[BITList] DNA

[John Feltham]

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Crick,  Francis Harry Compton  (1916-2004), molecular biologist, was born on 8 June 1916 at Holmgarth, Holmfield Way, Weston Favell, near Northampton, the elder son (there were no daughters) of Harry Crick (1887-1948), director of Crick & Co., boot and shoe manufacturers, and his wife, Annie Elizabeth (1878-1955), daughter of F. W. Wilkins, director of Wilkins and Darking Ltd, hatters and general outfitters. As a young boy he was intensely curious and obviously bright. His mother was very ambitious for her firstborn and keen that he should be brought up well mannered and well educated. She was a strong character, a teetotaller, well organized, and, as a trained nurse, very concerned about health and hygiene.

Crick's maternal aunt, Ethel M. Wilkins, a schoolteacher, taught him to read and his parents, finding his persistent questions more than they could handle, bought him Arthur Mee's Children's Encyclopedia. Here he found clear and engaging expositions of such subjects as 'What is water made of?', 'The making of other worlds', and 'Can chemistry build up life?'. He was not patronized, but made to feel the excitement of big mysteries to be solved, like the

riddle of the ether, for it comes into every scientific question, and is the unanswered problem at the bottom of everything. Yet there is reason to hope that the problem is not insoluble, and its solution will be the discovery of all time. (Children's Encyclopedia, 5.2886)
Crick was inspired by this look into the future and anxious to make a big discovery himself one day, but worried that all the important ones would have been made by the time he grew up. His family called him Craxie, on account of his volubility, and his school friends gave him the nickname Crackers.

Crick enjoyed his time at Northampton grammar school (1922-30) and thereafter as a boarder and scholar at Mill Hill School (1930-34), where he sang in the chapel choir and in light opera. In 1932 he won the mathematics and the physics prizes for his performance in the higher certificate, but failed two years later to win a scholarship to Oxford or Cambridge. Instead he entered the physics course at University College, London (1934-7). Although the course was not inspiring and his degree disappointing (second-class), he stayed on to do research under Edward Neville da Costa Andrade. When war broke out in September 1939 the complicated apparatus he had been building for his research on the viscosity of water above 100C was nearing completion. But then the college moved to Wales, leaving his apparatus behind.

War work and biophysics research

In 1940 Crick was recruited to work for the Royal Navy, as a temporary experimental officer. He worked at the Admiralty research laboratory in Bushy Park, Teddington, until November 1941, when the physicist Harrie Massey was given the task of revitalizing the mine design department at Havant, close to Portsmouth. For this assignment he took with him three mathematical physicists and one experimental physicist-Crick. The importance to Crick of working with this high-powered group in Havant should not be underestimated. It was Crick's first close encounter with brilliant theoretical physicists and mathematicians. It was also the first time of working under constant challenges. There was a desperate need to catch up with and move ahead of the enemy in designing mines that could not be cleared with minesweepers, constructing mines that would destroy the Germans' powerful Sperrbrecher sweeps, creating the element of surprise, and, in short, outwitting the enemy. These challenges brought out Crick's nascent powers of efficient organization and authority. Put in charge of designing the mines, and concentrating on diverse firing mechanisms, his enthusiasm and confidence swept the work along. The science was nothing fancy, but its application to mine design demanded sound common sense and inventiveness, laced with a good supply of lateral thinking. The latter was essential in formulating strategies of surprise and anticipations of responses. After the war the British naval mine programme in Europe was judged to have been twice as effective as that of their opponents, despite the technical proficiency of the German scientists. Crick's designs for magnetic, acoustic, and sonic mines proved five times as effective as the standard British contact mines.

It was as a research student at University College, London, that Crick had first met (Ruth) Doreen Dodd (1913-2011), a student of English literature, and the daughter of Samuel Dodd, engineer. On 18 February 1940 (by which time she was working as a clerk at the Ministry of Labour) they were married at St Pancras register office and went to live in Twickenham. In November 1940 they had a son, Michael Francis Compton Crick. A year later they moved close to Havant for Crick's new assignment. For the family the years at Havant proved difficult, and by 1944 the marriage had broken up, Michael going to live with his grandparents in Weston Favell.

Crick remained at Havant until 1946, when he was transferred to the Admiralty in London to work in the naval intelligence division, where he was appointed to a permanent position. Even so he could only afford the rent on a flat he found in St George's Square in Pimlico by sharing the cost with a fellow lodger. First came his war-time friend, the mathematical logician Georg Kreisel, and after him the broadcaster Robert Dougall, whom he had met during the war.

