Editing Francis Crick (section)

==Research==
{{Double helix}}
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.<ref name="CrickWMP17">[[#Crick|Crick (1990)]], p. 17</ref> He realised that his background made him more qualified for research on the first topic and the field of [[biophysics]]. It was at this time of Crick's transition from physics to biology that he was influenced by both Linus Pauling and [[Erwin Schrödinger]].<ref name=CrickWMP18>[[#Crick|Crick (1990)]], p. 18</ref> It was clear in theory that [[covalent bond]]s in biological molecules could provide the structural stability needed to hold [[genetics|genetic]] information in cells. It only remained as an exercise of experimental biology to discover exactly which molecule was the genetic molecule.<ref name="CrickWMPTalking">[[#Crick|Crick (1990)]], p. 22</ref><ref name="Judson30">Page 30 of ''The Eighth Day of Creation: Makers of the Revolution in Biology'' by [[Horace Freeland Judson]] published by Cold Spring Harbor Laboratory Press (1996) {{ISBN|0-87969-478-5}}.</ref> 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.<ref name="CrickWMP25">[[#Crick|Crick (1990)]], p. 25</ref> 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.<ref>{{cite web|url=http://www.estherlederberg.com/Anecdotes.html#INTERVIEW |title=Esther M. Zimmer Lederberg: Anecdotes |publisher=Estherlederberg.com }}</ref>

It was clear that some [[macromolecule]] such as a [[protein]] was likely to be the genetic molecule.<ref name="CrickWMP32">[[#Crick|Crick (1990)]], p. 32</ref> However, it was well known that proteins are structural and functional macromolecules, some of which carry out [[enzyme|enzymatic]] reactions of cells.<ref name="CrickWMP32"/> In the 1940s, some evidence had been found pointing to another macromolecule, DNA, the other major component of [[chromosome]]s, as a candidate genetic molecule. In the 1944 [[Avery-MacLeod-McCarty experiment]], [[Oswald Avery]] and his collaborators showed that a heritable [[phenotype|phenotypic]] difference could be caused in bacteria by providing them with a particular DNA molecule.<ref name="Judson30"/>

However, other evidence was interpreted as suggesting that DNA was structurally uninteresting and possibly just a molecular scaffold for the apparently more interesting protein molecules.<ref name="CrickWMP33">[[#Crick|Crick (1990)]], pp. 33–34</ref> 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.<ref name="CrickWMPCH4">[[#Crick|Crick (1990)]], Ch. 4</ref> 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.<ref name="CrickWMPCH4"/>

===1949–1950===
Crick taught himself the mathematical theory of X-ray crystallography.<ref name=CrickWMP46>[[#Crick|Crick (1990)]], p. 46: "there was no alternative but to teach X-ray diffraction to myself."</ref> 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<ref>{{Cite journal|vauthors=Pauling L, Corey RB |title=Atomic Coordinates and Structure Factors for Two Helical Configurations of Polypeptide Chains |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=37 |issue=5 |pages=235–40 |date=May 1951 |pmid=14834145 |pmc=1063348 |doi=10.1073/pnas.37.5.235|bibcode = 1951PNAS...37..235P |url=http://authors.library.caltech.edu/10215/1/PAUpnas51g.pdf |archive-url=https://web.archive.org/web/20170922115158/http://authors.library.caltech.edu/10215/1/PAUpnas51g.pdf |archive-date=2017-09-22 |url-status=live |doi-access=free }}</ref> the 3.6&nbsp;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<ref name="CrickWMP58">[[#Crick|Crick (1990)]], p. 58</ref> the importance of the structural rigidity that [[cis–trans isomerism|double bonds]] confer on molecular structures which is relevant both to [[peptide bond]]s in proteins and the structure of [[nucleotide]]s in DNA.

