John E. Sulston

Interview

Interview, December 2002

Interview with the 2002 Nobel Laureates in Physiology or Medicine, Sydney Brenner, John E. Sulston and H. Robert Horvitz, by science writer Peter Sylwan, 12 December 2002.

The Laureates introduce themselves and discuss great challenges in bioscience (4:09); the complexity problem (8:58); controversial ethical questions (17:41); reproductive cloning (20:30); and the Human Genome Project (24:47).

Interview transcript

“Man is but a worm,” that was the satirical, ironic comment that was given to Charles Darwin when he presented his theory of evolution. The same quotation was used in the Nobel Lecture by Robert Horvitz, and I suppose, Robert Horvitz, that there was a hidden meaning in you showing that picture and doing that quotation.

Robert Horvitz: I don’t know that the meaning was specifically hidden but the point was that it reflects in fact the findings of the three of us combined. Because as we have learned more and more about biology, we find that the biological principles, the biological mechanisms, the precise genes and proteins that one sees in a worm of the sort that we’ve studied, or probably in any other organism, are remarkably similar to those that are present in human beings.

“Science is at a crossroad,” is another quotation from the Nobel Lectures. ”Either you decide to do science by press releases or you do science by publication.” That quotation came from the lecture given by John Sulston, what was the meaning of that quotation?

John E. Sulston: I think to be honest probably it’s more biology at the moment. It’s an old issue with science I think, whether one is going to simply make claims. In a previous discussion we were saying how the alchemist practiced science by press release, and he didn’t do very well. The point about press releases is you don’t check the facts behind and what you should do with press releases is to say: Show me your data. Biology is now finding itself in this position because suddenly biology is of commercial value and there’s a great temptation to try to gain financial advantage by issuing statements but not publishing them properly. We’ve had some experience of this with genome work and so that’s why I made a particular point of this, that we must publish openly, show the data and that’s the way science proceeds properly.

“We’re drowning in an ocean, or a sea of data but we are starved from knowledge.” That is a quotation from Sydney Brenner’s Nobel Lecture. Sydney Brenner, could you expand a little on that?

Sydney Brenner: Yes, I think we now have unprecedented ability to collect data about nature. Generated of course by our ability to sequence the genomes of complex organisms. You might say that we could in principle make an atom-by-atom description of what there is in nature, but there is now a crisis developing in biology that that completely unstructured information does not enhance understanding. What people want is to understand, which means you must have a theoretical framework in which to embed this. It is interesting that the word science and the word knowledge actually is the same word, so that people who just collect data are not doing science in that sense. I think that this problem will occupy our attention for certainly the next coming decades. Because we need it not only for understanding, but to communicate it and teach it.

By this you have introduced yourselves, all the three Nobel Laureates in Physiology and Medicine. And welcome to the Nobel e-Museum and this interview on your prizes and the science around it. Let’s go back to this issue about differences between knowledge and data, Sydney Brenner. What are the great challenges that lie ahead of bioscience now when the human genome is almost, because it would always be almost completed?

Sydney Brenner: It was originally said that sequencing the human genome would be like sending a man to the moon, and if you reflect on it, it’s exactly the same. Because sending a man to the moon is very easy, it’s getting him back that’s the problem. I think the metaphor now extends, which is how can we get the human genome back from the moon, because we’ve done the first half. I think everybody knew that the major task would be to find the meaning of the genome, to interpret it. And I think that for more of the more sober people in this field, they’ve realised that the major part of the task still lies ahead. I think that that is going to be absolutely essential. Now there is a tendency in our science to say that everything could be done by this type of factory organisation, that was necessary to sequence the human genome and the other genomes. And there is now an idea afoot that we could just set up all of this to study proteins, to study cells, to study everything. But I’m a great believer in the fact that factories are not necessarily intelligent. And I think that what we’re going to need is human intelligence. I think the belief that we will put all this data into a computer and it will tell us the answer, this is ill-founded.

John E. Sulston: I think it’s a minority who really feel that. I think what you have to guard against is this tendency that people put “-omics” on the end of everything and feel that it’s a new field and it really isn’t. Truth to say, although much drama was made of it and this was really because of the issue of the data release, there was never a very large fraction of science funding spent on the sequencing and I think that’s probably the rule. I think one should continue with large scale projects which have to be highly justified, but always with regard to the problems that they’re going to address. I think it should always be the case that by far the larger part of the funding should be spent on individual problem-solving efforts. If we can keep that balance, then I think we’re alright.