Now Crick could shake off his conventional and provincial past and plan his future. Intelligence work on weapons did not appeal in the long term. Physics had moved on so far that it would be hard indeed to catch up. He could not complete his doctoral research because in 1941 a land mine had destroyed the complex apparatus he had assembled. Instead he turned to the borders between physics and other disciplines. Now what, he asked himself, do I chat to other people about? The answer was chromosomes, viruses, and penicillin. This 'gossip test', as he called it, pointed him in the direction of biophysics-the application of physical techniques to biological problems. He described his particular interest as 'the division between the living and the non-living, as typified by, say, proteins, viruses, bacteria and the structure of chromosomes'  (Crick, application for studentship for training in research methods, 7 July 1947, TNA: PRO, FD21/13). He wanted to attack the subject at the molecular level, for clues to the nature of life must surely lie there. He called it 'the chemical physics of biology'  (ibid.), and it would target the proteins wherein the mystery of life was, he believed, to be found. Behind this choice lay his desire to banish mysteries still serving to shore up religious beliefs. For, he argued, if 'detailed scientific knowledge' had rendered untenable some religious beliefs, why should science not do likewise to other religious beliefs?  (Crick, Mad Pursuit, 11). This scepticism towards religion was longstanding. He could trace it back to his boyhood, at about the age of twelve. It was this force, allied with his intense curiosity, that maintained his passionate commitment to research until the very end of his life.

In the immediate post-war period there was no master's course in biophysics. Crick had instead to find himself a laboratory, and apply to the Medical Research Council (MRC) for a studentship for training in research methods. He was strongly advised that he needed to become acquainted with biological material-living cells-before working on extracted material, and the advice was to go to Cambridge. But only one of those who saw him there offered him a place-Honor Fell, director of the Strangeways Laboratory and a pioneer of tissue culture. She and her colleague Arthur Hughes had just the problem that needed his knowledge of the physics of liquids and his laboratory experience in measuring viscosity.

Situated just outside Cambridge, the Strangeways Laboratory was a leading biomedical research institute. Among its research programmes was the study of cell division, a mysterious and fundamental process-especially that remarkable 'dance' of the chromosomes known as 'mitosis' that precedes the formation of the two daughter nuclei and the laying down of the cell walls between them. Cell division was also of major interest to medical researchers, for if uncontrolled it would very likely lead to cancer. One hypothesis was that forces in the semi-liquid content (cytoplasm) of the cell might be controlling the movements of the chromosomes. Hence the desire to establish the physical nature of the cytoplasm. Crick had to record thousands of tiresome measurements under the phase contrast microscope to yield for the first time a reliable figure for 'the order of magnitude' of the cytoplasm's elasticity. What could be inferred as to the nature of the cytoplasm? In this, his first scientific paper (with Arthur Hughes) he wrote: 'If we were compelled to suggest a model we would propose Mother's Work Basket-a jumble of beads and buttons of all shapes and sizes, with pins and threads for good measure, all jostling about and held together by colloidal forces'  (Crick and Hughes, 'The physical properties of cytoplasm: a study of the magnetic particle method', pt 1, 'Experimental', Experimental Cell Research, 1, 1950, 78).

Crick had no illusions about the rather trivial and unexciting nature of this work. But it gave him the time to read widely in the biological sciences and formulate his ideas. Being gregarious by nature, he soon established friendships with scientists in the university and in other research units, and these friends elected him to membership of the Hardy Club, formed in 1949 to discuss research in biophysics. Protein chemistry was also very much on Crick's and the club's agenda, and it was Frederick Sanger's work on the constitution of the polypeptide chains in the haemoglobins and in insulin that fired his imagination. How could such large three-dimensional 'globular' molecules, composed of several long chains, be replicated? It seemed inconceivable that a copy of the internal structure of such an object could be achieved in the manner that a sculptor makes a replica of his work, for the sculptor's mould follows only the external form of the original. One-dimensional templates must be essential to order the particular sequences of the amino acids on the chains that constitute the molecule. And for each protein these sequences should be distinctive, as Sanger's research was beginning to show.