===1951–1953: DNA structure===
In 1951 and 1952, together with [[William Cochran (physicist)|William Cochran]] and Vladimir Vand, Crick assisted in the development of a mathematical theory of X-ray diffraction by a helical molecule.<ref>{{Cite journal|doi=10.1107/S0365110X52001635 |title=The structure of synthetic polypeptides. I. The transform of atoms on a helix |year=1952 |last1=Cochran |first1=W. |last2=Crick |first2=F. H. |last3=Vand |first3=V. |journal=Acta Crystallographica |volume=5 |pages=581–6|issue=5|url=http://journals.iucr.org/q/issues/1952/05/00/a00699/a00699.pdf |archive-url=https://web.archive.org/web/20081010080525/http://journals.iucr.org/q/issues/1952/05/00/a00699/a00699.pdf |archive-date=2008-10-10 |url-status=live |doi-access=free |bibcode=1952AcCry...5..581C }}</ref> This theoretical result matched well with X-ray data for [[protein]]s that contain sequences of amino acids in the alpha helix conformation.<ref>{{Cite journal|doi=10.1038/169234a0 |url=https://profiles.nlm.nih.gov/SC/B/C/D/M/ |title=Evidence for the Pauling–Corey α-Helix in Synthetic Polypeptides |year=1952 |last1=Cochran |first1=W. |last2=Crick |first2=F. H. C. |journal=Nature |volume=169 |pages=234–235|bibcode = 1952Natur.169..234C |issue=4293|s2cid=4182175 }}</ref> Helical diffraction theory turned out to also be useful for understanding the structure of DNA.{{citation needed|date=July 2023}}

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.<ref>{{Cite journal|vauthors=Watson JD, Crick FH |title=Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid |journal=Nature |volume=171 |issue=4356 |pages=737–8 |year=1953 |pmid=13054692 |doi=10.1038/171737a0|bibcode = 1953Natur.171..737W |title-link=Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid |s2cid=4253007 }}</ref> For this and subsequent work they were jointly awarded the [[Nobel Prize in Physiology or Medicine]] in 1962 with Wilkins.<ref>Francis Crick's 1962 [http://nobelprize.org/medicine/laureates/1962/crick-bio.html Biography from the Nobel foundation].</ref><ref name="Profile">{{cite web |title=James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin |url=https://www.sciencehistory.org/historical-profile/james-watson-francis-crick-maurice-wilkins-and-rosalind-franklin |publisher=Science History Institute |access-date=20 March 2018|date=June 2016 }}</ref>

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.<ref name="CrickWMPgene">[[#Crick|Crick (1990)]], p. 22: Crick traced his interest in the physical nature of the gene back to the start of his work in biology, when he was in the Strangeways laboratory.</ref><ref name="JudsonOnWatson">In ''The Eighth Day of Creation'', [[Horace Freeland Judson|Horace Judson]] describes the development of Watson's thinking about the physical nature of genes. On page 89, Judson explains that by the time Watson came to Cambridge, he believed genes were made of DNA and he hoped that he could use X-ray diffraction data to determine the structure.</ref> Watson and Crick talked endlessly about DNA and the idea that it might be possible to guess a good molecular model of its structure.<ref name="CrickWMPTalking"/> A key piece of experimentally-derived information came from X-ray diffraction images that had been obtained by Wilkins, Franklin, and Gosling. In November 1951, Wilkins came to Cambridge and shared his data with Watson and Crick. [[Alex Stokes|Alexander Stokes]] (another expert in helical diffraction theory) and Wilkins (both at King's College) had reached the conclusion that X-ray diffraction data for DNA indicated that the molecule had a helical structure—but Franklin vehemently disputed this conclusion. Stimulated by their discussions with Wilkins and what Watson learned by attending a talk given by Franklin about her work on DNA, Crick and Watson produced and showed off an erroneous first model of DNA. Their hurry to produce a model of DNA structure was driven in part by the knowledge that they were competing against Linus Pauling. Given Pauling's recent success in discovering the Alpha helix, they feared that Pauling might also be the first to determine the structure of DNA.<ref name="WatsonOnPauling">Page 90, In ''The Eighth Day of Creation'' by Horace Judson.</ref>

Many have speculated about what might have happened had Pauling been able to travel to Britain as planned in May 1952.<ref name="OSUraceforDNA">{{cite web|title=Linus Pauling and the Race for DNA: A Documentary History|url=http://osulibrary.oregonstate.edu/specialcollections/coll/pauling/dna/narrative/page13.html |publisher=Special Collections, The Valley Library, Oregon State University.}}</ref> 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.<ref name="OSUraceforDNA" /><ref name="JudsonOnPauling">Chapter 3 in ''The Eighth Day of Creation'' by Horace Judson.</ref> 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.

