In 1951, together with
Cochran and V. 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 obtained for
proteins that contain sequences of
amino acids in the
Alpha helix conformation (published in
Nature in 1952). Helical
diffraction theory turned out to also be useful for understanding the structure of
DNA.
Late in 1951, Crick started working with
James D. Watson at
Cavendish Laboratory at the
University of Cambridge, England. Using the
X-ray diffraction results of
Raymond Gosling and
Rosalind Franklin of
King's College London, given to them by Gosling and Franklin's colleague
Maurice 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 awarded the
Nobel Prize in Physiology or Medicine in 1962, jointly with
Maurice Wilkins.
When
James D. Watson came to Cambridge, Crick was a 35 year old graduate student and Watson was only 23, but he already had a
Ph.D. 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. A key piece of experimentally-derived information came from
X-ray diffraction images that had been obtained by
Maurice Wilkins and his research student,
Raymond Gosling. In November 1951, Wilkins came to Cambridge and shared his data with Watson and Crick.
Alexander Stokes (another expert in helical diffraction theory) and Wilkins (both at
King's) had reached the conclusion that X-ray diffraction data for DNA indicated that the molecule had a helical structure. Stimulated by Wilkins, and a talk given by
Rosalind Franklin about her work on DNA, Crick and Watson produced and showed off an erroneous first model of DNA. Watson, in particular, thought they were competing against Pauling and feared that
Pauling might determine the structure of DNA.
Many have speculated about what might have happened had
Pauling been able to travel to
Britain as planned in May of 1952. He might have seen some of the
Wilkins/Gosling/Franklin X-ray diffraction data and such an event might have led him to a double helix model. As it was, his political activities caused his travel to be restricted by the
U. S. government and he did not visit the
UK until later, at which point he met none of the
DNA researchers in
England. Watson and Crick were not officially working on DNA. Crick was writing his
Ph.D. thesis. Watson also had other work such as trying to obtain crystals of
myoglobin for X-ray diffraction experiments. In 1952, Watson did
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 (1951, with the phosphates inside) was obviously wrong.
Crick described what he saw as the failure of
Maurice Wilkins and
Rosalind 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 make a molecular model of DNA. They asked for, and received, permission to do so from both
Bragg and Wilkins. In order 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 shared by Wilkins), and preliminary accounts of Franklin's detailed analysis of the
X-ray images that were included in a written progress report for the
King's laboratory of
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 that were included in the progress report. In an effort to clarify this issue,
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. Further, Perutz explained that the report was to a
Medical Research Council (MRC) committee that had been created in order to "establish contact between the different groups of people working for the Council". Randall's and Perutz's labs were both
MRC funded laboratories.
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 angstrom (0.34 nanometre) intervals in DNA. A citation to Astbury's earlier
X-ray diffraction work was one of only 8 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, Gosling 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 angstroms [2.7 nm] in the compact A form, 34 angstroms [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 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 published. 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 anti-parallel 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 another institution,
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
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 was 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.
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 recognized until Watson, persisting in building structural models, realized that A:T and C:G pairs are structurally similar. In particular, the length of each base pair is the same. The
base pairs are held together by
hydrogen bonds, the same non-covalent interaction that stabilizes the protein α helix. Watson’s recognition of the A:T and C:G pairs was aided by information from
Jerry Donohue about the most likely structures of the
nucleobases. After the discovery of the hydrogen bonded A:T and C:G pairs, Watson and Crick soon had their double helix 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 than an experimental biologist. There was another close approach to 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. 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
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 correct interpretation of the significance of experimental results that had been obtained by others.