Rosalind Franklin

by Brenda Maddox

  No sooner had Rosalind secured her fellowship when the direction of research at King’s College changed dramatically. In May, at a meeting of the Faraday Society (whose Transactions had carried three of Rosalind’s papers on coal), a Swiss scientist named Rudolf Signer from Berne displayed a specially prepared gel of nucleic acid which had extremely high molecular weight. Signer generously offered samples to his audience. One of the takers was Maurice Wilkins of King’s College physics department, who took his back for study.

  That hardly concerned Rosalind. Rather, she was over- whelmed with doubt now that her return to England was settled. She told Colin that her feelings ‘still oscillate wildly’. ‘When I left London I thought I’d convinced myself it wasn’t too bad but cycling along the Seine I was miserable’. She was touched that her personal assistant was heart-broken.

  As its name implies, the Strand, the busy thoroughfare that runs east from Trafalgar Square, once was a river bank. King’s College London faces the Strand on the north and the Thames on the south. As she prepared to move, the alliterative combination of ‘Seine’ and ‘Strand’ stuck in Rosalind’s mind, and she used it, sometimes intensifying the sound with ‘cellar’, in letter after letter: ‘to change the banks of the Seine for a cellar in The Strand seems to me quite insane’.

  Over and over, she cited reasons for dreading return. Britain’s nuclear deterrent was high on the list; she was appalled at her country’s willingness to side with the Americans. One of the things which made her feel more comfortable in France than in England was in France ‘there is a much healthier horror of war, and appreciation of its senselessness — but you won’t appreciate that — nobody who hasn’t lived outside England ever does’.

  Even so, she cast her mind to the prospects of finding a place to live in London, where housing was even harder to find than in Paris. Holidaying once more with the Luzzatis in the Haute Savoie in August (her third with them that year), she overheard English people talking about a flat in London near Gloucester Road in South Kensington. Eavesdropping eagerly, she gathered two details: the flat had a very low rent of £6 per month but high key money of £750. She wrote her parents immediately for advice: ‘I have no idea how immoral and illegal such deals are in England or what guarantee that low will stay low.’

  On that Alpine trip, the Luzzatis noticed how adept Rosalind was at keeping men at arm’s length. In a mountain hut one day, they met a climber who, to them, clearly fancied Rosalind. Chatting her up, the stranger mentioned that he had lost a button off his coat; could she help him? ‘Of course,’ Rosalind said, in her brisk, well-bred way, searched in her rucksack, found a needle and thread and handed them over for him to do the job himself. They were amused too, when at a large Luzzati family gathering, Rosalind was a bit shocked by all the kissing. She never kissed any of her family, she said, except her mother.

  By the end of October, with her return to London approaching, Ellis and Muriel urged her, as parents will, to use her family connections to help get the South Kensington flat. She protested. ‘I can’t possibly write to Lord Somebody or Other and say I’m Mamie’s niece and I want a flat . . .’ (As a member of the London County Council, ‘Mamie’ — Helen Bentwich — was a woman of influence.) Rosalind reminded her parents that she was by no means sure she wanted to come back: ‘I spend half my time wondering whether to chuck the whole thing up and stay here.’

  Her gloom at the prospect of re-entry was deepening. She poured out her complaints about England to Evi Ellis. Rosalind felt she could count on the Austrian-born Evi to understand her dislike of English parochialism. After making the Seine-Strand contrast, she warmed to her theme: ‘What depresses me most in the English is their vacant stupid faces and child-like complacency — I’m busy collecting the addresses of foreigners in London.’ She begged Evi to write and tell her how to get out of going back.

