Interview with the 2000 Nobel Laureate in Physiology or Medicine, Paul Greengard, 13 June 2008. The interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.
Paul Greengard talks about how the events of World War II influenced his choice to study biophysics, how a lecture by Nobel Laureate Allen Hodgkin inspired his research (5:16), the initial opposition to his ideas about nerve cell function (14:05), how 15 years of hard work and unswerving belief led to his Nobel Prize awarded discoveries (19:54), future challenges for the field (25:00), the wonderful questioning of students (41:27), and why he established the Pearl Meister Greengard Award for women working in science (44:29).
Interview with the 2000 Nobel Laureates in Physiology or Medicine, Eric R. Kandel, Paul Greengard and Arvid Carlsson, by science writer Peter Sylwan, 12 December 2000.
The Laureates discuss whether we ever will be able to understand the mechanisms of mind; talk about their work and discoveries (6.31); making a paradigm shift in the way of looking at the brain (12:25); going against a dominant field (16:15); and their view of the future (19:04).
Arvid Carlsson, sitting there next to me, welcome. Paul Greengard and Eric Kandel, welcome to us. Three scientists that have really taken us a giant leap on a journey that is, in my opinion, I have to say, the least far more exciting and maybe also far more important than any trip to the stars. The journey to understand our self and to the mechanism of our mind, and maybe at the end of the journey, also the possibility for the conscious experience to experience itself, or to know itself, understand itself. So why don’t we start with the end and ask you this very simple question, and I want a short yes or no on this one. Will conscious knowledge ever be capable of understanding consciousness itself? Arvid Carlsson?
Arvid Carlsson: My answer is no.
Paul Greengard: My answer is yes.
And Eric Kandel?
Eric R Kandel: My answer is probably.
So, there is a little discrepancy between you on this one anyhow. But if I rephrase the question and say, will it ever be possible to understand the mechanisms of mind? What is your answer then?
Arvid Carlsson: To understand there is physiological and physiochemical processes that underlie the mind, that we could perhaps reach. But the actual conversion, how these physical phenomena become consciousness, that is what I think is the real tough thing.
But if you understand the mechanisms or the things that are changing, you can see them, you can measure them, then you can influence the whole system.
Arvid Carlsson: That is very true.
In that way, if my question contains the possibility of interfere with all aspects of mind, your answer is yes.
Arvid Carlsson: Yes.
Paul Greengard: I think that the history of science indicates that one by one various barriers have disappeared in areas that the human race thought were impossible to resolve. And everything seems to be solvable. And I don’t see why an understanding of how we think and what consciousness is wouldn’t be approachable in the same way. I think it’s going to be a very long time till we understand the nature of consciousness, even today with these imaging techniques you can start finding out precisely which type of cells are active when you do this or this type of thinking. It certainly should be possible to do similar imaging and understand when people are awake and asleep and I don’t think it’s a huge step beyond that to understand the nature of consciousness.
So you’re only putting more weight to the answer that all the different mechanisms that at the end lead to the consciousness experience, those mechanisms can be known and cleared. Is science limitless?
Paul Greengard: In certain principles such as the Heisenberg uncertainty principle I think yes it’s limitless. I didn’t always feel that way, it just seems that if you look what happened in the last 30 years it’s unbelievable what the human mind can achieve.
Eric Kandel, on the mechanisms of mind, of course you would have to answer yes on that question as well.
Eric R Kandel: I sort of come down more on Paul’s side. First of all, I think one needs to distinguish between mechanisms of mind, which involves all operations related to mental processes, action, thoughts, memory, perception, and consciousness. There’s lots of perception, mental processes going on of which we’re unconscious for example. You’re shaking your head as we talk, you’re probably not completely aware of the fact that you’re engaged in sort of reflexive autonomic movements as you talk. Those are mental processes but they’re not necessarily conscious ones. And we have made very good progress in understanding aspects of perception and motor action and I’m confident we will continue to do that.
The mechanism of consciousness is a fascinating one, and one that is getting a lot of attention. Not necessarily a lot of scientific progress, but a lot of attention. Francis Crick has developed a paradigm for looking at attention and consciousness, saying that one ought to look at a simple version of it, which is selective attention. You know, when I sit in this room, I attend to you but I’m also in the background perceiving pictures on the wall and things like this. But there’s a special effort involved in selectively attending to you, so the difference between perceiving something and the heightened selection that goes on with attention, is something he’s been studying in experimental animals with the help of other people. And there is now pretty good understanding of how a monkey, for example, attends to a visual image compared to just looking at the image without attention. So simple cases of conscious awareness are beginning to be analysable. To what degree consciousness of oneself, the most interesting parts of consciousness, become understood is unclear as yet. I sort of agree with Paul that a lot of problems that seemed insoluble became soluble with time. When there’s no add of time, we haven’t reached the limit by any means. It is conceivable that this problem is so difficult that the human mind may not have the computational power to analyse it, but we are far from reaching that particular barrier.
