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.


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.


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.


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.


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.


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--


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.


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.


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.


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.


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.

And someone last night was telling me again that alcohol taken really early in life really can lead to much greater chance of becoming an alcoholic than if you start drinking alcohol at MIT, it's all right. But if you start drinking it in high school, it's really bad for you.

Now, whether that's a solid fact or not, it's a very important fact. I mean, it has enormous consequences as to the decline, you could say, of England, which is the decline of Eden. And they just drink, and drink, and drink in adolescence. So you could say it just makes them all alcoholic.

MODERATOR: Dr. Kandel.

KANDEL: Jim points out a very important issue that is commonly phrased in terms of critical periods. You've extended that. But one can show, for example, that certain kinds of insults, like closing a lid, which would have no effect on you and me as adults, has catastrophic effects on kittens' visions, for example. If you close the eye for a certain, even relatively brief period of time, a few days, it can alter the ability for that eye to be able to handle visual information later on. And this is a cortical damage. This is not a damage in the retina.

And for various kinds of things, for example, parenting-- there are experiments not only in primates, but also in people in which you show that if kids are deprived of appropriate paternal and maternal care, that has bad consequences of their ultimately maturing. So there are for many aspects of [? carrier ?] development critical periods in which the environment has to be supportive in an appropriate way in order for the brain to develop normally.

MODERATOR: Thanks. Tonegawa, you were talking--

TONEGAWA: I want to propose in relation to this critical period issue, and the nature, nurture relation, there are at least two real world experts in the audience. Michael Striker and Mark [? Bear. ?] Are they here?

MODERATOR: There's one.

TONEGAWA: Yeah. Right.

So Mark, do you have something to say about that?

AUDIENCE: Well, thank you, Susumu, for that.


TONEGAWA: What did he say?

MODERATOR: Thank you Susumu.

KANDEL: You can run, but you can't hide.

AUDIENCE: Well, what I have to say about that is that I think that the work that we have done suggests that it's far worse to have a bad experience than no experience at all. So this term deprivation has to be really defined.

So, for example, closing an eyelid is not the absence of light. But it's replacing the normal patterns of retinal activity that we use for vision with uncorrelated, or noisy, or static activity. And it's really that bad activity that causes the problem. It's not the absence of activity.

So it's better to have no experience at all than a bad experience, from that point of view.

MODERATOR: All right. Thank you.

Let me ask you, Dr. Tonegawa. You were talking about the hardware, inventing hardware that you don't know what it's going to be yet. Right? What do you want to measure with the hardware? How do you know what to invent? What would you like to measure with the hardware so that you can invent the hardware?


MODERATOR: And I'll ask that to all of you. What's the machine that you need to understand this machine that you have?

TONEGAWA: Well, Jim pointed out that we need to know much more about the anatomy. And this is what Francis Crick always told when he was healthy.

And I think this is very true, that we should know more about the basic anatomy of the brain. And this is a very difficult thing to convince younger people, because, first of all, this is difficult to be funded, that kind of research. But I think it's very important to really establish the basis over which we study the interaction with the environment. And I think very little is known.

For instance, people talk about the function of the prefrontal cortex. [? duray ?] cells for working memory and so on. But people don't know what cell, which kind of cells, how many different kinds of cells are composing the prefrontal cortex.

MODERATOR: Yeah. I was very surprised. I can't remember who showed this slide of the synapse that we don't know what this, and this, and this is on the synapse yet. And it was very interesting. And we lay people think that you know everything about nerve cells, and all the parts. And obviously there's still a lot to be studied, even the basic parts.

I guess what my point was, I mean, we talk about MRIs, X-Rays, all kinds of scanners. Do you have an idea what the scanner is, what you have to look at so you know how to design the new kind of scanner? What is the part that you're trying-- yes.

TONEGAWA: Should I say?

MODERATOR: Yeah. Sure.

TONEGAWA: Well, the scanner we have now is not measuring the real activity of neurons. It is measuring the metabolism, activity of metabolism. Right?


TONEGAWA: So we need to know the real property of the cell which is changing the electric potential across the neuronal cell membranes. And one should like to know this. One would like to know this at the very high resolution. So if a single cell have thousands of synapses, and in the different parts of the cell has a different level of potential, depending on how the stimulus went through that cell. And that's what we should know.

