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The structure of DNA

In the early 1950s, the identity of genetic material was still a matter of debate. The discovery of the helical structure of double-stranded DNA settled the matter — and changed biology forever.
Georgina Ferry is a science writer based in Oxford, UK. A revised edition of her biography Dorothy Crowfoot Hodgkin has just been published by Bloomsbury Reader.

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On 25 April 1953, James Watson and Francis Crick announced1 in Nature that they “wish to suggest” a structure for DNA. In an article of just over a page, with one diagram (Fig. 1), they transformed the future of biology and gave the world an icon — the double helix. Recognizing at once that their structure suggested a “possible copying mechanism for the genetic material”, they kick-started a process that, over the following decade, would lead to the cracking of the genetic code and, 50 years later, to the complete sequence of the human genome.

Figure 1 | The DNA double helix. This drawing appeared in Watson and Crick’s report1 of the structure of DNA, and was produced by Crick’s wife, Odile.

Until that time, biologists had still to be convinced that the genetic material was indeed DNA; proteins seemed a better bet. Yet the evidence for DNA was already available. In 1944, the Canadian–US medical researcher Oswald Avery and his colleagues had shown2 that the transfer of DNA from a virulent to a non-virulent strain of bacterium conferred virulence on the latter. And in 1952, the biologists Alfred Hershey and Martha Chase had published evidence3 that phage viruses infect bacteria by injecting viral DNA.

Watson, a 23-year-old US geneticist, arrived at the Cavendish Laboratory at the University of Cambridge, UK, in autumn 1951. He was convinced that the nature of the gene was the key problem in biology, and that the key to the gene was DNA. The Cavendish was a physics lab, but also housed the Medical Research Council’s Unit for Research on the Molecular Structure of Biological Systems, headed by chemist Max Perutz. Perutz’s group was using X-ray crystallography to unravel the structures of the proteins haemoglobin and myoglobin. His team included a 35-year-old graduate student who had given up physics and retrained in biology, and who was much happier working out the theoretical implications of other people’s results than doing experiments of his own: Francis Crick. In Crick, Watson found a ready ally in his DNA obsession.

However, DNA was the project of Maurice Wilkins at King’s College London. Crick was a friend of Wilkins’s, and it wasn’t the done thing for labs to compete over the same molecule. Moreover, the experienced X-ray crystallographer Rosalind Franklin had just taken over experimental work on DNA at King’s. Owing to a misunderstanding about their relative roles, Franklin’s relationship with Wilkins was frosty.

None of this stopped Watson and Crick from speculating about how the components of the DNA molecule — the four nucleotide bases adenine, guanine, thymine 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 co-workers had just demonstrated4 that peptide chains formed α-helices. Crick himself had co-authored a paper on the theory of diffraction of X-rays by helices5. In late 1951, he and Watson combined that theory with what they knew about the chemistry of DNA, and what they remembered of talks given by Wilkins and Franklin, to build a model of the DNA structure.

They got it badly wrong: Wilkins and Franklin quickly demolished it. The head of the Cavendish, Lawrence Bragg, was furious, and banned Watson and Crick from doing any further work on DNA. But then, in February 1952, the Cavendish team received a manuscript from Pauling that contained a DNA model. It was wrong, but Watson and Crick were alarmed that Pauling was potentially near a solution.

This time, Bragg agreed that they might try to get there first. Franklin was soon to move to Birkbeck College, London, and was leaving the DNA work to Wilkins. She and her graduate student, Raymond Gosling, had given Wilkins a photograph of the X-ray-diffraction pattern produced by the B form of DNA. Watson went to see Wilkins, who showed him the photograph, without Franklin and Gosling’s knowledge.

The now famous ‘Photograph 51’, together with other unpublished data of Franklin’s that Perutz had shown Watson and Crick, told the pair that DNA did indeed form a helix, and that the structure consisted of two chains running in opposite directions. Watson was stumped, however, over how the bases could pair up between the two. He made cardboard cutouts of the bases, trying to fit them together, but nothing seemed to work.

