Unravelling the Double Helix

by Gareth Williams

  Precocity and prodigy declared themselves early in Watson’s life. By the age of ten, he was a ‘bird buff’ with an encyclopaedic knowledge of ornithology, who read himself to sleep with the World Almanac.* He was bright and conspicuous enough to be awarded a degree course at the University of Chicago when only fifteen years old. By the time he graduated in 1947, aged nineteen, he had a reputation for both brilliance and oddness. Tall, lean and awkward, he ‘did not have a fund of small talk’, especially for his fellow students whom he passed in the corridor in silence and with ‘a far-away look in his eyes’. They thought him ‘way out’; the senior scientists whom Watson chatted up after their lectures saw him as someone to watch.

  Watson was another of those instantly converted to ‘finding out the secret of the gene’ by Schrödinger’s What is Life? He also read Arrowsmith by Sinclair Lewis, a splendid satire on medical research built around an institution suspiciously like the Rockefeller, where ‘bacteriophage’ (‘bacterium-eating’) viruses were exploited to treat plague. These two books – one pure speculation and the other impure fiction – guided him into a PhD on genetics at Indiana State University in Bloomington. The biggest name there was Herman Muller, the Nobel laureate who had mapped X-ray-induced mutations in Drosophila, but Watson chose to study the genetics of bacteriophage viruses (‘phage’) with Salvador Luria. His PhD, on ‘The biological properties of X-ray-inactivated bacteriophages’, was awarded in 1950 at the extraordinarily young age of twenty-two and produced a substantial paper for the Proceedings of the National Academy of Science.

  Figure 22.1 James D. Watson.

  Watson greatly impressed Luria and also Max Delbrück, a leading physicist who had begun thinking biologically after hearing Niels Bohr talk about genes and quantum mechanics during the 1930s. Luria and Delbrück ran the high-powered Phage Group, with courses and summer schools at Caltech and at Cold Spring Harbor. Both men were early believers in the story that emerged from the Rockefeller in 1944, claiming that DNA was the stuff of genes, at least in pneumococci. Luria knew Avery personally and was convinced that ‘DNA smells like the essential genetic material’. Delbrück worked at Vanderbilt in Nashville, and was a close friend of Roy Avery, Professor of Microbiology, who showed him the letter in which his elder brother Oswald concluded that DNA ‘may be a gene’.

  After his PhD, Watson was awarded a fellowship by the National Research Foundation, to work with Herman Kalckar in Copenhagen on the biochemistry of nucleic acids. The plan did not work out (‘a complete flop’, in Watson’s words), partly because Watson (who spoke no Danish) found Kalckar’s English incomprehensible. He transferred to Kalckar’s colleague, Ole Maaløe, who was using radioactive isotopes to mark DNA so that its fate could be followed after being injected by phage viruses into their target bacteria. This produced a second-author paper for Watson, who had not been stimulated in the slightest to do any experimental work in Kalckar’s lab.

  In spring 1951, Kalckar announced that he would spend a sabbatical on the Mediterranean coast, and asked if Watson wanted to go too. Watson jumped at the chance. Their destination was the Stazione Zoologica. Watson went to Naples disenchanted with biochemistry, irritated by the lack of ‘inspiring guidance’ from Kalckar, and hoping for a bolt from the blue which would show him how to answer the question posed in the title of Schrödinger’s little book. His reading about genetics had convinced him that the key was to find out the structure of genes, while recognising the risk that this might be ‘fantastically irregular’ and impossible to decipher.

  In late May, the routine at the Stazione was interrupted by the meeting on ‘Microscopical Structure of Protoplasm’. The proceedings were of little interest to Watson until the talk by Maurice Wilkins of King’s College, London, which began by putting two trigger words – ‘crystalline’ and ‘gene’ – in the same sentence, and ended with the symmetrical array of spots that proclaimed the regular, crystalline structure of DNA.

