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Professor Alan F. Williams, FRS
Journal of hnmunological Methods, 153 (1092) I-3 © 1992 Elsevier Science Publishers B.V. All rights reserved (X)22-1759/92/$05.1X)
I
JIM (16461 Obituary
Professor Alan F. Williams, FRS 25 May 1945-9 April 1992 Alan Williams died less than three months after he was found to have alveolar cell carcinoma. Given the tremendous impact that Alan had on developing methodologies to characterise ceil-surface molecules, it is appropriate that wc record in JIM some commentary and reflections on his achievements.
Alan arrived in Oxford from Adelaide in 1970 to join Rodney Porter's MRC lmmunochemistry Unit. He had just completed his PhD, on avian red cell differentiation, under the supervision of W.H. Elliott, following a Bachelor of Agricultural Science degree from Melbourne University. Porter's major research efforts we~'e shifting away
from antibody structure towards effector systems such as complement, although immunoglobulins were still being studied in the unit and A l a n initially characterised rat IgA and lgA-bearing lymphocytes. He realised the importance of determining the structure of lymphocyte cell surface molecules and in the early years initiated a substantial research effort aimed at characterising Thy-l, a major membrane component of thymocytes and neurones in the rat. To do this Alan's group had to overcome a considerable technical obstacle - that of working with lipophilic molecules - and in collaboration with Mike Crumpton he developed methods for solubilising and fractionating membr~me proteins in detergents, methods which are now widely used throughout the world. This work culminated in the publication of the complete amino acid sequence of Thy-l. This held two surprises, both of which were to lead to major advances in our understanding of cell surface molecules. First, despite having no known immune function, it had the appearance of an immunoglobulin domain; second, it contained no stretch of hydrophobic amino acids that could be envisaged to anchor it in the plasma membrane. The first observation led Alan to propose the existence of an immunoglobulin gene superfamily encoding cellsurface molecules involved in interacting with the external environment. Much of his subsequent research was devoted to characterising members of this family, which now number more than 100 extending far beyond the confines of the immune system. Alan's initial proposal of a fatty acid or lipid anchor to explain the second observation was greeted with scepticism from some other groups who suggested that he had missed or lost the crucial hydrophobic peptide. However, Alan subsequently demonstrated that Thy-1 has a glycosylphosphatidylinositol tail - the first mammalian protein in which this was found. Alan's constantly probing and questioning approach is well illustrated by his thoughts on the T cell receptor throughout the 70s. When he first arrived in Oxford, the B and T populations of lymphocytes had only recently been described and there was much speculation on the nature of the T cell antigen receptor. Alan joined the fray with his customary gusto, publishing vitally im-
portant papers, both practical and theoretical. The widely accepted notion at the time was that T ceils, like B cells, must be using antibodies or parts of antibodies to recogniz~ the surrounding world of epitopes. Despite the large number of papers published in su0port of this idea from what might be called the immunological in-crowd, Alan could see no evidence for it. He and several co-workers failed to substantiate such claims and they could not even repeat the work of others who had demonstrated the binding of haptens or native antigens to T cells. His efforts led him to co-author a review article, published in Nature in 1982, setting out our actual knowledge of the T cell receptor. In this and contemporary lectures he exhorted the immunological community to set out afresh in search of the receptor with no false preconceptions. He even suggested future work based upon monoclonal antibodies and cDNA cloning and within two years similar approaches had indeed proved successful. Throughout the 70s, he refused to swallow the conventional dogma without proof and in the end it was clear that, once again, he was right when so many others were wrong. Alan was first to exploit the tremendous potential of hybridoma technology in making monoclonal antibodies against molecules which were difficult to purify. Soon after Milstein and K6hler's classical paper, hybridoma supernatants were travelling between Cambridge and Oxford, and he published with Cesar Milstein and coworkers the development of three monocional antibodies against surface antigens on rat lymphocytes, one of which turned out to be CD4. From then on Alan remained at the forefront in demonstrating the uses of monoclonal antibodies: for example, in analysis of cell subpopulations, affinity purification and structural and functional characterisation of membrane molecules. Alan was appointed director of the MRC Cellular Immunology Unit in 1977 at the age of 32 an imaginative and adventurous act on the part of the appointment committee. He held this post until his death and amply justified the faith that had been placed in him. Together with long-term colleagues Don Mason and Neii Barclay and numerous postgraduate students, postdoctoral fellows and visiting scientists, he developed the ap-
plication of new molecular techniques to the cell surface. He received many national and international honours, including in 1990 a personal chair from Oxford University and fellowship of the Royal Society. Last summer, he accepted the appointment as head of the Sir William Dunn School of Pathology in Oxford. The diagnosis in January suddenly changed all of his many plans for this large department and in his remaining few weeks he put a considerable effort into arranging things for those left in the unit and department. For those who were lucky enough to know him, Alan Williams will always be a shini,g example of high ideals and scientific professionalism and integrity. He belonged to the tiny group of scientists who are so exceptional that the rest of us feel no resentment being pedestrian by comparison. Many have had the benefit of his penetrating questions at seminars; he was silent only when he felt that the work was not worth commenting upon. Despite his position he was always approachable: letters were answered promptly and few requests for assistance or reagents were not met. He did not suffer fools and would quickly cut through to the core ef the argument. However this was not gratuitous - he merely spoke his mind irrespective of the stature of the target and his incisive intellect and wide knowledge were more overawing than his temper. To balance this he had a great sense of humour. Despite the tremendous energy that he committed to science, his life was not all work. He enjoyed music and art, and emphasised the importance of taking holidays both as a means of relaxation and in order to spend time with his family: wife Ros and children Ben, 21, and Eliza, 19.