  In dealing with King’s College, however, she was very far from trying to get out of her new job. She put a great deal of thought into a long, respectful and detailed letter on 24 November to Randall, specifying, with a long numbered list, the equipment she would need. She was particularly concerned with the design of the camera being made for her. What was essential was to control the temperature inside the camera to prevent the solution from changing during its exposure. An economical move, she suggested, would be to put the specimen outside the vacuum cover, and only the camera inside. (A vacuum was necessary because X-rays are attenuated when they travel through air.) She offered some cost figures to suggest that the apparatus could be designed more cheaply and quickly in Paris, allowing her to get down to work as soon as she reached London. Then too she would need the new X-ray generating tube promised by Birkbeck College. If she could know when the order would be placed, she might ask for a few minor modifications.

  In conclusion, she apologised to her new boss: ‘Please forgive me for bothering you with so many questions after such a long silence.’

  Ten days later Randall replied. He was changing completely the direction of her planned research. His artful and ambiguous letter was packed with half-truths and buried meanings that would explode in Rosalind’s face before too long and, not incidentally, alter the course of scientific history. It began:

  After very careful consideration and discussion with the senior people concerned, it now seems that it would be a good deal more important for you to investigate the structure of certain biological fibres in which we are interested, both by low and high angle diffraction, rather than to continue with the original project of work on solutions as the major one.

  Randall then rattled off without explanation references to people of whom she may or may not have heard, including ‘Dr Stokes who now wished to concern himself almost entirely with theoretical problems’. Then came the critical sentence:

  This means that as far as the experimental X-ray effort is concerned there will be at the moment only yourself and Gosling, together with the temporary assistance of a graduate from Syracuse, Mrs Heller.

  Gosling, working in conjunction with Wilkins, has already found that fibres of desoxyribose nucleic acid derived from material provided by Professor Signer of Berne give remarkably good fibre diagrams.

  Having told her that she would have the X-ray work to herself, Randall held out the possibility that she might look at proteins in solutions at some future time but, for the moment, ‘we do feel that the work on fibres would be more immediately profitable and, perhaps, fundamental’.

  If she was startled by this change of assignment, Rosalind gave no sign. Paris had been good for her. She left it at Christmas 1950, an authority on the structure of coal and carbons, and thinking that perhaps she should consider staying in France indefinitely. She reminded her parents that she liked Europe and the Europeans so much better than England and the English; Italy and Italians would suit her just as well as the French and she had always liked ‘foreigners better than the English’. She dreamed of a job that would keep her half the year in Paris and the rest in London.

  She summed up her regrets in a strong letter to Colin and his new wife Charlotte (whom she liked very much), first thanking them for a copy of Christ Stopped at Eboli which she had read in Italian. Even her favourite brother, however, cannot have caught the subtle reference to the narrow and unsatisfactory relationship that told her she had no future in Paris:

  ... I still cannot believe that I’m leaving here next January — I can see no way out of it now, but I’m sure it was the biggest mistake of my life. At times I think seriously of just saying that I’ve changed my mind and will stay here. But at this stage it would mean upsetting such a lot of people that it’s not worth doing unless I really decide to stay here indefinitely — and I’m just not quite sure enough for that. If only I had managed to meet more of the right people here and had a wider circle I shouldn’t hesitate. Apart from that I far prefer here the place, the people, the life and the climate. I feel — and felt even before I came to France — far more European than English. Na
tional feeling, whether it be for England or any other country, is meaningless to me. However, I suppose my fate is decided and I ought to stop thinking about staying on here — though that is impossible. I am doomed to spend the next 3 months moaning about the future and a good many months after that moaning about the present.

  Her intimation of trouble ahead was well-founded but she was very far from making the biggest mistake of her life. J.T. Randall, however, had just made his.

  Part Two

  EIGHT

  What Is Life?

  THE FIRST HALF OF twentieth-century science belonged to physics, with the general theory of relativity, quantum mechanics and nuclear fission. The second half would belong to biology. In the post-war world, the secret of the gene - how hereditary characteristics pass from one generation to another - was the hottest topic in science.

