Picower Institute for Learning and Memory Inaugural Symposium: “The Future of the Brain," pt. 2

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MODERATOR: Everybody in the skybox has got the hint. I can see that very well. It's great. I'm glad everybody's back here and ready for a second session this morning, because we have a couple very interesting speakers to go. And then we'll have Q&A.

We'll have a panel discussion here, which I'll try to moderate and whip people into shape, and get some questions from you all in the audience. Our next speaker is Eric Kandel. His lab is studying the examples of the major forms of memory storage.

Dr. Kandel is studying explicit memory storage. That's the conscious recall of information about people, places, and objects in mice, and implicit memory storage, the unconscious recall, of perceptual and motor skills in the sea snail he's so famous for.

I remember going into his lab 25 years ago at Columbia when I was first starting out as a reporter and thinking, this looks like my aquarium back home. He's got only snails around here. I learned about how much he depends on those snails.

By probing these synaptic connections between nerve cells and the sea slug, Dr. Kandel has uncovered some of the basic molecular mechanisms underlying learning and memory in animals, ranging from snails, to flies, to mice, and even in humans.

You're all familiar with his work. He has shared the 2000 Nobel Prize in Physiology or Medicine. I'm sure he's going to be very interesting talking about what he does. Please welcome Dr. Eric Kandel.

[APPLAUSE]

KANDEL: Thank you, Ira, for that introduction. I want to join my voices to that of the other panelists, and congratulate the Picowers in [? Susumu ?] for this wonderful day, and this wonderful dedication in this magnificent building.

I want to discuss with you some very personal thoughts that I have about areas that I think are likely to emerge as powerful issues in brain sciences. I'm picking areas that are difficult and central to the field, but areas in which we have a perch. We have a beginning to indicate some directions in which you can move.

I want to begin with a discussion of the biology of conscious and unconscious mental processes. Richard already indicated how they are important in perception. You also will hear from other speakers how they are relevant for thought and action. And I want to emphasize, in particular, the importance of unconscious mental processes.

I then want to use that as a stepping stone to consider that we might very well expect a revolution in our understanding of psychiatric disorders. That I want to begin by discussing the possibility of having a biology of happiness, not only on the level of the individual, but at the level of the group. And two of the people who have contributed importantly to group happiness are in the audience, [? Corey ?] Bargmann and Tom [? Hinsell. ?]

And finally, I want to return to the point that Susumu made. And that is that brain science is going to be an important engine driving the future of knowledge. And that is going to be, I think, an important bridge between the humanities, the social sciences, and the natural sciences.

And I think it's wonderful, in a way, that Jim Watson is here. Because simply to remind you, it was really with the discovery of the structure of DNA by Watson and Crick, and the later realization of the central dogma in which Sidney Brenner was such an important participant, that biology became unified. Molecular biology provided a unification of the biological sciences, to which Susumu also contributed.

So by chemistry, [? biogenesis, ?] development, immunology were brought under a common intellectual framework. That was the task of the last 50 years. In the next 50 years it is going to be the opportunity for neuroscience to provide that kind of a cement, that kind of a linkage between a number of intellectual disciplines. And therefore, it's appropriate that one really restates the dogma, if you will, of the 21st century that the 21st century is going to be the problems of the mind what the 20th century was to the problems of the gene. Let me begin with the first problem, that of conscious and unconscious perception.

One commonly thinks of the fact that the idea of unconscious came from Sigmund Freud, but it did so only secondarily. The first person to really address himself to it in a powerful way was [? Harold Helmholtz, ?] an extraordinary physicist turned neuroscientist who carried out a number of fantastic experiments. He was the first one to measure the speed of conduction in axons an amazingly accurate estimation. And then he went on to ask himself, how long does it take for reaction time to occur? How long does it take for somebody to consciously perceive a visual object?

And he was amazed with how long it took, much longer than it took for the information to get into the nervous system. And he stated, quite clearly, that there must be a lot of processing going on in the brain, most of which we are unconscious about. And, of course, Richard so elegantly demonstrated, as the Jubelin wiesel, that there is a great deal of processing of sensory information going on, much of which we are unconscious about.

And there is, in fact, sort of consensus now within the scientific community that many of our mental activities are carried out at an unconscious level. But what is most surprising is an experiment that Ben Libet carried out much more recently. In which he pointed out that not only is a lot of our mental activity unconscious, but even what we consider free will is in part determined at an unconscious level. And they did this with a fantastically interesting experiment.