In one of his last major presentations, at King's College, London, in November, he was as lucid, far-ranging and impressive as ever. His obvious excitement and enthusiasm were contagious and no-one in the lecture theatre could have imagined that such a .source of constructive energy would be extinguished so ,soon. He made no secret of his illness and even produced and widely distributed a document detailing its course and his plans to cope with the changed circumstances; his amazing strength helped others to cope. There was no complaining at being afflicted with such a rare and malignant disease: "the 'why me' route has no attractions" - he simply regretted that he would "miss out on all the fun". His final days were spent in the same pragmatic constructive way that he had spent all of his research career: a New and Views article appeared in Nature a few weeks after his death and he worked on an encyclopedia of CD antigens until the day before he died. Alan will be missed not only as a scientist of great human qualities i~ut also as a friend who miraculously always had time to listen, argue and advise. He would, quite clearly, have continued to make major contributions for another 20 years. The tragic curtailment of such a dynamic mientific career is a great loss to the biological mientific community in the UK and around the world.
ALAN JOHNSTONE JENS JENSENIUS MICHELLE LETARTE JOHN FABRE KEN REID MIKE KERR
I
JIM (16461 Obituary
Professor Alan F. Williams, FRS 25 May 1945-9 April 1992 Alan Williams died less than three months after he was found to have alveolar cell carcinoma. Given the tremendous impact that Alan had on developing methodologies to characterise ceil-surface molecules, it is appropriate that wc record in JIM some commentary and reflections on his achievements.
Alan arrived in Oxford from Adelaide in 1970 to join Rodney Porter's MRC lmmunochemistry Unit. He had just completed his PhD, on avian red cell differentiation, under the supervision of W.H. Elliott, following a Bachelor of Agricultural Science degree from Melbourne University. Porter's major research efforts we~'e shifting away
from antibody structure towards effector systems such as complement, although immunoglobulins were still being studied in the unit and A l a n initially characterised rat IgA and lgA-bearing lymphocytes. He realised the importance of determining the structure of lymphocyte cell surface molecules and in the early years initiated a substantial research effort aimed at characterising Thy-l, a major membrane component of thymocytes and neurones in the rat. To do this Alan's group had to overcome a considerable technical obstacle - that of working with lipophilic molecules - and in collaboration with Mike Crumpton he developed methods for solubilising and fractionating membr~me proteins in detergents, methods which are now widely used throughout the world. This work culminated in the publication of the complete amino acid sequence of Thy-l. This held two surprises, both of which were to lead to major advances in our understanding of cell surface molecules. First, despite having no known immune function, it had the appearance of an immunoglobulin domain; second, it contained no stretch of hydrophobic amino acids that could be envisaged to anchor it in the plasma membrane. The first observation led Alan to propose the existence of an immunoglobulin gene superfamily encoding cellsurface molecules involved in interacting with the external environment. Much of his subsequent research was devoted to characterising members of this family, which now number more than 100 extending far beyond the confines of the immune system. Alan's initial proposal of a fatty acid or lipid anchor to explain the second observation was greeted with scepticism from some other groups who suggested that he had missed or lost the crucial hydrophobic peptide. However, Alan subsequently demonstrated that Thy-1 has a glycosylphosphatidylinositol tail - the first mammalian protein in which this was found. Alan's constantly probing and questioning approach is well illustrated by his thoughts on the T cell receptor throughout the 70s. When he first arrived in Oxford, the B and T populations of lymphocytes had only recently been described and there was much speculation on the nature of the T cell antigen receptor. Alan joined the fray with his customary gusto, publishing vitally im-