This brought Crick back to Erwin Schrodinger's little book What is Life? (1944) that had so excited him when he and his friend Kreisel read it in 1946. Conceiving the gene at the molecular level, Schrodinger explained that making a copy of the hereditary codescript of the gene was not just 'the dull device of repetition', as in a crystal of salt, but the replication of a unique 'aperiodic' structure. 'We believe', he declared, 'a gene-or perhaps the whole chromosome fibre-to be an aperiodic solid'  (What is Life?, 61). Here, surely, lay the secret of the hereditary transmission of the remarkable specificity found among the proteins. Witness the body's response to invading bacteria, foreign blood, and organ transplants: the gene must contain a specific sequence or pattern that determines the one-dimensional sequence of the building blocks (amino acids) constituting the framework (polypeptide chains) of a specific protein. These chains then fold up to form the three-dimensional molecules we know in the 'globular' proteins like haemoglobin, our antibodies, and the numerous enzymes we possess, each very specific in its action. But the hereditary transmission of this specificity must be one-dimensional.

Crick's move to Cambridge distanced him from the woman who was to become his second wife, Odile Speed (1920-2007), daughter of Alfred Valentine Speed, jeweller. They had first encountered each other at the Admiralty in 1945. Although brought up in King's Lynn, Odile had benefited from the cultural influence of her French mother and her experience as an art student in Vienna (1936-8) and her years in Paris living with her grandmother (1932-4 and 1938-9). She was a cultivated young woman, smart, fun-loving, and beautiful. When Crick first met her she was translating German documents for the Royal Navy's department of torpedoes and mines. Later she took up fashion design, but of science she knew nothing. Meanwhile Crick's divorce had been granted in 1947, but it was not until January 1949 that he and Odile became engaged. The marriage took place at Kensington register office on 13 August 1949. They had two daughters, Gabrielle (b. 1951) and Jacqueline (b. 1954).

The Cavendish Laboratory and helical polypeptides

As Crick's research at Strangeways drew to a close he became increasingly impatient to leave cell studies behind and turn to molecular structure. Kreisel had introduced him to Max Perutz in 1947. Now two years later Crick wanted to join his group and get to grips with the X-ray crystallography of proteins. He sought an interview with the secretary of the MRC, Sir Edward Mellanby, and persuaded him to agree to fund the move. In June he was appointed to an 'unestablished' position within Perutz's unit, the MRC unit for the study of the structure of biological systems, in Cambridge University's Cavendish Laboratory, with a salary of £700 per annum. Unestablished posts would normally be reviewed after three years, leaving the situation open-ended as to whether or not the council would consider offering further contracts.

The plan was that Crick should learn the methods used by Perutz and John Kendrew in their attempts to unravel the structure of the haemoglobin and myoglobin molecules. Then he should find a different protein that he could call his own, and begin to work out its structure. Crick dived into the literature to teach himself the theory behind these methods and worked through Perutz's papers on haemoglobin. To his amazement he judged that his own boss had been unjustified in the conclusions he had drawn from his data. So he wrote up a critique entitled 'The determination of the structure of proteins by X-ray crystallography: prospects and methods'. In this he attacked the assertion that proteins, although huge molecules, must have a simple structure, and that consequently solving their structure is not an impossible task. He found this a 'most dangerous argument'. For 'what is "simple" for the organism, may not necessarily appear simple to anyone looking at protein structure'  ('Determination of the structure of proteins', Mandeville special collections, University of California at San Diego, MS 600, 10A-2, p. 4). Just consider the complex biochemical pathways involving hosts of enzymes that biochemists have unearthed. (Crick, the colleagues around him all biophysicists, was arguing like a biologist.) Subsequently he gave the substance of this critique in a talk entitled 'What mad pursuit', at a conference held at the Cavendish Laboratory in 1951. Perutz had a model for the haemoglobin molecule rather like a hatbox or a cigar box, with the chains of the molecule like cigars lying parallel to one another in the box. Crick demolished this simple picture, concluding that the structure would prove to be more irregular and would best be represented by 'a three-dimensional framework, and may need a perspective drawing to show its main features'  (Crick, 'The height of the vector rods in the three-dimensional Patterson of haemoglobin', Acta Crystallographica, 5, 1952, 386).

Always concerned about the reliability and the limits of research methods, Crick had correctly assessed what information could be won from the X-ray data and what could not. The diffraction patterns produced by a crystal through which X-rays have passed cannot be focused because no lens can handle such tiny rays. Consequently the pattern is like a very out-of-focus picture constituted of numerous spots, the location and intensity of which are not sufficient to permit determination of the structure producing them-unless there is knowledge of the phases of the diffracted rays involved. Without the phases, however, one has only half the required information. Crick concluded by stressing that for large molecules such as haemoglobin the only promising way to discover the phases was to attach a heavy metal like mercury to the haemoglobin and use it as a 'flag' and to classify the phases of the other spots in relation to the flag. Then one could identify the constituents of the diffraction pattern (using Fourier analysis) and from these construct the molecule (Fourier synthesis).