[[File:DNA Structure.jpg|thumb|right|Diagram that emphasises the phosphate backbone of DNA. Watson and Crick first made helical models with the phosphates at the centre of the helices.]]
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 (molecule)|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 [[academic publishing|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,<ref>{{Cite journal|vauthors=Perutz MF, Randall JT, Thomson L, Wilkins MH, Watson JD |title=DNA helix |journal=Science |volume=164 |issue=3887 |pages=1537–9 |date=June 1969 |pmid=5796048 |doi=10.1126/science.164.3887.1537|bibcode = 1969Sci...164.1537W |doi-access= |s2cid=5263958 }}</ref> 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.<ref>Franklin's citation to the earlier work of W. T. Astbury is in:<br />{{Cite journal|vauthors=Franklin RE, Gosling RG |title=Molecular configuration in sodium thymonucleate |journal=Nature |volume=171 |issue=4356 |pages=740–1 |year=1953 |pmid=13054694 |doi= 10.1038/171740a0|url= http://www.nature.com/nature/dna50/franklingosling.pdf |archive-url=https://web.archive.org/web/20040610083152/http://www.nature.com/nature/dna50/franklingosling.pdf |archive-date=2004-06-10 |url-status=live |format=PDF reprint|bibcode = 1953Natur.171..740F |s2cid=4268222 }}</ref> 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&nbsp;nm] in the compact A form, 34 angströms [3.4&nbsp;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.<ref>{{Cite journal|author=Crick F |title=The double helix: a personal view |journal=Nature |volume=248 |issue=5451 |pages=766–9 |year=1974|pmid=4599081 |doi=10.1038/248766a0|bibcode = 1974Natur.248..766C |s2cid=4224441 }}</ref>

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 (biochemistry)|antiparallel]] orientation of the two nucleotide chain backbones worked best to orient the [[base pair]]s 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.<ref name="JudsonCh3modeling">In chapter 3 of ''The Eighth Day of Creation'', [[Horace Freeland Judson|Horace Judson]] describes the development of [[James Watson|Watson]]'s and Crick's thinking about the structure of DNA and how it evolved during their model building. Watson and Crick were open to the idea of tentatively ignoring all individual experimental results, in case they might be wrong or misleading. Judson describes how Watson spent a large amount of time ''ignoring'' Crick's belief (based on Franklin's determination of the space group) that the two backbone strands were antiparallel. On page 176, Judson quotes a letter written by Watson, "The model has been derived almost entirely from stereochemical considerations with the only X-ray consideration being the spacing between the pair of bases 3.4 A which was originally found by Astbury."</ref>

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.

[[File:DNA chemical structure.svg|thumb|right|Diagrammatic representation of some key structural features of DNA. The similar structures of [[guanine]]:[[cytosine]] and [[adenine]]:[[thymine]] base pairs is illustrated. The base pairs are held together by [[hydrogen bond]]s. The phosphate backbones are [[antiparallel (biochemistry)|anti-parallel]].]]
Another key to finding the correct structure of DNA was the so-called [[Chargaff's rules|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.{{citation needed|date=October 2017}} 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.<ref>See Chapter 3 of ''The Eighth Day of Creation: Makers of the Revolution in Biology'' by Horace Freeland Judson published by Cold Spring Harbor Laboratory Press (1996) {{ISBN|0-87969-478-5}}. Judson also lists the publications of W. T. Astbury that described his early X-ray diffraction results for DNA.</ref> The base pairs are held together by [[hydrogen bond]]s, 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 [[DNA replication|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.<ref name="WMP75">[[#Crick|Crick (1990)]], p. 75: "If Jim had been killed by a tennis ball, I am reasonably sure I would not have solved the structure alone".</ref>