A German neurologist by the name of [? Korkhooper ?] had shown that if you initiate a voluntary movement, if you move your hand or something like that, you have a readiness potential that you can detect on the surface of the skull. And that appears quite before the movement.

Libet carried this one step foot forward. He asked people to will movements, to consciously will movements, and to note exactly when their willing occurs. And he was sure that this would occur before the sign of the initiation of activity, before this readiness potential. And what he found was that it occurs substantially after that.

So I can look at your brain when you initiate a voluntary movement, and I can detect electro-physiologically that you're about to make a movement before you yourself are aware that you're making that movement. That's an astonishing result. That suggests that on some sophisticated level there is an unconscious decision to move prior to you knowing that you've made that decision.

So that really raised the question that to understand conscious mentation, you also need to understand unconscious mental processes, because so much of mental activity is unconscious. And this is particularly interesting to psychiatrists who have been dealing with the dynamic of unconscious.

How to tackle that? An approach that Christof [? Koch ?] here has suggested, together with this work of Francis Crick, is to take situations in which one is flipping back between conscious and unconscious states. And let me simply show you one common way of doing this, which is the figure ground illusion.

That is, if you look at this vase, you see a vase. But the outlines of it on either side also depict the face. So you could either see two faces or a vase, depending upon what you're consciously attending to. It's an almost all or none phenomenon. You focus on one. You don't see the others. If you focus on the others, you don't see the one.

This is an interesting situation in which the mind, if you will, that is the brain, is switching its conscious attention from one object to another. It turns out when you do imaging experiments while people are doing this, you find that when they are looking at the vase, the area that is concerned with object recognition lights up. And when you're looking at the faces the area concerned with face recognition lights up.

Richard pointed out to you all of these things are topographically organized in the brain. No surprise. But what is surprising is that conscious perception, it requires in addition the participation of cortical areas in the prefrontal region and in the parietal region. Both those regions seem to be involved in a number of different conscious processes.

So it struck us as seeing whether or not one could apply this approach to emotion, not just the cognition. And this is work [? Ahmed ?] [INAUDIBLE] carried out with Joy Hirsch at Columbia, in which they exposed normal subjects to a scary image, a threatening looking image. And did it under two ways. One, a very brief exposure in which the subject was not aware of the fact that they were seeing a frightening face, and a more legally exposure in which they could detect, consciously, the emotion. And they imaged to see what areas were involved.

They took 17 normal subjects. And they decided that emotion is likely to be different than cognition in the sense that people's sensitivity to threat might influence their perceptual capability. So they did a basal anxiety test, a Spielberg inventory, to get an estimate of basal anxiety. So they had that additional information beyond the imaging.

Let me first show you the imaging data. They focused on the amygdala, because it had been known from other people's work that this is important in the perception of all emotional stimuli. And they found that when you expose subjects to a conscious threat, so they perceived it and they could consciously tell you about it, a certain area, the dorsal amygdala, lit up. This is near the output region of the amygdala.

But when the subject unconsciously perceived a threat the lateral nucleus lit up. So two different regions in the amygdala light up depending upon whether the threat is perceived as unconscious or unconscious. It's conscious or unconscious.

Moreover, this was associated with different cortical networks. This, with unconscious perception. And this, with conscious perception. The critical point is that even if there's some overlap, only with conscious perception, here, as in the earlier experiments, the prefrontal cortex and the parietal cortex both together become active. So that suggests there may be some commonalities to the conscious perception of emotion, as well as to the conscious perception of cognitive stimuli.

But the most interesting result was that if you looked at the intensity of the image in the two areas that lit up with conscious and unconscious fear, you saw that with conscious threat, independent of the baseline anxiety, all subjects lit up the amygdala just about the same amount. But if you looked at unconscious threat, it varied a great deal depending upon the anxiety level of the subject.

People who were very relaxed, the Richard Axes of this world, no signal in the amygdala at all. It just wasn't there. People who were extremely anxious, a very dramatic signal.

Why is that interesting? It's really interesting from two points of view. First of all, it tells you that the unconscious perception is extremely important to people's actions. One way of thinking about this is once you see a face, once you have the leisure to really perceive clearly what it is, it isn't a threat. It's just a picture looking at you. But if you see a partial view, if you unconsciously perceive it so you are not sure of what's there, then you can allow your imagination to wander. And people who are anxious are going to think, this is terrible. People who are secure are not going to give a damn about it. So it gives you some idea of how the mind is working, if you will.

