Crick was interested in two fundamental unsolved problems of biology: how molecules make the transition from the non-living to the living, and how the brain makes a conscious mind. He realised that his background made him more qualified for research on the first topic and the field of
biophysics. In 1946 Crick read
Erwin Schrödinger's book,
What Is Life? and was influenced by it, and Linus Pauling, to switch from physics to biology. It was clear in theory that
covalent bonds in biological molecules could provide the structural stability needed to hold
genetic information in cells. It only remained as an exercise of experimental biology to discover exactly which molecule was the genetic molecule. In Crick's view, Charles Darwin's theory of
evolution by
natural selection,
Gregor Mendel's genetics and knowledge of the molecular basis of genetics, when combined, revealed the secret of life. Crick had the very optimistic view that life would very soon be created in a test tube. However, some people (such as fellow researcher and colleague
Esther Lederberg) thought that Crick was unduly optimistic. It was clear that some
macromolecule such as a
protein was likely to be the genetic molecule. However, it was well known that proteins are structural and functional macromolecules, some of which carry out
enzymatic reactions of cells. Crick was in the right place, in the right frame of mind, at the right time (1949), to join Max Perutz's project at the
University of Cambridge, and he began to work on the
X-ray crystallography of proteins. X-ray crystallography theoretically offered the opportunity to reveal the molecular structure of large molecules like proteins and DNA, but there were serious technical problems then preventing X-ray crystallography from being applicable to such large molecules. During the period of Crick's study of
X-ray diffraction, researchers in the Cambridge lab were attempting to determine the most stable helical conformation of
amino acid chains in proteins (the
alpha helix). Linus Pauling was the first to identify the 3.6 amino acids per helix turn ratio of the alpha helix. Crick was witness to the kinds of errors that his co-workers made in their failed attempts to make a correct molecular model of the alpha helix; these turned out to be important lessons that could be applied, in the future, to the helical structure of DNA. For example, he learned the importance of the structural rigidity that
double bonds confer on molecular structures which is relevant both to
peptide bonds in proteins and the structure of
nucleotides in DNA.
1951–1953: DNA structure In 1951 and 1952, together with
William Cochran and Vladimir Vand, Crick assisted in the development of a mathematical theory of X-ray diffraction by a helical molecule. This theoretical result matched well with X-ray data for
proteins that contain sequences of amino acids in the alpha helix conformation. Helical diffraction theory turned out to also be useful for understanding the structure of DNA. Late in 1951, Crick started working with James Watson at
Cavendish Laboratory at the
University of Cambridge, England. Using "
Photo 51" (the X-ray diffraction results of
Rosalind Franklin and her graduate student
Raymond Gosling of King's College London, given to them by Gosling and Franklin's colleague Wilkins), Watson and Crick together developed a model for a helical structure of DNA, which they published in 1953. For this and subsequent work they were jointly awarded the
Nobel Prize in Physiology or Medicine in 1962 with Wilkins. When Watson came to Cambridge, Crick was a 35-year-old graduate student (due to his work during WWII) and Watson was only 23, but had already obtained a PhD. They shared an interest in the fundamental problem of learning how genetic information might be stored in molecular form. Watson and Crick talked endlessly about DNA and the idea that it might be possible to guess a good molecular model of its structure. Many have speculated about what might have happened had Pauling been able to travel to Britain as planned in May 1952. As it was, his political activities caused his travel to be restricted by the
United States government and he did not visit the UK until later, at which point he met none of the DNA researchers in England. At any rate he was preoccupied with proteins at the time, not DNA. Watson and Crick were not officially working on DNA. Crick was writing his PhD thesis; Watson also had other work such as trying to obtain crystals of
myoglobin for X-ray diffraction experiments. In 1952, Watson performed X-ray diffraction on
tobacco mosaic virus and found results indicating that it had helical structure. Having failed once, Watson and Crick were now somewhat reluctant to try again and for a while they were forbidden to make further efforts to find a molecular model of DNA. Of great importance to the model building effort of Watson and Crick was Rosalind Franklin's understanding of basic chemistry, which indicated that the
hydrophilic phosphate-containing backbones of the nucleotide chains of DNA should be positioned so as to interact with