Nature PastCast: The other DNA papers

His colleague Jerry Donohue then pointed out that he was using the molecular structures of the enol isomers of the bases, which cannot form the hydrogen bonds necessary for base-pairing. Once Watson had made cutouts of the alternative keto isomers, he had the blinding revelation that when guanine bonded to cytosine, it made an identical shape to that of adenine bonded to thymine, and that the shapes fitted perfectly into the helical frame provided by the backbones of each DNA chain. This explained biochemist Erwin Chargaff’s discovery that the DNA of any species has the same amount of guanine as of cytosine, and of adenine as of thymine6. It also showed that each DNA chain in a helix provides a perfect template for the other, reading the base sequence in opposite directions.

Within days, Watson and Crick had built a new model of DNA from metal parts. Wilkins immediately accepted that it was correct. It was agreed between the two groups that they would publish three papers simultaneously in Nature, with the King’s researchers commenting on the fit of Watson and Crick’s structure to the experimental data, and Franklin and Gosling publishing Photograph 51 for the first time7,8.

The Cambridge pair acknowledged in their paper that they knew of “the general nature of the unpublished experimental results and ideas” of the King’s workers, but it wasn’t until The Double Helix, Watson’s explosive account of the discovery, was published in 1968 that it became clear how they obtained access to those results. Franklin had died of cancer a decade previously; her death prevented her from sharing the Nobel prize awarded to Watson, Crick and Wilkins in 1962.

The immediate reception of the double-helix model was surprisingly muted9, perhaps because there was no obvious mechanism to explain its role in protein synthesis. In a landmark talk in 1957, Crick proposed that the base sequence encoded the sequence of amino acids in a protein, and that protein production involved RNA both as a template and as an ‘adaptor’ that would enable amino acids to be attached to one another in the right order. He also supported the suggestion — originally made informally by the physicist George Gamow to the members of the ‘RNA Tie Club’ convened by Gamow and Watson, but also independently proposed by biologist Sydney Brenner10 — that triplets of bases (which Brenner called codons) encode the 20 amino acids commonly found in proteins. Finally, Crick expounded what he called the ‘central dogma’ of biology: that information can flow from nucleic acids to proteins, but not the other way round11.

These predictions were confirmed by experiment in the next few years. In 1958, the biochemists Matthew Meselson and Franklin Stahl showed that one DNA strand acts as a template for the formation of a new strand12. The same year, Arthur Kornberg and his colleagues published their discovery of the enzyme DNA polymerase13, which adds bases to newly forming strands. Messenger RNA, transfer RNA and ribosomal RNA were all quickly identified.

In 1961, Marshall Nirenberg and Heinrich Matthaei were the first to crack part of the genetic code, demonstrating that bacterial extracts synthesize only the amino acid phenylalanine from RNA that contains just one type of RNA base14 (uracil; U). The same year, Crick, his indispensable female technician Leslie Barnett and their co-workers reported mutation studies that confirmed the existence of the triplet-based code15, and which therefore suggested that the codon for phenylalanine was UUU. The race to identify the full set of codons was completed by 1966, with Har Gobind Khorana contributing the sequences of bases in several codons from his experiments with synthetic polynucleotides (see go.nature.com/2hebk3k).

With Fred Sanger and colleagues’ publication16 of an efficient method for sequencing DNA in 1977, the way was open for the complete reading of the genetic information in any species. The task was completed for the human genome by 2003, another milestone in the history of DNA.

Watson devoted most of the rest of his career to education and scientific administration as head of the Cold Spring Harbor Laboratory in Long Island, New York, and serving (briefly) as the first head of the US National Center for Human Genome Research, now the National Human Genome Research Institute. Always outspoken, he was eventually removed from his emeritus position at Cold Spring Harbor when he repeatedly aired controversial opinions about genetics, race and intelligence.

Crick continued to tackle hard problems in science, moving in 1977 from Cambridge to the Salk Institute in La Jolla, California, where he spent the rest of his life working on the neural basis of consciousness17 and, specifically, of visual perception. He died in 2004, aged 88.

The double helix put genetics on a physical footing that would shed light on almost every aspect of modern biology and medicine. Examples include the migration of human populations throughout history; ecology and biodiversity; cancer-causing mutations in tumours and their drug treatment; surveillance of microbial drug resistance in hospitals and the global population; and the diagnosis and treatment of rare congenital diseases. DNA analysis has long been established in forensics, and research into more-futuristic applications, such as DNA-based computing, is well advanced.

