Graham A. Dunn (1944–2024) – a pioneer of cell migration analysis

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With the sudden and unexpected death of Graham Dunn, the cell biology community in Britian and worldwide has lost an outstanding, imaginative scientist often working years ahead of the mainstream. For those who knew him well, the overwhelming response has been one of real loss, never again to hear his sharp humour, his approachable warmth and generosity of spirit that benefited so many. Graham was one of those exceedingly likeable and fascinating people; amazingly knowledgeable and insightful, insatiably curious, and enormously generous with his time and ideas. As Rick Horwitz said of him, the kind of colleague that we all want to work with.Graham A. DunnBorn in Oldham, Graham (George to his student friends) was academically very bright and progressed through his school years with no difficulty. He developed his love for science under teacher and mentor Michael Brook of Salandine Nook school, who remained a friend until his death.Graham selected to read Zoology at University College London in 1963. At that time, the head of the Department of Zoology was Michael Abercrombie, renowned for his pioneering studies on tissue cell migration (Dunn and Jones, 1998). Graham had a fascination for microscopes (Dunn and Jones, 2004) and this, plus his academic qualities, persuaded Abercrombie to take Graham as a PhD student. Graham's work at this time was to address long-standing questions on contact guidance, most famously espoused by Paul Weiss (Weiss, 1945). Graham developed methods to measure the geometry of nerve fibre outgrowths in plasma clot cultures. Using time-lapse optical birefringence of migrating nerve fibres, he was able to demonstrate that contact guidance was not of primary importance as had been thought previously, but rather mutual contact inhibition of fibres (Dunn, 1971). This early work was a typical example of what was to become a hallmark of Graham's scientific career – an ability to think beyond conventional ideas and devise new experimental approaches.There followed a short postdoctoral visit to the laboratory of Vernon Ingram at MIT to be taught the new science of molecular biology. As often recounted by Graham, it was here that he learned to smoke marijuana and to run SDS gels of cell extracts. After only 1 year, he became convinced that molecular biology was not for him, and he returned to join the laboratory of Abercrombie, who had moved to take on the directorship of the Strangeways Research Laboratory in Cambridge.Here, Graham proposed a hypothesis of cell movement linked to mechanical constraints on the formation of linear bundles of microfilaments within cells (Dunn and Heath, 1976). The restriction was experimentally confirmed by utilising prism-shaped substrata, a simple yet remarkable approach. Transmission electron microscope examination of whole-spread chick heart fibroblasts at 80 kV and 1 MV revealed the predicted discontinuities in the microfilament bundle system, which coincided with a discontinuity in the shape of the substratum.It was during his 10-year tenure at Strangeways that Graham met his wife Barbara, a fellow biologist at the institute. They were to remain together for over 40 years until his death. It was also arguably where his most significant finding was accomplished. Having utilised high voltage electron microscopy as part of his studies with Julian Heath, he noticed that the microfilament bundles of fibroblasts seemed to terminate at discreet foci near the leading edge of migrating cells. These foci were positioned very close to the plasma membrane on the cell–substratum interface. Paradoxically, a search for ‘focal adhesions’ in PubMed will now detect more than 7700 publications but doesn't catch the historical paper by Abercrombie and Dunn (1975) in which images of focal adhesions appeared for the very first time. In this paper, the authors simply called these structures ‘cell feet’ [and some years later, when focal adhesion studies entered the exponential phase, a Nature News & Views paper entitled ‘Hot Foot’ (Lloyd, 1980) repeated this unpretentious metaphor for the second, and last, time].How did things develop? In 1971, Abercrombie, Heaysman and Pegrum published electron microscopy images of cross-sections of crawling fibroblasts (Abercrombie et al., 1971), in which discrete electron-dense ‘adhesion plaques’ in the regions of closest apposition between the cell membrane and the substratum could be seen for the first time. The authors even suggested that “the plaques are linked up to the fibrillar system of the cell”, but how could they see the dynamics of such adhesion plaques as they come and go? Graham constructed an improved version of the interference reflection microscope (IRM) developed by ASG Curtis in 1964 to study the role of cell–substratum adhesion in living migrating cells. At the same time, Colin Izzard and Linda Lochner at the State University of New York, Albany, also tried to improve Curtis's technique. The two groups were in contact, and both obtained images that were much clearer than the original images by Curtis, and consistent with the electron microscopy images presented by Abercrombie et al. (The secret was simple – to use an objective with high numerical aperture!) But how could they prove that these dark patches (‘feet’), as well as being the regions of closest approach of the reflecting surface of the cell to that of the substratum, were in fact adhesions? Graham obtained elegant convincing evidence, and his paper (Abercrombie and Dunn, 1975) appeared just before the study published by Izzard and Lochner (1976).These visualizations of focal adhesions were followed by unequivocal demonstration that these structures are associated with bundles of actin filaments. While the idea of adhesions being associated with the microfilament network had already been proposed in the Abercrombie et al. (1971) paper, it was finally established by the correlated IRM and high-voltage stereo electron-microscopic study by Heath and Dunn (1978), which was published in Journal of Cell Science. These papers by Graham, in which he describes the architecture of focal adhesions for the very first time as we are used to seeing them now, can be compared in importance with the first descriptions of other basic cell organelles, such as the Golgi or centrosome.Outside of pure laboratory research, Graham also joined with Abercrombie in bringing a small obscure group of Russian scientists to the attention of the science community. Working in Moscow, Juri Vasiliev and his team were also doing pioneering work on cell migration. In the 1970s, Abercrombie ‘discovered’ their work and somehow managed to initiate a USSR–UK collaboration programme. After Abercrombie died in 1979, Graham became the coordinator of this venture and dived enthusiastically into a series of visits to Moscow, Leningrad and Tbilisi. The importance of these contacts for a small cell biology community in Moscow working in almost complete isolation is difficult to overestimate. Graham was more than an ambassador for western science; he was, for the likes of Vasiliev, Gelfand and Bershadsky, a rare example of scientific freedom and independence. In return, Graham came out of these interactions with a greater commitment to a mathematical approach to quantifying cell behaviour, garnered from his conversations with the famous mathematician and Vasiliev's great friend, Israel Gelfand.After Abercrombie's death, the Medical Research Council closed the unit at Strangeways and Graham was re-located to join an MRC Unit of Cell Biophysics housed at the Drury Lane campus of King's College London (1981). Here, with G. W. Ireland, he devised a miniature laminar flow pump to demonstrate that the so-called contact inhibition of proliferation in 3T3 cells can be released by circulating the medium. This study, so typical of Graham's scientific style, was published in Nature (Dunn and Ireland, 1984). It was also here that Graham became more interested in idea

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