But even more interestingly, I think one of the important things that we're going to need in the long run are markers for different mental illnesses. So we can use imaging as a way of evaluating the outcome of therapy.

And you can see that a result of perhaps cognitive behavioral therapy, or some kind of a scientifically validated form of psychotherapy, one might be able to take people that have a very large signal to threat and bring it down to this particular point as a result of the therapeutic experience. So what I'm suggesting is that one might be able to open up an approach to psychotherapy using these kinds of imaging methods.

But that takes one to the larger issue. And I'm sure Tom will talk about this. And that is, we've had an enormous explosion of progress in neurology as a result of molecular biology. In contrast, we have not seen comparable developments in psychiatry. And I fully expect the next 20 to 30 years we're going to see this.

One of the reasons it's been so is because there have been problems in psychiatry. We know very little about the neuroanatomical substrates of most mental illnesses. We know very little about the genes that are involved, except we know that the genetics is complex.

As a result of this, we haven't been able to identify many of the specific genes involved. And as a result, we haven't been able to do what people have been able to do in neurology with Huntington's disease, and various important genes in neurologic diseases. Put them into experimental animals and try to delineate the mechanisms of pathogenesis.

I'd like to suggest that this is beginning to be possible. That we're beginning to learn about anatomical substrates of a number of diseases, that we're beginning to identify certain genes. And I'd like to give you some insight into mechanisms of pathogenesis, just a little tidbit, if you will. And I'd like to focus on the most complex of all psychiatric disorders, schizophrenia.

As most of you know, schizophrenia has three types of symptoms. The positive symptoms, which is really the major evident aspect of the disorder when the disease presents, disordered thought, hallucinations, and delusions, these are difficult to model in the mice. How would you know whether a mouse is deluded, or whether a mouse is hallucinating?

When these pass you are left with two very bothersome residual symptoms. Social withdrawal and blunted affect, what are called the negative symptoms that is the lack of social interaction. And disordered life. Attentional deficits. Deficits in working memory.

We know that a lot of this involves the prefrontal cortex, the area that Earl Miller works in. And we know from [? Pat ?] [? Coleman ?] [INAUDIBLE] work and other people's work that this is a region that is defective in schizophrenia.

So Eleanor Simpson in my lab and Christof [? Kelendorf ?] have thought that they would try to model cognitive symptoms of schizophrenia in the mouse, using one fairly reliable genetic finding. Many patients with schizophrenia show an increased expression of D2 receptors in the striatum. So they engineered a mouse that expresses the D2 receptor only in the striatum. And they expressed it in a way that allowed them to turn the gene on and off.

When they turned the gene on only in the striatum, they showed a very characteristic working memory deficit in a number of different tasks. Now, one of the interesting things about this, one knows from treatments of patients with schizophrenia that if you give drugs that work in this disorder, and most of these are dopamine D2 receptor blockers, the same gene that's being expressed here, at just about the same level that you see it in patients with schizophrenia, that those drugs do not help the cognitive symptoms, and they don't help the negative symptoms significantly. They primarily work on the hallucinations and the delusions.

So here we can see what's going on. We can turn this gene off and see whether or not the cognitive deficit disappears. And we find that when we turn the gene off, just like giving drugs, the cognitive deficits persist, suggesting some secondary change has occurred. We've now shown that in the prefrontal cortex D1 receptor expression is decreased. And Pat [? Coleman ?] [INAUDIBLE] has shown that this causes a severe impairment in working memory.

So [? I'm ?] only indicating that one can begin to use mice to work out mechanisms of pathogenesis. And I think this is going to prove very productive in the future.

I've described to you that we are beginning to know something about the amygdala and its role in fear. But what about happiness, security? What is the nature of happiness? What are the biological underpinnings?

Now, there's an important clue that came from Tolstoy's Anna Karenina, which he pointed out that "Happy families are all alike. Every unhappy family is unhappy in its own way." So this suggests, probably not true, that there are universal mechanisms that you're likely to delineate when you come to happiness. And I have some personal experience to think that this is so.

Here are two people, for example, who are happy. Susumu is happy because he's wearing my tie. And I'm happy because I'm attending this marvelous opening. And notice the similarities. Not only are they both happy, but we've now used some of Sidney Brenner's assays on Susumu. And we found that there are a few genes in his genome that are Jewish genes.