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 Stanley Griffith|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 pair]]ing. The entire field of [[synthetic biology]] began with work by researchers such as Erik T Kool, in which 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 4<sup>3</sup> codons, if there are ''n'' new bases there could be as many as ''n''<sup>3</sup> 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.<ref name="Simon, Matthew 2005">Simon, Matthew (2005) ''Emergent Computation: emphasizing bioinformatics''. Springer. {{ISBN|0-387-22046-1}}.</ref>

The discovery was made on 28 February 1953; the first Watson/Crick paper appeared in ''[[Nature (journal)|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 (Cambridge)|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<ref>[http://news.msn.com/science-technology/letter-from-dna-discoverer-to-young-son-to-be-auctioned Letter from DNA discoverer to young son to be auctioned] {{Webarchive|url=https://web.archive.org/web/20130327010122/http://news.msn.com/science-technology/letter-from-dna-discoverer-to-young-son-to-be-auctioned |date=27 March 2013 }}. MSN. Retrieved 21 November 2013.</ref> 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".<ref name="sonletter">[https://www.nytimes.com/interactive/2013/02/26/science/crick-letter-on-dna-discovery.html My Dear Michael, We've Discovered DNA]. Crick's letter transcribed at ''The New York Times''. 26 February 2013</ref> The letter was put up for auction at [[Christie's]] New York on 10 April 2013 with an estimate of $1 to $2&nbsp;million, eventually selling for $6,059,750, the largest amount ever paid for a letter at auction.<ref name="letterauction">[http://www.christies.com/about/press-center/releases/pressrelease.aspx?pressreleaseid=6195 "The 'Secret of Life' Letter to Be Sold at Christie's On April 10: Remarkable Letter from Francis Crick to His Son, Outlining the Revolutionary Discovery of the Structure and Function of DNA Estimate: $1–2 million"] {{Webarchive|url=https://web.archive.org/web/20141129093523/http://www.christies.com/about/press-center/releases/pressrelease.aspx?pressreleaseid=6195 |date=29 November 2014 }}. [[Christie's]]. New York, Rockefeller Center. 26 February 2013</ref>

[[Sydney Brenner]], [[Jack D. Dunitz|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 [[University of Oxford|Oxford University]]'s Chemistry Department. All were impressed by the new DNA model, especially Brenner who subsequently worked with Crick at [[University of Cambridge|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.<ref>[[#Olby|Olby]], Ch. 10, p. 181</ref> 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.<ref>Watson's book ''The Double Helix'' painted a vivid image of Crick, starting with the famous line, "I have never seen Francis Crick in a modest mood." The first chapter of [[Horace Freeland Judson|Horace Judson]]'s book ''The Eighth Day of Creation'' describes the importance of Crick's talking and his boldness in his scientific style.</ref> 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.<ref>Describing Crick's influence on his scientific colleagues, Francis Crick Papers archivist Chris Beckett wrote of the importance of "Crick's presence and eloquence&nbsp;—direct and beguiling, by all accounts in the archive— at conference after conference, through formal lectures, extempore summaries, informal meetings and individual conversations. Indeed, one has the impression that it was through these frequent persuasive moments of personal delivery and purposive conversations that Crick was most influential."<br />{{Cite journal |author=Beckett C |year=2004 |title=For the Record: The Francis Crick Archive at the Wellcome Library |journal=Med Hist |volume=48 |issue=2 |pages=245–60 |doi=10.1017/S0025727300007419 |pmc=546341 |pmid=15151106}} Also described as an example of Crick's wide recognition and public profile are some of the times Crick was addressed as "Sir Francis Crick" with the assumption that someone so famous must have been knighted.</ref> 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.&nbsp;... 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."<ref>[[David Eagleman|Eagleman, D.M.]] (2005). [http://neuro.bcm.edu/eagleman/papers/Eagleman_Crick_VisionResearch2005.pdf Obituary: Francis H. C. Crick (1916–2004).] {{webarchive|url=https://web.archive.org/web/20070926121041/http://neuro.bcm.edu/eagleman/papers/Eagleman_Crick_VisionResearch2005.pdf|date=26 September 2007}} ''Vision Research''. 45: 391–393.</ref>

[[File:DNA Model Crick-Watson.jpg|thumb|right|Crick and Watson DNA model built in 1953, was reconstructed largely from its original pieces in 1973 and donated to the [[Science Museum (London)|National Science Museum]] in London.]]