  For a number of physicists who had worked on the Manhattan Project to develop the atomic bomb, the post-war shift into biology was a stark exchange of the science of death for the science of life. But their conversion was as much intellectual as ideological. Biology was now where the action lay. The war had interrupted a line of investigation leading towards understanding the chemical basis of heredity.

  That physical features are passed on by discrete units (later called genes) had been discovered in 1865 by the Austrian monk Gregor Mendel in his experiments with garden peas. Each gene determined a single characteristic, such as height or colour, in the next generation of plant. By 1905 it had been learned that within living cells the genes are strung together like beads on the chromosomes, which copy themselves and separate. But how does the genetic information get from the old chromosome to the new?

  Protein was the obvious candidate. By the 1920s it was thought that genes were made of protein. The other main ingredient in the chromosome is deoxyribonucleic acid, or DNA. DNA, a substance of high molecular weight, was identified in 1871 by a young Swiss scientist, Friedrich Miescher. (There is, in fact, a second kind of nucleic acid in the cell, called RNA, with a slightly different chemical composition.) The ‘D’ in DNA stands for ‘de- oxy’ — a prefix often spelled as ‘des’ in Rosalind’s day, a usage now obsolete — which identifies it as the ribonucleic acid with one fewer hydroxyl group. But as RNA exists in cells mainly outside the nucleus, it was unlikely to be the genetic vehicle.

  Protein was far more interesting to geneticists than DNA because there was a lot more of it and also because each protein molecule is a long chain of chemicals of which twenty kinds occur in living things. DNA, in contrast, contains only four kinds of the repeating units called nucleotides. Hence it seemed too simple to carry the complex instructions required to specify the distinct form of each of the infinite variety of cells that constitute living matter.

  In 1936, at the Rockefeller Institute on the Upper East Side of Manhattan, a microbiologist called Oswald Avery wondered aloud if the ‘transforming principle’ — that is, the carrier of the genetic information from old chromosomes to new — might not be the nucleic acid, DNA. No one took much notice. DNA seemed just a boring binding agent for the protein in the cell.

  During the pre-war years, in Britain, J.D. Bernal at Cambridge and William Astbury at Leeds, both crystallographers, began using X-rays to determine the structure of molecules in crystals. Astbury, interested in very large biological molecules, had taken hundreds of X-ray diffraction pictures of fibres prepared from DNA. From the diffraction patterns obtained, Astbury tried building a model of DNA. With metal plates and rods, he put together a Meccano-like model suggesting how DNA’s components — bases, sugars, phosphates — might fit together. Astbury concluded — correctly, as it turned out — that the bases lay flat, stacked on each other like a pile of pennies spaced 3.4 Ångströms apart. This ‘3.4 Ä’ was no gratuitous detail. Published with other measurements in an Astbury paper in Nature in 1938, it was to remain constant throughout all the attempts to solve DNA’s structure that were to come.

  But Astbury made serious errors, his work was tentative, and he had no clear idea of the way forward. By the time of the Second World War, no one knew that genes were composed entirely of DNA.

  In 1943 Avery, at sixty-seven, was too old for military service. Still working at the Rockefeller Institute and building on an experiment with pneumococcus (bacteria that cause pneumonia) done by the English physician Frederick Griffith in 1928, he made a revolutionary discovery. He found that when DNA was transferred from a dead strain of pneumoccous to a living strain, it brought with it the hereditary attributes of the donor.

  Was the ‘transforming principle’ so simple then — purely DNA? In science, where many grab for glory, there are some who thrust glory from them. Avery, a shy bachelor who wore a pince-nez, was one of those too modest for his own good. His discovery has been called worth two Nobel prizes, but he never got even one — perhaps because, rather than rushing into print, he put his findings in a letter to his brother Roy, a medical bacteriologist at Vanderbilt University Medical School in Nashville. ‘I have not published anything about it — indeed have discussed it only with a few,’ he said, ‘because I am not yet convinced that we have (as yet) sufficient evidence.’

