1.5 Francis Crick and James Watson proposed the now well- known model for the structure of DNA, the chemical that carries the instruction that determines heredity. In 1953 they suggested that the DNA molecule comprised a double spiral strand, with base-groups arranged linearly along each strand. In replication the two strands separated and synthesised new halves identical with the old ones. Thus in cell division one molecule of DNA would give rise to two identical molecules of DNA so that the two new cells would have the same set of instructions. Here was the physical basis for Mendelian genetics, which enabled studies on the genetic code to begin. Crick shared in the deciphering of that code, thus meriting a second Nobel prize. He proposed on theoretical grounds that a sequence of three bases along a strand of RNA could code for a particular amino-acid. Since there are four different bases this gives the possibility of specifying 43 = 64 amino acids. (As there are only 20 amino acids in cells there is, as we now know, a great deal of redundancy in this "triplet code"). Soon the sequences coding for all the acids were found. This "genetic code" is now printed as a standard table in most biology textbooks, a reminder of Crick's extraordinary achievement. Crick and Watson would not have been able to unravel the code without the earlier pioneering work of Maurice Wilkins and Rosalind Franklin, who first identified the basic double spiral skeleton of the DNA molecule. Watson made models based on their findings and his realisation that the two strands could unzip to become separate templates from which another pair of double spirals could be built, was his greatest triumph. He had been appointed professor of biology at Harvard by the time he shared the 1962 Nobel prize with Crick and Wilkins (Franklin had died), and was director of the Cold Harbour Springs Laboratory of Quantitative Biology, Long Island, when his famous book, The Double Helix, was published in 1968 @ 2.3 Two Britons and an American were today jointly awarded this year's Nobel Prize for medicine for work on heredity. The Britons are Dr. Francis Crick, 46, a molecular biologist at the Cavendish Laboratory in Cambridge, and Dr. Maurice Wilkins, 45, deputy director of the Medical Research Council's bio-physics research unit at King's College London. The American, Dr. James Watson, is Professor of Biology at Harvard, and worked at Cambridge, England, in 1951-52. Professor Ulf von Euler, chair of the Caroline Institute's Nobel committee, which selects the medicine prize winners, said the work of this year's winners was of great importance to the whole study of heredity and the reason for the passing on of hereditary diseases. It may even be found to provide an explanation for the deformities of thalidomide babies, he said. CODE DISCOVERED The work of the trio, meant, in effect, the discovery of a code, or working instructions, for the formation of enzymes which govern heredity. This was another link in the work of making clear the whole "blueprint" for the production of living beings, he said. It could lead to an explanation of why each individual was unique in some respect. The official announcement said the three men had received the award for their work in achieving a breakthrough on a "most fundamental biological problem" - the discovery of the molecular structure of deoxyribonucleic acid. This is a biological structure which makes possible the passing on of characteristics from parents to child. Earlier this month Dr. Crick was awarded the $25,000 (about Ł8,900) Gairdner Foundation prize. He was also one of three Britons who shared the 1960 Albert Lasker awards presented in New York by medical and health organizations. Dr. Wilkins was another of the joint winners. Dr. Wilkins, who is on a visit to America, was born in New Zealand and went to King Edward's school, Birmingham, and St. John's College, Cambridge. Dr. Watson, who is 34, was also named as one of the Albert Lasker award winners two years ago. A native of Chicago, he was a National Science Foundation fellow in Copenhagen in 1951. Asked by reporters at Cambridge Massachusetts, whether he was surprised at getting the Nobel Prize, Dr. Watson replied: "Somewhat, but not very." He said he had been told that research into heredity would win the scientists involved the award. @ 2.4 Book review Everyone knows that The Double Helix is a personal account, by one of the main actors, in what the author describes as "perhaps the most famous event in biology since Darwin's book," a claim which the writer of the blurb on the dust- jacket - a type of writer not usually given to understatement - cautiously modifies to "a discovery that many scientists now call the most significant since Mendeleyev's." Most people know also, by now, that a rather large number of Watson's biological colleagues are offended, some quite deeply, by the manner in which he has treated the subject. The editor of Nature pathetically confessed: "Before 'Nature' abandoned the attempt to complement the literary appraisal which will be published next week by a scientific opinion, no fewer than a dozen distinguished molecular biologists had declined an invitation to review the book, usually on the grounds that