60 years of DNA

Sixty years ago this weekend the race to pin down the structure of DNA, the molecule of inheritance, was at a critical stage. In Cambridge Francis Crick and Jim Watson were realising how well a double helix would fit the available data. Meanwhile at King’s College London the dysfunctional team of Maurice Wilkins and Rosalind Franklin, who had provided Crick and Watson with their most important evidence, were still unaware of the breakthrough in Cambridge.

At this point Wilkins sent Crick a letter looking forward to the imminent departure of “our dark lady” – Franklin – to a new job at Birkbeck College. This would leave him free to take part in a final push to discover how genes are encoded. “I have started up a general offensive on nature’s secret strongholds on all fronts,” he wrote. “At last the decks are clear and we can put all hands to the pumps! It won’t be long now.”

Crick and Watson then broke the news to Wilkins that they had beaten him to it and sent him the manuscript of the paper they planned to submit to Nature, revealing the secret of inheritance as a double helix – two intertwined molecular spirals. In response Wilkins wrote back: “I think you’re a couple of old rogues but you may well have something … I was a bit peeved but … there is no good grousing. I think it’s a very exciting notion and who the hell got it isn’t what matters.”

By 1953 scientists knew that deoxyribonucleic acid or DNA was the chemical that stores genetic information in the cellular nucleus and passes it on from cell to cell and from generation to generation. The race, involving research groups on both sides of the Atlantic, was to come up with a DNA structure that was consistent with the scientific evidence and allowed the molecule to replicate itself reliably.

In the end the key evidence for DNA came from X-ray crystallography, which deduces molecular structures from the way their atoms diffract X-rays. However the link between diffraction pattern and structure is not obvious; working it out requires mathematics and imagination. Crick and Watson, whose forte was thinking and building models, took X-ray data generated by the more experimentally minded Wilkins and Franklin – and came up with the double helix.

The molecule has two spiral strands with backbones made of alternating sugar and phosphate groups. Attached to each sugar is one of four chemical bases – adenine (A), cytosine (C), guanine (G), or thymine (T) – which form the “letters” of the genetic code. The strands are held together by weaker chemical bonds between the bases, like the rungs of a spiral ladder, A always linking with T and C with G. This enables the strands to separate and faithfully replicate new partners when cells divide.

The exchange of letters between Crick and Wilkins, laden with evocative 1950s phraseology, together with a huge volume of other material about modern genetics, will be available to anyone with an internet connection from next week when London’s Wellcome Library puts online the biggest scientific archive to be digitised so far.

The £4m project, “Codebreakers: Makers of Modern Genetics”, includes correspondence, notebooks, illustrations, ephemera and published material, beginning with the tentative exploration of the mechanisms of inheritance in the early-20th century, moving through the discovery of the DNA double helix and finishing with the decoding of the human genome at the end of the century.

“Codebreakers” is just the first step in a programme by the library, one of the world’s great stores of medical and scientific material, to digitise its entire holdings. “In the past libraries have been protective of their content,” says Simon Chaplin, Wellcome librarian. “Now we want to push out our material as much as possible.”

“We are fortunate to have the resources to do it,” he adds. The library comes under the wing of the Wellcome Trust, the wealthiest charity in the UK, with a £14.5bn investment portfolio.

The programme involves not only digitising all its material, with a target of 30 million images to be captured within 10 years, but also offering everyone an easy way to search the archive for interesting documents and then display them. So Wellcome – again deploying its financial muscle – developed a special player for the purpose, which will work on any computer or mobile device.

One of the project’s many achievements is to highlight the role played by women in genetic research. Perhaps the most remarkable of these unsung heroines was Honor Fell (1900-1986) who ran Strangeways Research Laboratory, Cambridge, from 1927 to 1970. She incidentally provided Francis Crick, who had trained in physics, with his first biological research project, working with geneticists at Strangeways on cell structures from 1947 to 1949.

“Fell pioneered the study of living cells under the microscope,” says Julia Nurse, the library’s content officer. “She had a beautiful way of putting things, and her drawings of cells [see illustrations] show that she was an incredible draughtswoman.” Fell is noted too for developing methods of tissue culture – growing cells outside the body in glass dishes where, as she herself put it in a 1936 lecture, “they can be watched and photographed whilst going about their ordinary business.”

Her lecture notes in the Wellcome archive contain some memorable language. For example: “The more closely we examine a natural object, the more beautiful, exciting and mysterious it becomes… A single living cell is much more beautiful and improbable than the solar system. So far scientists have not explained away the wonder of the cell nor stripped it of its mystery. On the contrary, in the words of Alice in Wonderland, the cell gets ‘curiouser and curiouser’ the more we learn about it.”

There is also a delightful response from Frederick Hutt, a Canadian geneticist, to a lecture by Fell on “fashion in cell biology”. “Well do I like thee Dr Fell / The reason why I fain would tell / Since fads in cells thou dost dispel / Well do I like thee Dr Fell.”

Even less known is her friend Rhoda Erdmann (1870-1935), a German scientist described by Fell as “one of the most distinguished figures in cell biology during the twenties and early thirties.” Erdmann worked at Yale University between 1913 and 1918, when she lost her job because of anti-German sentiment at the end of the first world war and returned to her native country. Like Fell, she was a tissue culture pioneer, focusing particularly on growing tumours to study in the lab.