But you stick to some of the mechanisms to start with, the one that Arvid Carlsson has discovered is dopamine, and I think there is a fascinating correlation between too little dopamine – then you lose control over your body – and too much dopamine – you lose control over your mind. Is that so Arvid Carlsson?
Arvid Carlsson: As well as the body.
But is there some sort of relation between the mind and the body in this respect that is basically the same mechanism that in a way controls the material world and the mental world?
Arvid Carlsson: That’s a very interesting question. Anatomically the wiring that analyse movements and the wiring that analyse mental processes are very similar. The balance between different neurotransmitters involved in either of these two is very similar. And have probably evolved along with each other which, in a way, makes a lot of sense because if one goes ahead of the other you’ll have no use for it. The mind and movement have to evolve in parallel.
And in this system you have discovered the chemical signal substances between the connection between the nerves, and Paul Greengard your discovery is really what is happening inside the cell. How does your discovery relate to how we react and how we are, how we experience the world? Are there any connections that you have thought of?
Paul Greengard: The work that we did elucidates how these chemicals, the neurotransmitters which are the mechanism by which the nerve cells communicate with each other, how they produce their responses in the target cells on which they act.
And they are related to what sort of mental phenomena?
Paul Greengard: All mental phenomena, memory, consciousness and everything else, is all attributable to the behaviour of nerve cells and what the three of us are doing is trying to understand how one nerve cell communicates with another. It’s through the release of a chemical, a neurotransmitter which activates the second nerve cell and then what happens in the second nerve cell once the neurotransmitter activates it and then how that in turn sends a neurotransmitter to the third nerve cell. What we’re doing at this present level, all three of us, is to understand these biological systems going on, these biochemical molecular systems. Other types of neuroscientists, brain scientists, will take the kind of things that we’re doing and try to relate them to the higher order of behaviour in the nervous system.
But if Arvid Carlsson has done something in between the synapses where the signals are changing the connections between them, you’re only working with molecules inside the cell and how molecules are changing their shape and their effectiveness, what they do, the proteins we are talking about.
Paul Greengard: What we’ve done is to take these neurotransmitters that Arvid Carlsson had been studying and study exactly how they produce chemical and electrical changes in the nerve cells, working out what those biochemical steps are.
And they are related to memory in what way?
Paul Greengard: That remains to be understood to a large extent. Except Eric Kandel’s work addresses that and maybe he’d like to speak to that.
So, memory and changes inside the nerve cells, Eric Kandel. What is the concept or idea?
Eric R Kandel: Let me pick up what Paul Greengard was saying. One way to conceive of the contribution the three of us have made is to think of two sets of processes in the brain – mediating and modulating. That there are vast synoptic connections that are responsible for mediating many of the actions, for example motor actions, sensory perception. But the wonderful thing about the brain is that it can regulate the strength of connections. And my colleagues and I have shown that this occurs during learning, that the strength of connections are not fixed, but that inputs such as serotonergic input or dopaminergic input can modulate the strength of synoptic connections. And it does so by activating processes similar to the kind that Paul Greengard has described. In Aplysia one can show …
Aplysia, that is the sea snake that you have been working with?
Yes, one can show that in fact that a very simple withdrawal reflex, like the withdrawal of a hand from a hot object, can be dramatically amplified by an aversive stimulus. And that amplification involves activation of one of these modular choice systems, the serotonergic system that activates a signalling system within the cell. And activation of that signalling system causes strengthening of the synoptic connection, which is responsible for the enhanced withdrawal.
That means that there is a physical change of the size, so memories are actually made of these changes.
Eric R Kandel: Anatomical changes. That’s right.
This is somewhat exciting that the fast reactions, that is electricity and the somewhat slower …
Eric R Kandel: The fast, and not simply electricity, the faster also chemical transmitters but they act on different receptors.
But long term things are also represented by long term changes.
Eric R Kandel: That’s right.
You have all been part of a dramatic shift in paradigm when it comes to looking at the brain because all electrophysiology before and when you entered this stage you changed the picture totally into biochemistry. Arvid Carlsson, why did you choose to go contrary and against everyone else?
