Unravelling the Double Helix

by Gareth Williams

  Now bring in Sven Furberg, the second abandoned PhD student. After publishing his brief note on the structure of cytidine in 1948, Furberg worked out theoretical structures of DNA with the help of the skeleton molecules which he made out of copper wire. Like Creeth’s sketch, these were hidden inside his thesis, filed away in the University of London library. His preferred model gives DNA a sugar-phosphate backbone, running vertically, from which the bases project at right angles, in the horizontal plane. It forms a single strand – but it is not straight. The DNA molecule is twisted into a graceful, regular helix, with eight bases per turn (Figure 19.2).

  Figure 19.2 Molecular structures for DNA proposed by Michael Creeth (top) and Sven Furberg. Creeth’s model comprised two broken chains held together by hydrogen bonds linking a purine on one chain with a pyrimidine on the other. Furberg postulated a single strand with a helical sugar-phosphate backbone from which the bases projected horizontally. The flat bases are viewed side-on and therefore appear linear; the helix can be appreciated from rotation of the pentagonal deoxyribose units.

  Who knows what structure of DNA might have emerged if Michael Creeth and Sven Furberg had been put in a room together sometime in the spring of 1949, and given the time and space to think laterally. Double-stranded along its entire length? Sugar-phosphate backbone on the outside, bases facing inwards? The two strands held together by hydrogen bonds, linking purines on one strand with pyrimidines on the other? And could the whole thing even be twisted into a double helix?

  * This was powerful stuff. It was calculated that half an ounce of pure pepsin would take only half an hour to digest half a ton of hard-boiled egg.

  † The University College of Nottingham was granted full university status in 1948.

  20

  MEETINGS OF MINDS

  King’s College (motto: ‘Holiness and Wisdom’), founded in 1829, was one of the original building-blocks of the University of London. It lies east of Trafalgar Square, sandwiched between the Thames and the Strand, where traffic flows around an island on which is marooned the attractive Wren church of St Mary le Strand. Waterloo Station is just across the river, a bracing ten-minute walk across Waterloo Bridge – but not for Professor John Randall FRS, who was met off the train every morning by his driver and delivered, complete with bow tie and briefcase, to his MRC Biophysics Unit.

  Randall moved down from St Andrew’s in September 1946, bringing Maurice Wilkins and four others with him. His first morning, accompanied by Wilkins, did not start well; a nervous porter stopped the short, bald, bespectacled man and wanted to know where he thought he was going. Randall explained that he was the new Wheatstone Professor of Physics, and was reluctantly allowed in. Previous holders of the Wheatstone Chair were difficult acts to follow – three of them had won Nobel Prizes – but Randall was determined to make his mark by going where no physicist had gone before. A reputation for forcefulness preceded him. It had taken just one phone call from St Andrew’s for the senior administrator at King’s to remark – correctly – that ‘I fear we are going to have trouble with this man’.

  The facilities at King’s were grander than Astbury’s badly converted house in Leeds, but did not match Randall’s aspirations. He was content with the crater (30 feet deep and 60 feet wide) which a German bomb had gouged out of the quadrangle one night in October 1940, because it helped to excavate the foundations for the new building he wanted.* However, he was dismayed at the ‘appalling and detestable’ condition of the rest of his estate.

  Luckily, lots of money poured in to assist the healing process. In addition to the massive MRC grant which had eviscerated Bill Astbury, there was a steady influx (unknown to the MRC) from the Rockefeller Foundation. The rest of King’s was paralysed by post-war austerity, but Randall’s new unit grew as shamelessly as a cuckoo chick, bloated with all the cash being stuffed down its throat. Other professors at King’s celebrated Randall’s success by blocking his nomination for fellowship of the college, and by making the principal write to ask the MRC to stop giving him so much money.

  By late 1950, the unit had twenty-four full-time scientists, together with technicians and half a dozen PhD students. Most were physicists or chemists with physical tendencies; biological credibility rested largely on Honor Fell, an authority on growing cells in culture (she called them her ‘little dears’), and Jean Hanson, who was working on contractile proteins in muscle. Fell was dignified with the title ‘Senior Biological Adviser’, but directed the Strangeways Laboratory in Cambridge and spent only a day a week at King’s.