In the absence of such knowledge it had become popular to calculate a Patterson map, also known as 'the poor man's Fourier', because it was constructed without the phases. This gave the directions and distances (vectors) between the strongly scattering regions, but involved making convolutions of the data, meaning that all these vectors were superimposed on the same origin. In the light of this knowledge, it is hardly surprising that errors of interpretation can occur. Moreover, when dealing with fibres, there may be an easier and more economical route to take. This was to be precisely Crick's approach to DNA.

This theoretical work was all very well, but not, in Perutz's opinion, very suitable for a PhD. Therefore it was time for Crick to find a protein that he could call his own and whose structure he could study. In 1950 Perutz had pressed Crick to enter the PhD programme and had arranged for the MRC to cover the costs. Although Crick went through all the laboratory procedures and explored several possible proteins, the results were disappointing. Then there were diversions that drew Crick away from this bench work. One such was the conformation of the polypeptide chains in fibrous proteins like keratin, and collagen. In 1950 Sir Lawrence Bragg, Cavendish professor of physics, had with Kendrew and Perutz published a number of molecular structures for them, all composed of helical chains, none of them convincing. But when Linus Pauling at the California Institute of Technology challenged Bragg and his colleagues with the publication of his a-helix a year later there was consternation in Cambridge, for, unlike their models, Pauling's looked right, and Perutz quickly found crucial evidence in its support. This event left an indelible impression on Crick. Like the Cambridge group, Pauling had arrived at his proposed structure by model building, but using a purpose-made construction kit based on the accurate distances between atoms and limitations on the orientations of their bonds that his group had established.

Later that year Crick was one of three authors (the others being William Cochran and Vladimir Vand) who used Fourier theory to derive the features of the diffraction pattern a helical molecule should yield. This proved to be a landmark for the study of both industrial and biological fibres, for it made possible the interpretation of the diffraction pattern of fibrous substances directly in terms of the structure of the molecules present. This, Crick's first significant achievement, together with two papers supporting Pauling's a-helix using their helical diffraction theory, demonstrated his ability and originality as a theoretician in the world of X-ray diffraction.

James Watson and DNA

The relation between Crick and his colleagues in the unit could be difficult. Kendrew and Perutz wished he would not spend so much time talking. Bragg could not stand his laugh and did not approve of the manner in which he involved himself in the work of others. At times Crick could become impatient, and if he lost his self-control an impetuousness would show. At a seminar he would interrupt the speaker, even-though very rarely-telling the unfortunate victim that the talk was terrible. Indeed, a confrontation he had with Bragg in 1952 over a method to determine phases seemed to have spelt the end of his hope to continue with the unit after completing his doctoral thesis.

Nevertheless Perutz greatly admired Crick and supported him consistently. After Bragg had complained to the MRC about Crick, Perutz wrote to calm troubled waters. He assured the council that the unit 'profits from Crick's astute criticism and his many suggestions'  (Perutz to J. G. Duncan, 11 Jan 1952, TNA: PRO, FD21/13). Perhaps, suggested Perutz, in order to concentrate Crick's attention on his own work, the next increment to his salary should be withheld until he received his PhD. The MRC's response was a definite 'no'. Later that year Perutz reluctantly acquiesced with Bragg's view that Crick should look for a university position in a year or so.

An incident that contributed to Bragg's displeasure had emerged from Crick's collaboration with James D. Watson, a post-doctoral student from America. Arriving in October 1951 to learn X-ray crystallography, he and Crick found common ground in their desire to discover how, in terms of molecular structure, the genetic material duplicates itself and performs its other functions. Watson was convinced, Crick not quite so convinced, that the hereditary material is not a protein, as had been formerly believed, but the nucleic acid DNA (deoxyribonucleic acid), a major constituent of the chromosomes.

Full of confidence, Crick felt that there was a good chance that he and Watson could discover the structure of DNA if they followed the approach Pauling had used to discover the a-helix. Once discovered, the structure might then reveal the secret of its power of duplication. The thesis research was put aside as they built a three-chain model that proved to be an absolute disaster, leading to the imposition of a moratorium, putting DNA off limits to them. The account of how they returned to make a successful attempt just over a year later, in the early months of 1953, was subsequently told many times, but most amusingly by Watson himself in The Double Helix (1968).