they were too close to the subject, too far away from it or too busy." That is enough to make any biologist-reviewer look to his own credentials. Is it a work of psychological insight which for the first times makes it possible for the general reader to realise what it feels like to be a productive and even creative young scientist in a major centre like Cambridge? Well, a little Yes, but mostly No. One surprise is the demureness of the picture Jim paints in one of his sub-themes - how he used to make time to go and drink sherry with au pair girls at the boarding house run by Camille Prior, one of the most formidable Establishment hostesses of Cambridge. In my day, the tough Thirties time of the Depression and the Spanish War, we certainly didn't make do with sherry in drawing-rooms. Still, there are, so far as I know, very few descriptions of the scientist's life which give even as much of this feeling as Watson's book does. Needham's essay "Cambridge Summer), is perhaps the neaerest to filling the bill, and to making the essential point that creative young scientists are, neaerly always, inhabitants of a demi-monde, a Bohemia, which has only the most uneasy of relation with the established world of Fellows of colleges and university staff. There has been more writing about this sort of situation in connection with painting than with science; but more usually by painters themselves. In this aspect, "The Double Helix" is quite comparable to that charming work "Picasso and his Friends" by Fernand Olivier, or even "Life with Picasso" by Francoise Gilot. And one finds that the comments which Picasso, a hundred per cent concentrated on his own line, would make about say, Matisse, who was on a different line, are little less biting than some of the opinions Jim Watson throws out about his colleagues and competitors. But perhaps Picasso was a little smoother; one of the major criticisms of Watson is that he seems to be some way towards the maniac egocentricity exhibited, in the world of painting, by Salvador Dali in his autobiographical works "In Modern Art" and "Autobiography of a Genius." And so we come to the major issue. Is the event that Watson chronicles the most significant discovery since Darwin (or Mendel); and does his account show us "how creative science really happens"? The short answer is that Jim Watson is writing about only the very final stages in a scientific advance which had been put firmly on the rails long before he came on the scene; but what he and Crick worked out in 1953 turned out to be enormously more suggestive than anyone had a right to expect, and led to an almost fantastic effloresence of new biological understanding, most of it dominated by the incisive intelligence of Crick. The actual "creative process" by which the 1953 "breakthrough" was achieved does not, however, in my opinion rank very high as scientific creation goes. The major discoveries in science consist in finding new ways of looking at a whole group of phenomena. Why did anyone ever come to feel that the structure of DNA was the secret of life? It was the result of a long battle. Right up to, and beyond the Crick-Watson breakthrough of 1953, biological orthodoxy held that the most important characteristic of living things is that they can take in simple food-stuffs and turn them into complicated flesh. It was back in the late Twenties that a few geneticists, particularly H.J Muller, began to urge that this view is inadequate, and that the real "secret of life" is to be sought in the hereditary material - not only what it is, but how it works. By the late Thirties there was a small group of adozen or so who had developed this subversive point of view to the state where one could begin formulating questions definite enough to be answerable. I was myself on the periphery of the group; the important ones were geneticists like Darlington in this country, Ephrussi in Paris, Timofeef-Ressovsky in Berlin; a few physicists, like Delbruch; and in particular, crystallographers like Astbury and Bernal. It was this group which changed the whole direction of fundamental biology from a concentration on metabolism to a focus on genetics; and they pointed out that the genetic material consists of protein and DNA, though they could not tell at that time which was the more important; and finally they suggested that the most promising way to investigate the structure of the material was X-ray crystallography. The work of this group was almost totally disrupted by the second world war, but their message was widely disseminated by the physicist Schrodinger, living in Ireland, in his elegant little book "What is Life?" published in 1944. During the war years another major step had been taken by Avery, who showed that of the two constituents of the genetic material, is is the DNA, not the protein, which is crucially important. So when Crick and Watson in Cambridge, and Wilkins and his associates in London, began working, the critical stage of asking the right questions had been accomplished. DNA was as Watson puts it, "up for grabs," and one could look on the search for its structure as a race, to be played with no holds barred. This is a rather abnormal situation in important science, and the overwhelming importance