Arvid Carlsson: I think it depended to some extent on ignorance. I was not so well read in the field of brain physiology, so I could look at the facts in a simple, straight forward way, whereas those people who were burdened by a lot of knowledge, they had to think in other terms. They were, so to speak, fixed in the dogma. I was outside, just because of my ignorance, I think.
Eric Kandel and Paul Greengard, what makes someone want to go towards the conventional wisdom of the time?
Paul Greengard: In the case of the study of the brain at the time that Arvid, Eric and I did our work, there were two approaches to understanding brain function. There were physiologists who worked in physiology departments and studied the electrical properties of nerve cells. And there were biochemists working in biochemistry laboratories who took a brain or a liver or a muscle and threw it into a homogeniser and studied the chemicals in the brain. And the two groups did not interact. The people sitting biochemistry were only interested in the biochemistry of the brain. The people doing physiology were only interested in the electrical property of the brain. In one sense we were not going against dogma. There was very little prior art out there. In my own case, my work was guided by the hypothesis that a particular mechanism that had been shown to work in the endocrine system, in which hormone released from one cell activates a target cell, that that system might be analogous to how two nerve cells communicate with each other. And that is through a chemical mechanism, that hypothesis turned out to be correct.
Eric Kandel, you started off as being a psychoanalyst interested in psychoanalysis and everyone thought that was the gateway to the brain at that time. How come that you didn’t believe it?
Eric R Kandel: I did at the beginning and I still find the psychoanalytic view a rich and nuance view of the mind. I just became disappointed as I continued my medical education with how much empirical evidence there was to support it and how devoid it was in thinking about the brain. I became a little bit interested in the brain and as I got more deeply involved I became fascinated with it. And it struck me that memory is the central question in psychoanalysis. And in the 1950s when I began, the dominant view of the brain was that of Karl Lashley at Harvard, who showed that memory was not localisable. That you could remove many regions of the brain and not interfere with memory. What Lashley did not realise is that animals are very smart and if you remove a part of the brain, for example, let’s just say they’re doing a spatial task, if you remove the visual part of the brain, they will use tactile stimuli to find the way, or smell. They have lots of different strategies they can use. I thought one needed to take an extremely simple animal, an extremely simple reflex, where there would be no question about localizability.
Excuse me for interrupting, but I got so curious, but this is true that you have all entered a new way of looking at things that were contrary to the conventional views of the time. And still the question I am really curious about is how is your mental set up to want to go against this?
Eric R Kandel: I think each of the three of us gave a somewhat similar answer, in the sense that we did not think of ourselves as revolutionaries at the barricades. We were working along and we thought that one way of moving in the field was the sound one, it’s almost an intuition that this is the right way to go. It turned out be in opposition to what other people were thinking, but one wants to think in original ways, you try to tackle a problem you think is interesting and approach it in the way that you think is most profound.
Paul Greengard: To amplify what Eric said, it’s not that we were going against conventional wisdom, we were following our own instinct. This must be the way it works. And then more conservative folks would say we were disagreeing with them, but we weren’t, we were just looking at things in a different way.
So in a way it was a very unconscious way of …
Eric R Kandel: That’s right. I think that’s absolutely right.
Paul Greengard: No, I don’t understand what you mean, an unconscious way?
You didn’t really think about going against what was the convention, you just did what you thought was working.
Paul Greengard: It was nothing that they had done was wrong, we were exploring an area that other people hadn’t explored, I would say.
Do you agree Arvid Carlsson?
Arvid Carlsson: No. I was taken by surprise, I must say, when we reported on our data and all the big figures in the field said, no this can’t be true.
Paul Greengard: But that’s true for all three of us.
Arvid Carlsson: I mean, I was right and they were wrong. I mean that is how I experienced it. I wouldn’t like to give them any sort of excuse that we were right, all of us, after all. I don’t agree.
Paul Greengard: Maybe add a certain limited truth, we said, look we think that there are other things going on than what you’ve been studying and there’s all this and this. And then we’d say, yes, there’s all this and this. And then we’d show it and they’d say, no, you’re wrong. We were never saying they were wrong, I don’t think. They were saying we were wrong.
Arvid Carlsson: They were wrong, in my opinion.
Eric R Kandel: I must say that Roy Spencer and I wrote an article in 1968, when we first began to realise that learning could be localised to specific synopses. And we pointed out that Lashley’s view, which was the dominant view, had misled the field.
But if we look then in the future, this is not the last time where things are going to be turned upside down. Have you seen anything in the current science that indicates that there will be maybe a totally new model coming up of how the brain is working? Maybe adding some fundamental new knowledge to the function of the brain?