[LAUGHTER]

And he used the same assay on me. And it's absolutely clear that I have a Japanese background. So there are obvious commonalities.

Mike Grogan in my lab was so impressed with that picture that he decided to do the following experiment. For years people had studied learned fear, which is very easy to produce in the mouse. What you do is you take a neutral tone. Boom. And you pair it with a shock that scares the hell out of a mouse. And you go, tone, shock, tone, shock. And after a while the animal gets frightened just of the tone.

And this simply shows you what these experiments are like. If you give an animal a tone-- this is just a normal animal-- walks around like a normal mouse. And that is, it walks on the outside of this box, occasionally making darting movements inside to make sure that it's not missing anything interesting. But most of the time it wants to protect itself. It walks on the outside. If you look at the response in the lateral nucleus of the amygdala, that's the nucleus that's involved in the perception of fear, you see that the tone produces a small signal.

If you now scare the animal so the animal responds to that same tone with fear, it now stays in one corner of that enclosure, that open field, and it just freezes there. And if you look at the signal, you see it's dramatically enhanced.

But if you teach the animal safety, if you teach the animal that whenever the tone comes on it'll never get shocked-- it gets shocked at other times, but never when the tone comes on, it realizes that the only time it can really enjoy itself is when the tone comes on, then under these circumstances it walks around like Susumu Tonegawa in the Picower as if it owns the place.

[LAUGHTER]

And if you look in the lateral nucleus, you see that the signal is depressed. So this is very interesting. But you could say, well, maybe what you're just doing is reducing a certain level of baseline anxiety. Is this true happiness? Are you lighting up the systems of the brain that make you genuinely happy? Are these the areas of the brain that light up when you take drugs that make you feel very good?

And the areas that light up are the striatum. And Mike Grogan was interested in knowing, does the striatum light up with learned safety? Is there actual joy in this? Is the actual happiness?

And he found that, indeed, there was. When he recorded the signal to safety in the dorsal striatum, he found there was an increase in response to the tone in the striatum, while the danger signal had no effect whatsoever. When the animal expressed learned fear, there was no change whatsoever.

This is the opposite of what I showed you before. With danger in the lateral amygdala, the signal gets larger. And with safety, the signal gets smaller. So you see that, in fact, one can begin to open up a biology of happiness. And clearly, these pathways that are recruited by various kinds of reinforcing stimuli seem to involved in that.

But I would suggest that perhaps an even more profound area, which the new biology of the mind is going to open up for us, is the area that Corey Bargmann and Tom [? Insul have ?] pioneered. And that's the understanding of social behavior.

Tom will probably return to this. So let me just give you two very simple examples. [? Corey, ?] in a very beautiful study, showed that there are different strains of worms, c elegans worms, that forage for food in different ways.

Some are loners. They like to go out by themselves. And they sort of crawl around, get bacteria, which is the source of their food, by just going as individuals. Others do it collectively, feasts, group get togethers.

And she analyzed the difference between them. And she found that it was due to a receptor to a particular neuropeptide. And as she pointed out, neuropeptides are regulators of lots of behavior.

And she showed one amino acid difference in this peptide receptor, a receptor for a neuropeptide, similar to neuropeptide [? Y, ?] that determined whether or not the worm moves as a solitary individual or as a social [? organism. ?] That's an extremely profound insight, that one can change the social behavior of organisms by really altering a single gene.

And Tom [? Insul ?] has explored this in even, if you will, a more dramatic and relevant to our own life situation with two different species of voles. These are rodent like animals. The prairie voles are highly social animals. They're constantly throwing parties, getting together, taking off their clothes, and dancing on the table. But they're very loyal to one another. They pair bond and they stick together all the time.

So this does not reflect what happens typically in the neuroscience community. The neuroscience community is more promiscuous, somewhat asocial. They move around more like the montane voles, as single individuals.

Again, Tom has found that this is due to an alteration in a single gene that encodes a peptide, a receptor to vasopressin, and has shown that the promoter region, the region that regulates it is different in these two species, and that promoter determines the exact level of expression of the gene in various regions, as [INAUDIBLE] expressed. In fact, he's been able to take mice that behave like this and put a social gene into it, and get them to become more social.

I think this is really quite remarkable when you think about it. Because looking at social behavior, you also get some insight in the biology of group behavior. And group behavior is not all positive. There is a tendency we've seen in all groups, including our own, to defend our own territory and fight everybody else. So aggression comes out of group behavior. So we might be able to get some insight into the biology of aggressive behavior as well.

