Seeing Further (29 page)

When he took the pepsin crystals out of the liquid in the tube he found that they quickly lost their crystalline form, so he mounted a crystal with some of the liquid inside a fine glass capillary before putting it in the X-ray beam. He obtained a pattern of spots, the first time anyone had successfully made a single protein crystal diffract. Crowfoot went on to take a further series of photographs of the crystal until they had enough for a letter to
Nature
,
¹¹
describing their preliminary observations. Protein molecules are so large, consisting of thousands of atoms arranged in folded chains, that the relationship between their X-ray reflections and atomic positions is far from straightforward. Trial-and-error methods could not begin to narrow down the range of possible structures that would produce such patterns. Nevertheless, the Bernal and Crowfoot paper heralded the modern era of protein structure analysis.

Already at the forefront of the field at the age of twenty-four, in 1934 Crowfoot returned to Oxford where Somerville College (a women-only college) had given her a fellowship, and embarked on an X-ray study of the
protein hormone insulin.
¹²
She married the historian Thomas Hodgkin, and despite his long absences promoting adult education in the north of England, had given birth to two children by the end of 1941. A supportive college, indulgent in-laws and cheap domestic labour enabled her to keep working with only the briefest of intervals, despite a severe attack of acute rheumatoid arthritis after the birth of her first child. During the Second World War she was recruited to the secret penicillin project, trying to solve the structure of the miraculously effective antibiotic that had been purified from mould by Howard Florey and his colleagues in Oxford’s Dunn School of Pathology. Penicillin molecules had only a couple of dozen atoms, but the substance proved difficult to crystallise.

Success followed in 1945 after Kathleen Lonsdale personally brought Hodgkin samples of a more easily crystallisable penicillin derivative from America, where efforts to start industrial production were under way. Hodgkin’s structure unequivocally confirmed the presence of a previously unseen ring of atoms in the molecule, known as a beta lactam ring, that was fundamental to the drug’s ability to incapacitate bacteria. Although this discovery did not immediately lead to the creation of synthetic antibiotics as the project’s industrial partners had hoped, it was one of the first examples of a drug’s function being explained in terms of its structure, a principle that underlies all drug discovery programmes today. Lonsdale was delighted, and hoped for the opportunity to exercise her brand-new status as a Royal Society Fellow on Hodgkin’s behalf:

As she had so fervently wished, Hodgkin was herself elected to the Royal Society two years later, aged only thirty-six and by then a mother of three. She went on to solve the structure of the anti-pernicious anaemia factor, Vitamin B12, and in 1960 the Society appointed her its first Wolfson Research Professor. Bernal’s prophecy came true when she was awarded the 1964 Nobel Prize for Chemistry, the first (and so far the only) British woman to win a science Nobel. The following year she was appointed to the Order of Merit, the first woman to receive the honour since Florence Nightingale.

While Hodgkin developed Bernal’s project in Oxford, another of his students kept it going in Cambridge after Bernal himself had departed for the chair in physics at Birkbeck in 1937. Max Perutz (FRS 1954)
¹⁴
came to Cambridge as a wealthy foreign research student, funded by an allowance from his father who ran a textile business in Vienna. He began work on the protein haemoglobin, the pigment in red blood cells that carries oxygen round the body. But with the Anschluss in 1938 his Jewish family lost everything and had to flee for their lives. His parents eventually arrived in Cambridge and became dependent on his support. Fortunately his excellent X-ray photographs of haemoglobin crystals so impressed the new Cavendish Professor of Physics – none other than Bragg junior, soon to be Sir Lawrence to distinguish him from his father – that he found himself taken on in 1939 as Bragg’s research assistant with a grant from the Rockefeller Foundation.