  A year later, however, Avery, with two colleagues, wrote out their research. In what became a classic paper, they described an intricate series of experiments using the two forms of pneumococcus, virulent and non-virulent. When they freed a purified form of DNA from heat-killed virulent pneumoccocus bacteria and injected it into a live, non-virulent strain, they found that it produced a permanent heritable change in the DNA of the recipient cells. Thus the fact was established — at least for the readers of The Journal of Experimental Medicine — that the nucleic acid DNA and not the protein was the genetic message-carrier.

  The essential mystery remained. How could a monotonous substance such as DNA, like an alphabet with only four letters, convey enough specific information to produce the enormous variety of living things, from daisies to dinosaurs? The answer must lie in the way the molecule was put together. Avery and his co-authors, Colin MacLeod and Maclyn McCarty could say no more than that ‘nucleic acids must be regarded as possessing biological specificity the chemical basis of which is as yet undetermined’.

  In 1943, another scientist at one remove from the world conflict (because he had been offered a haven in neutral Ireland) gave a series of lectures in Dublin, called provocatively ‘What Is Life?’ An audience of 400 for every lecture suggested that his supposedly difficult subject was of great general interest.

  Erwin Schrodinger, a Viennese, had shared the Nobel prize in physics in 1933 for laying the foundations of wave mechanics. That same year he left Berlin where he had been working because, although not himself Jewish, he would not remain in Germany when persecution of the Jews became national policy. A long odyssey through Europe brought him, in 1940, to Dublin at the invitation of Eamon de Valera, Ireland’s premier. De Valera had been a mathematician before he became a revolutionary, then a politician; in 1940 he set up the Dublin Institute of Advanced Studies. Schro dinger found Ireland ‘paradise’, not least because it allowed him the detachment to think about a very big question.

  In his Dublin lectures, Schro dinger addressed what puzzled many students — why biology was treated as a subject completely separate from physics and chemistry: frogs, fruit flies and cells on one side, atoms and molecules, electricity and magnetism, on the other. The time had come, Schro dinger declared from his Irish platform, to think of living organisms in terms of their molecular and atomic structure. There was no great divide between the living and non-living; they all obey the same laws of physics and chemistry.

  He put a physicist’s question to biology. If entropy is (according to the second law of thermodynamics) things falling apart, the natural disintegration of order into disorder, why don’t genes decay? Why are they instead passed intact from generation to generation?

  He gave his own answer. ‘Life’ is matter that is doing something. The technical term is me
tabolism — ‘eating, drinking, breathing, assimilating, replicating, avoiding entropy’. To Schro dinger, life could be defined as ‘negative entropy’ — something not falling into chaos and approaching ‘the dangerous state of maximum entropy, which is death’. Genes preserve their structure because the chromosome that carries them is an irregular crystal. The arrangement of units within the crystal constitutes the hereditary code.

  The lectures were published as a book the following year, ready for physicists to read as the war ended and they looked for new frontiers to explore. To the molecular biologist and scientific historian Gunther Stent of the University of California at Berkeley, What Is Life? was the Uncle Tom’s Cabin of biology — a small book that started a revolution. For post-war physicists, suffering from professional malaise, ‘When one of the inventors of quantum mechanics [could] ask ‘‘What is life?’’ ‘ Stent declared, ‘they were confronted with a fundamental problem worthy of their mettle.’ Biological problems could now be tackled with their own language, physics.

  Research into the new field of biophysics inched forward in the late 1940s. In 1949 another Austrian refugee scientist, Erwin Chargaff working at the Columbia College of Physicians and Surgeons in New York was one of the very few who took Avery’s results to heart and changed his research programme in consequence. He analysed the proportions of the four bases of DNA and found a curious correspondence. The numbers of molecules present of the two bases, adenine and guanine, called purines were always equal to the total amount of thymine and cytosine, the other two bases, called pyrimidines. This neat ratio, found in all forms of DNA, cried out for explanation, but Chargaff could not think what it might be.