by Andrew Brown
Nucleic acids, in Pirie’s words, were not fashionable at that date, and Wendell Stanley was one of many who initially refused to believe that RNA was present in the virus. Even Bernal underestimated the significance of Pirie and Bawden’s discovery, and he needed to be persuaded by Pirie to accept the last paragraph of the letter sent to Nature,21 which stated that while their results had a certain intrinsic interest, if it could be shown that the rods in their solution were in fact TMV particles, the interest would be greatly enhanced. ‘This conclusion seems to us both reasonable and probable, but we feel it is still not proved, nor is there any evidence that the particles we have observed exist as such in infected sap.’
Bernal was fascinated by the way the long rod-like particles were packed in a regular arrangement, parallel to each other, in solution: did this mean that there were long-range intermolecular forces between them? The X-ray photographs showed some consistent details whether the virus was in a wet gel or dried in air, suggesting that there was a high degree of structural order within the viral protein – it appeared to him ‘to have about the same order of complexity as that produced by feather keratin’.22 Fankuchen used his ingenious new apparatus to study other viruses prepared by Bawden and Pirie. These included potato virus X and a bacteriophage (a virus that attacks bacteria). Bernal wrote to his old friend Astbury in Leeds about the work and also mentioned ‘the most interesting thing… nucleic acid which I have got in fibre form and which shows very strong negative birefringence and rather a peculiar photograph with a particularly strong line at 11 Å and another at 4.5 Å with a fibre spacing at some multiples of 3.3 Å’.23 Bernal also thought he could see some evidence for the nucleic acid line on the bacteriophage photograph.
Research into the structure of viruses started by Bernal would flourish in his department at Birkbeck College in the 1950s, as we shall see. Two categories of virus structure would be identified, in ever-greater detail: helical and spherical. TMV is the prototypical helical virus in which the capsid or protein coat forms helical tubes through which the viral RNA is threaded. The other main class of viruses, spherical viruses, have icosahedral capsids – their protein coats form a symmetrical, twenty-faced, polyhedron that approximates to a sphere – that enclose their viral nucleic acid, protecting it from a hostile environment. Bawden and Pirie were the first to prepare crystals of a spherical virus – the tomato bushy stunt virus (TBSV) – although when they brought the tiny (0.01 mm) crystals to Bernal, they had no idea about the importance of their latest preparation. The crystals were too small for single crystal photographs and Fankuchen, working with Dennis Riley (a research student of Dorothy Hodgkin’s spending a few weeks in Bernal’s laboratory), took powder photographs of the crystals suspended in their mother liquor. Bernal, working with a pair of dividers, carefully measured the two very faint diffraction lines obtained after the long X-ray exposures and working from Federov’s Law deduced that the virus particle had a diameter of 340 Å and was probably a body-centred cubic lattice. He sent a draft of a letter to Nature24 to Pirie, who was unimpressed and commented, ‘I still feel that you haven’t much to say and not even anything to contradict.’25
Bernal and Fan continued the virus work over the next few years, but their initial optimism that they would be able to solve the detailed structure of viruses faded. They attempted to use Patterson analysis for the diffraction patterns, but the better the narrow-angle X-ray photographs became, the more reflection spots were obtained that could not be made to fit any symmetrical model they tried. Eventually they admitted defeat: ‘It appeared that it was quite impossible to explain the pattern on the existing theory of X-ray diffraction from a crystal, for any [unit] cell large enough to give the observed spots was found to be larger than the size of the particle as inferred from all the intermolecular measurements.’26 They were the first to discern repeated subunits in TMV protein, but were ultimately frustrated that ‘the crystalline nature of the viruses that we have studied cannot in itself be given a biological significance nor [can it] give an answer to the question as to whether they are or are not the infective agents, nor to the far more metaphysical question as to whether they are to be considered living organisms’.27 It would not be until the mid-1950s that virologists would finally realize that infectivity of TMV depended on its RNA core and indeed the RNA, not the protein, was the repository of its genome.