Robert Horvitz: I would absolutely agree with that. One of the comments that echoes in my mind is the comment “don’t forget the biology”. The sea of information indeed does sometimes mask, and the excitement of the acquisition of such amounts of data, sometimes masks the fact that this is simply the foundation. To understand, we do need the basic inquiry. I think that what is really vital is to keep in mind creativity as being much of the source of future progress. Creativity is not the product of either a factory or a committee, the creativity really comes from an individual or sometimes a very small group of individuals, and we must make sure in all contexts that we keep those paths to creativity as open and as supported as we possibly can.

John E. Sulston: I’m particularly pleased that we made a clear expression of this, since we’re here on behalf of the worm, the way the worm DNA sequence was published, it was entitled “A platform for investigating biology”. And there was a rather short paper about the genome itself surrounded by many other papers which were making the first steps towards the analysis that Sydney was speaking of. I’m very pleased that we did that because I think it expresses our feelings very well.

Does that mean that we are focusing in a way too much on the genes? There might be much more interesting knowledge to be gained from complexity and the interaction between all the other things that are around the gene. Who is deciding over the genes?

Sydney Brenner: I think the complexity problem is the problem. It’s going to be even more enhanced in later years as we begin to tackle such questions as how does the brain work? I think that we need to, and biological systems are unique in that they can encode their own complexity within themselves, so biological systems will be the ones where this new science can be investigated in an objective manner and will form a bridge between the complex systems we ourselves invent, in economic systems and the law governed systems that you find in physics and chemistry. I think biology will occupy intellectually a pivotal role.

Robert Horvitz: I think genes are very important but as we talk about biology, we are of necessity talking about biological complexity, and there are different levels of complexity. We have complexity at the level of genes; we have complexity at the level of cells; we have complexity at the level of networks of cells. As we talk for example about the nervous system, certainly genes provide the framework and the foundation for all that goes on, but some of the problems of the nervous system are probably best addressed not at the level of genes, but rather at the level of cell networks and neural networks. It’s only part of the problem, the genes, and we certainly want to understand at that level but my statement again is don’t forget the biology. The biology is much broader than genes. And some of the studies absolutely have to be carried at these higher levels.

But the exciting thing is that it sounds as if there were some general knowledge to be harvested from this theory of complexity that could be applied even to economics and to associated questions or to other complex systems. What is your idea on that, John Sulston?

John E. Sulston: I’m not sure. People talk a lot about complexity theory. There’s a web thing that keeps being sent to me and I’m not sure that I believe in this abstraction. But of course people should try, if they think they can produce generalisable rules that may be right. One other point, I think the construction of devices is immensely important. I must say, when we come to talk about the human brain, I am one of those who regard it as least as important, the attempt to make intelligent devices. At the moment the words are being misused because none of our devices are intelligent. But nevertheless, as soon as you begin to make machines that learn and indeed evolve in some fashion, then I think we are beginning to use messages from life. In that sense you might be saying that we are using some similar ideas. But whether or not some real understanding of complexity will emerge, or it will be rather the case as Sydney has often said, that you cannot make a description which is shorter than the thing itself. I think we have to find out. But I think we have to explore. I do emphasise, it’s so important that we should use our creativity in this way. I think it’s actually particularly important, it came to light in a comment the other day that maybe Mozart had a completely different sort of creativity from scientists because without Mozart the music wouldn’t have existed, whereas with science we only discover and it’s there. I don’t think that’s true as we go forward in the areas we’re talking about now, because I think our creation will be as important as our discovery.

Sydney Brenner: The answer to the Mozart thing is that the sounds exist in nature and he found the language to put them together in an interesting way. We could take exactly the same view which is that the objects exist in nature and it is the language that we use, whether it’s mathematics or scientific theory, to put them together. I don’t necessarily believe that there is a fundamental difference between them. I think the important thing is that it seems to me, that there are still enormous puzzles in this that are quite difficult to grasp. Because we have now systems of enormous complexity, like the human brain, which has arisen by an evolutionary process from the systems and shows continuity with C-elegans, that something came from C-elegans to reach this level of complexity by a process of mutation, accretion, but not by a process of design, which is the difference between this and man-made objects. And I think that that says to me that there must be some architecture within this that permits that flexibility because for many other systems, we know that if you change them, the most probable consequence is you break them. Whereas through this evolutionary process, nature has achieved something and to comprehend that I think is really a big challenge.

John E. Sulston: The major thing of course is the rearrangement of the parts. I think we now understand that that’s the most likely key role of sexual reproduction. It’s an old puzzle for the geneticists, how organisms are inconveniently diploid, they have two copies of everything. The reason is probably that every generation can get a great rearrangement. Although the process is blind, in fact evolution is indeed arranging the parts. This is more likely to be productive than mutation which is usually destructive or merely adding new bits, and where do you get the new bits from? But if you rearrange old parts which work together in slightly new combinations, you can make much more rapid progress. And I think it’s right to say that’s how evolution has proceeded.

