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Double (Helix) Trouble

Double (Helix) Trouble

Photo 51: Raymond Gosling/King’s College London  via Wikipedia

Photo 51: Raymond Gosling/King’s College London via Wikipedia

There’s a story I once heard and it goes something like this. Someone’s giving a lecture, and asks the audience “What did Watson and Crick discover?” A voice pipes up from the back “Rosalind Franklin’s notes!”

1953 was a historic year. Not only was Queen Elizabeth II crowned in Westminster Abbey in London, but one of the most famous discoveries in science was published in the journal Nature (albeit with a bit less fanfare).

The paper is less than a thousand words long, and begins with the immortal lines, “We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.” It was, of course, the first description of the double helical structure of DNA by American James Watson and Briton Francis Crick - one of the best-known double-acts in scientific history, who were based at the Cavendish Laboratory in Cambridge at the time.

The discovery earned the pair the 1962 Nobel prize in Physiology or Medicine, together with Maurice Wilkins from King’s College London. Watson and Crick did deserve their Nobel for their intellectual work in figuring out that DNA must be a twisted two-stranded ladder, rather than the other models that were being bandied about at the time, such as Linus Pauling’s peculiar triple-stranded helix.

But while they spent plenty of time playing around with cardboard models (not to mention chatting over beers in the Eagle pub) they never did any experimental work to prove that their structure was correct. All of that came from Wilkins’ lab at King’s, particularly one famous image, Photo 51, taken by Rosalind Franklin and her PhD student Ray Gosling, which provided the crucial evidence suggesting that DNA was indeed a double helix.

After World War II a new spirit of scientific discovery was in the air. Freed from their war efforts, chemists, physicists and biologists were all working together in the relatively new discipline of molecular biology, combining forces to develop the tools and techniques that would finally allow them to uncover the inner workings of life itself.

One of these was X-ray crystallography – effectively a method for taking images of the patterns created by X-rays as they scatter though the structures of crystallised biological molecules like proteins and DNA.  And John Randall’s Medical Research Council-funded Biophysics Unit at King’s College London was the place to be doing it.

Despite struggling with limited lab space – the physics buildings at King’s having mostly been destroyed in the war – Randall built up an impressive team. Wilkins recalls hilarious if slightly bawdy Christmas parties. Others in the university described the unit as “Randall’s Circus”, with Ray Gosling recalling, “Now, that's what attracted me in the first place! I heard about this strange bald-headed little man with a Napoleon complex who was running the circus in biophysics, and it sounded wonderful to me!"

By 1950, Randall’s deputy, Maurice Wilkins, was working together with Gosling to try and take X-ray pictures of DNA extracted from cuttlefish sperm that Wilkins had collected on a trip to Naples and turned into solid crystals.

These were the clearest pictures of DNA to date, revealing a strikingly regular pattern of scattered X-rays. This led their King’s colleague Alec Stokes – whose contribution to the story of DNA is also often overlooked – to suggest that the molecule might be a helix of some kind.

Randall was ahead of his time, not only in his vision of bringing biology and physics together but also in his championing of women in science. He brought in the renowned zoologist Honor Fell as the unit’s senior biological advisor and recruited a number of women, including muscle researcher Jean Hanson, who eventually took over as director of the unit when Randall moved to Edinburgh, and an up-and-coming young physicist named Rosalind Franklin. But here’s where the problems started.

Randall wrote to Franklin prior to her arrival in 1951, telling her that she would be in charge of the DNA studies at King’s and taking over supervising Gosling. But when she turned up, she found that Wilkins was still working on the problem. Combined with the mismatch between their personal styles – Franklin being far more direct and uncompromising than the retiring Wilkins - this “created tension and obstructed progress,” as Wilkins politely describes it in his biography of Randall.

Regardless of the interpersonal conflict, Franklin and Gosling got their heads down and set to work.

Franklin realised that DNA turned up in two different forms, A and B, which seemed to be interchangeable depending on how wet the samples were. Dry A-type fibres were short and fat, giving inconclusive X-ray patterns, while the long, stringy fibres in the wetter B form were much more amenable.

By carefully tweaking the water levels in samples of DNA extracted from calf thymus, Franklin and Gosling were able to achieve even clearer X-ray photos than before - the best of which was Photo 51 - revealing a regular repeating scattering pattern that strongly indicated a helix structure for the B form.

Presenting her data at a lecture in November 1951, Franklin noted, “The results suggest a helical structure (which must be very closely packed) containing 2, 3 or 4 co‐axial nucleic acid chains per helical unit.”

Over the next year or so, Franklin and Gosling continued their work, gathering ever more detailed information about the likely structure of DNA, and by January 1953 she was drafting papers explaining that DNA was likely to be a double helix. Yet she was cautious about publishing her findings until she was sure she was right – possibly because of the risks of failure as a woman in science at the time.

Then on 30th January 1953, Franklin received an unexpected visitor. It was James Watson, who had come down to London from Cambridge to see Wilkins, bringing with him an unpublished copy of a new paper from Linus Pauling at Stanford University, incorrectly outlining a three-stranded structure for DNA.

Wilkins wasn’t in his office, so Watson headed to Franklin’s lab instead. He urged her to collaborate with him and Crick but ended up annoying her by implying she couldn’t interpret her data. Ironically, Watson had been at a lecture by Franklin where she talked about the possible structure, but he didn’t take notes and misremembered what she’d said.

Given Watson’s patronising attitude to Franklin in his book, The Double Helix – such as referring to her as Rosy and suggesting that “the best home for a feminist was in another person's lab” - we can only imagine how that might have gone down. And so it’s not surprising that when Wilkins finally turned up, he chose to show Watson Franklin’s data and photos without asking her and risking further anger. It was Photo 51 in particular that set Watson’s pulse racing.

Franklin’s photo and measurements told him that he and Crick were along the right lines with their double helix model, and he rushed back to Cambridge to complete their work and prepare their manuscript for publication.

For his part, Francis Crick had also seen Franklin and Gosling’s data from a non-confidential Medical Research Council report passed to him by his Cambridge buddy Max Perutz. The result was the same. On the 25th April 1953, a trio of papers turned up in Nature – Watson and Crick’s, along with one from Wilkins, together with Alec Stokes and Herbert Wilson, and the third from Franklin and Gosling, complete with their beautiful photo.

Without seeing Franklin and Gosling’s data, it’s arguable that Watson and Crick might have taken longer to figure out the structure, or even been beaten to the punch by someone else. But however they came upon Photo 51 and Franklin’s careful measurements, there’s a strong case to be made that they – and Wilkins himself – didn’t acknowledge how important it had been to their model.

Finally, it’s worth remembering that Watson and Crick’s famous double helix was still just a bright idea, and although geneticists loved the way the structure explained how DNA could be read and copied, many biochemists were sceptical. It took seven more years of experiments by Wilkins and the team at King’s to prove that the twisted ladder was true, helping him to earn his place in the Nobel lineup.

Franklin, however, had had enough. By March 1953 – just before the three Nature papers came out – she had left King’s for a position at Birkbeck University, where she made key discoveries about the structure of viruses.  

Sadly, she died of ovarian cancer just five years later at the age of 37, possibly hastened by exposure to the X-rays that formed such an important part of her work. Her death came virtually five years to the day after that slew of papers, and although it’s tempting to speculate that she should have been in line for a Nobel prize, her premature death took her out of the running forever.

References and further reading:

Untying Nature's shoelaces

Untying Nature's shoelaces

Sweet Peas and Punnetts

Sweet Peas and Punnetts