We want to know the property, direct property of the cell, which is electrically expressed, because of the ion passing through the membrane.

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

WATSON: Well, just on the synapse, I think Seth Grant in Cambridge is trying to do proteomics. And it's about 800 proteins. And that's probably an underestimate.

KANDEL: Just published in '95.

WATSON: There will be many, many different mutations by which you can become stupid.


KANDEL: You're telling me.

WATSON: So you'll find a few that will stand out, like Fragile X, and so on. But you're probably just going to find-- and that's probably behind a lot of the difficulty in doing schizophrenia genetics, particularly when you're worried about these defects that are present at the age two or something. There's so many different ways in order not to be functional.

MODERATOR: When you said before that we haven't found the double helix of the brain yet, do you think there is some underlying mechanism that will take a paradigm shift for us to suddenly see it?

WATSON: No. Look, all the cortex looks the same. Information is likely stored in the same way. And I think we're going to find it out. But it's not clear what system we can look at to see it. And that's where ingenuity will come from, choosing the right organism to do it. Eric would-- it'd be nice if you could do it with a [INAUDIBLE], that you could get the big, general principal out of it. But I don't know.


KANDEL: I mean, one point that Jim made, which I think is a very good one. And that is comparative analyses. In the 1950s, many people in neuroscience were developing new model systems. And, in part, because of the success of certain systems, and in part because of funding, it's extremely difficult to develop new systems in neurobiology. And that has been a great impediment to the development of a comparative approach.

But I must say that the sort of neuroanatomical studies that have been coming out of the bird brain have been very illuminating. So there is some work going on. But I agree that it's not enough.

MODERATOR: If you have a question, just wave.

Yes. Up there, sir.

AUDIENCE: I would like to direct this question to [INAUDIBLE]. I wonder if you could briefly consider [? the impending ?] [INAUDIBLE] the next couple decades [INAUDIBLE] the possibilities of genetic engineering and [INAUDIBLE] enhanced [? pharmacological ?] drugs [INAUDIBLE] brain [INAUDIBLE]? And [INAUDIBLE] could you briefly discuss some of the [INAUDIBLE] scientists [INAUDIBLE] deal with the research that's coming out [? of our labs. ?]

MODERATOR: Dr. Brenner, did you hear that? He wants to know-- the question is about the ethical challenges facing neurological research and drugs that might come out to change neurology.

BRENNER: Well, I think we've got a terrific method of changing the brain. You just have to talk to people. So I think there's a big confusion in people's minds between being a person and being just a product of a genome. A person is much more than just the body and all the other stuff there.

Because when people talk about cloning people, and so on, they usually think of it as-- someone once asked me at a lecture, why can't I clone myself and keep the copies for spare parts? My reply was, be careful. One of the copies might keep you for spare parts.


He didn't consider the copies as persons. They were just things. You hung them up in a cupboard. You needed a new finger, you cut it off and glued it on.

And when people talk, we have remarkable social ways of cloning people. They're called armies. They're called schools. We are cloning persons. They were trying to make everybody with identical behavior. So the clue is for people, as I said at the beginning, I think just forget about biological evolution, whether spontaneous or engineered. We can change the phenotype of people very clearly.

And just to go back to one of the earlier questions, the nature, nurture one. See, as you go down in the scale, where you have the little roundworm, finite nervous system. We have the whole wiring diagram done. Most of the behavior is hard wired. Most of the behavior is hard wired. That is, this organism's genome and what it does in its life is effectively predetermined, very accurately predetermined. Then you can see as you ascend the evolutionary scale-- actually I think the nematode is going downhill basically. I think it's had its day. It's a degenerate animal.

It's not a primitive animal. It's degenerate. Anyway, that's another topic.


Just let me say finally that the other thing that struck me is that even in flies, it's hard to discover whether a single animal learns. The learning is statistical. Because what's the aim of the learning? It's to save the species. It's not to save you or me.

MODERATOR: Well, that seems to be one of the things we're talking about, is how does the actual learning--

BRENNER: So and as we go up the scale, once we come to people, I think we've got a completely thing. We have this wonderful invention. You take this hardwired nervous system, which essentially specifies the id, if I'm [INAUDIBLE] top there. The location of the id is in the hypothalamus basically, the center of greed, lust, avarice, and desire. That's why it's called the GLAD project, for happiness.


