Their double helix was not just neat stereochemically. It was the inviolable pairing of the bases that gave it ‘considerable biological interest’. They acknowledged this with another throw-away line to go down in history: ‘It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.’
Like the others, Watson and Crick ended with thanks. ‘We have been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr M.H.F. Wilkins, Dr R.E. Franklin and their co-workers at King’s College, London.’
Their paper was brief because of its economical prose, but mainly because it was not burdened by descriptions of the experiments and analyses that led them to their structure. Most of the necessary data could be found in the papers by Wilkins and Franklin. And the claim by Watson and Crick that ‘we were not aware of the details of the results’ was not challenged by any of those who knew it to be a lie.
Some discoveries just look right from the moment that they are unveiled. The double helix (Figure 24.4) was one of those: beautiful, elegant and with a stroke of pure genius in the way that A paired with T and C with G – so obvious, as soon as it was pointed out, that it had to be the truth.
A few wise men immediately spotted the wider implications. Max Delbrück wrote to Watson: ‘If the suggestion concerning the nature of replication has any validity at all, then all hell will break loose and theoretical biology will enter a most tumultuous phase.’ Linus Pauling thought that ‘their formulation of the structure’ would turn out to be ‘the greatest development in the field of molecular genetics in recent years’. And the entire Biochemistry Department at Oxford descended on Cambridge en masse to pay homage to the model. On their return, they sent a telegram which read simply ‘Congratulations’, from a sender identified as ‘Gene’. Others believed that this should have read, ‘Be careful’, from ‘God’.
Figure 24.4 Schematic drawing of the double helix, showing the deoxyribose-phosphate backbones as ribbons, bridged by the hydrogen bonds (dotted lines) joining the complementary bases, A with T and C with G. The two DNA strands are ‘anti-parallel’, one running ‘up’ and the other ‘down’.
On first seeing the Watson-Crick paper, Sir Lawrence Bragg had confessed that ‘It’s all Greek to me’, but was soon bubbling over with the excitement of the newly converted. In Watson’s words, he quickly ‘got out of control’ and was feeding the story to the lay press as well as the scientific community. This gave Watson an attack of cold feet and what might almost have been a spasm of guilty conscience, because ‘there are still those who think we pirated data and I’m of the belief that a few enemies are worse than a few admirers’. His conclusion was, ‘So the less publicity, the better.’
A few weeks later, Watson was invited to talk about their paper at the Hardy Club in Cambridge. Obtunded by dinner at Peter-house and overlubricated by sherry, he gave what Crick judged to be ‘an adequate description’ of their triumph. At the end, Watson was overcome with emotion and, very unusually, was lost for words. Gazing up at the double helix on the screen, all he could manage was: ‘It’s so beautiful.’
Maurice Wilkins was also there and sat through Watson’s talk, increasingly ‘puzzled’ that there was no reference to any of the work done in Randall’s Biophysics Unit. Afterwards, Watson came to find Wilkins and said he was sorry for having ‘forgotten to mention King’s’.
25
AFTERSHOCKS
This book set out to tell the story of DNA from its discovery in 1868 to the publication in April 1953 of the papers that, many believe, changed forever the world of biology. As such, it has run its natural course. However, observant readers will have spotted that there are still another thirty-seven pages to go, and may want to know what fills them.
There is no attempt to bring molecular genetics up to date. To do that would require a whole new book which I am not qualified to write – and even an expert would struggle to produce something that is not out of date by the time it is published. Instead, I have tried to tackle two questions which left me restless when I reached the end of those eighty-five years. Having got to know members of the cast, I wanted to find out what happened to them, and how their lives were changed by their entanglement with DNA. I was also curious about the double helix itself. Having assumed that the Watson-Crick model was perfect, I was surprised to discover that it was flawed – and that the work to fix it was not done by those whose names grace the structure.
Which takes us back to the spring of 1953 . . .
