Francis Crick

Francis Harry Compton Crick, biologist: born Northampton 8 June 1916; staff, MRC Unit for Molecular Biology/ Laboratory of Molecular Biology 1949-77; FRS 1959; Fellow, Churchill College, Cambridge 1960-61; Nobel Prize in Physiology or Medicine (jointly) 1962; Non-Resident Fellow, Salk Institute for Biological Studies 1962-73, Ferkhauf Foundation Visiting Professor 1962-77, J.W. Kieckhefer Distinguished Professor 1977-2004, President 1994-95; OM 1991; married 1940 Ruth Dodd (one son; marriage dissolved 1947), 1949 Odile Speed (two daughters); died San Diego, California 28 July 2004.

"Rather than believe that Watson and Crick made the DNA structure," wrote Francis Crick in 1974, "I would rather stress that the structure made Watson and Crick."

Francis Crick will be remembered as one of a small group of people who pioneered the revolution in our understanding of inheritance: how genetic information is coded in molecules and is then used to produce a living creature. Crick was seen, both by those inside and outside this group, as the intellectual genius at its heart.

Born in 1916 in Northampton, where his father had a shoe factory, he was educated at Northampton Grammar School, Mill Hill School and University College London, where he gained a middling degree in Physics. He continued there studying for a PhD with Edward Andrade, measuring the viscosity of water above its normal boiling point -- "the dullest problem imaginable". At the outbreak of the Second World War, he transferred to the Admiralty, designing magnetic and acoustic mines in which the circuitry would enable enemy ships and sweeps to be distinguished.

After the war, with his lab and apparatus in London fortunately destroyed by a land-mine, Crick realised that what interested him most was biology, especially the boundary between the living and non-living. His scientific naïveté turned out to be an advantage: he possessed no baggage but, for one starting out on a research career, he was unusually mature. He joined the Strangeways Laboratory in Cambridge in 1947 where, making use of his previous experiences, he studied the viscosity of the cytoplasm of cells by introducing into them small magnetic beads.

By early 1949, he had moved into town and joined Max Perutz and John Kendrew at the newly established Medical Research Council's Unit for the Study of the Molecular Structure of Biological Systems, in the Cavendish Laboratory. This group aimed to determine the structures of proteins by X-ray crystallography, Crick's project being to work on horse and ox haemoglobin. The unit had strong support from the Cavendish Professor Sir Lawrence Bragg who, with his father, had pioneered the use of X-rays for solving the structures of small molecules. To appreciate what came next, one must be aware of the emptiness in our understanding of inheritance at that time.

Geneticists had defined the existence of genes, abstract units of inheritance. Genes were widely believed to be made of proteins, perhaps with some nucleic acid included, although Oswald Avery and his colleagues in the United States had, by 1944, provided firm evidence that they were made of deoxyribonucleic acid (DNA). How could such information be accurately duplicated during cell division? Biochemists had discovered that the catalysts in our bodies - enzymes - are proteins, made of amino acid units in some sort of assembly. These accelerate all the chemical reactions of which life consists. But where these proteins came from, or where the information for them came from, was barely discussed.

Several milestones were then passed. The Cambridge biochemist Fred Sanger showed that insulin (a protein) had a unique linear amino acid sequence, being constructed from a standard set of 20 different kinds of amino acid. Alexander Todd and his colleagues, in Manchester and later in Cambridge, showed that DNA and its closely related RNA (ribonucleic acid) are linear molecules made of nucleotides, of which there are just four types: the DNA units all share the same backbone, but have one or other of the four bases A, C, G or T. (RNA molecules have almost the same four bases, A, C, G and U - U and T are very closely related - and a slightly modified backbone.)

While Crick started out working with Perutz on haemoglobin, his first theoretical contribution, with William Cochran and Vladimir Vand, was to calculate the X-ray pattern given by a helical molecule. At the time, protein crystallography seemed an impossible task and, when in 1951 James Watson joined the unit enthused about trying to find the structure of DNA, Crick was ready to change his focus.