Within days of receiving Bragg’s letter introducing Fankuchen, Bernal received another from his friend Hermann Mark recommending a young Viennese student, Max Perutz, to come to Cambridge to study X-ray crystallography. Mark had been in Cambridge, at a meeting of the Faraday Society devoted to macromolecules, at the end of September 1935. Before coming, he had been asked by Perutz to make enquiries about a research position in Hopkins’ biochemistry department. The Faraday meeting was attended by all the world’s leading researchers in polymer chemistry, and Mark completely forgot to ask Hopkins about Perutz. Mark also missed Bernal at the meeting, but heard that he was looking for a research student. On his return to Vienna, he strongly suggested to Perutz that he should go to Cambridge to work with Sage instead of with the more renowned Hopkins. Perutz pointed out that he did not know the first thing about crystallography, and Mark replied ‘Never mind my boy, you’ll learn it.’28
Max Ferdinand Perutz, as his middle name might suggest, was the product of a family that had prospered under the Austro-Hungarian Empire. He was born in 1914, one month before the Archduke Franz Ferdinand was assassinated, and both his parents came from families of textile manufacturers, who had made fortunes from introducing mechanical spinning and weaving into Austria. His father, Hugo, had been sent as a young man to Liverpool to learn the trade and was an unrestrained Anglophile. He coached his son in the ways of the English gentleman, emphasizing personal reserve and mode of dress. So it was the smartly dressed Perutz who presented himself at the Department of Mineralogy at the beginning of the 1936–7 academic year. As he entered the cramped and chaotic laboratory, not at all as he had imagined, he found himself being looked at suspiciously by three men working at one of the benches. The silence was broken by one of them barking at him in a thick New York accent: ‘What religion are you?’ Perutz said as calmly as he could ‘Roman Catholic’, to which came the immediate rejoinder ‘Don’t you know the Pope’s a bloody murderer.’29 Perutz understood this to refer to the Pope’s support for General Franco and soon came to the conclusion that the department was staffed entirely by communists. A few days later, Sage blew into the laboratory, sat on a table and talked with enthusiasm and charm about a bewildering range of subjects before suddenly looking at his watch and rushing off ‘with the air of somebody having to do something much more important’. At once, Perutz was fascinated by Sage, and readily imbibed his core belief that protein structure was the key to the understanding of living matter and that X-ray crystallography was the only method that could solve it. He asked to work on a biological problem, but Bernal had no crystals of biological interest available and instead gave him ‘some horrible chips of silicate from a slag heap’ to get started on.
Perutz inherited the gas-filled X-ray tube, originally built at the Royal Institution, that Helen Megaw had used. Like her, he had to master the tube’s idiosyncrasies, learning to adjust the valve to the vacuum pump so that the correct current was set up in the tube and the resultant X-rays would not be too hard (energetic) or too soft. He was taught experimental technique by Fankuchen, whose aggression was but a cloak for his essential good nature, and he received lessons in interpreting X-ray photographs from Bernal, who also instilled in him the importance of examining each crystal under the polarizing microscope first. At the end of his first year, Perutz returned to Europe for the summer and made a visit to Prague to see a cousin who was married to Felix Haurowitz, a biochemist. Haurowitz, who was working with crystals of horse haemoglobin,30 showed Perutz under the microscope how the purple plate-like crystals of deoxyhaemoglobin transform into scarlet needles of oxyhaemoglobin
as oxygen is taken up by the haemoglobin molecule. Perutz decided that this would be his crystal of biological interest and Haurowitz suggested he should approach Gilbert Adair, the Cambridge physiologist, for some specimens. Adair gave him some beautiful single crystals of horse haemoglobin, 0.5 mm in diameter, and within months Perutz was able to obtain rich X-ray diffraction photographs. The work was tiresome because the exposure times were so long, and Perutz had to resist the claims of others in the laboratory, who wished to use some of his apparatus. Excitedly, he wrote to Sage, who was staying in London, ‘Dear Mr Bernal, There are [sic] lots of news’ and asked whether there were any special photographs Bernal wanted to have taken because ‘I cannot hold back the 4 cameras very much longer against the claims of Wells and Knott.’31 Perutz proudly showed his photographs to his friends in Cambridge, but when they asked him what the photographs meant, he changed the subject because he had no idea!32
