A Life at the Heart of X-Ray Crystallography
Elspeth Garman discusses the area in X-ray crystallography she has helped to create
Interview by Dr Richard Lofthouse, Editor of Oxford Today
Professor Dr. Elspeth Garman throws me her famous set of coloured beads, the ones she audibly used in her already celebrated Radio 4 The Life Scientific – well worth listening to on BBC iPlayer.
Every protein is made of combinations of 20 different amino acids which join together like a string of beads, only also like beads they are malleable and floppy, ‘like wet spaghetti’ she says.
The field of X-Ray Crystallography, now a century old, has changed beyond all recognition during Garman’s career, not least because of her incredible achievements to do with techniques and processes. In respect of the ‘wet spaghetti’, what happens is that Professor Garman and her students make the folded strings of beads all stand to attention ‘like soldiers’, by managing to grow the protein molecules into a crystal. Once it possesses this form you can bombard it with X-rays, to ‘see through it’ much as the hospital can look at a broken bone. That, in a nut shell, is X-ray Crystallography and it has been responsible for 28 Nobel Prizes.
I ask Garman why this is. She explains – as patiently as she might to a fresher – that unlocking the 3-D structure of, say, insulin, or indeed penicillin, is to begin to grasp how it works. If you can grasp how it works you can make a synthetic imitation, perhaps with advantages. One of the most famous examples is Rosalind Franklin’s X-ray diffraction experiments in the 1950s that led subsequently to the Double Helix theory of DNA.
Famous among students for her extremely detailed notebooks of experiments, and her innovative techniques for ‘fishing’ and cooling to 100 K (-193 C) crystals that are ‘large’ even at 0.2mm and can only be manipulated under a microscope, Garman was the first woman to be made a Senior Kurti Fellow at Brasenose, the award named after Hungarian-born, Brasenose physicist Nicholas Kurti (1908-1998) – still remembered at the college for his inverse baked Alaska.
But Garman is not merely a physicist. In fact it is difficult to explain what she does to a lay audience. As a Professor of Molecular Biophysics, her job title hints that she works at the interface of both biology and physics, and this turns out to be correct, and also an insight as to why she has achieved such a profound impact on a field that is nothing if it isn’t inter-disciplinary.
Garman began her career at Durham as a physicist, doing an Oxford DPhil in nuclear structure physics in the late-1970s – the only woman in the lab in Oxford at the time. The big move to biophysics came in August 1987, when a particular line of funding was drying up and her fellow crystallographer at Somerville College, Dame Louise Johnson, formerly David Phillips Professor of Molecular Biophysics (1990-2007), asked her to ‘go over to biophysics’.
With the benefit of hindsight, Garman laughs – ‘I don’t recognise all these artificial barriers,’ she says, ‘I work with everyone from mathematicians to Big Data specialists. It’s all science in the end.’
Sitting in her colourful office in the recently built Biochemistry building off South Parks Road, before me is a sumptuous leather binder from the University of Hamburg. Inside it is another very prestigious award, the Mildred Dresselhaus Guest Professorship Award, ‘for [Garman’s] pioneering contributions to structural biology, especially in leading the field of radiation damage during macromolecular X-ray diffraction.’
The key word in that tribute is ‘damage’. ‘Radiation damage in crystallography,’ explains Garman, has morphed into a field of its own, and one that she is preeminent in, to the point where there is a thing called ‘the Garman limit’ – how much radiation a crystal can take before you wreck it. She has also pioneered manipulation of crystals for low temperature data collection, in some cases achieving up to 70x more data from the experiment than at room temperature. Such techniques development ‘Is not sexy but it’s very useful,’ Garman notes. For someone who spent her childhood being expected to dissemble her bicycle and reassemble it on her own, that’s a typically understated comment on a career that has fundamentally helped the techniques and methods now used all over the world.
Introduce radiation damage and you can ‘confound the biological interpretation of the structures.’ In short, bombarding molecules with radiation can not only throw open windows on what the underlying mechanism is, but lay bare how it works. Because the radiation can be damaging, a great deal of emphasis has come to rest on interpretation via a 3D computer code and ‘dose map’ that shows what energy has been absorbed and how, by the crystals.
Lots of people experimenting worldwide on lots of different proteins has allowed the creation of an open access protein databank which currently has over 125,000 entries giving the three dimensional shape of a great range of biologically important molecules. Diamond Light Source is the UK's national synchrotron facility at Harwell, Oxfordshire, and it comes up repeatedly in our conversation. Along with Nuclear Magnetic Resonance and Electron Microscopy –both techniques for also decoding proteins- Garman explains that the whole field is slowly beginning to be automated with the use of robots and cutting edge technology. The laboratory is not about to disappear, but she recognizes that methods that she has helped to pioneer will in due course be furthered by technology.