which Watson gives to "getting there first" is a violently exaggerated picture of what is usually an important but by no means dominating preoccupation of active scientists. Moveover, even in connection with DNA, getting there first was not so important in the long term. DNA plays a role in life rather like that played by the telephone directory in the social life of London: you can't do anything much without it, but, having it, you need a lot of other things - telephones, wires and so on - as well. It might have been - and Watson and Crick were aware of the possibility - that the structure of DNA would be as barren of suggestion as the enteries in a telephone directory. Watson records his "delight and amazement, the answer was turning out to be profoundly interesting." The real importance of the Watson-Crick-Wilkins structure was not simply that a race had been won against Pauling or any others, but much more that it suggested a whole series of new and fruitful questions about how it operates biologically - and Crick with his colleague, Sydney Brenner, has played a major part both in asking and answering them. Not only was the situation Watson describes, of a highly competitive race for a well-defined goal, rather unlike the conditions in which most science is done, but also the type of thinking he used is not typica l of most science. Watson approached DNA as though it were a super-complex jigsaw puzzle; a puzzle in three dimensions and with slightly flexible pieces. Solving a puzzle like that demands very high intelligence, and Watson gives a vivid blow by blow account of how he did it. But this is not the sort of operation that was involved in such major scientific advances as Darwin's theory of evolution, Einstein's relativity or Planck's quantum theory. And one is struck by how little Watson used a faculty which usually plays a large part in scientific discovery, namely intuitive understanding of the material. I will mention two examples, one more technical, one concerned with more abstract logic. When Watson was trying to fit together certain molecules, known as thymine and guanine, known to occur in two alternative forms, he just copied the shapes out of a chemical textbook and had not a trace of technical intuition as to which shape was more probable. Again, on the more abstract level, the whole of genetics is concerned with one thing turning into two, or occasionally two turning into one; the number three never comes into the picture. Yet Watson spent a lot of time trying to work out a three-stranded structure for DNA. The very idea of threes would make all one's biological intuition shudder. Of course, intuition can be drastically wrong; but it is usually astrong guide in innovative thinking. Watson's book, then, gives a vivid and exciting account of a dramatic episode in modern biology. The episode was enormously important, not so much because it led to the discovery of the structure of DNA, but because the structure discov ered turned out to be extremely suggestive of further lines of advance. But the situation he describes o well is not typical of most top-level science, either as an example of the sociology of science or in the type of thought process involved. @ 2.5 JUST 30 years ago in a pub by the Cavendish Laboratory in Cambridge two unorthodox young scientist announced that they had discovered the secret of life. Their official report which appeared in the journal Nature was rather more reticent. It proposed a chemical structure for a complicated substance found in living cells. The only reference to any wider implications was a brief passage which read: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a copying mechanism for the genetic material." The authors were James Watson and Francis Crick. The paper described their double helix structure for the genetic material DNA - deoxuribonucleic acid, organic matter resembling string which can only be seen under the microscope. Of the two reports the one delivered in the pub was the more honest. For the discovery immediately explained one of the central problems of biology: how genetic information is stored and copied so that it can be passed on from one generation to the next. Last week the 30th anniversary of the double helix was celebrated in Cambridge with a conference organised by Nature. "We deserved the Nobel Prize because we knew how important DNA was," Watson told the conference, with none of the reticence that characterised his and Crick's original paper. The double helix, with its two intertwined spirals of DNA which can unwind and separate, both becoming moulds for exact copies of the original double helix, was one of those flashes of insight which, like Newton's laws of gravity, suddenly unifies a whole body of existing knowledge. And it triggered off a burst of creativity with few parallels in the history of science. In the ensuing three decades all doubts that DNA is the material from which genes are made have been removed. Most of the mechanism of inheritance has been worked out at the most fundamental, molecular level. The code whereby information is stored in the genes had been cracked, the chemical processes through which this information Is translated and put into effect to control the workings of