And we've grafted onto this basic mechanism something which learns. When I think could we encode all of human products in DNA? I mean, if I were the intelligent designer, I mean that would be the stupid designer would try to write in genes everything that we can do. It wouldn't work.

What you do is you produce this thing. And by interacting with the environment, you can generate huge varieties of behavior. Well, that's the beauty of the nervous system. You wouldn't want to hard code it. You take something which is hard wired, because it has to be built. And then you have this wonderful flexibility.

Now, forget what [? you are. ?] You want to know the ethical things. Well, I think we should also talk about the ethics of trying to make people uniform. I think that's much more things that we have to think about.

WATSON: Could I--

MODERATOR: Dr. Watson.

WATSON: Yeah. Sydney, do you think any part of your uniqueness has been due to your environment?


WATSON: Okay. So when you really look at unique people, they don't seem to arise out of their environment.

BRENNER: No. I think someone asked me, how do you account for yourself? I say, I had good genes.

MODERATOR: And that's it?

BRENNER: I have good doctors.

MODERATOR: Good food.

BRENNER: I drink single malt whiskey.


MODERATOR: It didn't matter where you were born, or where you grew up, into what family?

BRENNER: No. I mean, it doesn't make sense to say whether you-- you're the product of both. You're the product of the interactions.

MODERATOR: But that's not what you said. You said you were just your genes.

BRENNER: Oh, no. That was a joke.


WATSON: No, but it might be true, Sydney.

MODERATOR: There are 10 million people watching this.

BRENNER: No. I've got some good genes.


TONEGAWA: You have to tell them which one is a joke and which one is not.

MODERATOR: We take you very seriously here.

BRENNER: No. For example, everybody knows there's a gene on the Y chromosome for reading in the toilet. I've got that gene.


MODERATOR: That's not the chromosome we males are all losing?

BRENNER: No. No. No.

MODERATOR: Dr. Axel, let me just drill down. And if you have a question-- a question out here. Let me go there. Then I'll go to my question. Yes.

AUDIENCE: Hi. This is a question for all the panelists. Dr. Axel, you mentioned how genes help lay the foundation for hardwired circuits. But we know that the brain changes and is modifiable by experience. So my question to you all is, as you advise those of us who are beginning our studies in the field, what are the foundations with which we should now use to study the rules of plasticity of how these hardwired circuits change in adulthood? Should we still study genes? Do the answers still lie in the genes, or should we move on to looking at protein pathways, or cortical network changes, or some combination of these fields?

KANDEL: I didn't understand.

BRENNER: I didn't understand it. Could you repeat it?

TONEGAWA: Could you summarize your question in one sentence?

MODERATOR: [INAUDIBLE] you want to [INAUDIBLE] if new students should study just genes or some other molecular pathways that they express themselves?


MODERATOR: Should you waste your time with anything but the genes is what she's asking.

AUDIENCE: It's clear that genetic studies have told us a lot about how hardwired circuits function. So my question is, as we move on to studying brain plasticity, neuroscience in the next decade, do you think genes still hold answers for us?

MODERATOR: Dr. Axel? Then I'll go Dr. Watson. Go ahead.

WATSON: I mean, obviously, you start with genes. That's the whole search for these genes behind mental disease. They give you enormous clues. But if you're just a gene jock and you've been trained to do it, just go work in industry. You don't belong here for a while.

I mean, it's not enough just to manipulate genes to really do something deep on the brain. You've got to be much more a biologist, or a neuroscientist, whatever term you want to use, or cognitive. Too much focus will make you very narrow and boring.

BRENNER: What does she want? What does she want? I don't know what her question [? is fully. ?] I can't even deduce it from Jim's answer. That's the problem.

AXEL: That was always true.


I think Sydney alluded to this. All of us alluded to this earlier. And that is we've emerged from 50 years of understanding the chemical nature of genes. And in other systems it's been possible to go from genotype to phenotype in a relatively clear way. It's not hard to equate a change in the growth hormone gene with short stature.

But in the nervous system moving from genotype to phenotype has been an elusive problem. That is we can't immediately move from a change in a gene to a cognitive or a behavioral defect. And that's because genotype and phenotype are separated by a neural network. And it's this neural network, both anatomically and functionally, that we need to understand in order to understand the consequence of an alteration in a neural peptide receptor on social behavior, or a vasopressin receptor on promiscuity. And so it's these circuits that lie between genotype and phenotype that to me are the--

MODERATOR: Dr. Kandel? Sorry.