And finally, I want to indicate, as Susumu did, that I think for a university, such as MIT, one of the most amazing things that's going to come out of brain science is how it's going to affect other areas of knowledge. And I'm just going to sort of list sort of obvious examples. You yourself will be able to think of them.

Just to continue the theme I had before, a molecular biology of social behavior is going to be important for several reasons. Sociology, academic sociology, is in a funk at the moment. It is not coming up with new ideas. It is in a holding operation. And I think an infusion of biological thought into social behavior is going to have a tremendous stimulus to the group, to sociology.

And I think it will allow us to get into things like empathy and aggression, and promiscuity, pair bonding, and interesting issues like that.

I showed you before how the biology of free will-- this is an interesting issue. If you're not aware consciously of your actions, are you legally responsible for your actions? You could have Talmudic arguments that can go on for three times the length of the symposium on that one issue alone. The nature of personal responsibility. These are important legal questions. And just like DNA fingerprinting has been so informative and useful to the law, my guess is that we will use brain biology in a similar way.

You'll hear this probably more from Pat [? Churchhill, ?] but all the issues we are talking about, my ability to image your brain and know before you know what you're going to do raises lots of ethical issues that need to be considered.

The whole nature of art appreciation is likely to undergo a radical change. Understanding how sensory systems-- and Richard gave you some beautiful examples of that-- process information is alone one aspect of it. An even deeper one is the aesthetic response. Why do two people look at the same object, and one finds it beautiful, and the other finds it boring? What is the nature of the response? And conceivably, we could get some handle on the basis of creativity as well.

Neurobiology is beginning to interact actively with economics and with business schools, because there is a biology opening up of decision and choice. Bill Newsome, for example, has been interested in these problems. There are really a group of people that are actually using economic models and applying it to neurobiological contexts in order to understand the rules that govern the biology of decision making. And people in economics are interested in seeing what the outcome of those results are.

And finally, I should say that there is a disappearance of conventional sciences. I think it's fair to say that psychology, insofar as it concerns itself with human psychology, the psychology of higher mental processes, now can't be distinguished from neuroscience. They're isomorphic. It is a point that Pat, of course, made. And it applies absolutely, as she has documented, to philosophy of mind. You can't do philosophy of mind unless you understand the neural science that she understands.

And if you look at the good philosophers of mind, as Pat or John Searles, they are essentially neurobiologists. They have the intellectual background.

Moreover, I think it's going to be a tremendous impact within medicine. We've so far been training neurologists and psychiatrists that there are two species apart even though they're looking at the same organ. And this is not to say that it takes a different character structure to work with patients that have mental illness than it works with neurological diseases. But this is a little bit like being a kidney specialist and being a heart specialist. You have to start off in internal medicine. You need a common base.

And I think Tom and I share the same sentiment that it would be important to change the whole pedagogy of neurology and psychiatry. But beginning with a common training to both disciplines at the very beginning of that experience so that both of them realize they're looking at different aspects of brain functions.

And this brings me to the romantic component in my Viennese character structure. And that is that I still have hopes of psychoanalysis. I know I'm probably the only one in this room. I know Jim feels very strongly about this. And he may very well be right. The point I'm not doing is selling you an analysis.

But to say that for the first time we're in a position to evaluate the efficacy of these psychotherapeutic procedures. And we can see whether or not they work, or whether or not they don't work. And I think, if you will, this biology offers a hope to these therapeutic approaches in order to see whether or not they can be put on a scientific basis as a result of this.

So I'd like to simply conclude by saying that the impact of neuroscience and the future of knowledge, the future of the university is enormous. I think there's practically no area of knowledge that is not going to be impacted by it. And I think that Picower is going to be in a great position to lead that charge. Thank you very much.

[APPLAUSE]

MODERATOR: Tom Cruise just called. He's working on a new movie where he knows what you're going to do in advance. Remember that movie? And he arrested people who are going to commit murder before cause they knew what they were going to do? Now he's got some backing for another movie.

We'll talk about that later during the panel discussion. That should be very interesting.

Another interesting gentleman, our last Nobel Prize-- well, how do you introduce James Watson? He really needs no introduction. Everybody knows who he is. He formally is chancellor of Cold Spring Harbor Laboratory, but is most famous, of course, as the research partner of Francis Crick. A little over 50 years ago Watson and Crick unraveled the shape of DNA, discovered that it was a double helix. And Dr. Watson remains an active scientist, and an author and lecturer.