The route by which they came to their celebrated model for the structure of DNA has been extensively analysed. The BBC later made a film, Life Story (1987, based in part on The Double Helix, Watson's best-selling "personal account" of 1968, with Tim Pigott-Smith as Crick and Jeff Goldblum as Watson), which provides an excellent history of the science and personalities surrounding their discovery. Suffice it to say that their success came from trying to build a model which would satisfy the many known chemical restraints, from a knowledge of unpublished X-ray studies of DNA by Rosalind Franklin, Raymond Gosling and Maurice Wilkins in London, from Crick's insight into his own helical diffraction theory and from Watson's discovery of how the bases could interact. Above all, they were hungry, eager to solve what they perceived to be the outstanding question of their time. And also, to deprive Linus Pauling of Pasadena, the doyen of theoretical chemistry, of that success.

Their model was published in Nature in April 1953. It consists of two DNA chains running in opposite directions and twisted around each other with base pairs in the middle - A with T, and G with C: the now familiar double helix. The specificity of the base pairing arises from the particular hydrogen bonds which each base can make only with its partner. This pairing also provided a basis for an earlier observation made by Erwin Chargaff at Columbia: by chemical analysis of DNA from different sources he found that the proportions of the bases varied from one organism to another, yet in each there seemed to be equal numbers of As and Ts, and of Gs and Cs. This fitted the proposed structure exactly.

At the end of one of the most profound scientific papers ever written, Watson and Crick added:

It has not escaped our attention that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.

This was added to pre-empt anyone else pointing out the obvious, and presaged their next paper, published five weeks later in Nature, which explained how the specific base pairing could provide a mechanism for gene - and information - duplication. In essence, each double helix contains the information twice, once in each strand. Separate the two strands and each can serve as a template for a new double helix.

With publication of the two papers, there was great excitement amongst the very few who saw their significance. The seismic upheaval which followed took about eight years to be noticed by the wider scientific community, including most biochemists. But during this interval powerful evidence in support of their model came from two sources: Matthew Meselson and Frank Stahl in 1957, then in Pasadena, showed that during replication the two strands of DNA are separated and each serves as a template for a new DNA molecule. And, in 1961, Arthur Kornberg and his colleagues at Stanford provided evidence for base pairing and that the two strands run in opposite directions (a requirement of the model).

Not only did their model indicate how genetic information might be multiplied, it also provided insight into the way genetic information might be encoded: as there was no informational content in DNA, other than the sequence of the bases in each chain, genetic information could only reside in that. This made thinking about how genes might be encoded much easier: a DNA molecule, known to be very long, could have a unique base sequence which might code in some way for the linear sequence of amino acids in proteins. A one-to-one relationship might exist, and this was formulated by Crick in 1957 as the "Sequence Hypothesis": the sequence of bases in a chain of DNA encodes the sequence of amino acids in proteins.

By now Crick was thinking about the genetic code: if the amino acid sequence of a protein is coded by the base sequence in DNA, what is the exact relationship? There seemed to be 20 different amino acids to be coded by just four bases. Also, as there are two DNA strands, do they both encode information? And how could Nature translate one molecule into another - on the face of it, a quite extraordinary concept.

The fact that amino acids and nucleotides are so different chemically led Crick to conclude that a nucleic acid presents little else than a shaped surface which can most easily be recognised by another nucleic acid, by Watson-Crick base pairing as it exists in DNA. He surmised therefore that, at the heart of the translation process, base pairing might also apply. He proposed his "Adaptor Hypothesis": that each amino acid to be built into a protein chain first becomes attached to a small nucleic acid molecule - a different one for each amino acid. These "adaptor" nucleic acids could then line up on the template nucleic acid by base pairing, so that each attached amino acid was brought to its correct place. In this way a unique nucleic acid sequence could determine a unique amino acid sequence. The lined-up amino acids could then become chemically joined to each other to yield a protein chain having a unique sequence.

Independently, and within a year, these adaptor nucleic acids were discovered by Mahlon Hoagland and Paul Zamecnik in Boston: they are small RNA molecules called "transfer RNAs" - they transfer the amino acids into the growing protein. This stunning insight by Crick was one of his greatest achievements.

The "coding problem" - the precise relationship between nucleotide sequence and amino acid sequence, was taking shape. There could not be a one-to-one correspondence, as no more than four amino acids could be encoded and a two-to-one correspondence could encode only 16 amino acids; there would have to be at least three bases for each amino acid, making 64 triplets for 20 amino acids.