KANDEL: Just to elaborate on that point, not only is the circuit complicated. But the individual nerve cell is complicated. So an individual nerve cell makes not 1, but 1,000 different synaptic connections with different target cells. Many of those synaptic connections can be regulated independently. And many of those synaptic connections have their own machinery for local protein synthesis. So that can be activated or shut off. So the possibilities within a given neuron alone are much larger than one would have thought 20 or 30 years ago.

Now, you put that into a neural circuit, and you'll see what the problem is in moving from a gene to a phenotype without having the analysis of what goes on. What is needed is, and this is what Jim has been saying, you need good cell biology in addition to molecular biology. You need the neuroanatomy. And you need good behavior. And you need appropriate systems in which these things can be put together.

Probably no single system, except if we can get a reductionist approach to people without interfering with their lives, in which this can be tackled satisfactorily.

MODERATOR: Dr. Tonegawa?

TONEGAWA: So I just want to balance what we are discussing here. Because the question is whether the glass is half full or half empty. And right now people have emphasized the difficulty, challenge of connecting genotype with a phenotype when it comes to the nervous system. But the other side is that, in fact, if you do the classical genetics, just a mutated gene for the entire body, entire period of a life of the animal, of course, it's become more difficult to interpret behavioral deficit.

So therefore, we struggle to try to restrict genetic mutation to a specific type of cells, and a specific part of the brain. And sometimes even specific period of [INAUDIBLE]. And then the interpretation becomes a little bit easier. So I don't want the students to go away and say, oh, this is impossible to do any genetics in a nervous system. That is not exactly true.

It is a difficult thing to do. But it's not as bad as like a classic genetics, and try to understand the function of a gene and the behavior.

MODERATOR: Dr. Brenner?

BRENNER: I'll just say one comment about that, which is that, of course, it's only the fact that the gene function is allocated to that set of cells inside the organism that allows you to change it in that set of cells. And that is something which I think we still need to uncover, which I call the instantiation problem.

There's no such thing as a gene. But I'll leave that for another Institute opening. But just let me add one comment which I think will illuminate this discussion.

I was asked, and, in fact, if my memory is correct, it was at MIT in a lecture I gave a long time ago, a student came up to me, and he said, Dr. Brenner, what is the breakthrough in the nervous system? And I said you're almost 100 years too late. It's called the neuron hypothesis.

And that is the breakthrough. It is. We've got the way to think about it. It is cells. Cells have functions. They are connected. It is the network. The key thing is, of course, it's harder to think about a network than it is to think about a double helical molecule. But the network is going to be the foundation of the way we've got to think about this.

MODERATOR: Dr. Kandel?

KANDEL: I can't resist listening to this and being reminded of a sociological fact that some people in the audience may not know about. And that is 50 years ago-- what you are hearing about is the enormous problems we confront in studying the nervous system. And I think we'll all grant that that's true. What you may not be aware of is the shift in scientific manpower.

Now, in the 1950s, let's say, 1961, you would have gone into Jim Watson's office and told him you wanted to study the brain. He would have said, probably quite correctly, this is premature. And he was encouraging his best students to tackle other problems. Neurobiology was a small, relatively isolated community that had very few experienced people. This has changed dramatically.

Everyone sitting here now is a neurobiologist. I mean, Jim Watson is a neurobiologist. The most gifted people in the biological sciences are likely to go into neurobiology. The whole nature of the workforce has changed. So it's very difficult to predict where we will be 10 or 20 years from now.

If you look-- now, granted, it was a much easier problem-- as to what happened in molecular biology in the first 50 years, it was spectacular. And there is no reason to believe, although the pace is not going to be comparable, that we will not make great breakthroughs in understanding neural circuitry. And as everyone here agrees that that is the intervening step between genes and behavior.

And I think there will be principles that emerge. I mean, Sydney's emphasis on the neuron doctrine is absolutely right. If we begin to analyze local motor patterns, for example, and see that there are general anatomical and functional principles in all local motor patterns, which are very likely to be, we will begin to have some rules. If we understand perceptual processing and see what goes on, how does information from different sources come together?

