Lives of the fellows

Peter Brian (Sir) Medawar

b.28 February 1915 d.2 October 1987
Kt(1965) OM(1981) CH(1972) CBE(1958) FRS(1949) BA Oxon(1935) MA(1939) Hon FRCP(1974) Nobel Prize 1960

There were many extraordinary facets to Peter Medawar’s personality and life. Not least among them was the fact that, following his first and very serious cerebral haemorrhage in 1969 and a series of subsequently progressively debilitating strokes, he not only continued to lead an experimental research programme at the Clinical Research Centre in Northwick Park but published six books that received much acclaim and had a wide readership. Although his most innovative and creative period as a scientist ended tragically and prematurely at the age of 54, he thus added immensely to his reputation as a writer who invariably discussed matters concerning science, the scientific method and the relationship between science and society with wisdom, insight and wit, and who set down his ideas with a lucidity and elegance of style rare among scientists.

Peter Medawar was born in Rio de Janeiro to an English mother, Edith Muriel Dowling and a Lebanese father, Nicholas. Anxious for their son to receive an English education they sent him to Marlborough College, where he was deeply unhappy but where he nevertheless developed his interest in biological science. He went on to Magdalen College, Oxford, to obtain a first class degree in zoology in 1935. The next three years were spent in the Sir William Dunn School of Pathology, and there he was exposed to the influence of Howard Florey, later Lord Florey [Munk's Roll, Vol.VI, p.178], whom he came to admire greatly. Peter became a lecturer and fellow of Magdalen College at the age of 23, having married a fellow student, Jean Shinglewood Taylor, the year before. Thus began a partnership that proved to be a vital factor in his life, for Jean not only gave her husband the unstinting support he needed to be able to function in top gear but sustained him in his last 18 years of increasing disability - years that put his patience, courage and determination to keep going severely to the test. She was also co-author of two later books, The Life Science..., London, Wildwood House, 1977, and Aristotle to Zoos....,London, Weidenfeld and Nicolson, 1984, which was originally published in Cambridge, Mass., USA, by Harvard, in 1983. She also saw his last book, the autobiographical Memoirs of a thinking radish, Oxford, Oxford University Press, 1986, through to publication.

Soon after graduating Medawar became interested in mathematical logic and a mathematical approach to biological problems, having been strongly influenced by the writings of Bertrand Russell. The first laboratory project that came his way involved the use of tissue culture in an attempt to identify a substance in malt extract that inhibited cell growth. He discontinued this in favour of a mathematical study of scalar growth of cells, again in culture, followed by an analysis of growth data already available on the human foetus, in an attempt to test the ideas of D’Arcy Wentworth Thompson on growth and form. He then turned to the question of why tissue grafts transplanted from one individual to another of the same species (allografts) are rejected, and it was in this field that he was to establish his towering reputation as a pioneer and a brilliant experimental scientist. Graft rejection had become an urgent concern early in the war because of the large number of airmen who received severe and extensive bums demanding treatment with skin grafts, and the Medical Research Council therefore invited Medawar to study it. Much work had been done since the turn of the century to elucidate the problem of graft rejection, and both skin and kidney allografts had been used experimentally in several species. Although there was tacit, but not universal, agreement that all allografts failed as a result of some sort of genetically determined incompatibility, it was left to Medawar to demonstrate beyond doubt that rejection is brought about by a specific immunological response against the histocompatibility antigens of the donor. Complementary evidence was provided by Peter Gorer, working at Guy’s Hospital, and the American George Snell in Bar Harbor.

Medawar’s conclusion derived from two separate studies, both bearing the hallmark of his subsequent work: simplicity of design, meticulous planning and perfect execution, followed by careful analysis and lucid exposition. The first study, published in 1943, was done with human skin allografts in collaboration with a Scottish surgeon, Thomas Gibson. It showed that skin grafts are rejected very promptly after a latent period, that the body develops ‘memory’ for a second graft from the same donor, and that the accelerated rejection of a second graft occurs only when it comes from the donor who had also provided the first graft, i.e. the rejection phenomenon has the latency and specificity typical of immunological responses. The second study (1944-45) was carried out in rabbits and, apart from confirming the human data in every detail and on a larger scale, it added a careful and systematic description of how skin grafts are rejected macro- and microscopically. Furthermore, it drew attention to the presence of large numbers of mononuclear cells (mainly small lymphocytes) in the graft at and just before the time of rejection, raising the possibility that rejection was cell-mediated rather than caused by the production of antibodies. Any doubts there may have been about the immunological nature of the rejection process were now wholly dispelled, and the field of cellular immunology was opened up. It was mainly for this work, as well as for some other interesting observations (for example, that the anterior chamber of the eye and the brain are to some degree ‘privileged sites’ in which allografts are not rejected as rapidly as might be expected, and that cortisone has a marked effect in prolonging skin graft survival -work done with P L Krohn) that Medawar was elected to the fellowship of the Royal Society at the unusually early age of 34.