the living cell have been identified. Knowledge of DNA itself has become so detailed that it is possible to point to a single chemical unit among the thousand million in the human genes and say that it is a mistake here that causes a disease like sickle cell anaemia, or to write down the complete chemical formula of the genes of a simple virus. But what use is it all? For the first 20 years the DNA "researchers" only answer was that fundamental understanding of basic biological processes had to pay off one day. Not that they cared very much whether it did or not so long as research funds were forthcoming. The sheer intellectual excitement of it all was enough. Then in the early Seventies came the discoveries of American scientists like Herbert Boyer, Stanley Cohen and Paul Berg, which opened up a range of practical applications for DNA research as dazzling as the intellectual ones of the original discovery. They demonstrate as vividly as the outcome of early research on the atom the impossibility of foreseeing where a fundamental discovery will lead. These new discoveries were not unifying insights but a set of techniques: for chopping up the long spirals of DNA with the chemical equivalent of scissors, sticking fragments together again in arrangements that never occur in nature, and introducing these artificial DNAs into the cells of bacteria and other organisms. They make it possible to splice, say, a human gene into a chemical factory for making some scarce biological product. This kind of genetic engineering is already being used to turn out things like insulin and interferon cheaply and in quantity, and for making ultra-safe vaccines. It can improve the efficiency of the organisms used in existing biological processes like fermentation, and create new ones tailored for specific jobs such as destroying dangerous pollutants. Related techniques make it possible to detect early in pregnancy the defective genes in the foetus responsible for diseases like thalassaemia. The mother can then be offered an abortion. Genetic disease detectable in this way may soon include cystic fibrosis and muscular dystrophy. Within the last year or two scientists have isolated from human tumours bits of DNA which appear to be capable of causing cancer, but to be present in healthy people too. Nobody yet understands what is going on, but it could lead to the identification for the first time of the primary events when a cell turns cancerous. But 30 years on there are still two major unsolved mysteries connected with DNA. One is how genes are switched on and off so that cells containing identical sets of genes can form things as different as nerves, bones, skin and muscle. The other is how DNA-based life ever got started. No one has yet been able to suggest how it could have evolved through simpler forms that might have arisen by chance to the incredibly complicated system we find today. The problem is so difficult that Crick seriously espouses the theory that life did not originate on earth at all but came from outer space. Perhaps that particular problem will never be solved, but Watson and Crick's discovery is now undeniably established as one of the central insights of biology. @ 2.6 Advanced biotechnology refined genetic engineering will be much more widely used in medicine in the 1990's. Today's treatments will begin to be replaced by the most natural of all possible therapies, the substances the human body makes and uses to combat disease. Work on a variety of techniques is being done all over the world. Natural curative substances will be produced outside the body by human genes implanted into cell cultures grown in bio-reactors. A rising number of bio-pharmaceuticals, all as potent as interferon or insulin, will be harvested in this way. New antibiotics are urgently needed to attack, among other things, the hospital "superbugs" which have become resistant to all existing antibiotics. A second generation, made by genetic engineering, will be coming on the market. These will have been produced by introducing new genes into the moulds and other organisms that produce antibiotics, making hybrid antibiotics which could never be produced naturally. The body's natural defences against disease, human antibodies, will increasingly be made outside the body by genetic engineering. They will become cheap and be widely available and will be used to diagnose and treat diseases including cancer. Antibody therapy is among the most natural forms of treatment, since it uses only the human body's natural defences against disease. Catalytic antibodies, or abzymes, made to act like natural enzymes, will be used as new medical drugs able to destroy blood clots. These will prevent coronary heart disease, soften and remove scar tissue, or perform other tasks in ways no existing drugs can match. Vaccines made by genetic engineering to protect against malaria should be in widespread use by 2000. So, with a bit of luck, will be vaccines against AIDS, although drugs able to cure this condition are unlikely in the next 10 years. Some of the new bio-pharmaceuticals will be extracted from the milk of farm animals, such as cows or sheep, grown from eggs with human or other foreign genes implanted them. Herds of such transgenic