  During the early 1950s, academia was not spared the stuffy formality, partly a hangover from the war, which pervaded Britain. The BBC News was read in a frightful cut-glass accent; a letter that began ‘Dear Smith’ was between friends, while ‘Dear John’ signified real closeness; and certain hierarchies were unquestioningly observed. King’s was averagely stuffy. The leather armchairs in the Senior Common Room overlooking the Thames were reserved for senior male academics; other ranks and all women (even eminent academics such as Honor Fell) met elsewhere for lunch and conversation. That apart, the group that became known as ‘Randall’s Circus’ was a happy breed of men, and of women.

  The ringmaster of the circus was desperate to continue his own research, despite the spiralling demands of keeping the money pouring in and the show on the road. Randall had intended to study the optical and X-ray properties of single chromosomes, as isolated by Alfred Mirsky. That idea collapsed when W.P.G. Lamb, a PhD student in the unit, showed that Mirsky’s ‘isolated chromosomes’ were just scraps of nuclear waste. The equipment that killed them off was a Siemens Übermikroskop, one of the first electron microscopes in the UK, acquired as war booty in Berlin and then plundered from the military by Randall.

  Next, Randall’s interest settled on the DNA that fills the heads of spermatozoa. Particularly promising were the ‘orientated’ sperm of Sepia (cuttlefish), stacked in parallel layers inside the sperm sacs which the males keep up their sleeve while cruising expectantly through the mating season. Unfortunately, the sperm sacs were fragile and impossible to dissect without scattering the spermatozoa. Randall made do with ram semen, which was easily obtained but full of independent-minded spermatozoa doing their own thing. Their DNA could, in theory, be ‘orientated’ if they could be persuaded to swim in formation like a salvo of torpedoes, perhaps through a hair-fine glass tube. Randall assigned a PhD student, Ray Gosling, to look into the problem.

  Gosling had read physics at university, then was knocked off course by the war and ended up working in the medical physics department at the Middlesex Hospital in London. He was intrigued by Randall’s eclectic circus and the ‘strange, bald-headed little man with a Napoleonic complex’ who ran it. To get himself up to speed for the PhD, Gosling took evening classes in biology while continuing his day job at the Middlesex. After arriving in 1949, he quickly provided Randall with enough material for several papers on the electron and ultraviolet microscopy of ram sperm. X-ray diffraction was much less rewarding, even with the expert input of Alec Stokes, a bright young crystallographer from Cambridge. The best they managed, by X-raying a smear of ram semen between two glass plates, was an almost featureless image that told them nothing.

  Purity and clarity

  Maurice Wilkins, brought down from Scotland to be Assistant Director of the MRC Biophysics Unit, started at King’s on a high. His two years with Randall at St Andrew’s had persuaded him that there was more to life than ‘the somewhat inhuman study of physics’, and a whole new world was now opening up, populated by ‘marvellous living things, with all their exotic forms and strange mechanisms and movements’.

  He arrived with a high-energy ultrasound generator, intending to damage chromosomes and induce interesting mutations. It took him a year to realise that ultrasound was vastly inferior to the million-volt X-rays which had already won Herman Muller his Nobel Prize. Next, he turned his attention to DNA, which he believed was the stuff of genes. Returning to his c
hildhood obsession with optics, he designed ingenious microscopes to measure DNA in living cells, exploiting its ability to absorb ultraviolet light.

  Wilkins also became intrigued by X-ray diffraction, a technique that was new to him. The equipment at King’s was poor: a clapped-out X-ray tube salvaged from an Admiralty hospital, and a basic camera that took reasonable photographs of proper crystals but was hopeless with tiny samples of biological material. Randall supplied a tip from his own brief encounter with X-ray diffraction before the war: taking the photographs in hydrogen rather than air would reduce the scattering of X-rays and give a clearer image. Wilkins built an almost hydrogen-tight housing for the apparatus; when Gosling found a couple of leaks, Wilkins fixed one with plasticine and the other with a sleeve of latex, snipped from a condom which he fished out of his pocket. As Wilkins said later, it was ‘either a real bodge-up or a brilliant improvisation’. Unfortunately, the new photographs of ram sperm were no better.