Erdmann ran the Institute for Experimental Cell Research at Berlin’s Charité teaching hospital until 1934 when she was dismissed under Nazi pressure, as a non-Jew who spoke up for her persecuted Jewish colleagues. Erdmann was very outspoken – “I cannot put coats on my words,” she told Fell.

But, of course, far more men than women feature in “Codebreakers”. Perhaps the most distinguished, at least in looks and voice, is Sir Peter Medawar (1915-1987), the immunologist and philosopher of science. As Jim Watson put it, “Medawar has a physical appearance and manner which are almost uncannily suited to a man of distinction. He is very tall and thin, with a striking, dark aquiline face [he was half-Lebanese], and he moves easily and confidently through a world which has always treated him with the greatest consideration.”

Medawar won the Nobel medicine prize in 1960 for work on suppressing immune rejection in tissue and organ transplants. The Wellcome archive has a lot of Medawar material – much from the last 18 years of his life, as he kept working through a series of increasingly debilitating strokes. For example, in 1981 he explained how he coped with his strokes to a conference on managing disability. His notes for the talk read poignantly: “Special disabil for opera goer must end sadly, boheme, traviata, both built in remedies Boheme send for medicine, Traviata send for doctor.” Medawar doggedly kept going, though a note to himself reads: “Since your stroke what do you find you most lack? Confidence.”

Considering the variety in size and shape of the papers in the archive – some stuck together with corroded clips and staples – digitisation proceeds surprisingly fast. “I’ve done a little over 300 pages in just over three hours today,” says Thomas Cox when I pay a late morning visit to the library’s digitising studio. “Yesterday I did some 700 pages.”

Cox lays each sheet of paper on a self-levelling pneumatic cradle, covered with black flocking material, which is then pushed gently up against a glass plate. Images are captured using a Canon 5D MkIII digital camera with a 100mm macro lens, varying the height between 20cm to a maximum height 150cm above the glass, and connected to an Apple computer. “We’re picking up momentum,” Chaplin says. “We’ll have done 1.5m images by the end of this [Codebreakers] project and 4m in all.”

Similar digitising exercises are getting under way at other libraries with substantial genetics archives, including Cold Spring Harbor in New York (Jim Watson); the Churchill Archives Centre in Cambridge (Rosalind Franklin); King’s College London (Maurice Wilkins); and University College London (J.B.S. Haldane).

Besides the technical challenges, Wellcome faces legal, moral and ethical issues that libraries digitising ancient books and manuscripts do not have. “No one else has attempted to put online a major archive of the 20th century,” Chaplin says. “We’ve had to work with all the challenges of dealing with the work of people who are still alive or whose children or grandchildren are alive.”

Only a tiny proportion of the archive is so sensitive, for medical and other personal reasons, that it is not available at all. “For a lot more material we ask users to accept certain terms and conditions,” Chaplin continues. “We’ve instituted a log-in system so that we know people have accepted them. We think this is a brave attempt to get round the barriers.”

Copyright is another obstacle. In theory all unpublished material is in copyright until 2039. Wellcome has obtained permission from all the families that contributed material to the archive but “going through the archive to trace all individual copyright holders would be impossible,” Chaplin admits. “We are testing the waters here.”

In addition to all the unpublished material, the library is digitising 1,800 books published about genetics that are still in copyright but out of print, using licensing societies to track down as many copyright owners as possible. Most have agreed readily to their books becoming available online.

A modern archive is not a static collection. As digitising proceeds, Wellcome is constantly adding new material, contacting scientists involved in the human genome project over the past 25 years or so and asking them not to chuck out interesting papers. It is becoming more proactive in obtaining material, rather than just sitting back and waiting for scientists and their families to donate archives.

Of course exchanges of handwritten or typed letters such as those between Crick and Wilkins are exceptional today, having been replaced by email. Last year the library accepted its first email archive but Chaplin confesses that he and his staff have not yet worked out how best to preserve and display email correspondence. It also remains to be seen how people, whether interested members of the public or professional researchers, will use the new online resources. The demand is likely to be substantial – the library already receives 40,000 visitors a year at its building on Euston Road, while the Wellcome Collection, the biomedical museum next door, gets 500,000. “I hope that in 50 or 100 years time people will still be looking online at what we’re digitising now,” says Chaplin, “but I’m sure there will be ways of searching the archive that we can’t imagine today.”

For professional researchers, however, who would otherwise be digging around the physical papers in the search for undiscovered historical gems, digitisation and online access may not be an unalloyed blessing. “As a scholar I have an ambivalent attitude,” admits Christine Aicardi, a postdoctoral researcher at UCL working on the scientific life of Francis Crick. “Of course it is going to make my work easier but the feeling that I’ll be the first to get my hands on a particular letter or document will disappear.”

Meanwhile for people who want to savour the atmosphere of the race to the double helix 60 years on, beyond reading the online archive, staff at the Wellcome Library recommend getting hold of the BBC’s excellent 1987 docudrama, Life Story. The recommendation is endorsed by Jim Watson, now working on cancer genetics at Cold Spring Harbor. Initially somewhat hostile to the film, Watson has come round to it – even Jeff Goldblum’s rather manic portrayal of himself. “It really gives a remarkably good impression of what happened,” he says.”

Clive Cookson is the FT’s science editor

‘Codebreakers: Makers of Modern Genetics’ is at wellcomelibrary.org/codebreakers.

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