  Wilkins provided the bolt of inspiration, but on questioning did not seem to know much about phage viruses or genetics. Having written off King’s as the place to go next, Watson’s attention settled on the Cavendish Laboratory in Cambridge, where he heard that Max Perutz was planning a bold offensive on the structure of large molecules. Delbrück and Luria approved of Watson’s plan; Delbrück ran into John Kendrew at a meeting; strings were pulled; and in October 1951, Jim Watson walked away from Kalckar and Copenhagen, taking the rest of his fellowship money with him to Cambridge.

  A beautiful place

  Odile Crick met Jim Watson before her husband did. One evening in early October, she mentioned that Max Perutz had called in to introduce a young American ‘with no hair’ (actually a crew cut). Crick encountered the newcomer the following morning, and they clicked immediately, like two complementary bases snapped together by hydrogen bonding.

  Watson was bowled over by the ‘fun of talking to Francis Crick’, twelve years his senior and ‘still almost totally unknown’. Crick talked ‘louder and faster than everybody else’ and was a man in perpetual motion, constantly dreaming up and throwing out new ideas. For his part, Crick was ‘electrified’ by Watson, brash and arrogant but with a mind as sharp as his own. They talked science non-stop, in the Cavendish, over lunch in the Eagle (a nearby pub that would become a landmark in the folklore of the double helix), in punts heading upriver to Grantchester, and over suppers cooked by Odile. The volume and energy of their conversations were such that Perutz gave them a room to share so that they ‘could talk to each other without disturbing anyone else’. From the start, they took it for granted that they were intellectual equals, ready to throw and catch criticism – ‘perfectly candid . . . almost rude’, as Crick said – but both forgot that others might not be so robust.

  Watson’s first impressions of Cambridge ranged from the sublime to the ridiculous. He had ‘never seen such a beautiful place in all my life’ as the colleges beside the Cam, but the beauty was offset by the tiny and ‘unbelievably damp’ room with its elderly electric heater which the Kendrews provided for him, the ‘terrible’ English food, and the stuffy hierarchy in the Cavendish. He refused to be overawed by the top people in the lab. Max Perutz had been ‘collecting X-ray data on haemoglobin for over ten years and was just beginning to get somewhere’. Sir Lawrence Bragg, one of the grand old men of X-ray crystallography, was merely ‘an establishment administrator, largely ineffectual except when things had to be fixed over lunch in the Athenaeum’. Watson noted with great amusement Bragg’s very obvious allergy to Crick.

  Initially, the science which bounced between Watson and Crick was wide-ranging – physics, mathematics and protein chemistry from Crick, genetics and bacteriophages from Watson. Before long, their interests converged on a single topic which had nothing to do with the protein structures which each of them was supposed to be pursuing (Watson was trying and failing to make crystals of myoglobin from the heart of a retired racehorse). Watson saw himself as the driving force in the transition: ‘Before my arrival in Cambridge, Francis only occasionally thought about DNA and its role in heredity.’

  Once on that track, it was inevitable that a friend of Crick in London would come into the conversation: a man whom Watson later described as ‘a bachelor who worked at King’s . . . who had been a physicist and used X-ray diffraction as his principal tool in research’. And so Maurice Wilkins was reintroduced to the gangly American he had tried so hard to avoid in Naples.

  During his visit to Cambridge on the weekend of 9–11 November 1951, Wilkins talked freely about the work on DNA at King’s – as far as he knew. As well as his own optical and X-ray studies, there were Stokes’s ‘Waves at Bessel-on-Sea’ and the vital statistics which he had derived from the rather murky images of DNA in sperm. He also told Crick and Watson about the unknown quantity: whatever Rosalind Franklin had found, and might be keeping to herself.

  By now, Wilkins was persuaded that DNA was a helix, and Crick and Watson agreed. Wilkins was struck by the very high
density of DNA and thought that this ruled out a single helix, simply because more atoms had to be packed in to make the structure sufficiently heavyweight. His hunch – with no hard evidence – was that DNA consisted of three spiral chains, intertwined like amorous snakes. But precisely how the spirals were held together, and what the overall structure looked like, were complete mysteries. Franklin’s data might fill in some of those gaps, and there was a potential ray of hope to illuminate the darkness. A colloquium was to be held at King’s in ten days’ time, at which Wilkins, Stokes and Franklin were due to talk about their research. Watson asked if he could attend, and was formally invited by Wilkins.