Follow through
Even as the trio of papers was incubating in press at Nature, Watson and Crick were staking their next claim, in another Nature paper that came out in May 1953. They followed up the notion which ‘had not escaped our notice’: the mechanism by which a stretch of DNA could duplicate itself in preparation for cell division. The DNA strands in the double helix were ‘a pair of templates, each of which is complementary to the other’. Watson and Crick suggested that the hydrogen bonds are broken before duplication, somehow allowing the strands to unwind and separate ‘without everything getting tangled’. Each chain then ‘acts as a template for the formation on to itself of a new companion chain’, producing two pairs of chains with exactly the same sequence of bases as in the original (Figure 25.1).
Figure 25.1 Mechanism of duplication of the two strands of DNA. The ‘old’ DNA strands of the parent double helix separate and, because of the pairing of complementary bases, each will rebuild a perfect replica of its original opposing strand.
Shortly after, Watson and Crick went their separate ways. In early summer 1953, Watson left the popsie fields of Cambridge and returned to Max Delbrück at Caltech. The timing was good, as Delbrück was organising that year’s Cold Spring Harbor Symposium. It was about viruses, but Delbrück presented all 270 participants with copies of the Nature papers, and gave Watson a prime slot to talk about the double helix. Watson was also the front man for the model in September at Linus Pauling’s Pasadena Conference on protein structure. The list of delegates was almost a potted history of the race to the double helix: Crick and Wilkins, Bragg and Perutz, John Randall, Bill Astbury, and even Lindo Patterson. But not Rosalind Franklin, who was now working on viruses at Birkbeck and supposedly had left DNA behind at King’s.
Watson revelled in it all. He delivered his Cold Spring Harbor talk in shorts and sneakers, speaking in the strange mid-Atlantic accent which had irritated Chargaff. To Crick’s annoyance, Watson appeared alongside film stars and pop singers in Vogue in July 1954, as the ‘scientist with the bemused look of a British poet’ and a fine example of ‘Young American Talent’. However, Watson’s new line of research – X-ray studies of RNA – was not going well. Crick’s verdict was blunt: ‘I find it very difficult to get a clear idea of what he has done.’
Crick and Watson were briefly reunited in late 1955 when Watson took a year’s sabbatical in Cambridge to explore the structure of small viruses; their combined magic produced a major paper in Nature. Then Watson was off again, to Harvard in autumn 1956. He returned to RNA, and the theory that a particular type of RNA somehow carried information from DNA and drove protein synthesis in the cytoplasm. The end result was one of a pair of papers in Nature in 1961, describing a short-lived RNA. (The other paper was by Sydney Brenner at the MRC Unit in Cambridge, who got there first but held back publication on receiving an anguished telegram from Watson.) This RNA was later called ‘messenger RNA’ because it is formed on the DNA template of the relevant gene inside the nucleus, then travels into the cytoplasm and itself acts as a template for the synthesis of the protein encoded by the gene.
*
Meanwhile, Francis Crick had been pursuing other stages in the ‘flow of information’ from DNA to protein synthesis. After finally handing in his PhD, he spent an unrewarding year at the Polytechnic Institute in Brooklyn and then returned to Cambridge to tackle the genetic code – or, as he put it, �
��how a sequence of four things (the nucleotides) can determine a sequence of 20 things (the amino acids)’. His talk ‘On protein synthesis’, given in London in late September 1957, has been described as an hour that ‘permanently altered the logic of biology’. In it, Crick laid out his ‘Central Dogma’, namely that the sequence of bases in DNA is translated into the sequence of amino acids in a protein, and that the flow of information cannot be reversed: once a protein is made, it cannot influence the DNA that created it.
Crick set down the theoretical framework for the genetic code, which turned out to consist of ‘triplets’, specific sequences of three adjacent nucleotides (e.g. GGC) which each code for one of the twenty amino acids (GGC is the ‘codon’ for the simplest amino acid, alanine). He also saw that a fleet of two-faced ‘adaptor molecules’ would be needed to translate the sequence of a messenger RNA into the protein: one face of the ‘adaptor’ would clamp on to the triplet sequence of RNA while the other end brought in the corresponding amino acid to join the forming protein chain. Crick’s theoretical ‘adaptor molecules’ were soon shown to exist, as the small RNA species which became known as ‘transfer RNA’.