And as he says in his own biography, "My long term interest in education is most tangibly demonstrated by my helping generate three widely used textbooks, Molecular Biology of the Gene, Molecular Biology of the Cell, and Recombinant DNA." Please welcome Dr. James Watson.

[APPLAUSE]

WATSON: Well, I'll be unlike the other speakers and won't congratulate the Picowers. I'm going to congratulate MIT. Because MIT has managed to get two really gigantic donors to neuroscience. And these donors being very intelligent and wise people didn't want to waste their money. And so they chose MIT.

So I think we really should congratulate the vision of MIT as expressed in its long history, and in its past president, Charles West. And in its current president, Sue [? Hawkfeld, ?] for really providing, have momentum, which sort of scares the shit out of us, who don't have the resources of MIT, or the Picowers, [? McGovern. ?]

So I'm asked to sort of predict where the future is. So how can we with-- that's [INAUDIBLE]-- however, with much less money be as important as MIT. Just to compete and be as good? And I think the answer is you have to know a lot and really have a history of where you're going.

And I'll start by saying maybe it was six months before Francis Crick died, I went and saw him. Cause he had spent 25 years thinking about the brain, and particularly consciousness. And said we hadn't found the double helix of the brain. That is we don't know how to think about it. And so what would be the double helix?

And to me there's just two really just gigantic problems which haven't been really mentioned here at all. Well, one is just how is perceptual information stored? What does it look like?

When we saw the double helix we saw it was just the sequence of bases. But we don't have any idea how the information is stored.

The second is-- and maybe this isn't a real problem-- how is this information pushed from one part of the brain to another? Does it really go from the hippocampus to the prefrontal cortex? I mean, how can you do it? I mean, it just seems totally that you need-- no designer could be intelligent enough to really move it from one part of the brain. So I really worry about. But maybe this problem will disappear the moment we know what we're storing. But in any case, we have to know what we're storing.

Then and again, thinking about the double helix, the double helix was made possible because chemists had come along before and essentially gave the circuitry, how the sugar was linked to the phosphate. So we had a two dimensional chemistry. And then we could put it in three dimensions. And I'm sort of struck there hasn't been much real mention of anatomy. It maybe just sounds too boring for an institution as high powered as MIT. But I think you got to do a lot of it here. You really got to know the circuits.

I was very struck by-- we had a meeting in Cold Spring Harbor on the [? gavaneurgic ?] systems, and the work in Lausanne of [? Markov ?] and his group. And he was really trying to get the anatomy of micro columns, a cortical column. And I think we just have to do this anatomy.

And the question is, do you want to do it on the mouse? Or wouldn't it really be better to just do everything on yourself? And I think it's really open, that is whether the mouse, despite all the things you can do with it, is just too complicated ever to see the information.

Now, the only one who's seen the information is [? Harry. ?] The synapse got thicker. But that's one synapse. So how are you going to go along and see just what's happening? And I think the winner will be someone who chooses the right system. Not necessarily the one with the most money.

So it's not clear that this building will be where the great discovery will be made. Okay. So that's where the real thought will be.

And what else is really missing here? Well, you're not biologists. You're molecular biologists. That's sort of the basis of it. And there was one word mentioned of evolution here.

How did the brain develop? What did it have to do? And it's not surprising the striatum does something first. It's an old part of the brain. And the prefrontal cortex is last. So you sort of think it would go in that direction. So there really seemed to be no one's really thinking of how the brain developed in its different ways.

Now, this was sort of speculation 75 years ago, that people were more evolutionary or [INAUDIBLE] than they are now. But I think you sort of totally forgot it.

And we had a course this past summer at Cold Spring Harbor in schizophrenia. And John Listman came from Brandeis to do the systems. But what it just proved is that a bright physicist can only think about three things.

So the brain is more than three things. It's an awful lot of things, all working together. And you got to know them all. And almost none of the conversation really tries to link them all in terms of evolutionary histories. Where did the hippocampus come? Just how did the whole system evolve?

So I just think you ought to get someone who knows evolution. That's just my guess. I mean, you'll go on and do nice work. But I don't think you'll do anything profound. Despite all your money. Because maybe you quite haven't asked how the whole thing came together.

All right. I hope that's true, because we're going to think, evolutionarily, we don't have any money. And so, you know--

[LAUGHTER]

So we'll see what we can do.