In April 1953 the brief paper in Nature announcing Crick and Watson's model for DNA did not cause wide interest, being too technical for the non-specialist. But Bragg became very enthusiastic, his whole attitude to Crick changing from considering him a nuisance to appreciating his qualities. Pauling, although he had recently published a model for DNA himself, without delay judged the Watson-Crick model broadly correct. Their model consisted of two sugar-phosphate chains on the outside of a helix and, as Crick proposed, one of the chains running in the opposite direction to the other. Attached to the chains were the four bases, adenine, thymine, guanine, and cytosine, all flat ring structures lying across and within the cylindrical molecule. But as Watson discovered, the bases from one chain could be fitted neatly with those from the other only if adenine on one chain was always paired by weak hydrogen bonds with thymine on the other, and guanine likewise with cytosine. They noted that 'the sequence of bases on a single chain does not appear to be restricted in any way. However, if only specific pairs of bases are formed, it follows that if the sequence of bases on one chain is given, then the sequence on the other chain is automatically determined'  (Watson and Crick, 'A structure for deoxyribose nucleic acid', Nature, 171, 25 April 1953, 737).

The general reaction to Watson and Crick's second paper on DNA, 'Genetical implications of the structure of deoxyribonucleic acid', written almost entirely by Crick, and again published in Nature in 1953, was much more positive. Here the reader could begin to appreciate how suggestive was their structure for the manner in which the genetic material might carry the genetic information, duplicate itself, and mutate. In the first paper Crick had inserted the sentence: 'It has not escaped our notice that the specific pairing that we have postulated immediately suggests a possible copying mechanism for the genetic material'  (Watson and Crick, 'A structure', 737). In their second paper this point was developed. As they explained:

Now our model ... is, in effect, a pair of templates, each of which is complementary to the other. We imagine that prior to duplication the hydrogen bonds are broken, and the two chains unwind and separate. Each chain then acts as a template for the formation on to itself of a new companion chain, so that eventually we shall have two pairs of chains, where we only had one before. Moreover the sequence of the pairs of bases will have been duplicated exactly. (Watson and Crick, 'Genetical implications of the structure of deoxyribonucleic acid', Nature, 171, 30 May 1953, 966)

Basking in the good fortune of this incredible discovery, Crick lectured visitor after visitor as they came to see the model. To those on the floor above it was as if steam were rising such was the excitement below, and above it all Crick's excited voice could be heard as he directed his expository skill to yet another visitor. Watson became irritated by Crick's unending enthusiasm. After all, their model was a proposal, not an established fact, and it might prove wrong. Crick was more confident and went ahead with a broadcast about the model for the BBC's Overseas Programme in Europe that summer. Watson refused to permit the broadcast to be put on the air in the UK. Nevertheless over the next few years it became clear that Crick's confidence was indeed well placed, and both Watson and Crick received accolades for their pioneering work, culminating in the Nobel prize for physiology or medicine in 1962, awarded jointly to Crick, Watson, and Maurice Wilkins.

Subsequent research

Bragg's change of heart towards Crick came too late for Crick to alter his plans for the forthcoming academic year. He had already accepted an invitation to spend a year in David Harker's protein structure project at Brooklyn Polytechnic, and the family would be setting sail for New York in the Mauretania on 22 August, just four days after Crick's oral examination for the PhD. He had accepted Harker's offer because his future at that time was uncertain. Now Perutz was suggesting that Crick might return to the unit after Brooklyn. Crick forthwith made clear to the new secretary of the MRC, Sir Harold Himsworth, how attractive was this suggestion. At thirty-seven years of age, he pointed out, he needed to give serious consideration to his professional future, and added:

after making one career for myself in the Admiralty, I gave it up at the age of 30, and with the help of the M.R.C. started again, in biophysics, as I believed my interests lay there rather than in making weapons. I now have to decide whether I should attempt to enter academic life proper. This would mean, in effect, starting at (or near) the bottom once again, as I have no academic experience at all. This, as you can imagine, I am most reluctant to do. (Crick to Himsworth, 15 June 1953, TNA: PRO, FD21/13)
Crick proved his worth at Brooklyn and Harker sought to persuade him to stay, but Crick declined, and he did not pursue the offer of work with Linus Pauling in Pasadena. Instead, when it finally arrived, he accepted the offer of a seven-year contract with the MRC in Cambridge.

During the year at Brooklyn Crick visited many centres in America and laid the basis for what was to become a very considerable reputation there. But for Odile and their first daughter, Gabrielle, transplanted from the cosiness of Cambridge to the drabness of a suburb of Brooklyn, it had been hard. Their second daughter, Jacqueline, being due in March 1954, Odile and Gabrielle returned to England and lived with Odile's family in King's Lynn, where Jacqueline was born. Thirteen-year-old Michael enjoyed his time in Brooklyn, attending the local Quaker school, and staying on with his father after Odile and Gabrielle had departed.