A possible solution to this conundrum was first proposed by George Gamow of Washington in 1954, and others followed, including one by Crick, John Griffiths and Leslie Orgel: all were wrong. Until biochemical evidence came along in 1961, the guessing game was all one could do. The only substantial type of evidence which existed was that gleaned from mutations: for example, it was known that in patients having sickle-cell disease there is a change of a single amino acid (glutamic acid) for another (valine) in the haemoglobin sequence. If this change were the result of one base being altered to another, then a code-word for glutamic acid would be identical to that for valine except for one base.

In 1953-54 Crick had met Sydney Brenner, who had come from South Africa to Oxford to do a DPhil, and the two found themselves of similar minds on many scientific problems. Brenner joined the unit in 1957, sharing an office with Crick until 1977 when Crick moved to the Salk Institute. When two minds are focused on a problem, and look at the problem with similar prejudices of what is correct and what is not, conversations need no preliminaries. Both parties were wonderful conversationalists: Brenner read widely and remembered almost everything; Crick had the sharpest and most incisive way of arguing. They made a formidable pair.

Brenner was interested in solving problems through genetics; together with Alice Orgel, they published a paper on the "Theory of Mutagenesis". They distinguished two different kinds of mutagens, chemicals which induce mutations in DNA: those that induce the change of one base into another (as happens in sickle-cell disease) and those that insert an extra base into the DNA sequence. This latter class was called acridine mutations, after the chemical used as mutagen.

In 1961, three different discoveries led directly to how information flows from DNA into proteins and hence to the solution of the genetic code. Brenner, with François Jacob (of Paris) and Meselson, discovered a new intermediate which carries the information for making proteins from DNA to ribosomes, tiny particles in the cell. This intermediate is an RNA copy of one strand of a DNA and they named it messenger RNA.

The messenger carries the genetic message from DNA to ribosomes, and the ribosome - a complicated workbench - is where it is translated from the language of nucleic acids into that of proteins. The actual translation is effected by the transfer RNAs. Related experiments discovering messenger RNA were carried out simultaneously by a group at Harvard. According to Crick, the discovery of messenger RNA was the most important concept, after the structure of DNA, in establishing the framework of how information is held and expressed. With it, everything (save the detail) was in place.

Shortly after this, two workers at the National Institutes of Health in Bethesda, Marshall Nirenberg and Heinrich Matthaei, discovered that, when a synthetic messenger RNA composed of a string of just one kind of base, U, (and called polyU) is added to a cell extract, a single kind of amino acid (phenylalanine) was built into the protein chain (to make polyphenylalanine). The artificial messenger had directed the synthesis of an artificial protein! And hence, the code-word, or codon, for the amino acid phenylalanine was a series of U bases.

In the meantime, Crick had set about constructing a series of acridine mutants. Late one night he discovered that, when three mutations are combined, the resulting gene behaved as if there were no mutation at all. This suggested that the genetic code was a triplet code and therefore that a codon for phenylalanine is UUU. These results were reported by Crick, Brenner, Leslie Barnett and Richard Watts-Tobin in Nature at the end of 1961. This is one of the finest papers ever published in genetics: its scope is remarkable. From a study of the behaviour of certain mutants, the general molecular nature of the genetic code had been deduced.

A more detailed paper was published some four years later. In this, a minor technical mistake made in the earlier paper was recorded "due to the inexperience of one of us (FHCC)". After 1961, a complete and detailed elucidation of the code was simply a matter of time; it was largely achieved in the United States by biochemists using increasingly complex synthetic messenger RNAs and determining the nature of the proteins they encoded.

In this area, there remained one last important problem for Crick to solve: a problem which no one else even recognised. How do the adaptor RNAs, or transfer RNAs, actually recognise the messenger RNA? Everyone assumed it would be by standard Watson-Crick base-pairing. Actually, Crick showed that there is a modified recognition process at work, a somewhat downgraded form of standard base-pairing. He called this the "Wobble Hypothesis" and we now know that it accurately describes the molecular interactions that occur.

Thus ended a personal quest for solving how genetic information is held and translated. This was celebrated by a Symposium on the Genetic Code at Cold Spring Harbor on Long Island in the summer of 1966, presided over by Jim Watson. It was a joyous occasion, Francis Crick at the peak of his powers, delivering a historical introduction which was rapturously received. There, for his 50th birthday, he was presented with a huge package out of which popped a lightly clad young woman. Embarrassed, Crick laughed it off; he was known (from his entry in Who's Who) to enjoy "conversation, especially with pretty women".

