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Published online by Cambridge University Press: 26 July 2012
“This is an historic occasion”, announced Francis Crick on 2 June 1966, as he began the opening address of the annual meeting of molecular biologists at Cold Spring Harbor. “There have been many meetings”, he continued, “about the genetic code during the past ten or twelve years but this is the first important one to be held since the code became known.” Such bold pronouncements usually guarantee that an occasion will linger in history's footnotes and never shine centre-page. But, as the first public presentation of the complete genetic code, the moment had some claim to being historically complementary to the publication of James Watson and Crick's first paper in Nature. In April 1953, in fourteen paragraphs and a diagrammatic sketch (contributed by Odile Crick), they had announced—with a minimalism that came more of urgent certainty than of diffidence or reticence—not just a physical structure for DNA, but something far more. “It has not escaped our notice that the specific pairing [of purine and pyrimidine bases] we have postulated immediately suggests a possible copying mechanism for the genetic material.” The trajectory begun in 1953 with the suggestion of “a possible copying mechanism” completed its public arc at Cold Spring Harbor in 1966 with a very specific and (almost) complete table showing the genetic code. The occasion “marked”, as Crick later judged, “the end of classical molecular biology”.
1 F H Crick, ‘The genetic code—yesterday, today, and tomorrow’, Cold Spring Harbor Symp. Quant. Biol, 1966, 31: 3–9, on p.3.
2 J D Watson and F H Crick, ‘Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid’, Nature, 1953, 171: 737–8.
3 What remained of the table to be completed were three codons: “the triplets UAA, UAG, and UGA, had no amino acids assigned to them. One by one, in experiments in phage genetics by [Sydney] Brenner and independently by Alan Garen at Yale, and then last by Brenner and Crick in 1967, these three triplets were proved to be nonsense codons, whose function was to signal the end of the polypeptide chain.” Horace Freeland Judson, The eighth day of creation: makers of the revolution in biology, Harmondsworth, Penguin, 1995, p. 480.
4 Francis Crick, What mad pursuit: a personal view of scientific discovery, New York, Basic Books, 1988, p. 143 (hereafter, WMP). For the genetic code table, see p. 170.
5 Judson, op. cit., note 3 above, pp. 463ff.
6 Matthew Meselson, quoted in Judson, ibid., p. 481: “And here was some guy named Marshall Nirenberg; his results were unlikely to be correct, because he wasn't in the club. And nobody bothered to be there to hear him. Anyway, I was bowled over by the results, and I went and chased down Francis, and told him that he must have a private talk with this man.”
7 For Nirenberg's relevant papers, and a draft of his Moscow presentation, visit: <http://profiles.nlm.nih.gov/JJ/Views/Exhibit/documents/syntheticrna.html>.
8 Judson, op. cit., note 3 above, p. 480, notes three attendees: “[Alfred] Tissières, [Walter] Gilbert and [Matthew] Meselson were almost alone.” Crick recalls: “Matt Meselson, whom I ran into in a corridor, alerted me to Marshall's talk in a remote seminar room” (WMP, p. 130).
9WMP, p. 130.
10 In December 2001, the Wellcome Trust purchased, with the assistance of the Heritage Lottery Fund, the scientific papers of Francis Crick for the sum of US$2.4 million, beating-off a rival bid from a private source(s). For the circumstances surrounding the purchase, and issues raised, see Rex Dalton, ‘The history man’, Nature, 2001, 411: 732–3; Alison Abbott and Rex Dalton, ‘Wellcome bid sees Crick archive return home’, Nature, 2001, 414: 678, and the conference paper by Julia Sheppard, ‘Molecular biology: the issues surrounding the purchase of the archives of leading molecular biologists by an American collector’, available at: <http://www.bath.ac.uk/ncuacs/FP_Sheppard.htm>. See also, for subsequent developments, ‘Auction of DNA archive cancelled’, Nature, 2003, 422: 102.
11WMP, p. 146.
12 PP/CRI is arranged as follows: A/Personal Material, B/Medical Research Council, C/Salk Institute for Biological Studies, D/Correspondence, E/Travels and Meetings, F/Doctorate, G/Notebooks, H/Notes and Drafts, I/Publication.