Robert Horvitz: I think evolution is also a key word in the context of the question you raised a few moments ago about complexity. And the question is biological complexity likely to provide models for complexity of other systems? I think the answer is that evolution has done the work of generating a number of solutions and that if we understand those solutions, we can then see at least some cases in which complexity has been defined and we can then ask whether we can apply that knowledge, that framework, in other spheres. My guess is actually that we will be able to do so but probably not in ways that we’ll anticipate until we see what the answers really are. I think in part about devices that have been made in bioengineering, where people have made a variety of prosthetics and other devices, always with the notion that they’re copying biological systems but by and large, what is done before the knowledge of the biology is actually very unlike the biology. But the knowledge of the biology can then change what one can do in the future. I’m perhaps a little bit more optimistic than John of the general principles emerging, but we don’t know ahead of time what they are. Evolution has solved problems.

John E. Sulston: The reason I speak about it negatively, I do feel that complexity is now a buzz word just as chaos was about 10 years ago and it annoys me. It’s like “-omics” over again. Let’s just find out how it works.

Along the path you understand more and more about how life works, but what would you say would be the most serious challenge to our ethics? What is the most controvert ethical question that will arise out of the science that you are a part of?

John E. Sulston: I think the challenge to the ethics is ourselves and our social systems actually. I don’t think inherently we are creating worse ethical problems with biology than we did by, for example, inventing nuclear weapons. But in both cases, if we don’t apply the democratic process properly, and of course we do have to bear in mind all the time, as Winston Churchill said that “Democracy is most awful way of governing ourselves until you think about the alternatives.” I think it’s very true that we don’t have any alternative to democracy and unless we apply it properly, and that means a rather full democracy, not a microsecond response referendum but a full democracy in which everybody has a chance to learn and to participate, then I think we might be in some trouble through discrimination of various kinds, and people have painted various horror stories of how we might actually specie-ate ourselves, if the rich ought to start breeding themselves in some clever way. I believe that properly applied social democracy will be a sufficient check on excesses of that kind.

Robert Horvitz: One comment that was made really can be seen in a book written some years ago by Jacques Monod, which he entitled Chance and Necessity. In that he took this topic that Sydney has alluded to, and that is the knowledge that essentially biological organisms have not been designed, they have evolved by chance. And what we see before us just is the consequence of a large number of random events and the selection of those that happened to work better than others. That may, as Monod very well discussed, interface with the issue of ethics because we have to begin to think of ourselves in different ways than perhaps much of human society has thought in the past. Particularly in the context of religion and ethics that are driven by religion. I think what we’re going to need is basically an ethical foundation that is humanity driven as some of these concepts really change with time. But I think those ethics inherently shouldn’t be altered by knowledge, but it’s the responsibility of all of us to make sure that the ethics are very much front and centre stage.

Given that reproductive cloning could be done as safely as IVF and IXa today without any risk for the child or for the mother. Would reproductive cloning fit into that ethical framework in the future? Sydney Brenner?

Sydney Brenner: I think your assumption has to be questioned, whether it could be done. No, because I think that I can imagine a society that would accept that. There was a tremendous row over the case of in-vitro fertilisation and many people thought that it was unethical. Of course the argument was that this was of great benefit to a certain group of individuals. In that way now the machinery exists for those people to benefit from it and it’s a safe procedure. What worries me more is that the objectives of human beings in different countries differ, and we have to sit and ponder not so much on the ethics of any procedure, but the ethics of spending large resources say on cardiac transplantation, just to keep away from the genetics, and very little on famine. And I mean it’s that that worries me more, that the world is not a uniform place with a uniform set of standards. I think we have to be careful when we are thinking which leaf is higher than another leaf to be sure which branch we are standing on.

John E. Sulston: In fact I think I would go a little further than that, I would say that the world is in danger of being pushed towards a uniform standard. The standard of the unadulterated marketplace, where indeed the money will continue to be spent on cardiac transplants and drugs that are used mainly by the rich countries, because that’s where the markets are, and the others are neglected. I think in a sense we have a uniform principle and I think it’s wrong. I think we’ve got to have a new principle where we deliberately try and spread the healthcare more evenly and I think this is something we desperately need today.

And you have a recipe or any road ahead for that?