And most importantly, why is it when groups of cells fire that I experience something? An issue we have not, but Pat [? Chechen ?] will certainly address. I mean, the ghost in the machine is we are the ghost in the machine. Somehow activity gives rise to conscious feeling.

MODERATOR: Well, that raises the whole issue. We're going to get around to this after lunch, but while I have you all here on the stage, cause you're not going to be here after lunch to be quizzed when we talk to the people about consciousness, how does this get you closer to consciousness? I mean, can your dissections and your deconstruction of the brain bring us closer to consciousness?

WATSON: I mean, you could really ask that we should ignore the problem for the next 25 years.

MODERATOR: You want to ignore it.


BRENNER: I think it's going to vanish as a problem.


BRENNER: It'll never be solved. It'll disappear. That's my prediction. And I think--

MODERATOR: Can't wait til after lunch for this one.

BRENNER: Let me tell you a problem that disappeared, which Jim once refused to let me talk about at a meeting.


It was embryological determination. And is determination different from differentiation or the same? There were endless discussions. What was it? Did it have a specific flavor [INAUDIBLE]?

Where's the problem now? It's gone. It's vanished. It's what happens to a lot of scientific problems. They're never solved. And 30 years later people will look back and say, why were they worried about this? What stupid people had in their minds to worry about consciousness?

So I believe it's not worthwhile working on, because it's going to disappear?

MODERATOR: And what's going to take its place?

BRENNER: It's the machine. It's the machine in me. Not the ghost in the machine. It's the machine in me which will take the place.

MODERATOR: Dr. Kandel?

KANDEL: I was simply going to say, I think that's a very higher order problem. And we ought to see how far we get with just the run of the mill neural machinery before we tear into that. There may be something very important left. But I think we are likely to make more progress.

Don't get me wrong. I think people like the two of you should continue to think about consciousness. But I think the majority of people ought to work on lower level problems, because that's going to give us insight into how neural circuitry leads to behavior. And what remains will put us in a position to tackle these higher order problems.

AUDIENCE: I think that's essentially right.

MODERATOR: Let's bring the microphone to Dr. Churchill.

AUDIENCE: I don't want to steal my own fire here. But I essentially agree with what Sydney says, and also with what Eric says. I think that the problem of consciousness, once we understand the fundamentals of nervous system function of how neurons code information, of what the heck attention is, and how motor control is organized, the problem of consciousness will essentially fall out of all that. And it's not going to be a separate problem that we need to solve by a different sort of technique.

MODERATOR: Sort of like string theory is today. That's a different topic.

Yes. Sir, yes.

AUDIENCE: Doctor Kandel, you mentioned that many more researchers are now going into neurobiology. I'd be very interested to hear why each of you went into neurobiology, either initially, or after starting in a different area of science? Thank you.

TONEGAWA: Why did we go to neurobiology?

KANDEL: I went into neurobiology--

TONEGAWA: Psychiatrist.

MODERATOR: You wanted to be a psychiatrist. Didn't you? He won't admit it now.

KANDEL: I am Viennese. And every Viennese Jewish boy has to go into psychoanalysis.


So I went to medical school to become a psychoanalyst, and had no interest in fundamental biology whatsoever. And I took an elective period, because I thought even a psychoanalyst should know something about the brain. And that was so exhilarating that it redirected my career.

And as I got into it, I began to realize that the problems that initially attracted me were not tractable. And I recommend to all psychoanalysts that they give it up and they go into neurobiology.


MODERATOR: Anyone else want to share their why? Dr. Tonegawa?

TONEGAWA: Well, I'm often asked that question, because people know my work more in immunology than the neurobiology. So my answer is different depending on who asked.


The true answer is that I felt that immunology is not exciting enough anymore. And, of course, when I say that, immunologists get very angry at me. And I don't think there are many immunologists here, except my friend Antonio. So it's all right.

But another reason is because I made too many enemies in immunology. So I wanted to go into another field.


MODERATOR: Many years ago there was a physicist who won the Nobel Prize here in this town. And I came to this fair city and sat down and asked him-- this is like I think 1975. And I looked forward to 2000. I said, where do you see the future of physics in 2000? And he thought about it for a second. And he said, I think it'll become as boring as chemistry.