animals will be grazing in pharmaceutical farmyards by the turn of the century. These animals will also have been made disease-resistant by other added genes and, contrary to the fears of animal-rights activists, should enjoy unusually well-protected lives because of their very high value. By 2000 attempts will have begun to treat diseases caused by genetic defects by implanting into the sufferer healthy genes to take the place of defective ones. And it should have become easier to prevent the birth of handicapped babies by the use of sophisticated pre-natal tests. By that stage, another extraordinary development will be on the horizon the growing of new limbs or organs to replace those lost in accidents or wasted through disease. This will be made possible by stimulating genes that are normally active only during embryonic development. @ 2.7 Few scientists would seek to start serious work in a new field at 60, and few would be given the opportunity. But Francis Crick's solution to the problem of growing old in science has been just that. Nine years ago, he ended a 30-year sojourn in Cambridge to join the Salk Institute in Southern California, and decided to think properly about the brain. The motive was simple: "Because it's a lot of fun". Now nearly 70, Crick still gives the impression that being active in science is the most fun you can have. And by his account he has found the ideal conditions to carry on. The sun shines, he is well paid, has no specific duties, and can work as he pleases. "It's difficult to convey how nice it is working there." But perhaps there are other motives besides financial security and fun. It would surely have been difficult to sustain the level of his contribution to the subject he helped found just after the war - molecular biology; not because his stature has diminished but because of the enormous scope of the subject as success has prompted expansion. For many years, as richly documented in Horace Judson's history of the subject in The Eighth Day of Creation, Crick was the universal catalyst in studies of how genes and proteins work at the molecular level. Judson quotes another great theoretician, Jacques Monod: "No one man discovered or created molecular biology. But one man dominates intellectually the whole field because he knows the most and understands the most. Francis Crick." For a deeper motivation, go back to Crick's re-entry into research after war service designing mines for the Admiralty. Although trained as a physicist, his strong materialist conviction drew him to two new areas - how genes worked, and the problem of consciousness. Both seemed to offer a chance of removing the mystery from biology. He plumped for genes, then, but the other interest remained. And the same optimistic atheist, still convinced science must make its own way forward without reference to other belief systems: the Crick who resigned his founding fellowship of Churchill College, Cambridge, when they built the college chapel. Returning to neurobiology now carries the echoes of the state of molecular biology immediately before and after the war. As Crick sees it: "It's in a very primitive and simple state. It's rather like people in the 1920s and 1930s trying to imagine what the structure of a gene should be. "But it was not possible to wait any longer for light to dawn - when he decided to go to California he was mindful of his age; "I thought if I was going to make the change I'd better get on with it." Not that Crick's powers show any serious decline. The sandy hair is now white, but he is still the tall, lean, garrulous figure who directed the traffic of ideas in molecular biology for so long. Crick is not the cartoon Crick of Watson's stylised memoir The Double Helix, with its famous opening: "I have never seen Francis Crick in a modest mood." It is a Crick still deep in the business of science, and eager to talk about the field which now fills his thoughts. And a remarkably complex field it is. The few pounds weight of grey matter in our heads contains around one hundred thousand million neurons - the building blocks of the nervous system. And each neuron is linked to as many as ten thousand others, and influences them through a combination of chemical and electrical signals. Although the system's speed of operation at the level of cellular messages is slow compared with human-built computers, its richness of interconnection still makes a myriad of tasks which leave computers looking stupid so simple for us we rarely realise how remarkable they are - seeing, hearing, speaking or listening all remain essentially mysterious. But of course Crick's attitude to neurobiology is shaped by his deep knowledge of a molecular biology, as well as being influenced by the same underlying metaphysical conviction. His own focus is on the visual system, partly because it is the subject of a long tradition of work in the field, partly because he has a sense it may be possible to make progress here. And Crick is not especially interested in "black box" descriptions of vision, or in whether it can be successfully modelled with some electronic device - he wants to know how it actually works in the brain; "you have to think in a very different way - once you've got away from the idea