water molecules on the outside of the molecule while the
hydrophobic bases should be packed into the core. Franklin shared this chemical knowledge with Watson and Crick when she pointed out to them that their first model (from 1951, with the phosphates inside) was obviously wrong. Crick described what he saw as the failure of Wilkins and Franklin to cooperate and work towards finding a molecular model of DNA as a major reason why he and Watson eventually made a second attempt to do so. They asked for, and received, permission to do so from both William Lawrence Bragg and Wilkins. To construct their model of DNA, Watson and Crick made use of information from unpublished X-ray diffraction images of Franklin's (shown at meetings and freely shared by Wilkins), including preliminary accounts of Franklin's results/photographs of the X-ray images that were included in a written progress report for the King's College laboratory of Sir John Randall from late 1952. It is a matter of debate whether Watson and Crick should have had access to Franklin's results without her knowledge or permission, and before she had a chance to
formally publish the results of her detailed analysis of her X-ray diffraction data which were included in the progress report. However, Watson and Crick found fault in her steadfast assertion that, according to her data, a helical structure was not the only possible shape for DNA—so they had a dilemma. In an effort to clarify this issue, Max Ferdinand Perutz later published what had been in the progress report, and suggested that nothing was in the report that Franklin herself had not said in her talk (attended by Watson) in late 1951. Perutz explained that the report was to a Medical Research Council (MRC) committee that had been created to "establish contact between the different groups of people working for the Council". Randall's and Perutz's laboratories were both funded by the MRC. It is also not clear how important Franklin's unpublished results from the progress report actually were for the model-building done by Watson and Crick. After the first crude X-ray diffraction images of DNA were collected in the 1930s,
William Astbury had talked about stacks of nucleotides spaced at 3.4 angström (0.34 nanometre) intervals in DNA. A citation to Astbury's earlier X-ray diffraction work was one of only eight references in Franklin's first paper on DNA. Analysis of Astbury's published DNA results and the better X-ray diffraction images collected by Wilkins and Franklin revealed the helical nature of DNA. It was possible to predict the number of bases stacked within a single turn of the DNA helix (10 per turn; a full turn of the helix is 27 angströms [2.7 nm] in the compact A form, 34 angströms [3.4 nm] in the wetter B form). Wilkins shared this information about the B form of DNA with Crick and Watson. Crick did not see Franklin's B form X-ray images (
Photo 51) until after the DNA double helix model was published. One of the few references cited by Watson and Crick when they published their model of DNA was to a published article that included Sven Furberg's DNA model that had the bases on the inside. Thus, the Watson and Crick model was not the first "bases in" model to be proposed. Furberg's results had also provided the correct orientation of the DNA sugars with respect to the bases. During their model building, Crick and Watson learned that an
antiparallel orientation of the two nucleotide chain backbones worked best to orient the
base pairs in the centre of a double helix. Crick's access to Franklin's progress report of late 1952 is what made Crick confident that DNA was a double helix with antiparallel chains, but there were other chains of reasoning and sources of information that also led to these conclusions. As a result of leaving King's College for
Birkbeck College, Franklin was asked by John Randall to give up her work on DNA. When it became clear to Wilkins and the supervisors of Watson and Crick that Franklin was going to the new job, and that Linus Pauling was working on the structure of DNA, they were willing to share Franklin's data with Watson and Crick, in the hope that they could find a good model of DNA before Pauling was able. Franklin's X-ray diffraction data for DNA and her systematic analysis of DNA's structural features were useful to Watson and Crick in guiding them towards a correct molecular model. The key problem for Watson and Crick, which could not be resolved by the data from King's College, was to guess how the nucleotide bases pack into the core of the DNA double helix. :
cytosine and
adenine:
thymine base pairs is illustrated. The base pairs are held together by
hydrogen bonds. The phosphate backbones are
anti-parallel. Another key to finding the correct structure of DNA was the so-called
Chargaff ratios, experimentally determined ratios of the nucleotide subunits of DNA: the amount of
guanine is equal to
cytosine and the amount of
adenine is equal to
thymine. A visit by