By now, Crick was a solid Cambridge fixture. The house in Portugal Place had a brass helix (single) over the front door and had been renamed accordingly. In 1959, he was made a Fellow of the Royal Society – the honour that, he said, gave him the greatest pleasure of all. In 1960, he was awarded fellowship of the new Churchill College, only to resign in disgust when the college accepted a generous donation to build a chapel.
Maurice Wilkins also won his FRS in 1959; John Randall had proposed him soon after the double helix papers were published in 1953, but Bragg had decreed that Wilkins should not beat Crick. Wilkins had not been seduced by the genetic code or RNA. Instead, he stuck doggedly to the double helix which, as far as he was concerned, was still a work in progress. The A structure was incomplete and even the B structure contained uncertainties; for example, the deoxyribose sugar molecule was flat in the Watson-Crick model, but almost certainly puckered in real life. Moreover, other models continued to appear, with two, three or four chains, linked by forces other than hydrogen bonding between bases – and a couple of these iconoclastic offerings were thrown in by Jerry Donohue, who had shared the office and the excitement with Watson and Crick.
Wilkins and his team quietly got on with ironing out the errors in the double helix. To this end, they used human DNA prepared from the white blood cells of leukaemia patients; bigger and better X-ray cameras; epic X-ray exposures of up to eight weeks; and a new IBM computer that had an astonishing (for the day) 2 kilobytes of memory storage. Despite being nagged by Crick to get on with it, Wilkins took as long as was necessary to do the job properly. ‘Years seemed to slip by,’ Wilkins wrote later. And they did – seven of them.
By then, they had nailed the position of every atom in the double helix and consigned the alternative models to the scrapheap. The B structure was now rock-solid; some of the hydrogen bonds were a touch shorter (10.7 Å instead of 11.0 Å), the sugars were puckered, and everything fitted beautifully (Figure 25.2). The A structure turned out to be squashed vertically by the removal of water, with eleven nucleotides per turn instead of ten, and the bases were tilted at 20 degrees to the horizontal; these features gave the X-ray pattern its regular ‘crystalline’ appearance. Wilkins also found another, drier DNA structure (the ‘C’ form), which was semi-crystalline.
At this point, having proved that the double helix was ‘a fundamental part of living matter’, Wilkins decided that further X-ray studies were ‘not likely to reveal much of real biological interest’. After a decade with DNA, he began looking for new challenges.
Meanwhile, his life had entered a whole new phase. In 1955, he met Patricia Chidgey, working as a teacher in a school for children with special needs. She was beautiful, artistic and spirited, and passed the acid test of being approved by Wilkins’s elder sister. They married in 1958, in a register office with ‘artistic friends’ as witnesses, and spent their honeymoon in Dorset.
Figure 25.2 The double helix, refined by Maurice Wilkins and colleagues. Left: space-filling model, showing the overall double helical structure. Right: skeleton drawing of the two spiral backbones of deoxyribose and phosphate, with the pairs of flat bases (viewed end-on and therefore appearing linear) holding them together.
Clarity and perfection
In March 1953, the Biomolecular Research Laboratory at Birkbeck College was an extraordinary place: a shabby terraced facade which sheltered a hatchery for brilliant ideas and world-class scientists. When Rosalind Franklin moved there from King’s, she was thirty-three years old, untenured and had less than a year’s salary. She would spend four highly successful and mostly happy years there, winning international recognition in an entirely new field.
Franklin had known that she was swapping ‘a palace for a slum’, even if the graffiti were by Picasso. Her office was in the attic of 21 Torrington Place and her X-ray equipment five floors down in the basement (protected by an umbrella whenever the ceiling leaked). J.D. Bernal continued to command her respect, despite his adulation of the Soviets and the froideur which had to be projected by women who wanted to stay off his list of sexual conquests. She was slow to settle in, with a personality described as ‘prickly, difficult and forceful’ and a habit of passing people on the stairs without saying anything.
