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10 Extraordinary Papers Highlights from 150 years of Nature 10 extraordinary papers nucleotide bases adenine, guanine, thymine Genetics and cytosine, connected to a backbone of sugars and phosphates — might assemble into fibres. They thought that a helix was a likely option: the US chemist Linus Pauling and his The structure of DNA co-workers had just demonstrated4 that pep- tide chains formed α-helices. Crick himself had Georgina Ferry co-authored a paper on the theory of diffrac- tion of X-rays by helices5. In late 1951, he and In the early 1950s, the identity of genetic material was still Watson combined that theory with what they a matter of debate. The discovery of the helical structure knew about the chemistry of DNA, and what of double-stranded DNA settled the matter — and changed they remembered of talks given by Wilkins and biology forever. Franklin, to build a model of the DNA structure. They got it badly wrong: Wilkins and Franklin quickly demolished it. The head of the Caven- dish, Lawrence Bragg, was furious, and banned On 25 April 1953, James Watson and Francis Watson and Crick from doing any further work Crick announced1 in Nature that they “wish to on DNA. But then, in February 1952, the Caven- suggest” a structure for DNA. In an article of dish team received a manuscript from Pauling just over a page, with one diagram (Fig. 1), they that contained a DNA model. It was wrong, but transformed the future of biology and gave Watson and Crick were alarmed that Pauling the world an icon — the double helix. Recog- was potentially near a solution. nizing at once that their structure suggested a This time, Bragg agreed that they might try “possible copying mechanism for the genetic to get there first. Franklin was soon to move material”, they kick-started a process that, over to Birkbeck College, London, and was leaving the following decade, would lead to the crack- the DNA work to Wilkins. She and her graduate ing of the genetic code and, 50 years later, to student, Raymond Gosling, had given Wilkins the complete sequence of the human genome. a photograph of the X-ray-diffraction pattern Until that time, biologists had still to be produced by the B form of DNA. Watson went to convinced that the genetic material was see Wilkins, who showed him the photograph, indeed DNA; proteins seemed a better bet. Yet without Franklin and Gosling’s knowledge. the evidence for DNA was already available. In The now famous ‘Photograph 51’, together 1944, the Canadian–US medical researcher with other unpublished data of Franklin’s that Oswald Avery and his colleagues had shown2 Perutz had shown Watson and Crick, told the that the transfer of DNA from a virulent to a pair that DNA did indeed form a helix, and that non-virulent strain of bacterium conferred the structure consisted of two chains running virulence on the latter. And in 1952, the biol- in opposite directions. Watson was stumped, ogists Alfred Hershey and Martha Chase had however, over how the bases could pair up published evidence3 that phage viruses infect between the two. He made cardboard cutouts bacteria by injecting viral DNA. of the bases, trying to fit them together, but Watson, a 23-year-old US geneticist, arrived nothing seemed to work. at the Cavendish Laboratory at the University His colleague Jerry Donohue then pointed of Cambridge, UK, in autumn 1951. He was Figure 1 | The DNA double helix. This drawing out that he was using the molecular struc- 1 convinced that the nature of the gene was appeared in Watson and Crick’s report of tures of the enol isomers of the bases, which the key problem in biology, and that the key the structure of DNA, and was produced by cannot form the hydrogen bonds necessary to the gene was DNA. The Cavendish was a phys- Crick’s wife, Odile. for base-pairing. Once Watson had made cut- ics lab, but also housed the Medical Research outs of the alternative keto isomers, he had the Council’s Unit for Research on the Molecular However, DNA was the project of Maurice blinding revelation that when guanine bonded Structure of Biological Systems, headed by Wilkins at King’s College London. Crick was a to cytosine, it made an identical shape to that chemist Max Perutz. Perutz’s group was using friend of Wilkins’s, and it wasn’t the done thing of adenine bonded to thymine, and that the X-ray crystallography to unravel the structures for labs to compete over the same molecule. shapes fitted perfectly into the helical frame of the proteins haemoglobin and myoglobin. Moreover, the experienced X-ray crystallo- provided by the backbones of each DNA chain. His team included a 35-year-old graduate stu- grapher Rosalind Franklin