  Wilkins’s luck improved dramatically on 12 May 1950, when he went to a meeting at the Faraday Society in London. One of the invited speakers was Rudolf Signer, Professor of Organic Chemistry in Bern, who talked enthusiastically about the highly purified DNA he had extracted with great care from calf thymus. His DNA came in pristine white fibres and was described as ‘the best in the world’; its molecular weight was an astounding 7 million, which made even Gulland’s DNA (molecular weight 3 million) look as though it had been badly bruised during extraction. Signer’s generosity went beyond the sharing of data. He brought several vials of DNA, for anyone who wanted a couple of grammes to experiment with. Wilkins was one of those who took Signer’s gift home with him. This DNA, the closest yet to that in the living nucleus, was extraordinary stuff. Adding a drop of water turned a pinch of fibres into a blob of thick gel; on touching the surface with a glass rod, Wilkins could draw out an almost invisible strand, like a filament from a spider’s web.†

  Signer’s DNA was an obvious target for X-ray diffraction. Ray Gosling’s first attempts, using a thin film of gel, produced nothing useful. The spider’s web filaments seemed much more promising, but they were too fine for the ungainly camera. Wilkins solved that problem with an array of over thirty filaments, which he drew one by one from a blob of DNA gel with a glass rod and glued side by side in a tiny rectangular frame of tungsten wire. Remembering that Bernal’s best photographs of pepsin came from wet crystals, Wilkins kept the DNA filaments moist by bubbling the hydrogen through water to humidify it before feeding it into the X-ray housing.

  Gosling’s first photograph of the damp DNA filaments was dramatic enough to drive him and Wilkins to drink. Gosling took the film straight to Wilkins in a state of high excitement (Figure 20.1). This was the most vivid X-ray image ever taken of DNA: a magnificent, if baffling, array of over a hundred arcs and spots, and far more thrilling than Astbury’s tired old pictures. They celebrated by knocking back several glasses of the sherry which Wilkins kept in the bottom of his filing cabinet to entertain VIPs. As Wilkins later recalled, the photograph was shouting, ‘Look at me, I’m regular!’ A mountain of mathematics stood in the way of working out what it all meant, but a glance at the image told them that the DNA they had photographed was crystalline.

  This was an astonishing moment of truth – and a prophecy come true for believers in Schrödinger’s notion that genes were ‘aperiodic crystals’.

  Figure 20.1 Ray Gosling’s X-ray photograph of ‘crystalline’ DNA.

  All this happened within two weeks of the afternoon when Signer handed over his ‘pristine’ DNA to Wilkins. Frustration soon followed, when the old X-ray tube burned out in mid-exposure on Sunday 4 June 1950. A sophisticated new X-ray tube, developed by Werner Ehrenberg in Bernal’s group at Birkbeck, had recently been delivered to Randall and was sitting in a store-room, waiting to be unwrapped. This would have been ideal for studying Signer’s DNA; it was eventually put to that purpose, but not by Wilkins. In the meantime, he and Gosling did what they could with some equipment which the Chemistry Department kept in a nearby sub-basement.

  The rest of June was exhilarating and frantically busy. Wilkins recalled ‘hilarious times’ working long and late into the night with Gosling, often ending with a ‘rather scary’ lift home on the pillion of Gosling’s motorbike. Wilkins was so carried away by DNA that he had to send an apologetic letter to a friend who had planned to bring his new wife down from Cambridge to spend the weekend in Wilkins’s flat in Soho.

  ‘So glad to hear you are coming up . . .’ Wilkins wrote, and asked the guest to bring, in addition to his wife, ‘some nice young woman who will have no interest in proteins or nucleic acids . . . ideally really attractive . . . unattached or at least unaccompanied by her husband.’ Unfortunately, there were ‘snags’ with the original plan for the couple to stay the night, because ‘I am in such a state of nervous exhaustion that I intend not waking up all day Sunday’. Wilkins would explain when they met, but it was something big. He added, ‘Please don’t mention it to anyone yet.’

  Wilkins ended his letter with a jovial ‘Love to Odile, down with science, M.’ Odile’s maiden name had been Speed; her married name was Crick.

  Tall, fair and very English

  It was not surprising that Francis Crick and Maurice Wilkins clicked on first acquaintance. When they were introduced in spring 1947, both were physicists whose eyes had been opened to the enticements of biology by Schrödinger’s small but mystical book – and both were thirty-one years old and recovering from a failed marriage that had produced a son.