Is there anything to be learned from other scientists, collaboratively speaking? And working together, maybe with physicists and whatever, just exchanging information that might open up-- having coffee in the morning, or I know you were talking much about buildings in the Picower Institute where people can see each other, and bump into the halls, and things like that. Is there anything to be learned from these other people? Or are you so elitist that--

BRENNER: Oh, no. No. No. No. They don't want to talk to us.

MODERATOR: They don't want to talk to you.

KANDEL: That's not true.

BRENNER: No. I think I still remain a geneticist. I just think the brain is a very interesting phenotype. It's not boring like most of the other phenotypes we have.

And as Jim will tell you, we both believe there's only one thing worse than bad. It's to be boring.


MODERATOR: So you think it's possible for one machine, the same machine to understand its own machine?


WATSON: Why not?


WATSON: Why not?

MODERATOR: I've just asked the question.

BRENNER: I mean, even [? Goethe ?] believed that. Even [? Goethe ?] believed that.

WATSON: I mean, that question sounds like philosophy. And I know Pat is here, but just absolutely avoid any discussion of logic in your life.

BRENNER: That's Gunther [? Stent ?] philosophy.

MODERATOR: To avoid that.


Yes, sir.

AUDIENCE: The basic question that we're here to study, all of us, is how does the mind emerge from the brain? And this is a question that mankind's been studying for centuries. And we've been trying to reconcile that.


AUDIENCE: So my question is, where are we? What is the state of progress? Is the neuron doctoring going to be sufficient? Will we require a paradigm shift in terms of complex systems and emergent phenomenon? If you were to try to place in context our state of understanding how the mind emerges from the brain in terms of, say, physics, where are we with landmarks like Galileo, Newton, Maxwell, Einstein? How far along are we?

WATSON: We have no idea.

BRENNER: That's right.

WATSON: We don't know how the brain works yet. And when we do, then you won't ask that question.


KANDEL: I think what's also important to emphasize is that that's the excitement of the field.


KANDEL: The reason Susumu got out of immunology is because he thought some of the most interesting problems have been solved. That's when people get out of the field. You are entering, or neurobiology is a field that can be entered because most of the important problems have not been solved. I mean, that's the great challenge. And this is why I think young people find it attractive.

MODERATOR: Let me pick up on that idea cause I had a similar sort of question. And I was asking Dr. Axel about this before. And he showed these wonderful pictures of-- what was it? Cherries, and lemons, and the stimulation of the smells in the brain. But it didn't show something that when I smell something it evokes a memory of something else. How is that hardwired into the cherries and lemon spots in the brain? Or do we just not even know that part yet?

WATSON: We know nothing. Just don't ask the question. It's good for a radio program.

MODERATOR: That's why I stand here, and you sit over there.

WATSON: Enough is enough.


KANDEL: He's great. Thank you.

MODERATOR: Are you his press agent now? You're not going to let him answer?

Question remains on the floor, Dr. Axel.

AXEL: Jim gave you the answer. We know nothing. But what we've all demonstrated is the capability to talk about things we don't know about.


MODERATOR: So do I detect some frustration in this here now, that you [? feel ?] frustrated about things you don't know about more than--

WATSON: No. We're not frustrated. I mean, we're curious.


WATSON: I mean, you may be frustrated, because you can't put together a good program which is understandable.


You can put together a good program on DNA. But talking about this, it gets so close to bullshit, It's not worth doing. Just do it.

MODERATOR: Better watch out. I'll ask about your opinions about God in a second and we'll all be out of here.

Any other questions? Yes. Why don't you wait for the microphone. Wait, miss, for the microphone to come over.

AUDIENCE: Okay. Yeah. I'm Laurie McGovern. And at the risk of having a mutation and exhibiting greater stupidity than has been exhibited obviously already, I have a question. Since our nervous system is hardwired, is prejudice hardwired in our system?

WATSON: I don't understand the question. Richard, you're--


MODERATOR: He needs a very simple question. Is prejudice hard wired, Dr. Watson? That's the simple question. Right? Did I understand that right?

BRENNER: Well, look, your eye is wired to the right part of your brain. Right? If you take the precursor of the eye and stick it on the back of a frog, it goes up the spinal cord. The fibers run up the spinal cord. And they just'll end up nowhere.