Perutz was anxious to have Crick return to the unit in 1954, not just because of what he might achieve himself, but because of the stimulation he would provide and the assistance he would give to others in the group. No matter what subject was raised, Crick would take an interesting, often novel approach in response. He would be there in the front row at seminars ready to challenge the speaker and open up discussion. His very presence gave zest to the research environment. He was shrewd and his advice was often sought.

Most of Crick's research was carried out in collaboration with others. On collagen it was Alexander Rich, on viruses it was Watson, on ribonuclease, Beatrice Magdoff. In 1957 Sydney Brenner, working on bacterial viruses (or phages), gave up his lectureship in Johannesburg to come to the unit, so that he could collaborate with Crick. That same year brought two friends from America, the leading experts in phage genetics worldwide, Seymour Benzer and George Streisinger. Their presence strengthened the phage genetics programme at the unit. Then came the biochemist Mahlon Hoagland to set up a tiny biochemical laboratory in a vacant room in the Molteno Institute nearby, and to work at the bench with Crick. The unit that had begun life with X-rays in the physics department was now in 1957 expanding into other fields and other buildings. This called for a change of name to 'the MRC unit for molecular biology', and in 1962, 'the MRC Laboratory of Molecular Biology'. Crick, meanwhile, had not quite yet forsaken his role as an experimentalist.

The reason for the expansion of the agenda was to answer some of the questions raised by the DNA structure of Watson and Crick. Here the sequences of bases on one of the chains, they suggested, specify the sequences of amino acids on the polypeptide chains that constitute proteins. What, then, are the rules that govern the translation from the 'language' of the bases into the 'language' of the amino acids? In short, what is the genetic code? This was part of 'the secret of life', contained, Crick claimed, in the structure of DNA, for all life depends on proteins, and it is the DNA surely that specifies the kinds of proteins that are made. Several approaches were used to seek the answer. The least demanding of bench work was to treat it as a problem in cryptography. Many attempts were made, including an attractive one by Crick and his colleagues called 'The commaless code'. But as Crick demonstrated, they all failed because they imposed too many restrictions on possible nearest neighbours in the polypeptide chains. Nature is not thus limited.

In the years 1956 to 1961 Crick (who was elected a fellow of the Royal Society in 1959) sought experimental approaches to the problem aggressively. Working with him were the chemist Vernon Ingram, and from 1957 the biologist Sydney Brenner. These were the halcyon years laying the foundations of molecular biology. By the summer of 1961 Crick and Brenner's programme in the genetics of phage had reached an exciting stage. During Brenner's temporary absence Crick took over the experimental work. Running two series of experiments per day, working through the weekends and taking Mondays off for washing the equipment, he and the technician, Leslie Barnett, capped the evidence they already had that three bases (or a multiple of three) code for one amino acid; that these triplets are read in one direction only along the DNA chain, starting at a fixed point; and that mutations (hereditary variations) are produced not only by a change in a base, but by the deletion or addition of bases.

Excitedly Crick ended his and his colleagues' paper on this and other work declaring: 'If the coding ratio is indeed three, as our results suggest, and if the code is the same throughout nature, then the genetic code may well be solved within a year'  (F. H. C. Crick, L. Barnett, S. Brenner, and R. J. Watts-Tobin, 'General nature of the genetic code for proteins', Nature, 192, 1961, 1232). In fact it took until 1966, when Crick reached his fiftieth birthday. Then, as the plenary speaker at the Cold Spring Harbor symposium on the genetic code, he could produce his table of the assignment of all twenty amino acids (the vocabulary of proteins) to their respective base triplets. The remarkable power subsequently enjoyed by scientists to manipulate the genetic material at will was based on this fundamental achievement, and the human genome project later identified the vast sequences of bases in the DNA of humankind and many other species.

Knowing the rule book for translating the messages in the genes into proteins did not answer just how these messages in the cell nucleus reach the site of protein synthesis, known to be outside the nucleus, and find their appropriate amino acids. Crick faced this challenge in an essay he wrote in 1955 that was circulated but not published and in a celebrated talk, 'On protein synthesis', given in London in 1957. Here he set out the ground rules for discussion of the subject, enunciating two principles: the sequence hypothesis and the 'central dogma' that for many years served to shape the development of the subject.