that there's someone inside you head looking at what's going on. You have to explain how it is that you perceive things is all done by neurons firing. It's a very , very strange thing." One product of his research was an assault on human dreaming. A widely publicised joint paper in Nature two years ago proposed that the function of dream sleep is "to remove certain undesirable modes of interaction in networks of cells in the cerebral cortex," through a mechanism of reverse learning. This paper, which Crick now seems to regard as a bit of a sideline, nevertheless bears all the hallmarks of his scientific style: there is a carefully constructed theoretical argument - there needs to be a way of activating spurious links between neurons, and modifying the connections so they are less likely to recur; the argument is tightly linked to evidence about sleep and about properties of neural networks; it is elegantly expressed - "we dream in order to forget," the authors write at one point. All it lacks is any way of testing the proposal rigorously by experiment. It also shows why his style is often unpalatable to non- scientists. The dreams paper is fascinating to read, but puts forward ideas which rob the nocturnal images we remember of any meaning. By this argument, the dreams which stay in the mind are aberrations, failures to erase nonsense messages in an information processing system. It is this treatment of problems which have wide popular resonance - the origin of life, the nature of inheritance, consciousness, dreaming - in what Crick regards as a properly scientific spirit which makes one believe the feeling he describes in Life Itself, that a modern scientist lives in a different culture. In some ways, he now finds it easier to find common ground in chance encounters. He recalls how 20 years ago you could go to a party in Cambridge and talk to a perfectly intelligent person who didn't even know the sun was a star." That happens less often now, but it is still hard to put across the thinking behind work in progress, especially work on the brain where we have many problems and few solutions. On a more philosophical level, he now takes a long view. "If you want to establish that dualism is wrong, for example, it's not going to be done in a short time - there will be many tens of years of work." Even in molecular biology, the reductionist approach is not completely secure, though there is every reason to be confident. "We can see how powerful it is to have genes producing proteins and proteins interacting...but we couldn't answer someone who was extremely sceptical because we just don't have detailed answers. We couldn't say how you build a hand." But again the difference in lookin g at the brain is that we do not yet see how such a problem could be answered. As Crick puts it, we have not yet found the right idiom for solving problems of brain function. Artificial intelligence research has been helpful, but chiefly in showing how complex faculties like vision are. And even if there are hints about how to solve problems of vision for machines, they do not look to Crick as though they are going to be the same as the solutions which have evolved in side the head, "any more than the flight of aeroplanes is exactly like the flight of birds". If the hope of progress in brain research stretches far into the future, Crick's own scientific life clearly can not. But he intends to remain active in the field for a while yet. He gives the impression of preparing to grow old, but he is certainly not ready yet. And while he is prepared to debate the merits of returning to London when he finally retires, perhaps to write a book on the brain, he also avers that he and his artist wife Odile now feel like natives in California. His career has spanned an extraordinary era in biology. The science-obsessed Mill Hill schoolboy who began work as a physicist before the war can now look back on a string of remarkable successes in unravelling the intimate workings of the cell. Along the way, he acquired a Nobel prize, for the solution of the double helix with which his name will always be linked, and a kind of celebrity. (He relates with a grin how he did not have the heart to tell the Cambridge publican who showed him the helical plant frame in his garden that he had built a wrong-handed helix.) Yet for all the changes the last 40 years have seen, his own pattern of work has remained unusually stable. He has taught little, and never directed any large-scale research. He declares himself allergic to committees, and turned down a couple of Cambridge masterhips because they involved all the things he did not like. In a way, it has been an indulgent life, talking, reading and writing - and Crick can talk on a sparkling variety of subjects. But the indulgence has always been underpinned by a fecundity of ideas and intellectual zest rarely matched in any field. No doubt the luminosity of Crick's intelligence has dimmed some-what since he first started to exercise his talent for solving problems of biological gadgetry. But that seems no reason to stop work altogether. Asked to describe his role in neurobiology today, he laughs and recommends asking others how they see him. "My point of view is that I'm having a good time."