But that specification is not a recognition in the eye that says, get there into the [? tactum. ?] That's where you got to go. What a specification is it says, recognize this molecule and keep on going till we tell you to stop. Okay?

And it just so happens incidentally much of the same specificity is in the spinal cord. But you know that never occurs in nature. Nature doesn't have to eliminate unknown things. That is the beauty of natural selection.

So we don't have to puzzle, how did the eye know to do this? It just happened to be there, and it's of no account in normal development.

I give you this as the example that if we tried to specify everything by a certain number, we're going to be wrong. Because there are many things, even at the lowest level of the genome that are [INAUDIBLE] conditions. It doesn't matter whether it's up or down. It works.

MODERATOR: Can I sum that up by saying-- and tell me if I'm wrong-- that the kind of question she's asking is a consciousness question. And you folks don't study consciousness. So you couldn't answer that kind of question?

BRENNER: No. I still don't know what the question was. She said, she is hard wired.

MODERATOR: She's asking, back to a nature, nurture question. She's saying is prejudice hardwired into your system? It's basically a nature, nurture question.

BRENNER: It could be. It could be. It may have been advantageous 25,000 years. I have strong prejudice.

KANDEL: That's right.

WATSON: No. I think something that's illogical, our brain doesn't really like illogical things. And so when we hear illogic, we just say, crap. And you could say that's prejudice that I'm using the word crap. But that's just response. It's [INAUDIBLE].

BRENNER: No. I think you have to conceive of this animal that we used to be. And you have to ask yourself, what were we selected for in the environment that disappeared thousands of years ago? We have still inherited that genome. And our problem is how to sort of confront the products of our brain with that animal that is still within us, if I can put it in crude terms.

WATSON: But I think there's sort of the feeling that society now is not evolving at the genetic level. I think it is. And there's probably a fairly strong selection, probably selection for less aggressive people. Because if you're aggressive at a very early age, you're put away. And so that's certainly a trend.

And so you could say there's certainly a selection because our groups get bigger and bigger for us being more politically correct. I mean, there are real selections for that because society sort of demands it.

And that's sort of for developing an illogical brain. You do something because you're supposed to do it rather than you believe you should do it. But I think we're, on the whole, survive only because our brain really is pretty logical.

AUDIENCE: But can I--

MODERATOR: Dr. Churchill, go ahead.

AUDIENCE: Yeah. Can I just have a crack at answering that? Or at least see whether this is more or less along the lines that you were thinking. And that is that presumably humans, along with other social animals like baboons, wolves, and chimpanzees, have dispositions for sociability, like the prairie voles. We have vasopressin and oxytocin. We form social groups. And part of that, I think, looks like we have very strong adherence to the group, and very strong rejection of the out group.

So in that sense, I think that there is an early imprinting on the types of individuals within your in group. And so you are more likely to feel comfortable and appropriate with the people who belonged to your small group, whatever it happened to be, your family or your clan, and so on.

But then, as Jim rightly points out, as society changes, and we live not just in these small clans, then some of the in group, out group stuff becomes really a problem. And the name that it often gets is prejudice. So something along those lines seems to me to be the way to explain this really very natural, but tremendously strong feeling of connection to the clan, or family, or group that you're born into.

WATSON: Yeah. The Irish.

MODERATOR: Yes. The lady right back there. Stand up. Got the mic?

AUDIENCE: Could you come to the front?

AUDIENCE: Sure. Okay?

MODERATOR: Out into the sunshine.

AUDIENCE: At the risk of asking another consciousness question, I'm really curious about how fruitful you think the researchers who are working with the Dalai Lama and other meditators, people who've spent their lives trying to develop their consciousness and develop their understanding of consciousness-- do you think that these studies will prove to be fruitful and open up new doors for neuroscience?

BRENNER: I'll tell you the answer to that question. It depends on your age. If you're 20s to 30s, people will say, hey, man, this is a great thing. A new insight into everything. If you're 40 you'll get a judicious reply, saying we can't say what this is. There's some probability it might have an effect. We don't want to rule it out completely.

But when you get to our age, you just say it's a lot of rubbish.


Just forget about it. From a point of view of science. If it makes you feel good, I'm not going to stop you.

MODERATOR: Well, that goes back to what you were saying, that scientists have done their best work by the time they're 30 or so.