Cambridge, La Jolla, and neuroscience

When Crick had arrived in Cambridge in 1947 he had had high hopes of what he would find, but had became somewhat disillusioned. The democratic administration of the university seemed unwieldy, the inertia of tradition stifling, and the influence of the Anglican church was still permeating the colleges and their traditions. Up to this point he had not aired his agnosticism publicly, but his experience in Cambridge changed his mind. His lectures to the Cambridge Humanists, reported in the local press, helped to establish his reputation as a controversial figure and opponent of established religion.

Crick had been 'smuggled' into Gonville and Caius College early in his career at Cambridge, and on entering the PhD programme in 1950 he became a member of the university. In 1956 an attempt was made by his friends in King's College to obtain a fellowship for him, but his advocates, Brenner among them, were informed that sufficient funds were not available. Apparently his work on DNA was considered a passing fad. Although Crick had so far avoided any teaching duties at Cambridge, in 1957 he was encouraged by the retiring professor of genetics, Sir Ronald Fisher, to apply to become his successor. Fortunately, he recalled in retrospect, his application was turned down since he was considered not to be a geneticist. Thus he was never employed by the university, although he was once asked to give a series of lectures. He replied stating his fee, then heard no more. Offered an 'extraordinary' fellowship at Churchill College in 1960, he accepted until the decision was made to build a college chapel, whereupon he resigned. Five years later, when tempers had cooled, the college offered him an honorary fellowship, which he accepted.

The masters of Gonville and Caius College had for many years been scientists, and when Joseph Needham retired from the position in 1976 Crick was approached to ask if he would put his name forward. He consented, but after serious consideration withdrew. At that point he became an honorary fellow of the college. He was then also in the middle of negotiating a sabbatical at the Salk Institute in La Jolla, California. Retirement was close at hand, but for several reasons-changes in the taxation of overseas earnings for one-he wished to continue earning. Nor was he ready for retirement. His association with the Salk Institute went back to the very beginning when Jonas Salk was formulating its legal constitution in 1960. Two years later Crick became a visiting fellow and attended the annual meetings each February. When arranging the sabbatical it was therefore natural to think of the Salk Institute, but he had had no thought of making a permanent move from England. It was the institute's president, Frederic de Hoffmann, who raised the possibility, and when the Cricks were settled in La Jolla for the year he made such a reasonable offer for the future that it was difficult to refuse. Then as Kieckhefer distinguished professor, from 1977, he began to consider seriously his long held wish to explore the brain and consciousness.

Crick followed his usual rule of avoiding any formal responsibility for planning and administration at the Salk Institute, but behind the scenes he was very influential in guiding the policy of the nascent institute and seeking candidates for fellowships. He lived to see it become second to none in the neurosciences. In making an entry into the field himself he decided first to learn as much as he could about the brain in general. Then he turned to vision, for vision is the foremost of our senses and intensively researched. He explored a variety of approaches-the computational approach of artificial intelligence, the parallel distributed processing (PDP) approach of the group at the University of California at San Diego, close by the Salk, and the functional anatomy of Harvard University's David Hubel and Torsten Wiesel. From these experiences he came away most attracted to functional anatomy because it delved into the machinery within the brain. 'Black box' approaches could be suggestive, but so many of the imaginative models dreamed up by cognitive psychologists had no semblance of biological realism. Modelling with the computer was fun, but the brain is not a serial processor, and although so much of the brain's wiring is in parallel, it is not a parallel processor of the kind envisioned by the PDP group in San Diego. Crick enjoyed debating with philosophers, but he criticized those among them who had no desire to learn anything about the neurons-the essential hardware of the brain. Listen to the interesting questions they raise, but not to their answers, was his advice.

It was not until 1979 that Crick began to publish on neuroscience, and a further decade before he focused on consciousness. It resulted from his growing collaboration with the young neuroscientist Christof Koch. During some fourteen years of close collaboration they worked to make consciousness a subject worthy of experimental analysis and accepted as respectable science. Admitting the difficulty of conceiving how physiological events in the brain can give rise to subjective mental experiences (qualia), they argued that the first step was to discover the 'neural correlates' of consciousness: what processes, not normally present during mental activity, are active in states of conscious experience, and what parts of the brain are particularly active in those states? Crick did not at his time of life expect to achieve in neuroscience what he had achieved in molecular biology, but he 'hoped to build bridges between the scientific disciplines, all of which studied the brain from one point of view or another ... I thought I might interact fruitfully with younger scientists'. In any case he reckoned he had at his time of life 'a right to do things for my own amusement, provided I could make an occasional useful contribution'  (Crick, Mad Pursuit, 152).