Soon after Crick's death, there have been allegations about him having used [[Lysergic acid diethylamide|LSD]] when he came to the idea of the helix structure of the DNA.<ref>{{cite web|url=https://www.nytimes.com/2006/07/11/science/11book.html|title=A Peek into the Remarkable Mind Behind the Genetic Code|first=Nicholas|last=Wade|date=11 July 2006|work=The New York Times}}</ref><ref>{{cite web|url=http://www.mayanmajix.com/art1699.html|title=Nobel Prize genius Crick was high on LSD|website=mayanmajix.com}}</ref> While he almost certainly did use LSD, it is unlikely that he did so as early as 1953.<ref>{{cite web|url=http://realitysandwich.com/314873/francis-crick-dna-lsd/|title=Francis Crick, DNA & LSD – Reality Sandwich|website=realitysandwich.com|date=4 May 2015}}</ref>

===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 [[Polytechnic University of New York|Brooklyn Polytechnic Institute]], where he continued to develop his skills in the analysis of [[X-ray crystallography|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.{{citation needed|date=March 2015}}

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".<ref>{{Cite journal|vauthors=Watson JD, Crick FH |title=Genetical implications of the structure of deoxyribonucleic acid |journal=Nature |volume=171 |issue=4361 |pages=964–7 |date=May 1953 |pmid=13063483 |doi= 10.1038/171964b0|url= https://profiles.nlm.nih.gov/SC/B/B/Y/X/_/scbbyx.pdf |archive-url=https://web.archive.org/web/20050912214219/http://profiles.nlm.nih.gov/SC/B/B/Y/X/_/scbbyx.pdf |archive-date=2005-09-12 |url-status=live |format=PDF reprint|bibcode = 1953Natur.171..964W |s2cid=4256010 }}</ref>

[[File:Collagentriplehelix.png|thumb|left|99px|Collagen triple helix.]]

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.<ref>{{Cite journal|author=Morgan GJ |title=Historical review: viruses, crystals and geodesic domes |journal=Trends in Biochemical Sciences |volume=28 |issue=2 |pages=86–90 |date=February 2003 |pmid=12575996 |doi=10.1016/S0968-0004(02)00007-5|doi-access=free }}</ref>

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]].<ref>{{Cite journal|vauthors=Rich A, Crick FH |title=The structure of collagen |journal=Nature |volume=176 |issue=4489 |pages=915–6 |date=November 1955 |pmid=13272717 |doi= 10.1038/176915a0|url=https://profiles.nlm.nih.gov/SC/B/B/Z/L/_/scbbzl.pdf |archive-url=https://web.archive.org/web/20050912214247/http://profiles.nlm.nih.gov/SC/B/B/Z/L/_/scbbzl.pdf |archive-date=2005-09-12 |url-status=live |format=PDF reprint|bibcode = 1955Natur.176..915R |s2cid=9611917 }}</ref> 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 (cell)|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 code|genetic coding]] problem for the small group of scientists in Gamow's RNA group.<ref>"[https://profiles.nlm.nih.gov/SC/B/B/G/F/_/scbbgf.pdf On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club]" by Francis Crick (1956).</ref> 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.