  It was a busy few days for Watson. The following weekend was blotted out by a party at Christ’s College, followed by a day for recovery and then a sherry party at the Braggs’ house. In between, Watson crammed in as much crystallography as he could. Even for his brain, it was an unreasonable demand. Rosalind Franklin had spent five years learning X-ray diffraction, and he only had ten days.

  A foggy day

  The centre of London was blanketed in fog on 21 November 1951, the day of the colloquium in the Biophysics Unit at King’s. For Jim Watson, clarity was also lacking inside the dingy lecture theatre where fifteen or so people had gathered to hear the latest on DNA.

  Wilkins opened the session. He had little to add to his presentation at Perutz’s meeting back in July, which had provoked Franklin’s demand that he should return to microscopy. And Watson had heard it all during Wilkins’s visit to Cambridge, just ten days earlier. Alec Stokes’s talk was mathematically impenetrable. It would have been comprehensible to Crick; thanks to Wilkins’s briefing, Watson grasped the basic message that the diffraction pattern portrayed by the trains of waves, as produced by a theoretical helix, was a reasonable match for that produced by the DNA in sperm heads.

  Then Franklin spoke. This was a presentation by a professional crystallographer for other crystallographers; she made no concessions for amateurs, and Watson’s crash course on the subject was of little use. The content would have gone straight over Watson’s head, even if he had not been distracted by the speaker. He thought Franklin was ‘not totally uninteresting’ and found himself wondering ‘how she would look if she took off her glasses and did something novel with her hair’. She spoke ‘without a trace of warmth or frivolity’, and – as far as he could remember afterwards – without any reference to helices. The water content of DNA seemed to be important to her, but he didn’t understand why. Watson prided himself on never taking notes during lectures; this was one occasion when he later wished he had.

  Franklin had prepared thoroughly for the talk, jotting down detailed ideas about the structure of DNA and how this was altered by changes in its water content. She showed her underexposed photograph of what she called the ‘wet’ form of DNA with its rudimentary ‘X’ pattern that revealed itself only to those who knew what to look for. Her notes show that she believed that DNA consisted of a ‘big helix’ or ‘several chains’, in which the backbones with the phosphate groups lay outermost. The phosphate groups were heavy and water-loving (‘hydrophilic’); placing these on the outside would explain both the easy entry of water into the structure, and X-ray data suggesting that the exterior of the molecule was denser than its core. On the day, she spoke in detail about the crystalline form, and how cylindrical DNA molecules could be packed together, like a handful of cigarettes, to make a regular structure. She left Watson blinded with science and hopelessly confused. He could not even remember how much water was in the various forms of DNA.

  Afterwards, Wilkins took Watson into Soho for a Chinese meal. Wilkins seemed more relaxed, but did nothing to fill in Watson’s many lacunae of ignorance about the new insights into the structure of DNA which the colloquium had revealed. Looking back years later, Wilkins wrote that the patterns shown by Franklin ‘needed careful study’ and that she ‘did not show the correspondence with a helical pattern’ – all of which was ‘quite likely not absorbed by the beginner Watson’.

  Triple fault

  A few days after the colloquium, Wilkins was taken to see something completely unexpected. It was the brainchild of Bruce Fraser, the research student who was studying the internal structure of DNA with infrared light. Fraser introduced it with ‘a mysterious smile’: a three-dimensional molecular model of DNA that embodied the state-of-the-art.

  Fraser’s model consisted of three spiral strands of DNA, rising vertically and intertwined, with the bases stacked horizontally into the space between them. Wilkins thought it ‘a good job’; each of the DNA chains had the dimensions calculated by Stokes, and the heavy phosphate groups were on the outside, as predicted by Franklin. However, on closer inspection it became clear that the model did not fit other crystallographic data – and that it revealed a fundamental flaw in their reasoning. The balance of evidence had pushed Wilkins and the others towards a structure that contained three helices, but it now seemed that three could not be the right answer.