Tall, slightly stooping in later years, with an inquisitive face, bushy eyebrows, and searching blue eyes, Crick was memorable for his body language, a half wink at the hidden meaning of a phrase, a smile and suppressed snigger, catching his breath at the amusing side of an incident. Those who met him could sometimes feel as if they were in court for cross-examination. He seemed to some to know what they were going to say before they had finished speaking and was already waiting politely for them to finish, his response prepared. For he was one of the world's greatest listeners, and his concentration was remarkable. But rare were the occasions when he was not in control of the situation. Above all it was Crick's friendly, outgoing, jovial, and immensely kind nature that was noticeable. He disliked pomposity, pretentiousness, and stupidity, and to those who displayed it he could be devastating. Equally to the incompetent he could prove ruthless.

Crick was at the centre of the revolution in biology of the twentieth century. He and his circle were for twentieth-century biology what Darwin and his circle were for the nineteenth. He wrote four books: an attack on vitalism entitled Of Molecules and Men (1966), an imaginary scenario for life arriving from a distant planet, Life Itself: its Origin and Nature (1981), his autobiography, What Mad Pursuit (1988), and his introduction to the brain and consciousness, The Amazing Hypothesis (1994). Besides the Nobel prize he received many awards and honours, including the Royal and Copley medals of the Royal Society (1972 and 1975), and the Order of Merit (1991).

Crick was just finishing a paper on a region of the brain he believed to be particularly associated with consciousness, the claustrum, when his three-year struggle with colon cancer came to an end and he died in the Thornton Hospital in San Diego on 28 July 2004. He was survived by his wife, Odile, and his three children. A private funeral was held in La Jolla and Crick's ashes were scattered in the ocean. There followed a memorial meeting at the Salk Institute at which his close associates, together with his daughter Jacqueline and his son Michael, paid tribute to his life.

Robert Olby 

Sources  'Francis Crick', biography, http://nobelprize.org/nobel_prizes/medicine/laureates/1962/crick-bio.html,  accessed on 16 Aug 2007 + F. Crick, 'On the genetic code', Nobel lecture, http://nobelprize.org/nobel_prizes/medicine/laureates/1962/crick-lecture.html + J. D. Watson, The double helix: a personal account of the discovery of the structure of DNA (1968) + F. H. C. Crick, What mad pursuit: a personal view of scientific discovery (1988) + R. C. Olby, The path to the double helix, rev. edn (1994) + S. Chomet, ed., DNA: genesis of a discovery (1994) + E. Edelson, Francis Crick and James Watson and the building blocks of life (2000) + S. De Chadarevian, Designs for life: molecular biology after World War II (2002) + J. Bankston, F. Crick, and J. D. Watson, Francis Crick and James Watson: pioneers in DNA research (2002) + M. Wilkins, The third man of the double helix: the autobiography of Maurice Wilkins (2003) + The Times (30 July 2004); (3 Aug 2004); (6 Aug 2004) + Financial Times (30 July 2004) + Daily Telegraph (30 July 2004) + The Guardian (30 July 2004) + The Independent (30 July 2004); (3 Aug 2004) + New York Times (30 July 2004) + Washington Post (30 July 2004) + The Economist (7 Aug 2004) + S. Pincock, The Lancet, 364/9434 (14 Aug 2004), 576 + A. Rich and C. F. Stevens, Nature, 430/7002 (19 Aug 2004), 845-7 + T. J. Sejnowski, Neuron, 43 (2 Sept 2004), 619-21 + J. Thomas, The Biochemist (Oct 2004), 80-81 + D. M. Eagleman, Vision Research, 45 (2005), 391-3 + G. S. Stent, Proceedings of the American Philosophical Society, 150/3 (Sept 2006), 467-74 + M. Ridley, Francis Crick: discoverer of the genetic code (2006) + R. C. Olby, Francis Crick: hunter of life's secrets (c.2008) + WW (2004) + TNA: PRO, MRC files, FD 21/13 + personal knowledge (2008) + private information (2008) + b. cert. + m. certs.
Archives U. Cal., San Diego + Wellcome L. | CAC Cam., A. V. Hill papers + TNA: PRO, MRC files FILM BFINA, 'The race for the double helix', Horizon, R. Fouracre (director), BBC2, 8 July 1974 SOUND BL NSA, documentary recordings
Likenesses  I. Yeomans, photograph, 1962, TopFoto [see illus.] · obituary photographs



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