Erwin Chargaff to England, in 1952, reinforced the salience of this important fact for Watson and Crick. The significance of these ratios for the structure of DNA were not recognised until Watson, persisting in building structural models, realised that A:T and C:G pairs are structurally similar. In particular, the length of each base pair is the same. Chargaff had also pointed out to Watson that, in the aqueous, saline environment of the cell, the predominant tautomers of the pyrimidine (C and T) bases would be the amine and keto configurations of cytosine and thymine, rather than the imino and enol forms that Crick and Watson had assumed. They consulted
Jerry Donohue who confirmed the most likely structures of the nucleotide bases. The base pairs are held together by
hydrogen bonds, the same non-covalent interaction that stabilise the protein α-helix. The correct structures were essential for the positioning of the hydrogen bonds. These insights led Watson to deduce the true biological relationships of the A:T and C:G pairs. After the discovery of the hydrogen bonded A:T and C:G pairs, Watson and Crick soon had their anti-parallel, double helical model of DNA, with the hydrogen bonds at the core of the helix providing a way to "unzip" the two complementary strands for easy
replication: the last key requirement for a likely model of the genetic molecule. As important as Crick's contributions to the discovery of the double helical DNA model were, he stated that without the chance to collaborate with Watson, he would not have found the structure by himself. Crick did tentatively attempt to perform some experiments on nucleotide base pairing, but he was more of a theoretical biologist than an experimental biologist. There was another near-discovery of the base pairing rules in early 1952. Crick had started to think about interactions between the bases. He asked
John Griffith to try to calculate attractive interactions between the DNA bases from chemical principles and
quantum mechanics. Griffith's best guess was that A:T and G:C were attractive pairs. At that time, Crick was not aware of Chargaff's rules and he made little of Griffith's calculations, although it did start him thinking about complementary replication. Identification of the correct base-pairing rules (A-T, G-C) was achieved by Watson "playing" with cardboard cut-out models of the nucleotide bases, much in the manner that Linus Pauling had discovered the protein alpha helix a few years earlier. The Watson and Crick discovery of the DNA double helix structure was made possible by their willingness to combine theory, modelling and experimental results (albeit mostly done by others) to achieve their goal. The DNA double helix structure proposed by Watson and Crick was based upon "Watson-Crick" bonds between the four bases most frequently found in DNA (A, C, T, G) and RNA (A, C, U, G). However, later research showed that triple-stranded, quadruple-stranded and other more complex DNA molecular structures required
Hoogsteen base pairing. In the field of
synthetic biology, bases other than A, C, T and G are used in a synthetic DNA. In addition to synthetic DNA there are also attempts to construct synthetic
codons, synthetic
endonucleases, synthetic proteins and synthetic
zinc fingers. Using synthetic DNA, instead of there being 43 codons, if there are
n new bases there could be as many as
n3 codons. Research is currently being done to see if codons can be expanded to more than 3 bases. These new codons can code for new amino acids. These synthetic molecules can be used not only in medicine, but in creation of new materials. The discovery was made on 28 February 1953; the first Watson/Crick paper appeared in
Nature on 25 April 1953. Sir Lawrence Bragg, the director of the
Cavendish Laboratory, where Watson and Crick worked, gave a talk at
Guy's Hospital Medical School in London on Thursday 14 May 1953 which resulted in an article by Ritchie Calder in the
News Chronicle of London, on Friday 15 May 1953, entitled "Why You Are You. Nearer Secret of Life." The news reached readers of
The New York Times the next day;
Victor K. McElheny, in researching his biography, "Watson and DNA: Making a Scientific Revolution", found a clipping of a six-paragraph
New York Times article written from London and dated 16 May 1953 with the headline "Form of 'Life Unit' in Cell Is Scanned". The article ran in an early edition and was then pulled to make space for news deemed more important. (
The New York Times subsequently ran a longer article on 12 June 1953). The university's undergraduate newspaper
Varsity also ran its own short article on the discovery on Saturday 30 May 1953. Bragg's original announcement of the discovery at a
Solvay conference on
proteins in Belgium on 8 April 1953 went unreported by the British press. In a seven-page, handwritten letter to his son at a British boarding school on 19 March 1953 Crick explained his discovery, beginning the letter "My Dear Michael, Jim Watson and I have probably made a most important discovery". The letter was put up for auction at
Christie's New York on 10 April 2013 with an estimate of $1 to $2 million, eventually selling for $6,059,750, the largest amount ever paid for a letter at auction.