Paul Greengard: It’s exactly what I’m saying. There will be totally new ways of looking that will not necessarily be contradictory to what we did. What we’re doing is eliminating truths just like the people before us had even more eliminating truths, and the next people add on to that. And they’re not going to prove that the work that we did was incorrect, they’re going to show a new dimension.
Eric R Kandel: It’s almost probabilistic in a sense. The views that we have ended up supporting existed before, just to a minor degree, so people had seen in the endocrine system the kinds of things that Paul discovered in the nervous system. Kajal had spoken about the fact that synopsis could be the site of memory storage. But at the time that we were working those views were rare, very few people held that. Most people held the opposing point of view. For example, many people felt that Bernhard Katz and Eccles had described synoptic transmission in the nervous system, it was fast synoptic transmission. So they thought all synoptic transmission in the brain was fast. When Paul and I began to study slow synoptic transmission, they thought there’s something unusual about this and people were initially sceptical that this could be of importance.
But when the two models that has exchanged for each other, the electrophysiological model, the biochemistry model, what do you think about the future, Arvid Carlsson, are there totally new things coming up?
Arvid Carlsson: I guess there will be paradigm shifts in the future. But I think it’s inherent in the definition of dogma that we cannot identify it. As soon as we identify it as a dogma, it’s no more a dogma.
But before there’s a thunderstorm coming up you can always see a little glimpse of the lightening coming, do you see any glimpse here?
Eric R Kandel: We certainly see that. For example, we thought that the nervous system by the time a child is four or five years old, does not generate any more nerve cells. We thought that the number of nerve cells in the brain are limited – if you lose nerve cells as a result of disease, stroke, Alzheimer’s disease, there’s no way of replenishing those nerve cells from the cells in the brain. There’s now increasing evidence that there is a primitive population of cells that stays around in the brain and they can be the source of additional cells later on. That could be the basis of a new development that would enrich our understanding. So I think that’s a very important development.
And what would be the conceptual change of that idea?
Paul Greengard: Right now it’s thought that the brain has very little ability to repair itself. And with these new ideas that’s not the case. I would like to go back and correct something that I said, refer to something Arvid said on this. The people who are our predecessors, what they did was not wrong, their interpretation was wrong. For example, in his case, they said no, this molecule dopamine cannot be a neurotransmitter, so in that sense they were wrong. The experimental work they had done was correct, their interpretation was not correct. This is, in my case, they said these slow biochemical reactions cannot be involved in mediating communication between nerve cells, they were wrong about that.
But then finally, Arvid Carlsson, do you agree with Eric Kandel that there may be a totally new way of looking on the dynamics of the brain, which is really at the heart of his statements?
Arvid Carlsson: One direction that I think will become very important is the understanding of the interaction between the different neurotransmitters in complex neuro-circuitries. And there are new possibilities to approach these complex problems. And that deals with something that we can call pattern analysis. You can collect enormous number of data and feed into computers and the computers will feed back to you pictures of the data, that actually are patterns of very, very complex processes in the brain, by means of which you can come closer to these very, very complex mechanisms that deal with the mind, feelings and cognition and so forth.
And maybe even get a picture of the conscious experience then on the screen.
Arvid Carlsson: Yes, and also to distinguish between different personalities. By means of imaging you will tell this is a happy fellow and this other fellow here has a short fuse, that kind of thing.
Eric R Kandel: I also think that the human genome is going to enlighten our understanding of mental processes. One of the deep questions that is a confronted analysis of the mind, has been to what degree is the mind built on the base of genetic information? What is nature versus nurture? What do you inherit versus what do you acquire? And most personality traits are quite complex, so they’re not attributable to one or two genes, so they’ve been very hard to decipher. But now that we will have the whole human genome, we’ll be able to look at patterns of genes and we’ll see to what degree any of our behavioural patterns derive from familial traits versus acquired or learned traits. I think that’s going to be a very rich area for investigation.
Paul Greengard: I would like to go back to your original question and ask you and my two colleagues whether there is any reason to think that we won’t be able to understand the nature of consciousness or any other aspect of the brain. What reason is there for pessimism, given the history of the last decade?
Eric R Kandel: I think it’s hard to know what the limitations of knowledge are. I think it is hard to know at this particular point whether the optimism that we all share, that science can solve all problems in the universe, is in fact true. We’ve solved many problems so far, but there is the possibility that there are limitations to human understanding which we and the computers that we develop will not be able to solve.
Paul Greengard: At the moment we have not reached that point.
Eric R Kandel: We have not reached that point.
Thank you gentlemen for sharing of your knowledge with us.
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