13 PP/CRI/D/2/45.
14 PP/CRI/E/1/13/4.
15 PP/CRI/E/1/13/19.
16 Crick later made the generalization: “If elegance and simplicity are, in biology, dangerous guides to the correct answer, what constraints can be used as a guide through the jungle of possible theories? It seems to me that the only really useful constraints are contained in the experimental evidence. Even this information is not without its hazards since … experimental facts are often misleading or even plain wrong. It is thus not sufficient to have a rough acquaintance with the experimental evidence, but rather a deep and critical knowledge of many different types of evidence is required, since one never knows what type of fact is likely to give the game away” (WMP, p. 141).
17 PP/CRI/D/1/2/17.
18 PP/CRI/E/1/14/5.
19 PP/CRI/E/2/2.
20 PP/CRI/E/1/13/4.
21 PP/CRI/E/1/25/13.
22 PP/CRI/E/1/13/4.
23 PP/CRI/E/2/4, an ‘Invitations Refused’ file. Another bold Crick brushstroke was as signatory to the SOMA full-page statement which appeared in The Times, Monday, 24 July 1967, suggesting to the Home Secretary that he implement a five point programme of cannabis reform. For the statement, visit: <http://www.drugtext.org/library/articles/TimesAd.html>
24 PP/CRI/E/1/15/3. Noll's next fulsome paragraph is all news, the information that nourishes theory: “We have what I consider definitive evidence that there are at least three classes of ribosomes…”.
25 PP/CRI/A/1/2/8.
26 ‘The computer, the eye, the soul’, Saturday Review, 3 Sept. 1966, pp. 53–5.
27 PP/CRI/D/1/4/18.
28 Sir Aaron Klug, ‘Anniversary address 1999’, Royal Society News, Dec. 1999, p. 1. Sir Aaron Klug was President of the Royal Society from 1995 to 2000.
29 “Carefully we double-checked the numbers on the petri dishes to make sure we had looked at the correct plate. Everything was in order. I looked across at Leslie [Barnett]. ‘Do you realise,’ I said, ‘that you and I are the only people in the world who know it's a triple code?’” (WMP, p. 133).
30 F H Crick, L Barnett, S Brenner, R J Watts-Tobin, ‘General nature of the genetic code for proteins’, Nature, 1961, 192: 1227–32.
31 PP/CRI/D/1/1/14.
32 M W Nirenberg and J H Matthaei, ‘The dependence of cell-free protein synthesis in E. coli upon naturally occurring or synthetic polynucleotides’, Proc. Natl. Acad. Sci. USA, 1961, 47: 1558–602.
33 “While many a general reader … may regard the lowly footnote or the remote endnote or the bibliographic parenthesis as a dispensable nuisance, it can be argued that these are in truth central to the incentive system and an underlying sense of distributive justice that do much to energize the advancement of knowledge.” Robert K Merton, ‘The Matthew effect in science. II. Cumulative advantage and the symbolism of intellectual property’, Isis, 1988, 79: 621. Consider, in this regard, the troublesome drafting of the penultimate sentence of the first Watson and Crick paper (effectively, a footnote), in which the authors express their indebtedness to the King's College team. See PP/CRI/H/1/11 (for first paper typescripts) and PP/CRI/H/1/42/4 (Maurice Wilkins to Crick [18 March 1953], headed “Suggested modification to your MSS”).
34 PP/CRI/E/1/9/5. Amongst the other delegates at Col de Voza were James Watson, Maurice Wilkins, Jacques Monod, Gunther Stent, Seymour Benzer, François Jacob, Arthur Kornberg, Erwin Chargaff, and Gobind Khorana. For Crick's “report”, see ‘Genetic studies concerning the lysozyme of phage T4’, Société de Chimie Physique, Deoxyribonucleic acid: structure, synthesis and function: proceedings of the 11th Annual Reunion of the Société de Chimie Physique, June 1961, Oxford, Pergamon Press, 1962, p. 188.
35 PP/CRI/E/1/10/4/2.
36 PP/CRI/H/3/9.
37 Judson, op. cit., note 3 above, p. 486.
38WMP, p. 75.
39 Watson gave the first George Gamow Memorial Lecture, on 17 April 1978, at the University of Colorado at Boulder, with the title ‘The RNA Tie Club’.
40 PP/CRI/D/2/45.
41 Cited in the bibliography to Robert Olby, The path to the double helix, London, Constable, 1994, p. 467.
42 For the period Feb. to June 1961, cited in Judson, op. cit., note 3 above, p. 457. See note p. 657: “notebook entries, 8 May 1961 and after—Laboratory notebooks, in Crick's hand, and in his files.”