Her immediate priority was the remaining DNA research with Ray Gosling, who had been abandoned to finish his PhD without a supervisor. In mid-April 1953, a fortnight before Nature published its trilogy, she received a shirty letter from John Randall reminding her that she was banned from working on DNA; she ignored it. Acta Crystallographica had already accepted the first two papers on the A and B forms, but she and Gosling put two fingers up to Randall by sending an article on the A form to Nature, which was published in July. They concluded, as Wilkins later did, that the A form was also helical but that the removal of water had shortened the structure and tilted the bases. This was later described as ‘a most elegant application of the Patterson method’, although Wilkins was able to pick a few holes in it.
The first Acta Crystallographica paper by Franklin and Gosling was published in September 1953. As the editor had received the manuscript on 6 March, this was the first ever paper to suggest that DNA has a helical structure. Their parting shot was to show that advanced Patterson analysis confirmed the Watson-Crick model in principle, but not in every detail. This marked the end of Gosling’s thesis and of Franklin’s involvement with DNA.
In autumn 1953, Franklin began her new research into the structure of viruses. First on the list was tobacco mosaic virus (TMV), which had been shown by Jim Watson (during Bragg’s moratorium) to consist of a tight spiral of subunits, like a stylised cob of maize. TMV had a catalytic effect on Franklin’s career: it lifted her science on to a higher plane and brought her into contact with people who helped her. These people comprised both new friends and former rivals. Foremost among her new friends was Aaron Klug, a brilliant South African crystallographer who, even at the age of twenty-two, was clearly going places.* Klug joined her in 1953, having been seduced (‘my fate was sealed’) by the beauty of one of Franklin’s X-ray photographs of TMV. Her former rivals included Francis Crick and Jim Watson; the DNA business had blown over by now, and both were friendly and constructive.
In mid-1955, Franklin was back in demand with invitations to speak at international meetings in Zagreb, Paris and the Gordon Conference in New Hampshire – not about DNA, but coal. The Gordon Conference, in the same place where Maurice Wilkins had talked about crystalline DNA four years earlier, reunited her with Jacques Mering and was a springboard for a busy American tour, visiting labs, making contacts and giving talks on TMV. In Woods Hole, she encountered a hurricane and Jim Watson, who offered to drive her (with Sydney Brenner) across America to California; she had to decline, because she was due to meet Francis Crick in Brooklyn. Other highlights were a descent on mule
-back into the Grand Canyon, Linus Pauling in Cal Tech, and Don Caspar, a young crystallographer from Yale who was also working on TMV.
Back home, she tackled TMV with renewed energy. Her breakthrough was to use the Patterson analysis on X-ray photographs of TMV particles in which specific parts of the protein subunits were highlighted by slipping in mercury atoms. Don Caspar, now in Cambridge on a scholarship, asked to join her group and a highly profitable partnership began. An early result was a pair of papers in Nature, in which he showed that TMV was hollow, as if the core had been drilled out of the cob of maize, and she proved that its RNA was wound in a spiral up the inside. This led to an awe-inspiring three-dimensional model of TMV, which stood four feet high. (The prototype used bicycle handlebar grips to represent the ovoid protein subunits, and cleaned out the entire stock of Woolworth’s on Oxford Street.) By now, Franklin had reinvented herself as a structural virologist. In March 1956, she presented at the prestigious Ciba Symposium on viruses held in London – the only woman, alongside Crick, Watson, Klug, Caspar and thirty others of international renown. More of the same followed a few weeks later at the International Crystallography Conference in Madrid. There, she got on particularly well with Francis and Odile Crick and joined them for a tour of southern Spain after the meeting.
After that, she switched to another virus and bigger doors began opening for Rosalind Franklin. Her new target was the poliovirus, a scourge that had paralysed America with fear (and had struck down Werner Ehrenberg who built the X-ray camera with which she took Photograph 51). The first polio vaccine had recently been introduced by Jonas Salk, but the American Public Health Department was still throwing money at the poliovirus, including a massive grant to Franklin.
Unravelling the Double Helix Page 38