Okay. Then the last thing. And I was sort of scared when Harry talked, because I read his autobiography. And he said so many things, that he'd actually say what I'm going to say. But thank god he didn't.

And so basically mental disease of various forms, and the effort we should place toward trying to find the genetic basis of it. And this isn't a function of this building. You've got the [? Broad. ?] And Eric [? just ?] got another $100 million. So he should get somewhere. But I'm not sure he will. Because you've got to really think about what schizophrenia is. It's got to be [? close ?] [? to it. ?]

And so I think about it an awful lot, for a very tragic reason. I have a son with schizophrenia. And for the most part, the psychiatrists aren't up to it. And that's not to say they're stupid. But some of them aren't very bright. I'll tell you that.

[LAUGHTER]

You see this when your children are with them. Jesus Christ. And so right now we sort of have this dichotomy in the bipolar disease and schizophrenia. And my son, they couldn't tell me what he had. And finally they ended up, he had a pervasive developmental disability not otherwise specified. [INAUDIBLE] we don't know anything.

Now, people have tried to separate these things into two categories, bipolar schizophrenia. And they've done the genetics, tried to do genetics. And it's the general impression that it has failed. It's not true. It's given some really important [? things. ?]

The most important is that both diseases you end up with not a completely overlapping set of genes. But a lot of them are just the same. So what does that mean? It means that there is something really in common.

So the disease is really two things. One, schizophrenia, when it was first described, is a thought disorder. People can't think. Very disorganized thought. And cause we're more than just your prefrontal, you can't move your body right. You're not going to ever be a great pitcher, or anything like that. The whole brain really just can't learn. And that's why.

And then the second part of the disease, or it looks like what's studied by these genes, is sort of going into psychosis, where the cause of all your dilemmas is not the genes, but CIA, which is listening in and providing a reason for it. All right.

So what is this common genetics? Well, there's the disk disrupted in schizophrenia on chromosome one found out of Edinburgh. And then there's chromosome 10, I think it is. I think it's 10. There's nitric oxide. Nitric acid. [? Nac. ?] Okay?

And what do those things have in common? They're probably signals for neurogenesis. So the underlying defect may be-- and people when they look at the hippocampus in schizophrenia, it just seems small. And if you ask them, well, what's missing? It's the granule cells. It's the neurogenesis.

So whether all learning has to involve new cells in the striatum or something, probably not. But what really is happening when you learn? A sort of awful fact we heard in the course was that if your child walks six months later than the average he has a three times greater risk for schizophrenia. That just means there's something. The learning is slowed down, much more difficult. They can't learn faces. All these things. Why don't they want to be with people? It's hard for them to learn the face.

It's not that they don't want to. But it's a very deep learning defect. So if I can give you any advice-- and I don't want to give it to you because that's what we're going to do-- is that probably your institute will move really fast if it spends half its effort on schizophrenia and bipolar disease, because it's really a learning defect. And that's what you say you're learning. I mean, that's your objective.

And so it wouldn't be surprising with the finding I guess which came out of PNS first, the extraordinary finding that anti-depressives work by promoting neurogenesis. I mean, that's really important.

And so if we're finding these several genes involved in DNA replication, which really says producing new cells is awfully important, awfully important, I think what you want to do is, how do you produce new cells? Is there some way you can do it?

Now, for those of us who sort of think we're normal, the chief problem, which should be affecting everyone in this room, at least downstairs everyone seems to be over 30. And that means you're way past your prime in being able to learn. And if we're like mice, the neurogenesis is steadily slowing down. And so is there any way that we can actually, with adults, speed up neurogenesis? And it would probably raise the IQ.

Because your IQ goes down. The psychologists don't like to tell you these sort of things. You have to [? relate it to ?] age and all. So whether my playing tennis is a general stimulant for neurogenesis, or is it only doing something to the striatum, I don't know. And is reading a book actually, in some sense, creating a signal which leads to neurogenesis, I hope so. Certainly, they say the hippocampus there is more neurogenesis in London cabdrivers. They really have to remember that.

So I think it's both very important and it's pure science. And it's very, very important practically really to get at neurogenesis. And if I had arranged the symposium, I would have had Pat [? Gage ?] here. Just saying. Because I think it's damn important.

And to sort of conclude, I've been trying to think of an evolutionary reason why we lose the ability to learn as we get older. And I think the reason must be that actually the brain is pretty finite, and you can only have so much stored. And to put new things in you got to get rid of old things.