Paradoxically, Watson and Crick’s iconic structure has also made it possible to recognize the shortcomings of the central dogma, with the discovery of small RNAs that can regulate gene expression, and of environmental factors that induce heritable epigenetic change. No doubt, the concept of the double helix will continue to underpin discoveries in biology for decades to come.

Nature 575, 35-36 (2019)

doi: 10.1038/d41586-019-02554-z

References

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    Watson, J. D. & Crick, F. H. C. Nature 171, 737–738 (1953).

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    Avery, O. T., MacLeod, C. M. & McCarty, M. J. Exp. Med. 79, 137–158 (1944).

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    Hershey, A. D. & Chase, M. J. Gen. Physiol. 36, 39–56 (1952).

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    Pauling, L., Corey, R. B. & Branson, H. R. Proc. Natl Acad. Sci. USA 37, 205–211 (1951).

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    Cochran, W., Crick, F. H. & Vand, V. Acta Crystallogr. 5, 581–586 (1952).

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    Vischer, E. & Chargaff, E. J. Biol. Chem. 176, 703–714 (1948).

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    Wilkins, M. H. F., Stokes, A. R. & Wilson, H. R. Nature 171, 738–740 (1953).

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    Franklin, R. E. & Gosling, R. G. Nature 171, 740–741 (1953).

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    Olby, R. Nature 421, 402–405 (2003).

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    Brenner, S. Proc. Natl Acad. Sci. USA 43, 687–694 (1957).

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    Crick, F. H. C. Symp. Soc. Exp. Biol. 12, 138–163 (1958).

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    Meselson, M. & Stahl, F. W. Proc. Natl Acad. Sci. USA 44, 671–682 (1958).

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    Lehman, I. R., Bessman, M. J., Simms, E. S. & Kornberg, A. J. Biol. Chem. 233, 163–170 (1958).

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    Nirenberg, M. W. & Matthaei, J. H. Proc. Natl Acad. Sci. USA 47, 1588–1602 (1961).

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    Crick, F. H. C., Barnett, L., Brenner, S. & Watts-Tobin, R. J. Nature 192, 1227–1232 (1961).

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    Sanger, F., Nicklen, S. & Coulson, A. R. Proc. Natl Acad. Sci. USA 74, 5463–5467 (1977).

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    Crick, F. H. C. The Astonishing Hypothesis: The Scientific Search for the Soul (Simon & Schuster, 1994).

Download references

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Transcript

Nature PastCast: The other DNA papers

Host: Kerri Smith

This is the Nature PastCast, each month raiding Nature’s archive and looking at key moments in science. In this show, we’re going back to the 1950s.

Music: I’ve Got the World on a String by Ella Fitzgerald

Voice of Nature: John Howe

From the Editorial and Publishing Offices of Nature, Macmillan and Co., St Martin’s Street, London. Nature, April 25th 1953.

Music: I’ve Got the World on a String by Ella Fitzgerald

Voice of Nature: John Howe

Page 734, Microsomal particles of normal cow’s milk. Page 737, Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid, J. D. Watson and F. H. C. Crick.

Music: I’ve Got the World on a String by Ella Fitzgerald

Raymond Gosling

Walking into the lab and seeing this double helix, of course, it looked familiar because all of the stator of the dimensions was the stuff that we got from our X-ray diffraction patterns. So, it looked right and it was sheer elegance.

Music: I’ve Got the World on a String by Ella Fitzgerald

Raymond Gosling

I’m Raymond Gosling, co-author of one of the papers in Nature, 1953, April, on the structure of DNA.

Music: I’ve Got the World on a String by Ella Fitzgerald

Melinda Baldwin

My name is Melinda Baldwin. I’m a historian of science at the American Academy of Arts and Sciences in Cambridge, Massachusetts. I think a lot of people don’t necessarily know that there were three DNA papers instead of just the one, and I think the big reason that the Watson and Crick paper became the one that we do remember is because that’s the one where the structure of DNA was published, and I think as a consequence the second two papers have really fallen out a bit of consciousness. The Franklin and Gosling paper was primarily about crystallographic work.