43WMP, p. 66.
44 Crick's PhD thesis (Gonville and Caius College, University of Cambridge) was submitted in July 1953.
45 Wilkins, letter to Crick, 7 March 1953 (PP/CRI/H/1/42/4).
46 See Robert Olby, ‘Francis Crick, DNA and the central dogma’, Daedalus, 1970, 99 (4): 950.
47 In Watson's account of his and Crick's presentation of their incorrect model (to Maurice Wilkins, Rosalind Franklin, William Seeds and Ray Gosling), he notes: “Most annoyingly, [Franklin's] objects were not mere perversity: at this stage the embarrassing fact came out that my recollection of the water content of Rosy's DNA samples could not be right. The awkward truth became apparent that the correct DNA model must contain at least ten times more water than was found in our model … As soon as the possibility arose that much more water was involved, the number of potential DNA models alarmingly increased.” (The double helix, London, Weidenfeld & Nicolson, 1997, pp. 79–80.)
48 Robert Olby, ‘Quiet debut for the double helix’, Nature, 2003, 421: 402–5.
49WMP, p. 73.
50 Ibid.
51 F H Crick, ‘On protein synthesis’, in The biological replication of macromolecules, Symposia of the Society for Experimental Biology, vol. 12, Cambridge University Press, 1958, pp. 138–63. For an earlier typescript, see ‘Ideas on protein synthesis (Oct. 1956)’ (PP/CRI/H/2/6).
52 F H Crick, ‘Central dogma of molecular biology’, Nature, 1970, 227: 561–3.
53WMP, p. 168.
54 Ibid.
56 Temin to Crick, 27 July 1970, PP/CRI/D/1/1/19.
57 Steven Henikoff, ‘Beyond the central dogma’, Bioinformatics, 2002, 18 (2): 223–5.
58 “The phosphate-sugar backbone of our model is completely regular, but any sequence of the pairs of bases can fit into the structure. It follows that in a long molecule many different permutations are possible, and it therefore seems likely that the precise sequence of the bases is the code which carries the genetical information.” J D Watson and F H Crick, ‘Genetical implications of the structure of deoxyribonucleic acid’, Nature, 1953, 171: 964–7. See PP/CRI/H/1/12 for seven drafts of the paper.
59 Crick, op. cit., note 51 above, p. 153.
60 Sahotra Sarkar, ‘Biological information: a skeptical look at some central dogmas of molecular biology’, in Sahotra Sarkar (ed.), The philosophy and history of molecular biology: new perspectives, Dordrecht, Kluwer Academic Publishers, 1996, p. 187. See also Jesper Hoffmeyer, ‘The central dogma: a joke that became real’, Semiotica, 2002, 138: 1–13: “In the absence of any rigid definition of the term ‘information’ the instructional conception of this word imperceptibly slid into the matrix of tacit metaphors nourishing the minds of modern biologists” (p. 6).
61 Jon Beckwith, ‘The hegemony of the gene: reductionism in molecular biology’, in Sarkar (ed.), op. cit., note 60 above, p. 171.
62 Philip Ball, ‘Portait of a molecule’, Nature, 2003, 421: 421–2, on p. 421.
63 Gary Felsenfeld and Mark Groudine, ‘Controlling the double helix’, Nature, 2003, 421: 448–53, on p. 452.
64 Ball, op. cit., note 62 above, p. 421.
65 Crick, op. cit., note 52 above, p. 561: “The central dogma was put forward at a period when much of what we now know in molecular genetics was not established. All we had to work on were certain fragmentary experimental results, themselves often uncertain and confused, and a boundless optimism that the basic concepts involved were rather simple and probably much the same in all living things. In such a situation well constructed theories can play a really useful part in stating problems clearly and thus guiding experiment.”
66 Leroy Hood and David Galas, ‘The digital code of DNA’, Nature, 2003, 421: 444–8, on pp. 446, 448. See also, for an overview, Tom Sgouros Jr, ‘Figure and ground: translating the genome’, available at: <http://www.as220.org/~tomfool/meta/dnachap.html>
67 In 1977, Horace Judson proposed editing a selection of papers, including correspondence extracts, but Crick declined (PP/CRI/D/2/15).
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