And in the past we wanted to retain the past in the brain. We evolved to retain the past because we had no books or maps. So old people were actually useful. They had crossed the mountain, knew where the rivers went, and where there was water. But now you could just look it up in the map. I mean, you don't need old people at all.

[LAUGHTER]

A big message for Japan. But you could say, well, this is an unpleasant fact. OK? So we won't accept it. But what we have to learn is that we have to accept the truth that comes out of biology. And it may not be pleasant. But that sometimes we can do something about.

So instead of spending money for more teachers in the New York City system, maybe we should be spending the money on how to increase neurogenesis. Same effect. I don't know.

But I do think the genetics of schizophrenia is really telling us something very important. And that the next couple years are going to be very exciting. Thank you.

[APPLAUSE]

MODERATOR: Thank you, Dr. Watson. I'd like to invite all our panelists to come up to the stage because we'll start talking about what you've heard today.

And I've written like two dozen questions that I wanted to ask. And I think I have to rip them all up now because there's so much more interesting things that I had heard.

And I will also invite people from the audience. We have a couple of microphones down here to take questions. If you sort of stand up and be recognized, or form a little line in the aisle there. I am also informed by the architects, who truly love the acoustics, like I do of the building, they said you can get questions from up there in the seats also. And I'd be happy if you want to shout down a question, if you have one, to take a question from up there. And I'll repeat the question if people can't hear you.

So I would like to start something different in starting off the discussion and ask any of our panelists if they heard something they'd like to ask someone else about on the panel? Hear something provocative, or something you'd like to know more about? Make believe we're sitting in your coffee [? klatch. ?] Did you hear something you need to know more about?

Well, let me just bring an overall theme that I detected that I thought we would detect when we talked about research. And that's the, it seems, the nature, nurture question. I mean, we're all just talking about brain chemistry and biology here. Is there no nature involved in shaping any of these things, any of these behaviors and influences that become a permanent part? And how important is it to study that?

Let me just say more. I see the people looking at me like I'm crazy, which I might be. You've talked about the influence of DNA and the genes on the structure of the brain. Where does nature come in that affects that behavior? How much does that change the plasticity of what's going on there? Dr. Kandel?

KANDEL: Yeah. Maybe I would begin. I think you were using the terms in somewhat different ways.

MODERATOR: Yes.

KANDEL: We refer to nurture as being the thing that the environment gives you, and nature is the DNA.

MODERATOR: Right. Right.

KANDEL: Okay. Well, I think one of the sort of significant insights that come along is that nurture works through nature. That is, environmental contingencies, learning new experiences affect alterations of gene expression in the brain, and can lead to anatomical changes. So although these are not herited, you have changes in gene expression that lead to growth in the brain as a result of various environmental impacts.

MODERATOR: Yes, Dr. Axel?

AXEL: I think it's important. I'll make an extreme statement. And that is, the nervous system of all organisms is hard wired. And that hard wiring is dictated by genes. That hard wired nervous system has evolved to accommodate the particular evolutionary needs of an individual species.

So your nervous system is innately determined. And that innately determined set of connections then forms the substrate upon which experience can shape the way you perceive the world. So you have to remember the innately determined structure with which all individuals are endowed.

MODERATOR: Okay. Anybody? Dr. Tonegawa?

TONEGAWA: Is this on?

MODERATOR: Yeah. It's working.

TONEGAWA: When we study the mutants, the behavior of mutants, basically what we are doing is trying to understand the limit of nature. In other words, we have genes, which give us a framework of what this machine can do. Right? And then within that framework, this machine happened to be the one which interacts. It is made in such a way that it interacts with the environment and incorporates information into it.

And, in fact, it alters. It even alters the hard wiring. All right? So that is the nature, nurture relationship. That's the way I look at it.

So then memory, learning, is the nurture, as we know. But you can't learn something beyond the limitation of the nature we have. I mean, we can't [? learn ?] the 100 meter dash with one second, even if you want to. However [INAUDIBLE] you do it, you don't do that.

MODERATOR: Dr. Watson, did you want to say something?

WATSON: Well, someone asked me to write a preface to a book on nature and nurture. So I've been just reading the articles. And one was just on the influence of smoking pot on your chance of coming down with schizophrenia. And it really seems to me really nasty. I mean, it's a real cause if you take it in adolescence, but not in adults. So I think the brain isn't really totally wired in adolescence. And it's really rather fragile. And we probably have to be much more firm to our children, really the harm they can do.