Voice of Nature: John Howe

Page 740, Rosalind E. Franklin and R. G. Gosling, King’s College London, Molecular Configuration in Sodium Thymonucleate.

Georgina Ferry

I’m Georgina Ferry. I’m a science writer and author. At the time, X-ray crystallography of large molecules – the sort of molecules that you get in living bodies – was still a very, very small field. It had really started in the 1930s. Everybody was interested in the structure of proteins back in the 30s because nobody thought that DNA could possibly be complicated enough to be the molecule of life. That wasn’t really discovered until the mid-40s and then, obviously, it became very important to study its structure.

Raymond Gosling

The only time I could get at the X-ray set in King’s, the only one that existed, was in the basement of the chemistry department, and that was below the level of the Thames and I was only allowed to play with it in the evenings.

Georgina Ferry

What you need is an X-ray source, which in those days would have been an X-ray tube. I mean it was a form of technology that was available from the 19th century but it’s a tube full of gas that you run an electric current through and it emits X-rays, and then in order to study your molecule, the thing you’re interested in, you have to crystallise it. You surround that, in the early days, with photographic film so that when the X-rays come in, they hit the atoms in the crystal and they’re diffracted out and they make spots on the photographic film.

Raymond Gosling

I needed lots of fibres. One would produce the diffraction pattern so weak that you’d never see it, so I wound 35 fibres round a paperclip and then pushed the clip open a bit to make the fibres taught.

Voice of Nature: John Howe

Sodium thymonucleate fibres give two distinct types of X-ray diagram. The first corresponds to a crystalline form, structure A. At higher humidities, a different structure, structure B, appears.

Raymond Gosling

And the best structure B pattern we ever got is photo 51, which I took and was called 51 because that was the 51st photograph that we’d taken, Rosalind and I, in our efforts to sort out this A and B difference.

Melinda Baldwin

It’s a really beautiful photo. It’s very crisp, it’s very clean, it’s got this really neat ‘X’ shape, and apparently if you know something about crystallography, this photo just screams helix.

Georgina Ferry

What is puzzling, I think is still puzzling, is why they didn’t pursue that photograph once they had it.

Raymond Gosling

Now, Rosalind was absolutely determined that there was so much information in structure A’s diffraction pattern that was what she wanted to do and therefore put this photo 51 on one side and said we’ll come back to that. I only wish I’d been able to plug the value of looking at structure B as well as Structure A.

Ella Fitzgerald – I’ve Got the World on a String

Melinda Baldwin

So, Rosalind Franklin was working with Maurice Wilkins but the two of them had a pretty bad working relationship. Apparently, Franklin thought that she was being brought to King’s College London as an independent investigator who would be in charge of her own research. Wilkins thought that she was being brought in as an assistant, and eventually the relationship grew so fraught that Franklin stopped showing him her data, and she was planning on moving to Birkbeck College. Somehow, Wilkins got a copy of photo 51.

Raymond Gosling

I took it down the corridor and gave it to him because it had reached the stage now when Rosalind was going to leave, so she suggested that I go down the corridor and give this beautiful structure B pattern, this photo 51, to Maurice. Maurice couldn’t believe it when I offered it to him. He couldn’t believe that I hadn’t stolen it from her desk. He didn’t think that she could ever offer him something as interesting as this. He’d only had it for two or three days when Watson chipped up.

Melinda Baldwin

He showed it to James Watson when James came down to visit him and to chat a little bit about DNA.

Raymond Gosling

Who of course knew what a helical diffraction pattern would look like because Crick had two years previously published a theoretical paper of what the diffraction pattern of a helix would look like.

Melinda Baldwin

Watson’s got this great passage in The Double Helix where he said my pulse sped up and my heart began to race because he looked at this photo and realised immediately that DNA was helical and that he knew what size the turns had to be. So, this photo contained all of the information that he needed to build the model that he and Crick ended up being famous for.

Ella Fitzgerald – I’ve Got the World on a String

Voice of Nature: John Howe

We wish to suggest a structure for the salt of deoxyribose nucleic acid (D. N. A). This structure has two helical chains, each coiled round the same axis.