  It was unfortunate that Alex Stokes dashed off his ‘Waves at Bessel-on-Sea’ so easily that he did not think it worth publishing. This meant that Crick scored a palpable hit with the first paper to predict the X-ray diffraction pattern that would be produced by a helical molecule. Shortly before the colloquium at King’s, Bragg had been sent a draft manuscript by Vladimir Vand, a Czech crystallographer working in Glasgow. Vand had noted the Cavendish’s interest in helical protein structures and evidently was not put off by the fact that Bragg et al had got it all so embarrassingly wrong. Vand’s draft contained his mathematical derivation, using an advanced Fourier method, of the X-ray characteristics of a helix.

  Bragg asked the opinions of both Crick and Bill Cochrane, an experienced crystallographer at the Cavendish. Crick and Cochrane worked independently on Vand’s theorem (Crick being burdened first by a headache and then a pressing deadline for a wine-tasting), and both came up with the same answer, reached by two different routes. Vand had nearly got it right. Crick and Cochrane made the necessary corrections, tried out their method on a synthetic polypeptide which could only have a helical structure, and proved that it worked. They wrote up their paper for Nature, pipping to the post both Vand and Stokes – and for the first time, Bragg was impressed by Crick.

  Crick and Watson were also busy with another project, which took shape a couple of days after the colloquium at King’s. They were on a train to Oxford, for Crick to discuss his helical X-ray analysis with Dorothy Hodgkin. Jotting notes and formulae in the margin of The Times, Crick began to work out a plausible structure of DNA, using the data which Wilkins had told them during his weekend visit, and whatever Watson could recall from the colloquium at King’s. Crick was obviously irritated that Watson had not taken notes, especially when he tried to remember what Franklin said about the water content of DNA – an omission that turned out to be crucial.

  On returning to Cambridge, they settled down to turn their virtual mathematical structure into a three-dimensional model, using wooden spheres to represent the atoms, lengths of wooden dowel as chemical bonds, and copper wire to fill in gaps. They completed their model on Friday 6 December, and it looked so impressive that they believed they had cracked the structure of this impenetrable molecule. Watson went home, thrilled with their ‘scoop’, while Crick telephoned Wilkins to invite up him to Cambridge to inspect the solution to the problem that the King’s team had worked on for all those months. After a short delay, Wilkins rang back to say that they were coming up by train in the morning.

  Ray Gosling later recalled the trip to Cambridge, sharing a compartment with Wilkins, Franklin, Alex Stokes and Bill Seeds, another member of Wilkins’s group. They were all ‘rather quiet’, not just because of the tension between Wilkins and Franklin, but also because of their collective reaction to the summons by Crick. The two men in Cambridge were newcomers to the scene; they had never done any X-ray diffraction work on DNA, and the only information they had to play with – apart from historical dat
a such as Astbury’s pile of pennies – were the results from King’s, which had been shared with them in good faith. Now, the people who had done all the hard work were to be presented with a fait accompli, based on their own data. As Gosling said, there was real apprehension that ‘the pair in the Cavendish might have scooped all our efforts’.

  But when the King’s contingent gathered around and looked at the model, their relief was ‘palpable’. The Crick-Watson structure was a comedy of errors. Franklin began to reel off, in ‘her best pedagogic style’, all the things that were wrong with it. They had followed up Wilkins’s notion of three intertwined helices, but mainly because Watson had failed to grasp anything useful from Franklin’s talk, it was ‘completely inside out’. Crick and Watson had twisted together the three backbones (the long strings of deoxyribose coupled to phosphate) to form the core of the structure, with the bases sticking out from its sides.

  Franklin explained why this was fundamentally wrong. The ease with which water entered and left DNA meant that the hydrophilic phosphate groups must be on the outside; the hydrophobic (‘water-hating’) bases would repel water and must therefore sit innermost. Moreover, the diffraction data she had shown at the colloquium also pointed to the densest part of the molecule (the phosphate groups) being on the outside. Even the water content was wrong, by a factor of ten. These and other flaws were fatal; they were also obvious to anyone who knew a bit of chemistry and crystallography.