John E. Sulston: The road ahead? I’m afraid I have to say democracy again, because in the end if it’s not a democratic voice then it won’t work. But I think what’s happening is that our great world organisations, the World Trade Organisation and also the World Health Organisation, are much more nearly one vote, one dollar than one vote, one person or one country as they should be. I think it’s up to us. I think we actually share a rather higher platform than we did a couple of months ago for speaking about these matters, so it’s important that we do think about them. I think that we should press for this.

Robert Horvitz: I think democracy is a key word, but I think what we need is an enlightened democracy, because in a democracy there is always the risk of the rule of the majority to the detriment of the minority. In this case we’re talking about the rule of the minority to the detriment of the majority, so it’s more extreme. But I think even in the case where it’s a majority we have to make sure that the rights and privileges of the minority are very well maintained and supported. I think that we need education. I think we need leadership to really inform and perhaps even persuade the majority of people who are making decisions that it is in their interest as well as in the interest of humanity in general to follow the kinds of paths that have just been described.

When the genome project was almost finished, President Clinton and the British Prime Minister met at a press conference announcing this completion of the genome. Then President Clinton said: “Now, maybe we have seen the language in which God created Man”, and Sydney Brenner, you wrote a comment on that.

Sydney Brenner: I think that what I wrote on that is in the same way we could view the Bible as the language which man used to create God. That was just a comment like that. I think that that’s a very, how shall I say, exaggerated way of putting it.

Your saying or Clinton’s saying?

Sydney Brenner: Clinton’s saying. Because I think it has to pay respects to certain views in society and it’s not the language which anybody used to create man.

Because you have said very clearly that the architecture is inside the structure.

Sydney Brenner: The architecture is inside and I still think that that is the question of how this … This is why I think ordinary people don’t believe in evolution because we’re telling them by random changes that we can change a black and white television set into a colour television set. And everybody says there’s no way that can happen because if I try and change a television set, I’ll break it. That’s what will happen. And that is why a lot of questions about the internal architecture become important. That mutation happens but certain mutations carry a greater value than others. And we need to understand, so clearly mutations which affect the language of gene regulation are going to be more profoundly important than ones which just might affect the function of a protein.

Maybe Robert Horvitz, couldn’t Sydney Brenner’s statement about the Bible be interpreted seriously? Given the mutations work finally gives us consciousness and awareness and we have created God or made him. The Bible was the language in which we describe what we think is the higher meaning for life.

Sydney Brenner: Exactly, yes, it’s a deeper thought than is done in terms of what it was alluding to. It was double edged, and one edge was what you said, the other edge was to say, it’s a more comic way of looking at the human genome.

John E. Sulston: I think that there is a serious point there. But incidentally, what I would like just to replace the President’s remark with is that what we’ve done is to read the language of evolution. As Sydney emphasises, and he’s absolutely right, we don’t understand it. But nevertheless, we have the hieroglyph, we know how we brush the sand off the hieroglyph and now we’re working on its interpretation, I think. But to the other point, I think we do have, and that’s why I agree so much with what Bob said about trying to develop a real humanist basis for ethics. Because after all it’s not just the Bible, it’s the Koran, it’s a zillion other writings, all of which are more or less contradictory, all of which incidentally are very capable of leading people to physical combat and really serious warfare over points which were written in these books. I think we can develop serious humanism, but we do only have a limited amount of time because I do think we are going to understand the workings of our brain in much greater detail. I do think that we’re going to come much closer maybe to have a full understanding of what we really mean by self-consciousness and free will. By understanding what I mean is, and it is going to be complex, that in some fashion we’ll be able to write down all the components. Now the question is what will that mean? How can one comprehend oneself? It’s like trying to understand the Klein bottle. It’s a real paradox.

I suspect the way we shall do it is to actually understand all the pieces but nevertheless not be able to hold an image of how it works all at once in our own heads. You can sort of trace around the pathway and do each bit at a time. I think most of us actually feel like that thinking about relativity, I certainly do. I can do the bits but just getting the whole thing, it just won’t gel for me. Now the reason I say it’s urgent is that I think we are going to, at the same time, be increasing our physical power, our power of the biological world and we have got to come to a way of making responsible decisions about how to use these things, and to come to the point where we’re going to do it in the knowledge where we really cannot sustain the idea reasonably of us being driven all the time by some higher thing, but rather seriously regard ourselves as products of the evolution. I think we are going to have to have that sort of social ethical revolution. It’s going to be needed over the next 50 years or so. I think it’s a very, very urgent matter and one that’s very worth paying attention to, to try and contribute.

Time is running out. Thank you very much for sharing your time with us and your views and telling about your science. Thank you, gentlemen.

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