Georgina Ferry

So, it was pretty out of order for Watson and Crick to start working on DNA because they knew full well that Maurice Wilkins was working on it at King’s and subsequently Rosalind Franklin joined him there and she was also working on it. But it was King’s’ problem, and there was very much a sort of unspoken gentleman’s agreement – it would be understood that a particular group or lab was working on one problem and you wouldn’t then go and do that one.

Raymond Gosling

You didn’t go to work on another man’s problem, especially if he’d got a whole team working on it.

Melinda Baldwin

In the Watson and Crick paper, it’s not credited. Watson and Crick say they were stimulated by a general knowledge of the unpublished results of Wilkins and Franklin.

Voice of Nature: John Howe

We have been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr Wilkins, Dr Franklin and…

Melinda Baldwin

But they don’t cite photo 51 specifically and then Franklin and Gosling, in their paper, say this photo clearly supports the model that Watson and Crick had put forth.

Raymond Gosling

Rosalind’s reaction was, I think, typical of Rosalind. She wasn’t furious or didn’t use the word ‘scooped’. What she actually said was we all stand on each other’s shoulders. We had this second-, third-prize feeling that we were within a millimetre or two of the right answer ourselves.

Melinda Baldwin

So, Watson and Crick had their paper ready to go. They had the structure solved. They wanted to publish it in Nature. Apparently, John Randall, the uber-head of the Kings College London Laboratory, was a member of The Athenaeum, the British social club in London, and so was L. J. F. Brimble, then one of the co-editors of Nature. So, apparently, Brimble approached Randall to say well, we’ve got this paper under consideration, don’t you want the King’s work represented as well? And I think Watson and Crick and Wilkins had already agreed that they would publish two papers side-by-side. Wilkins sort of knew that his work was going to be outshone by Watson and Crick, but he certainly wanted it published. And then apparently after the two of them had agreed to publish the two papers together, Rosalind Franklin said, well, I want a paper on the crystallographic work that Ray Gosling and I did in there as well, and so it was really by conversation by the editors and the heads of the laboratories that the editors agreed to print these paper as quickly as possible. So, famously, the three DNA papers were not peer-reviewed. I think that was quite typically for the Brimble-and-Gale editorship, that they placed a lot of trust in particular laboratory heads and particular friends in the British scientific community and so if Laurence Bragg said that something was good and important, they were going to print it.

Georgina Ferry

There wasn’t a huge fuss made, even within science, about the DNA structure until probably the early 60s when the code began to be cracked because obviously – as Watson and Crick famously said –

Voice of Nature: John Howe

It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.

Georgina Ferry

But the actual code wasn’t cracked until the early 60s, and that was when the power of this discovery really started to make a big difference.

Music: I’ve Got the World on a String by Ella Fitzgerald

Voice of Nature: John Howe

Elsewhere in Nature, Page 757, Appointments vacant. Physicists wanted for fundamental research on felt and applied research of the felt-making industry, The British Hat and Allied Felt-makers Research Association, Manchester.

Music: I’ve Got the World on a String by Ella Fitzgerald

Voice of Nature: John Howe

Page 716, Department of Scientific and Industrial Research UK, The gross expenditure of the department was £5.5 million as against £5 million in the previous year.

Georgina Ferry

The climbing of Mount Everest and the coronation of the Queen and all these things came together so that ’53 in that lab was seen as an almost miraculous time.

Raymond Gosling

Everywhere you looked you could see that it fitted a double helix. It was uncanny. It just screamed at you. I’ve often asked how long would it have been before we as a group saw that and I really don’t know the answer to that. It was a stroke of genius on his part.

Music: I’ve Got the World on a String by Ella Fitzgerald

Voice of Nature: John Howe

Nature. Annual subscription £6. Payable in advance. Postage paid to any part of the world.

Kerri Smith

The Nature PastCast was produced by me, Kerri Smith, with contributions from Raymond Gosling, writer Georgina Ferry and historian Melinda Baldwin. In episode two of this twelve-part series on the history of science, we’re heading back to the 1980s.