As an ‘enemy alien’, Perutz suffered internment in 1940–41, but on his return was recruited (thanks to Bernal, and to a brief pre-war foray into glaciology) to one of the most audacious scientific projects of the war.
Project Habbakuk,
¹⁵
misspelled and misguided, aimed to build a huge fleet of aircraft carriers out of ice to enable planes to refuel as they crossed the Atlantic. Perutz carried out successful experiments on making ice stronger, but the project ran for months before its American partners calculated that construction of the vessels would be hopelessly costly and impractical, and cancelled it. For Perutz, however, its value was incalculable: through it he gained a British passport and the security he had lacked for so long.

More successful wartime scientific projects, such as penicillin, code-breaking and radar, led the government to increase budgets for peacetime research. Perutz’s work on haemoglobin, championed by Bragg, seemed sufficiently promising for the Medical Research Council to fund a unit on the Molecular Structure of Biological Systems (later called simply Molecular Biology) in the Cavendish Laboratory, under Perutz’s leadership. The crowded but exceptionally well-equipped unit’s mix of physics, chemistry, biology and mathematics proved a magnet for curious minds, especially physicists who had become disillusioned with their subject after Hiroshima.

Francis Crick (FRS 1959) was one of these, joining Perutz’s unit in 1949 and contributing a new mathematical rigour to his studies of proteins. The restless young American geneticist James Watson (For.Mem.RS 1981) arrived two years later. Informed by fibre diffraction photographs by Maurice Wilkins (FRS 1959) and Rosalind Franklin at King’s College London, the two of them discovered the double helix structure of DNA in
1953.
¹⁶
The structure was the most important discovery of twentieth-century biology, providing a mechanism that could unite Charles Darwin’s theory of evolution and Gregor Mendel’s model of heredity. A ‘spiral staircase’ of two linked chains of complementary pairs of the four nucleotide bases adenine, thymine, guanine and cytosine, it immediately revealed how such a chemically simple molecule could account for life in all its abundant diversity. ‘It has not escaped our notice’, famously wrote the authors of their classic paper in
Nature,
¹⁷
‘that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.’ Each chain could make a new double helix, enabling cells and organisms to replicate themselves. Crick and Watson also realised that the infinite number of ‘words’ that could be written in the four-letter alphabet A, T, G and C provided a genetic code to direct the construction of protein chains, though it took the efforts of many scientists until the mid-1960s to crack the code. The discovery ushered in the modern era of biotechnology, in which scientists not only read but edit genetic information to produce animals, plants, medicines or industrial processes tailored to human demands.

Perutz himself and his colleague John Kendrew (FRS 1960) continued with the much more difficult problem of protein structure. In 1953 Perutz discovered that introducing mercury atoms into the haemoglobin molecule could remove ambiguities in the results obtained from such large, irregular molecules. Combining this technique with pioneering computer analysis, Kendrew solved the structure of myoglobin, an oxygen-carrying protein a quarter of the size of haemoglobin, in 1957. Two years later Perutz and his team finally succeeded with haemoglobin. For the first time it was possible to see how the protein chain encoded by a DNA sequence folded itself into a characteristic, compact shape, as specific to its purpose as the nuts, bolts, valves, pistons, sparkplugs and gearwheels of a motor car. Perutz continued to work on haemoglobin for the rest of his life, describing the mechanism by which the ‘breathing molecule’ seizes and releases oxygen, exploring the evolutionary relationships between haemoglobins of different species, and
linking abnormal haemoglobin to disease. Today’s structural biologists use essentially the same technique, though with much better X-ray sources and computer analysis, to explore the whole toolbox of molecular machines that make up the living body. These include the enzyme DNA polymerase that builds new DNA chains on the template of a single DNA strand, and the bacterial flagellar motor, a protein complex that rotates the tiny flails that propel bacteria through their fluid worlds.