The next few years were spent looking for a new problem suited to his way of thinking. He worked with the Cambridge developmental biologist Peter Lawrence on the idea of concentration gradients of "morphogens" and how they might control patterning in development. He thought about the highly folded form of DNA found in chromosomes and published an important paper on the theory of DNA supercoiling.

In 1949 he had married Odile Speed, a French artist, who was to remain a mainstay throughout his complex life. Together, they moved in 1977 to La Jolla, where Crick took up a post at the Salk Institute. He had always been interested in how the brain works and now he decided to work on that. His particular interest became: how is it that we are aware of things, what sort of neural circuits are needed? How do the known existing layers of neurons in the brain, and possibly unknown ones, contribute to our sense of consciousness? In this he collaborated extensively with Kristof Koch and published a book, The Astonishing Hypothesis: the scientific search for the soul (1994), whose aim is to explain how "each of us is the behaviour of a vast, interacting set of neurons". He continued reading and thinking about this right up to his death.

Crick's fascination with how genes work, or how the brain functions, grew out of his loathing of the irrational. He was deeply consumed by the questions, "Why are we here?", "How did we get here?" He abhorred mysticism and religion. He joked about Molecular Theology: he was sure that in the future there would be university departments trying to understand what special neural connections might be made by prayer. He enjoyed speculating about the origins of life: maybe life came here from outer space, by panspermia, so, how big would a spacecraft have to be, what sort of shielding to protect the occupants from radiation damage, and so on.

As a scientist, and as the leading theoretical biologist of our time, he had a healthy scepticism of theoreticians. Too often, he felt, theoreticians like to make their theories fit the facts. For him, a good theory would take the few essential facts - only those one could be sure were right - and, with some ingenious new view of the problem, suggest a different way of looking at it; a way which, to be useful, would have to make unexpected predictions. He felt that good experiments were worth a lot of theory and, as such, was especially careful to give those individuals who had done the work at the bench due recognition. He was scrupulously fair and never added his name to his colleagues' papers, a generous trait he shared with Watson, unless without his ideas the work would never have been conceived. It is the individual who makes a discovery; a new way of thinking about a problem rarely comes from a group. Honours to him were an obstacle to communication with one's peers.

Francis Crick's greatest assets were his curiosity and ruthless intellect. At seminars or meetings, it was often he alone who saw the point of a question, and he would not hesitate to rephrase it, if he thought it unclear. He could be uncharacteristically mean to a pompous speaker; his presence at meetings made sure everyone was on their toes. He had a fine sense for aesthetic elegance, reflected in his scientific discoveries and writing. His wonderful humour, accompanied by a somewhat raucous laugh, was infectious. He was a great entertainer. In dress, he was always careful, well groomed, usually with a colourful tie and always enjoying life.

In early 1962 the unit in the Cavendish closed and the new MRC Laboratory of Molecular Biology was opened by the Queen. In October that year a succession of Thursdays brought home to all the achievements of the members of the laboratory. The first Thursday, Crick and Watson shared the Leopold Mayer Prize, their first substantial award. The following Thursday, news came that Kendrew and Perutz were to share that year's Nobel Prize for Chemistry. On the third Thursday, Crick, Watson and Wilkins shared the Nobel Prize for Physiology or Medicine.

That evening there was champagne at the Golden Helix, Francis and Odile Crick's home in central Cambridge. A thoughtful American came loaded with a box of fireworks - it was five days before Guy Fawkes Night. Late in the evening these were taken up the five flights to the Cricks' roof garden; there, the rockets were lit and released over Cambridge. Others at the party scaled the tiled roof and, holding on to chimney pots, lit bangers and tossed them into Portugal Place below. Francis was downstairs, unaware of all this. However, a policeman shortly arrived. He had been sent to investigate a complaint that bangs were disturbing a neighbour's greyhounds. Francis, at the front door, deployed all his diplomatic skills and his exquisite charm. He explained to the policeman what a special occasion it was, how he would be able to read about it all in the papers the next day, how he would personally make sure that there were no more bangs.

In no time at all, the policeman was inside the house, helmet off and sipping a glass of champagne.

Mark S. Bretscher