portant papers, both practical and theoretical. The widely accepted notion at the time was that T ceils, like B cells, must be using antibodies or parts of antibodies to recogniz~ the surrounding world of epitopes. Despite the large number of papers published in su0port of this idea from what might be called the immunological in-crowd, Alan could see no evidence for it. He and several co-workers failed to substantiate such claims and they could not even repeat the work of others who had demonstrated the binding of haptens or native antigens to T cells. His efforts led him to co-author a review article, published in Nature in 1982, setting out our actual knowledge of the T cell receptor. In this and contemporary lectures he exhorted the immunological community to set out afresh in search of the receptor with no false preconceptions. He even suggested future work based upon monoclonal antibodies and cDNA cloning and within two years similar approaches had indeed proved successful. Throughout the 70s, he refused to swallow the conventional dogma without proof and in the end it was clear that, once again, he was right when so many others were wrong. Alan was first to exploit the tremendous potential of hybridoma technology in making monoclonal antibodies against molecules which were difficult to purify. Soon after Milstein and K6hler's classical paper, hybridoma supernatants were travelling between Cambridge and Oxford, and he published with Cesar Milstein and coworkers the development of three monocional antibodies against surface antigens on rat lymphocytes, one of which turned out to be CD4. From then on Alan remained at the forefront in demonstrating the uses of monoclonal antibodies: for example, in analysis of cell subpopulations, affinity purification and structural and functional characterisation of membrane molecules. Alan was appointed director of the MRC Cellular Immunology Unit in 1977 at the age of 32 an imaginative and adventurous act on the part of the appointment committee. He held this post until his death and amply justified the faith that had been placed in him. Together with long-term colleagues Don Mason and Neii Barclay and numerous postgraduate students, postdoctoral fellows and visiting scientists, he developed the ap-
plication of new molecular techniques to the cell surface. He received many national and international honours, including in 1990 a personal chair from Oxford University and fellowship of the Royal Society. Last summer, he accepted the appointment as head of the Sir William Dunn School of Pathology in Oxford. The diagnosis in January suddenly changed all of his many plans for this large department and in his remaining few weeks he put a considerable effort into arranging things for those left in the unit and department. For those who were lucky enough to know him, Alan Williams will always be a shini,g example of high ideals and scientific professionalism and integrity. He belonged to the tiny group of scientists who are so exceptional that the rest of us feel no resentment being pedestrian by comparison. Many have had the benefit of his penetrating questions at seminars; he was silent only when he felt that the work was not worth commenting upon. Despite his position he was always approachable: letters were answered promptly and few requests for assistance or reagents were not met. He did not suffer fools and would quickly cut through to the core ef the argument. However this was not gratuitous - he merely spoke his mind irrespective of the stature of the target and his incisive intellect and wide knowledge were more overawing than his temper. To balance this he had a great sense of humour. Despite the tremendous energy that he committed to science, his life was not all work. He enjoyed music and art, and emphasised the importance of taking holidays both as a means of relaxation and in order to spend time with his family: wife Ros and children Ben, 21, and Eliza, 19.
In one of his last major presentations, at King's College, London, in November, he was as lucid, far-ranging and impressive as ever. His obvious excitement and enthusiasm were contagious and no-one in the lecture theatre could have imagined that such a .source of constructive energy would be extinguished so ,soon. He made no secret of his illness and even produced and widely distributed a document detailing its course and his plans to cope with the changed circumstances; his amazing strength helped others to cope. There was no complaining at being afflicted with such a rare and malignant disease: "the 'why me' route has no attractions" - he simply regretted that he would "miss out on all the fun". His final days were spent in the same pragmatic constructive way that he had spent all of his research career: a New and Views article appeared in Nature a few weeks after his death and he worked on an encyclopedia of CD antigens until the day before he died. Alan will be missed not only as a scientist of great human qualities i~ut also as a friend who miraculously always had time to listen, argue and advise. He would, quite clearly, have continued to make major contributions for another 20 years. The tragic curtailment of such a dynamic mientific career is a great loss to the biological mientific community in the UK and around the world.
ALAN JOHNSTONE JENS JENSENIUS MICHELLE LETARTE JOHN FABRE KEN REID MIKE KERR