. Number one.
Number two, the research that I have done and other people have done, not only in the snail but also in the mouse...in 1990 we began to do parallel studies in the mouse and we found that the details are different, but the principles are very much the same. [This] began to give us insights into what happens to the brain of the mouse when the animal ages.
We found that the ability to throw these switches that we are talking about, to turn on the long-term process, to alter genes, to grow connections, is weakened because certain modulatory systems are compromised, and that if you give some of the modulatory signals back or if you enhance the signaling process in the brain, you can in the mouse restore age-related memory loss.
We are not talking about Alzheimer's disease. We are talking about the more common, weakening of memory with age, which does not progress as devastatingly as Alzheimer's disease. In mice we have very good drugs that are useful for age-related memory loss. So as I am fond of saying, if you are a mouse, we can do a lot for you.
Cohen: You are beginning to identify dynamics. But everybody's genetic makeup is different, right?
Kandel: Right, but there are lots of commonalities to the makeup of people, including commonalities in the genetic programs. So the basic outline of the memory storage process is pretty much maintained.
Now the particular structure of certain of these common molecules, what we call variants, or the quantitative presence of some of these, may differ. So for example, we found to our surprise that when you turn on long-term memory, you need to turn on an activator of genes. That's in line with what I told you before.
But what we found more surprisingly is that you also have to remove an inhibitory constraint, a repressor. That was a surprise. You would think you want to put things into long-term memory very easily. It's not true. It is very hard to put things into long-term memory. You have to overcome a whole family of these inhibitory processes.
So let's say you were born with less of these inhibitory processes than I was. It might be conceivable that it's easier for you to put things into long-term memory than it is for me and therefore you might have a more powerful long-term memory than I have.
So you can see how quantitative variations in common molecules could contribute to individual differences.
Cohen: Brain science is really the final frontier of medicine, isn't it?
Kandel: Yes, because we stand before it in such humility. There is so much to be understood. It is such a profound process. What is the nature of conscious experience? How do I think about myself? This is a machine that reflects upon itself.
We realize that it was difficult. But we realized even more when computer science became of age. Because when computer science became of age, we for the first time had a machine that could try to simulate the actions of the mind. We would ask computers to do object recognition, to recognize the difference between faces, and we realized boy, this is pretty complicated.
You know, we recognize one another extremely easily. You ask a machine to do it and you realize what a complicated process this is—language recognition, extremely difficult for computers to do. So the kinds of machinery that the brain uses for perception, for action, for willing movements precisely to an object...if you ask robots to do this, they struggle. So we realize that the brain has techniques as well as machinery for accomplishing things that are really quite remarkable.
Cohen: We have seen such exponential moves forward in other areas of medicine, cancer and specific illnesses—why is it that whenever people talk about brain science, they talk about it in an infancy that stands in high contrast to every other area?
Kandel: There are hierarchy of complexities. You know, we understood genes by looking at viruses and bugs, and we began to understand cells by looking at yeast and simple single cell organisms. We began to understand how organs develop by genetic approaches in worms and flies and now mice.
We are using the mouse now as a simple genetic system to understand the higher order of mental processes, hippocampal-based memory storage.
We are making very good progress but this is an immensely deep problem. This is not only the deepest problem that biology has ever faced. This is probably the deepest problem science has ever faced, because here you are asking the machine to look at itself. I mean all we have available to us is the human mind and its extensions. You know, microscopes, various instruments that we invent and develop.
So this is an extremely self-reflective process and it has enormous difficulties.
Cohen: Where do you think it's going to take us, though?
Kandel: I think it is going to give us a completely new understanding of how we work, of how we perceive the world, how we act upon it, how we feel, what we mean by processes like attention, emotion. These are meaningful but slightly ill-defined concepts as memory storage was 50 years ago, much better defined, much better understood. And we will have, I think, a much richer understanding of the nature of the individual mind. We will have a beginning understanding of biological components of social behavior.
I think it is going to make us much richer people as a result of understanding how the mind works.
Cohen: Let me introduce a word, "manipulation."
Kandel: That is a word that is worrisome.
Cohen: Talk about it.
Kandel: You know any time a scientist makes a discovery, there is the danger as there is with atomic energy that society will use it for ill. The scientist's function is to find out how things work. It is society's moral responsibility to take that insight and use it for good and not for evil, and I think the task here as well.
We want to use insights into the mind to treat schizophrenia, to treat depression, to treat multiple sclerosis, amyotrophic lateral sclerosis, these scourges of humanity. In order to do that, we need to understand how the brain works, how the mind works, that some Hitler may come in the future and try to manipulate these biological processes so as to get control of human behavior. There is no doubt people will try to do that. But we have to put up safeguards so that people determine their own faith and not that the state determines the faith for them.
Cohen: It is one thing to frame this in terms of the state. It is another thing to frame it in terms of the corporation, it seems to me.
Kandel: We have to protect ourselves against the corporation.
Cohen: Because the corporation owes allegiance to its shareholders and one can question all the ethical—whether there are necessarily ethical implications.
Kandel: I think eternal vigilance is the price of a democracy and I think that needs to be exercised at every level. I do not consider corporations as being intrinsically, genetically determined moral institutions. They have their own agenda and it is society's function to monitor their agenda.
Cohen: Is there a single breakthrough that's out there that you think is imminent?
Kandel: I think are two major classes of memory storage: implicit and explicit.
Implicit or procedural memory is a memory that I studied in Aplysia, which is the unconscious recall of free-flexing perceptual scales...so classical conditioning, sensitization, habituation, very simple forms of learning.
That does not involve any conscious participation for recall. But explicit memory or declarative memory is a memory of people, places and objects, of facts and events. That requires conscious participation for recall.
How consciousness comes to bear upon memory storage, how attention bears upon memory storage, how attention works in the brain, we are just beginning to focus on. I think understanding how attention and memory interact is a beautiful problem that would be a major breakthrough.
Cohen: Looking down the road, maybe not in your lifetime or mine, where could this research take us?
Kandel: The research for memory storage could have profound influences. For example, there are many kids now born with forms of mental retardation, kids born with autism that have language defects, kids born with fragile X, kids born Down syndrome, people born with as yet uncharacterized etiologically forms of mental retardation. We would like to help those kids. You have memory loss associated with Parkinson's disease. You have memory loss associated with age, with Alzheimer's disease, with stroke, with cardiovascular surgery, with blood clots going to the brain, God, it would be wonderful to have some really good therapeutic approaches to that.
Biologists are delusionally optimistic. They are just so impressed with what biology has accomplished in the last 50 years, they can't get over it. If you even ask in the brain where things are inordinately complicated, how much better we understand things now than in 1960. There is just no comparison.
This has been from you know, Watson and Crick, '51 to now, the golden age for the biological sciences. This is an incomparable period of laying out not only a set of findings, but a logical foundation for biology on the cellular, molecular level. That's quite extraordinary in combination with the genomes not only of humans but also of appropriate experimental animals that allow us to explore how human genes work.
We are moving into a new phase, the phase of brain complexity. We are no longer going to be able to simply study things at the level of individual cells. We are going to have to look at systems of cells, particularly in the brain. This is a major challenge in which new combinations of disciplines are going to be recruited, mathematicians for model building, computer sciences for trying to help us to store this information, and as well as you know, molecular and cell biologists.
So I think this is a fantastic period really. Completely new logic in biology and hopefully a new logic for brain.