BRENNER: Exactly.

MODERATOR: I see. I see.

BRENNER: The ones who have done any work at all.


MODERATOR: There was a question over here. Somebody right behind you. All right. Okay. [INAUDIBLE] fine.

AUDIENCE: Hi. You spoke earlier about possibly coming back in 2053 and seeing what had happened in the field. And my question was more about the practical applications of your work. So not what would happen in science and what would be the fruit of your labors and those that come after you, but more how would the world look different as a result of the things we hope to learn in the coming years?

MODERATOR: Dr. Kandel, let me spin that question a little bit cause I see everybody's mouths are open a little. You mentioned about all the implications, art, culture, whatever, the impacts that this work is going to have. Do these disciplines understand that themselves? Do the people who work there understand how brain research, or understanding the brain is going to affect their own disciplines?

KANDEL: By and large, no. I mean, let me indicate that Tom [? Insul ?] that may be too young to realize that when I entered psychiatry many psychiatrists didn't believe that illnesses other than the major psychoses occurred in the brain.

So you could understand if a medically trained discipline was so unaware of what the brain does, you can understand how people who are art historians, or economists do not. But in every one of those fields, one of the reasons I specifically selected them, there is a significant avant garde group that is sensitive to it and is trying to do it.

In fact, Richard, David [? Friedberg, ?] and I are trying to organize something at Columbia in neurobiology and art. Certainly lots of groups are doing this. This is an interesting area. And in each one of the topics that are listed there are people within the discipline that are trying to do that.

MODERATOR: But if you're cataloging, I think also the legal and social ramifications--

KANDEL: I think are enormous.

MODERATOR: --would be tremendous. I mean, you're cataloging all the genes.

KANDEL: But the simplest one, to come back to what Sydney said, is if we understood more about learning and memory, for example, and we had some insight that could not only be used in experimental animals, but could give us insights into how we could improve learning-- for example, if neurogenesis is important-- we know that exercise stimulates neurogenesis-- you would encourage people to exercise more particularly at certain phases of their career. I'm making this up.


KANDEL: But you are certainly likely to get biological insights that will lead you to altering child-rearing patterns, educational patterns. That's the hope.

MODERATOR: But also on the other hand, if you understood that if the flies have 900 genes for smell, or different genes, if I understood you correctly, could you then give me that gene for a pheromone that I don't smell now, and I could use later on?

BRENNER: Yeah, probably.

MODERATOR: Is it possible to do that?

AXEL: Yeah. It's been done. It's been done. I mean, that experiment's been done in the worm by [? Corey ?] Bargmann.

You can change either the sensitivity of an organism to its world. Or you can change the behavioral response of an organism by putting a gene in a different neuron.


BRENNER: What we need to do is to wire up the auditory input to the visual analyzer. Then we could really see what Beethoven's quartets look like.


MODERATOR: Are there any other questions?

BRENNER: That experiment has been done actually.

MODERATOR: I'll take one more question. Then we'll have to break for lunch.

TONEGAWA: Yeah. No. No. [INAUDIBLE] has done that. Yeah.


AUDIENCE: Dr. Watson said that we hadn't found the double helix of the brain. I wonder whether the panel would like to comment on Dawkins' notion of a meme? And if I may, a second question, five Nobel laureates, five great senses of humor, nature, or nurture?

MODERATOR: I think that answers itself, that question. Anybody respond to the first one?

KANDEL: Jim? Jim?

MODERATOR: Did you forget the question?

WATSON: Yeah. I forgot the question. Or I didn't really understand the question.

AUDIENCE: Richard Dawkin came up with the idea of a replicator of the mind called memes.

BRENNER: Dawkins. Yes.

AUDIENCE: Any analogy between that and the missing spiral DNA?

WATSON: No. I don't think so. I mean, a meme is a religion or something like that. You sort of understand how these things started and so on.

It's a useful way of looking at society, but Richard's not a neuroscientist so he worries about these things. We've got more serious things to worry about.

MODERATOR: All right. Our serious things we have to do now is to thank our panel. Thank you for taking time.


Let me announce lunch plans. If you have a badge, lunch will be served behind the curtains, or behind this side. If you have signed up for lunch on the internet, there are boxed lunches on the sixth floor upstairs. We'll see you all back here after lunch at about 2:20.