had just taken over This explained biochemist Erwin Chargaff’s dent who had given up physics and retrained experimental work on DNA at King’s. Owing to discovery that the DNA of any species has in biology, and who was much happier working a misunderstanding about their relative roles, the same amount of guanine as of cytosine, out the theoretical implications of other peo- Franklin’s relationship with Wilkins was frosty. and of adenine as of thymine6. It also showed ple’s results than doing experiments of his own: None of this stopped Watson and Crick that each DNA chain in a helix provides a per- Francis Crick. In Crick, Watson found a ready from speculating about how the com- fect template for the other, reading the base ally in his DNA obsession. ponents of the DNA molecule — the four sequence in opposite directions. Nature | Vol 575 | 7 November 2019 | 35 ©2019 Spri nger Nature Li mited. All ri ghts reserved. 10 extraordinary papers Within days, Watson and Crick had built a identify the full set of codons was completed in forensics, and research into more-futuristic new model of DNA from metal parts. Wilkins by 1966, with Har Gobind Khorana contributing applications, such as DNA-based computing, immediately accepted that it was correct. It the sequences of bases in several codons from is well advanced. was agreed between the two groups that they his experiments with synthetic polynucleotides Paradoxically, Watson and Crick’s iconic would publish three papers simultaneously in (see go.nature.com/2hebk3k). structure has also made it possible to recog- Nature, with the King’s researchers comment- With Fred Sanger and colleagues’ publica- nize the shortcomings of the central dogma, ing on the fit of Watson and Crick’s structure tion16 of an efficient method for sequencing with the discovery of small RNAs that can reg- to the experimental data, and Franklin and DNA in 1977, the way was open for the com- ulate gene expression, and of environmental Gosling publishing Photograph 51 for the plete reading of the genetic information in factors that induce heritable epigenetic first time7,8. any species. The task was completed for the change. No doubt, the concept of the double The Cambridge pair acknowledged in their human genome by 2003, another milestone helix will continue to underpin discoveries in paper that they knew of “the general nature in the history of DNA. biology for decades to come. of the unpublished experimental results and Watson devoted most of the rest of his ideas” of the King’s workers, but it wasn’t until career to education and scientific administra- Georgina Ferry is a science writer based in The Double Helix, Watson’s explosive account tion as head of the Cold Spring Harbor Labo- Oxford, UK. A revised edition of her biography of the discovery, was published in 1968 that ratory in Long Island, New York, and serving Dorothy Crowfoot Hodgkin has just been it became clear how they obtained access to (briefly) as the first head of the US National published by Bloomsbury Reader. those results. Franklin had died of cancer a Center for Human Genome Research, now the 1. Watson, J. D. & Crick, F. H. C. Nature 171, 737–738 (1953). decade previously; her death prevented her National Human Genome Research Institute. 2. Avery, O. T., MacLeod, C. M. & McCarty, M. J. Exp. Med. 79, from sharing the Nobel prize awarded to Always outspoken, he was eventually removed 137–158 (1944). Watson, Crick and Wilkins in 1962. from his emeritus position at Cold Spring Har- 3. Hershey, A. D. & Chase, M. J. Gen. Physiol. 36, 39–56 The immediate reception of the double-he- bor when he repeatedly aired controversial (1952). 4. Pauling, L., Corey, R. B. & Branson, H. R. Proc. Natl Acad. 9 lix model was surprisingly muted ,perhaps opinions about genetics, race and intelligence. Sci. USA 37, 205–211 (1951). because there was no obvious mechanism Crick continued to tackle hard problems in 5. Cochran, W., Crick, F. H. & Vand, V. Acta Crystallogr. 5, to explain its role in protein synthesis. In a science, moving in 1977 from Cambridge to the 581–586 (1952). 6. Vischer, E. & Chargaff, E. J. Biol. Chem. 176, 703–714 landmark talk in 1957, Crick proposed that Salk Institute in La Jolla, California, where he (1948). the base sequence encoded the sequence spent the rest of his life working on the neural 7. Wilkins, M. H. F., Stokes, A. R. & Wilson, H. R. Nature 171, of amino acids in a protein, and that protein basis of consciousness17 and, specifically, of 738–740 (1953). 8. Franklin, R. E. & Gosling, R. G. Nature 171, 740–741 (1953). production involved RNA both as a template visual perception. He died in 2004, aged 88.
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