Perutz’s difficulty was essentially the one that confronted Bernal and Fankuchen in the interpretation of the X-ray data from viruses – there was no information about the phases (relative peaks and troughs) of the diffracted X-rays that is necessary to determine the electron densities of the molecule in question. Perutz was able to deduce the size and space group of the unit cell, which contained two haemoglobin molecules and possessed a two-fold axis of symmetry. By combining this information with the optical properties of the wet crystal, Perutz was able to define the orientation of the iron-containing, haem part of the molecule – by itself a new important detail about such a complex substance. He took photographs of wet and dry haemoglobin and showed that the intensity patterns were similar, suggesting that the protein molecules were not extensively altered by the loss of water around them. Bernal emphasized this point in the letter they wrote to Nature and believed it might offer ‘an opportunity of separating the effects of intermolecular and intramolecular scattering. This may make possible the direct Fourier [Patterson] analysis of the molecular structure once complete sets of reflections are available in different states of hydration.’33
Perutz had taken to heart Bernal’s advice about carefully examining crystals under the polarizing microscope, and as a result had noticed that his haemoglobin crystals acted like sponges: ‘They shrank and lost most of their X-ray diffraction pattern on complete drying, but I found that I could dry them in discrete stages, each of which still gave detailed diffraction patterns from which I could derive Patterson projections. These projections all showed the same pattern of vector peaks as that of the fully wet crystals, indicating that the interior of the haemoglobin molecules was rigid and impenetrable to water, which must therefore be filling the interstices between them.’34 Bernal’s idea was, both for proteins like haemoglobin and for viruses, that if they were studied in different states of hydration (where they might be swollen or shrunk), variations in the spacing and intensity of the diffraction patterns would be due to differences in the way the molecules were packed together, but any constancy would be due to the molecular structure itself. As a theory, it was correct, but in practice it did not lead to a foolproof way of separating the wheat from the chaff.
When Bernal accepted the position of Assistant Director of Research in 1934, he was not accorded life tenure under the new University Statutes, although he previously held tenure as a lecturer in mineralogy. Rutherford accepted administrative responsibility for X-ray crystallography through the Cavendish Laboratory, as long as its activities were satisfactorily financed and ‘the reasonable development of the subject’ was assured.35 Thus the department as a whole was adopted under sufferance, and Bernal especially so. J.G. Crowther, the science correspondent of the Manchester Guardian, witnessed the clash of temperaments between Rutherford and Sage during one visit to the Cavendish. Rutherford had little patience with any of his researchers, not because of personal intolerance but because his appetite for new data was insatiable, and he could be particularly harsh with those who did not approach a problem directly. Sage was much more discursive and could always see complications ahead that Rutherford would rather not be warned about. On the occasion that Crowther was interviewing Lord Rutherford, Bernal came in to the room to talk to Rutherford, who was ‘explosively critical’ of Bernal’s points of view. Bernal showed submission, ‘hanging his head’, but was ‘still unable to forget the complications’ that Rutherford did not want to be bothered with.36
In 1935, the Jacksonian Chair in Natural Philosophy fell vacant through the retirement of C.T.R. Wilson. Joseph Needham waged a one-man campaign to have the Chair ‘occupied by a crystal physicist… one deeply interested in the biological implications of his subject’.37 He gently stated that perhaps ‘the biological importance of crystal physics is not yet as widely appreciated as would be desirable’ within the University, before summarizing the central role of molecular fibres in living organisms – linking the linearity of the chromosome and of the muscle fibre with the linearity of ‘crystalline’ protein molecules. He also referred to the liquid crystal as ‘not merely a model for what goes on in the living cell… [but] a state of organization actually found in the living cell’. Without mentioning him by name, Needham provided one further example where Bernal’s work had made a valuable contribution – the structure of the sterols, which could not have been solved by chemistry alone. It was a well-intentioned effort to seat Sage in the Jacksonian Chair, but Rutherford was still riding the crest of the nuclear physics wave that he had created and saw no reason to diversify the department. Indeed he had just lost three of his most valued juniors in quick succession – Kapitza, Chadwick and Oliphant – and was therefore especially eager to appoint another nuclear physicist. In the event, Needham’s memorandum may have been useful to those who thought the Cavendish had become too narrow in its focus, and Edward Appleton, the radiowave expert, was appointed. Many years later, Sage told Helen Megaw that he believed Rutherford had not wanted him appointed to the Chair because of his age, not because of his politics.38