Sydney Brenner,
Jack Dunitz,
Dorothy Hodgkin,
Leslie Orgel, and Beryl M Oughton, were some of the first people in April 1953 to see the model of the structure of
DNA, constructed by Crick and Watson; at the time they were working at
Oxford University's Chemistry Department. All were impressed by the new DNA model, especially Brenner who subsequently worked with Crick at
Cambridge in the Cavendish Laboratory and the new
Laboratory of Molecular Biology. According to the late Dr. Beryl Oughton, later Rimmer, they all travelled together in two cars once Dorothy Hodgkin announced to them that they were off to Cambridge to see the model of the structure of DNA. Orgel also later worked with Crick at the
Salk Institute for Biological Studies. Crick was often described as very talkative, with Watson – in
The Double Helix – implying lack of modesty. His personality combined with his scientific accomplishments produced many opportunities for Crick to stimulate reactions from others, both inside and outside the scientific world, which was the centre of his intellectual and professional life. Crick spoke rapidly, and rather loudly, and had an infectious and reverberating laugh, and a lively sense of humour. One colleague from the Salk Institute described him as "a brainstorming intellectual powerhouse with a mischievous smile. ... Francis was never mean-spirited, just incisive. He detected microscopic flaws in logic. In a room full of smart scientists, Francis continually re-earned his position as the heavyweight champ." in London. Soon after Crick's death, there have been allegations about him having used
LSD when he came to the idea of the helix structure of the DNA. While he almost certainly did use LSD, it is unlikely that he did so as early as 1953. In the late 1960s he was given LSD by
Henry Todd who met Crick through his girlfriend who had modelled for Crick's wife.
Molecular biology In 1954, at the age of 37, Crick completed his PhD thesis: "
X-Ray Diffraction: Polypeptides and Proteins" and received his degree. Crick then worked in the laboratory of
David Harker at
Brooklyn Polytechnic Institute, where he continued to develop his skills in the analysis of
X-ray diffraction data for proteins, working primarily on
ribonuclease and the mechanisms of
protein synthesis. David Harker, the American X-ray crystallographer, was described as "the John Wayne of crystallography" by Vittorio Luzzati, a crystallographer at the Centre for Molecular Genetics in Gif-sur-Yvette near Paris, who had worked with Rosalind Franklin. After the discovery of the double helix model of DNA, Crick's interests quickly turned to the biological implications of the structure. In 1953, Watson and Crick published another article in
Nature which stated: "it therefore seems likely that the precise sequence of the bases is the code that carries the genetical information". In 1956, Crick and Watson speculated on the structure of small viruses. They suggested that spherical viruses such as
Tomato bushy stunt virus had icosahedral symmetry and were made from 60 identical subunits. After his short time in New York, Crick returned to Cambridge where he worked until 1976, at which time he moved to California. Crick engaged in several X-ray diffraction collaborations such as one with
Alexander Rich on the structure of
collagen. However, Crick was quickly drifting away from continued work related to his expertise in the interpretation of X-ray diffraction patterns of proteins.
George Gamow established a group of scientists interested in the role of
RNA as an intermediary between DNA as the genetic storage molecule in the
nucleus of cells and the synthesis of proteins in the
cytoplasm (the
RNA Tie Club). It was clear to Crick that there had to be a code by which a short sequence of nucleotides would specify a particular
amino acid in a newly synthesised protein. In 1956, Crick wrote an informal paper about the
genetic coding problem for the small group of scientists in Gamow's RNA group. In this article, Crick reviewed the evidence supporting the idea that there was a common set of about 20 amino acids used to synthesise proteins. Crick proposed that there was a corresponding set of small "adaptor molecules" that would
hydrogen bond to short sequences of a nucleic acid, and also link to one of the amino acids. He also explored the many theoretical possibilities by which short nucleic acid sequences might code for the 20 amino acids. molecule. Crick predicted that such adaptor molecules might exist as the links between
codons and
amino acids. During the mid-to-late 1950s Crick was very much intellectually engaged in sorting out the mystery of how proteins are synthesised. By 1958, Crick's thinking had matured and he could list in an orderly way all of the key features of the protein synthesis process: Later that summer, Brenner, Jacob, and
Matthew Meselson conducted an experiment which was the first to prove the existence of messenger RNA. Experimental results were needed; theory alone could not decide the nature of the code. Crick also used the term "
central dogma" to summarise an idea that implies that genetic information flow between macromolecules would be essentially one-way: :
DNA → RNA → protein Some critics thought that by using the word "dogma", Crick was implying that this was a rule that could not be questioned, but all he really meant was that it was a compelling idea without much solid evidence to support it. In his thinking about the biological processes linking DNA genes to proteins, Crick made explicit the distinction between the materials involved, the energy required, and the information flow. Crick was focused on this third component (information) and it became the organising principle of what became known as molecular biology. Crick had by this time become a highly influential theoretical molecular biologist. Proof that the genetic code is a degenerate triplet code finally came from genetics experiments, some of which were performed by Crick. The details of the code came mostly from work by
Marshall Nirenberg and others who synthesised synthetic RNA molecules and used them as templates for
in vitro protein synthesis. Nirenberg first announced his results to a small audience in Moscow at a 1961 conference. Crick's reaction was to invite Nirenberg to deliver his talk to a larger audience. ==Controversy==