  Like many lively chemical reactions, their relationship needed a catalyst to get it started. Their catalyst was Harrie Massey, the multitalented physicist who had lent Wilkins his copy of What is Life? when working on the Manhattan atom bomb project in Berkeley. After returning to England, Massey was diverted into military research for the Admiralty, which is where he met a shockingly intelligent and irreverent physics graduate whose PhD had – mercifully – been terminated by enemy action.

  Francis Crick (Figure 20.2) was born near Northampton in April 1916 – six months before Wilkins – into a well-heeled, middle-class family which owed its wealth to a successful shoe business. As a child, he was intensely curious and worried that everything would have been discovered by the time he grew up. Like the young Wilkins, he was fond of making things – in his case, radios and improvised explosive devices that he detonated in the garden by remote control.

  Figure 20.2 Francis Crick.

  At school, Crick was unexcited by Latin, which was obligatory for Oxbridge entrance, and so went to study physics at University College in London. He graduated in 1937 with a solid but unspectacular 2:1; he also married an English student and they had a son in November 1940. After graduating, he stayed on to do a PhD with Neville da Costa Andrade, who had been brilliant as a Christmas lecturer at the Royal Institution; the project, on the viscosity of superheated water, turned out to be ‘the dullest problem imaginable’. Luckily, the Luftwaffe came to the rescue; also luckily, Crick was elsewhere on the night in October 1940 when his experimental rig took a direct hit. He then moved to Harrie Massey’s lab at the Admiralty, working on how to blow up ships and U-boats with mines triggered by magnetism or sound. The project became an intricate game of cat-and-mouse, and Crick proved adept at responding to the enemy’s twists and turns. Opinion about him was divided. His fellow scientists admired him as ‘a clear and incisive thinker’, while the military thought him ‘impatient, arrogant and insubordinate’.

  When the war ended, his marriage had also run its course, leaving Crick disorientated and uncertain about what to do next. He remained at the Admiralty – appropriately enough, in intelligence – but spent most of his time reading and trying to find something that excited him. After ploughing through What is Life? and books on chemistry, bacteria and the brain, he settled on ‘the borderline between the living and the non-living’ – which translated most closely into the emerging discipline of molecular biology.


  Harrie Massey provided the introduction to Maurice Wilkins, his former colleague from Berkeley; noting Massey’s enigmatic smile, Crick deduced that Wilkins was ‘in some way unusual’. They met at King’s and instantly got on well, but despite Wilkins’s warmth and enthusiasm, Crick was ‘not entirely convinced that this was the way to go’. John Randall was even less convinced; his reason for not offering Crick a place was that he was ‘too boisterous and talked too much’.

  While Crick continued to search for a job, Wilkins kept in touch with him and his new girlfriend, Odile Speed, a former Wren in Naval Intelligence. Crick’s next target – despite being warned off by someone he trusted at the Medical Research Council – was J.D. Bernal at Birkbeck. Crick got no further than the ‘amiable dragon’ of a secretary who guarded the entrance to Sage’s cave and demanded to know why Crick thought that the professor would want to take him on. Then, even though Odile was anchored in London, Crick tried Cambridge. The only place with a suitable vacancy, recently created by the death of the incumbent physicist, was the Strangeways Research Laboratory. Supported by an MRC studentship and money from his family, Crick began another project on viscosity – of the cytoplasm, deep inside living cells.

  The Strangeways was an unconventional place. It was founded in 1908 by Thomas Strangeways, an arthritis specialist who was inspired by cell culture research at the Rockefeller and during the 1920s turned his laboratory into a leading centre for growing cells, tissues and even organs in the test tube. Strangeways’s last lecture, given in 1928, was entitled ‘Death and immortality’ and reported that he had generated healthy pig tissues from a sausage. Honor Fell took over as director when Strangeways died suddenly soon after; the problems she had to overcome included a chronic shortage of money and an undercover journalist who told the world that she was about to grow babies in bottles. Research at the Strangeways was now less febrile. Crick’s first two scientific papers were on cultured cells that had been tricked into engulfing tiny magnetic particles. After two years, he decided to move on; he respected Honor Fell, but let slip that the place was ‘aptly named’.