[[File:3d tRNA.png|thumb|right|Molecular model of a [[tRNA]] molecule.{{citation needed|date=October 2011}} Crick predicted that such adaptor molecules might exist as the links between [[codon]]s and [[amino acid]]s.]]
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:<ref name="auto"/>
* genetic information stored in the sequence of DNA molecules
* a "messenger" RNA molecule to carry the instructions for making one protein to the cytoplasm
* adaptor molecules ("they might contain nucleotides") to match short sequences of nucleotides in the RNA messenger molecules to specific amino acids
* ribonucleic-protein complexes that catalyse the assembly of amino acids into proteins according to the messenger RNA

The adaptor molecules were eventually shown to be [[tRNA]]s and the catalytic "ribonucleic-protein complexes" became known as [[ribosome]]s. An important step was the realisation by Crick and Brenner on 15 April 1960 during a conversation with [[François Jacob]] that [[messenger RNA]] was not the same thing as [[ribosomal RNA]].<ref name="Cobb">{{cite journal |author-link1=Matthew Cobb |vauthors=Cobb M |date=29 June 2015 |title=Who discovered messenger RNA? |journal=Current Biology |volume=25 |issue=13 |pages=R526–R532 |doi=10.1016/j.cub.2015.05.032 |pmid=26126273 |doi-access=free|bibcode=2015CBio...25.R526C }}</ref>  Later that summer, Brenner, Jacob, and [[Matthew Meselson]] conducted an experiment which was the first to prove the existence of messenger RNA.<ref name="Cobb" />  None of this, however, answered the fundamental theoretical question of the exact nature of the genetic code. In his 1958 article, Crick speculated, as had others, that a triplet of nucleotides could code for an amino acid. Such a code might be "degenerate", with 4×4×4=64 possible triplets of the four nucleotide subunits while there were only 20 amino acids. Some amino acids might have multiple triplet codes. Crick also explored other codes in which, for various reasons, only some of the triplets were used, "magically" producing just the 20 needed combinations.<ref>{{cite journal|last1=Hayes|first1=Brian|journal=American Scientist|year=1998|access-date=11 January 2017|url=http://www.americanscientist.org/issues/pub/the-invention-of-the-genetic-code|title=The Invention of the Genetic Code|volume=86|pages=8|doi=10.1511/1998.17.3338|s2cid=121907709 }}</ref> Experimental results were needed; theory alone could not decide the nature of the code. Crick also used the term "[[central dogma of molecular biology|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.<ref>{{Cite journal|vauthors=Crick FH, Barnett L, Brenner S, Watts-Tobin RJ |title=General nature of the genetic code for proteins |journal=Nature |volume=192 |issue= 4809|pages=1227–32 |date=December 1961 |pmid=13882203 |doi= 10.1038/1921227a0|url=https://profiles.nlm.nih.gov/SC/B/C/B/J/_/scbcbj.pdf |archive-url=https://web.archive.org/web/20050912214328/http://profiles.nlm.nih.gov/SC/B/C/B/J/_/scbcbj.pdf |archive-date=2005-09-12 |url-status=live |format=PDF reprint|bibcode = 1961Natur.192.1227C |s2cid=4276146 }}</ref> The details of the code came mostly from work by [[Marshall Warren Nirenberg|Marshall Nirenberg]] and others who synthesized synthetic RNA molecules and used them as templates for ''[[in vitro]]'' protein synthesis.<ref>{{Cite journal|author=Crick FH |title=The Croonian lecture, 1966. The genetic code |journal=Proc. R. Soc. Lond. B Biol. Sci. |volume=167 |issue=9 |pages=331–47 |year=1967 |pmid=4382798 |doi= 10.1098/rspb.1967.0031|url= https://profiles.nlm.nih.gov/SC/B/C/B/X/_/scbcbx.pdf |archive-url=https://web.archive.org/web/20050912214319/http://profiles.nlm.nih.gov/SC/B/C/B/X/_/scbcbx.pdf |archive-date=2005-09-12 |url-status=live |format=PDF reprint|bibcode = 1967RSPSB.167..331C |s2cid=11131727 }}</ref> 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.<ref name=NautilusGoldstein>{{cite web |url=https://nautil.us/issue/72/quandary/the-thrill-of-defeat-rp |title=The Thrill of Defeat: What Francis Crick and Sydney Brenner taught me about being scooped |last=Goldstein |first=Bob |date=30 May 2019 |publisher=Nautilus |access-date=21 January 2021 |archive-date=10 December 2021 |archive-url=https://web.archive.org/web/20211210101407/https://nautil.us/issue/72/quandary/the-thrill-of-defeat-rp |url-status=dead }}</ref>