A light for life : The impact of X-rays on structural biology and its pioneers

David Stuart (University of Oxford/Diamond Light Source and Instruct Director)

In Gallery 38 of the National Portrait Gallery in London there is a portrait of Dorothy Hodgkin in her study, her desk littered with papers, and in the foreground is a model of the structure of insulin (Figure 1). The portrait is naturalistic apart from one small detail: Dorothy has four hands. Perhaps this goes some way to explaining her extraordinary achievements, which are still having a huge impact a century after her birth.

Much of Dorothy's research was carried out at the University of Oxford, where my group is based. But it was in Cambridge in 1934, working with J.D. Bernal, that she began her ventures into protein crystallography. She followed Bernal's lead in studying pepsin molecules, where she used X-ray diffraction to establish that “the arrangement of atoms inside the protein molecule is also of a perfectly definite kind.” Interestingly, the same experiment was the first to show that exposure to X-ray radiation damages the crystal – a problem crystallographers still face today.

Figure 1. Dorothy Mary Crowfoot Hodgkin by Maggi Hambling. Oil on canvas, 1985. Painted in Hodgkin’s study at home in Warwickshire, a structural model of the four molecules of insulin stands in the foreground. Courtesy of the National Portrait Gallery, London

The birth of structural biology

Not long after these results were published, Dorothy returned to Oxford. In 1935, she grew crystals of insulin, and was delighted when, on developing the X-ray photograph, she saw a regular array of tiny spots, indicating underlying atomic order within the crystal. However, it would be another 34 years before the tertiary structure could be solved. Dorothy later said: “I used to say the evening that I developed the first X-ray photograph I took of insulin in 1935 was the most exciting moment of my life. But the Saturday afternoon in late July 1969, when we realised that the insulin electron density map was interpretable, runs that moment very close.”

Insulin was a particularly complex molecule by the standards of the day, and, in the intervening years, alongside teaching and bringing up a family, Dorothy went on to solve the three-dimensional atomic structures of a string of other important biological molecules; starting with cholesterol in 1937, penicillin 8 years later and vitamin B12 in 1954. She received the Nobel Prize in Chemistry in 1964 for her work on penicillin, but this also recognised that her research had helped to pioneer a whole new field: structural biology. Throughout her career, Dorothy had the knack of working on problems of fundamental relevance to medicine, and this spirit led us to establish the Division of Structural Biology (Strubi) in the Nuffield Department of Medicine in 1999.

International relations

The foot-and-mouth disease virus is a tiny bundle of genetic material carried in a shell, shown here as a computer representation (reduced type O)

Dorothy was also a lifelong internationalist, keeping up contact with friends in countries such as the Soviet Union and China throughout the Cold War. Because of this, Dorothy was hugely respected in China and, through her contacts there and the efforts of her and David Phillips in the UK, I was able to spend a year and a half working on insulin structures in China from 1981 to 1983. I spent most of this time in the laboratory of Liang Dong-cai, one of the founders of structural biology in China, who had himself worked briefly with Dorothy in Oxford, before returning prematurely to China at the outbreak of the Cultural Revolution. There is still a strong link between structural biology in Oxford and China which stems directly from Dorothy.

Developing synchrotron light

As structural biologists were realizing the power of using X-ray diffraction to determine protein structures, the field of particle physics was also rapidly advancing. The end of the Second World War was something of a golden era, as both scientists and resources were released from the war effort. Before the war, cyclotrons were at the cutting edge of particle accelerators, but as physicists demanded higher and higher energies, the effects of relativity became significant. Cyclotrons were not able to support relativistic particles, and in 1945 the physicist Edwin McMillan proposed a new machine, the electron synchrotron, which would allow their relativistic acceleration.

The first of the machines was constructed in Woolwich, UK, in 1947, quickly followed by a machine built by General Electric (GE) in Schenectady in the USA. In the GE model, the electrons travelled in a glass vacuum chamber, and so it was here that a new phenomenon was observed for the first time: synchrotron light. The existence of synchrotron light had already been predicted, but the conditions that would determine the frequency were unknown, so it was sheer coincidence that this machine generated visible light.

As synchrotrons increased in size to accommodate higher-energy particles, thedominant frequency of radiation shifted into the X-ray region. However, synchrotron light continued to be seen as a waste of energy, to be eradicated as far as possible. In 1956, Tomboulian and Hartman were granted two weeks’ use of a synchrotron at Cornell, where they not only confirmed the spectral and angular distribution of synchrotron light, but also carried out an X-ray spectroscopy experi- ment parasitically attached to the side of the machine.

The Biochemical Society archive contains an extended videotape interview of Dorothy Hodgkin, conducted by Guy Dodson in 1990. This can be viewed online ( www.filmandsound.ac.uk/access/ ) in an easily searchable format by members of subscribing institutions (mainly universities in the UK). Please contact the Honorary Archivist, Dr John Lagnado, with any enquiries.

Thank you to the Biochemical Society for their permission to reproduce this article.

References

  1. Bernal, J.D. and Crowfoot, D. (1934) Nature 133, 794–795
  2. Hodgkin, D.C. (1971) Br. Med. J. 4, 447–451
  3. McMillan, E.M. (1945) Phys. Rev. 68, 143–144
  4. Acharya, R., Fry, E., Stuart, D., Fox, G., Rowlands, D. and Brown, F. (1989) Nature 337, 709–716

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