In 1962 Perutz and Kendrew shared the Nobel Prize for Chemistry, while Crick, Watson and Wilkins received the accolade for Physiology: an extraordinary sweep for one country, let alone a single laboratory. Sir Lawrence Bragg had been instrumental in forwarding all their claims: he heard of the awards while recovering in hospital from an operation for prostate cancer, leading his doctor to tell his wife that he was ‘over the worst, but now I think he may die of excitement’.
¹⁸
He had left Cambridge in 1953 to take up his father’s old job as Director of the Royal Institution. Having failed in his first plan of moving Perutz and Kendrew to the RI with him, Bragg started his own protein structure group there. It included David Phillips (FRS 1967), a young post-doctoral researcher from Cardiff, who led a team that solved the next protein structure, the enzyme lysozyme,
¹⁹
in 1965. With his student Louise Johnson (FRS 1990), he was the first to shed light on the molecular interactions that give enzymes their catalytic effect, without which the chemical reactions that power our lives would be impossible.

Bragg dedicated his last years to restoring the RI, which had gone through a fallow period, to the glory days of Faraday or indeed his own father. Apart from sorting out its finances and establishing a first-class programme of research, he devoted most of his own energies to promoting science literacy. With enormous enjoyment and a knack for the felicitous analogy, he launched a year-round programme of lectures for schools, accompanied by the most spectacular
demonstrations his inventive mind could conjure. Not a man for political activism, he took every opportunity through lecturing and broadcasting to present his vision of science as a benign, humanising activity that transcended class, gender and national boundaries. The RI continues this work today.

The triumphant successes of Cambridge molecular biology had been carried out largely in a ‘temporary’ shed outside the Cavendish Laboratory, known as The Hut. In 1962 they moved to the purpose-built Medical Research Council Laboratory of Molecular Biology, which has continued to expand ever since. Max Perutz chose to be chairman of the lab, not director as was usual in MRC units. He pursued a policy of attracting good people, giving them a share in the resources of the lab, and letting them get on with their research with a minimum of interference while he got on with his. The model also included more or less compulsory tea and coffee breaks in the communal canteen, where even the starriest prima donna would sit down next to the most junior graduate student and discuss science.

It paid off. The tally of Nobel Prize-winners steadily rose, with Fred Sanger (his second), Cesar Milstein, Georges Köhler, Aaron Klug, John Walker, Sydney Brenner, Robert Horvitz, John Sulston and Venkatramen Ramakrishnan joining the list. In 1993 Sulston (FRS 1986) moved to become founding director of the nearby Wellcome Trust Sanger Institute. Its major role in the international Human Genome Project, which published the complete human sequence in 2003, grew directly from Sulston’s work at the LMB on sequencing the genome of the nematode worm, work supported by Jim Watson in his role as head of the US Office of Genome Research. Both the LMB and the Sanger Institute continue as international centres of molecular biology, while labs throughout the world are peopled with those who imbibed the LMB philosophy as young researchers. Sulston, supported by the Wellcome Trust, has continued to champion the free availability of biological information and oppose ‘land grabs’ in the genome for private gain.
²⁰

Perutz retired as chairman of the LMB in 1979, but never gave up
research. In his latter years he became a frequent contributor to the
New York Review of Books,
writing witty and lucid essay-reviews on science and scientists. Though he abhorred political extremes of both right and left, he shared Bernal’s view of science as a force for good and set out to counter the anti-science movement with his 1989 collection of essays
Is Science Necessary?
²¹
His main concern was to promote health and well-being in developing countries, and to that end he advocated birth control, intensive agriculture and nuclear power (later with reservations). Like his more politically motivated colleagues, he argued passionately for an end to nuclear weapons and indeed all forms of warfare:

As for John Kendrew, after his solution of myoglobin he turned to government advice and scientific organisation. He had a close exposure to nuclear matters during two years’ tenure as deputy to the chief scientific adviser of the Ministry of Defence at the time of the Polaris Sales Agreement between Britain and the US. He subsequently became a member of the Council for Scientific Policy, created under the Labour government in 1964, and was knighted. A committed internationalist, he chaired the International Council of Scientific Unions and in 1978 became the founding director of the European Molecular Biology Laboratory, now a flourishing centre for research and training in the subject with a membership of twenty European countries.