Aside from the Jacksonian Chair, Needham was at the heart of another attempt to establish inter-disciplinary research in Cambridge in 1935. The tandem scheme involved approaching the Rockefeller Foundation (RF) to fund an Insitute of Mathematico-physico-chemical Morphology at the University, with five division chiefs, all of whom had been founder members of the Biotheoretical Gathering that had first met at Woodger’s house in the summer of 1932.39 The RF had begun to foster the application of physical sciences to aid biological research, and were, for example, already supporting Astbury’s department in Leeds. The idea for the Biotheoretical Gathering to put itself on a more formal footing, as an institute funded by the RF, was Dorothy Wrinch’s, and she persuaded Needham to join her in approaching the Foundation. As part of their proposal they included a five page memorandum from Bernal, outlining a programme for the application of crystal physics to biology. He suggested a systematic survey of ‘typical proteins’ such as albumens and globulins, to determine their characteristic architectures as well as a more detailed structural analysis of those proteins that seemed the most likely to yield information about their molecular structures. He lamented the difficulty of obtaining suitable crystals to study in Cambridge, now that Miss Crowfoot was back in Oxford, and sought to assure the RF that if it ‘could see its way to providing this assistance’ it would be ‘coming to the help of research in what I am convinced is a most promising junction between biology and physics at a critical stage in its development’.40
The whole scheme was remarkably similar to the fictional National Institute for Biophysical Research that had featured in C.P. Snow’s novel, The Search. In the novel, Constantine, the character based on Bernal, calls for ad hoc teams of scientists to be formed to attack whatever problem seems the most promising, ‘all the workers having a share in deciding the programme to be followed. It may take years, you would want biochemists, a zoologist or two, an organic chemist, a crystallographer and so on.’41 Needham, who with his wife had written a favourable review of The Search,
wrote to the RF about the ideal of ‘achieving institutional freedom for a small body of picked investigators… enabled by adequate endowments to work for certain periods on whatever may seem best’42 – words that were almost identical to those used by Constantine in the novel. Needham met high-level officers of the RF who were well disposed towards the revolutionary science embodied in his grand scheme, but alarmed by the absence of administrative details (an aspect not ignored in The Search). After visiting Cambridge, the RF officers decided to start small by giving out a few individual grants, and stated that the ‘large plan was not under active consideration’43 until they became convinced of its viability within the university system. Over the next few years, any residual hopes still harboured by Needham and Bernal were dashed by the University hierarchy, reflecting both academic conservatism and personal antipathies.
The first to receive RF funding was Dorothy Wrinch, who was awarded a grant for five years to study theoretical biology. Wrinch, then in her early forties, was an applied mathematician of the highest pedigree. She had studied at Cambridge in the Great War and graduated as a Wrangler. While still an undergraduate, she sought out Bertrand Russell becoming an acolyte and a friend. She published influential mathematical papers, including one on seismic waves, before marrying an Oxford physics don in 1923. She then moved to Oxford and tutored mathematics in all five women’s colleges. Her husband was an alcoholic and after a few years they separated, leaving Dorothy with a young daughter to look after. Whether or not she was embittered by her failed marriage, Dorothy was combative and sharp-tongued, but found herself welcomed into the avant-garde Biotheoretical Gathering for her originality of thought and not handicapped by her lack of biological training. At the group’s summer meeting in Cambridge in 1934, she advanced the idea that there was a direct link between the sequence of amino acids assumed to be present in the genetic material of chromosomes and the sequence of amino acids in proteins. This was the same basis for gene specificity that Bernal had adduced in his talk for the International Congress on the History of Science in London three years before, but unlike Bernal, Wrinch committed her ideas to paper in a subsequent note to Nature.44