He had meanwhile been appointed to the Mason chair of zoology at the University of Birmingham and had taken with him a postdoctoral fellow, Rupert E Billingham, who had completed his doctoral thesis in Oxford after war service in the Royal Navy. It was in Birmingham that the scene was set for the later studies on immunological tolerance. Sponsored by the Agricultural Research Council, Medawar and Billingham (aided by G H Lampkin) set out to devise a simple skin graft test that would distinguish clearly between dizygotic and monozygotic twins, on the assumption that the former but not the latter would reject skin grafts exchanged between them. Agriculturally this was of some importance because a female calf twinned with a male was known to lose both its secondary sexual characteristics and its fertility. Identification of such ‘freemartms’ was therefore both necessary and difficult. The results were unexpected in that all twins, regardless of sex, accepted each others’ grafts, and Medawar and Billingham soon realized that the reason for this must have been the fact (known to embryologists since the beginning of the century) that cattle twins usually share their blood circulation in utero. This, as the American immunogeneticist Ray D Owen had demonstrated as early as 1945, leads to an exchange of blood from an early enough foetal stage for the establishment, from blood cell precursors, of red cell chimerism. By showing that the unresponsiveness to red cell antigens extended to skin they established the concept of immunological tolerance, and much of Medawar’s energy in the ’50s was directed at proving experimentally its existence and characteristics. They were encouraged in this enterprise by the far-sighted speculations of two Australians, Macfarlane Burnet (q.v.) and Frank Fenner who, in their 1949 monograph on The Production of Antibodies, 2nd ed., Melbourne, Macmillan, developed a complex theory of self and non-self recognition, (Burnet, who was to share the Nobel Prize with Medawar in 1960 and who, too, was later knighted, had attempted to demonstrate the induction of tolerance to viral antigens but had failed.)

The beginning of the tolerance studies in 1951 coincided with Medawar’s appointment to the Jodrell chair of zoology at University College London, and he took with him Rupert Billingham and Leslie Brent - the latter an ex-serviceman who had just taken his first degree in Medawar’s department and who was to commence his postgraduate studies. Medawar led this small team with great verve and geniality, and set out to reproduce the naturally occurring cattle chimerism and tolerance in mice by the inoculation of first foetal, then neonatal, mice with viable allogeneic cells. Their task was considerably simpified by the use of inbred strains of mice obtained from G D Snell at Bar Harbor. After many failures they succeeded in showing that an immunologically immature mouse thus inoculated became a cellular chimera and failed to reject skin grafts transplanted later in life, that this unresponsiveness was strictly specific for the histocompatibility antigens of the donor strain, and that it was brought about not so much by the development of a positive controlling/suppressing mechanism as by some form of clonal deletion or permanent inactivation of lymphocytes. Later, when suppressor cells became demonstrable, this hypothesis fell into disfavour but it has recently, with the benefit of modern knowledge of the T cell receptor and of histocompatibility antigens, received significant support. The experimental demonstration of tolerance, which was first published in Nature in 1953, and in greater detail in the Philosophical Transactions of the Royal Society in 1956, caused a great stir among immunologists and transplant surgeons because it showed dramatically and for the first time that the barrier standing in the way of allotransplantation could be overcome after all, and because it provided a cogent explanation of the distinction made by the body between self and non-self molecules, thus ensuring that auto-immune responses and disorders are the exception rather than the rule. Further, it led directly to the discovery by Billingham and Brent of graft-versus-host disease (GVHD), a condition frequently suffered by experimental animals rendered tolerant by cell populations comprising significant numbers of T lymphocytes. In their tolerance studies GVHD was avoided by the use of F1 hybrid donor cells, but the recognition of GVHD pointed to the difficulties - still not entirely overcome - of transplanting allogeneic bone marrow to patients.

Another area opened up by Medawar and his colleagues at UCL was the study of the antigens responsible for allograft rejection, for they were the first to show that non-viable cells, and tissue extracts, can be immunogenic. Here, for once, their hypothesis (that the histo-compatibility antigens were DNA-proteins) proved to be erroneous. During this highly creative period of his life, in which Medawar headed a thriving and multifarious department of zoology with an exceptionally talented staff, he found the time to publish some brilliant speculations on the possible reasons for the survival of the mammalian foetus in its immunologically alien environment -speculations that continue to be of interest today.

Medawar’s contribution to transplantation immunology was recognized in 1960 by the award of the Nobel Prize for physiology and medicine, and honours both scientific, civil and royal, were heaped upon him. The former included a Royal medal in 1959, the Copley medal in 1969, and, in his last year, the Royal Society’s Michael Faraday medal, not to mention 17 honorary doctorates from universities in Britain and abroad. He was elected an Honorary Fellow of the College in 1974. It says much for Medawar’s strength of character that all this did not affect him adversely: whilst he derived great pleasure from the recognition he received, life went on normally and he did not allow himself to be deflected from his real and abiding interest, laboratory based research, which continued even when, in 1962, he became director of the National Institute for Medical Research in Mill Hill.

He had seven years as director before he became partially incapacitated by his first haemorrhage. In that period his intellectual brilliance and integrity, his continuing research with colleagues (for example, on the effects of irradiation on graft rejection, the use of cell-free tissue extracts in the induction of unresponsiveness, the properties of antilymphocyte serum, and an in vivo tissue typing test) and his outstanding personality as a leader who had the knack of drawing the best out of people without imposing himself, coupled with an extraordinary capacity for relentlessly hard work, made him an outstanding director. Indeed, in his time at the NIMR, the Institute became renowned internationally as a centre of excellence, and its reputation in immunology soared. This led to a constant stream of visiting workers who added further to the Institute’s intellectual stature and creativity. He nevertheless found - or made - time to sit on all kinds of public bodies (the Medical and Agricultural Research Councils, the University Grants Committee, the Governing Body of the BBC), he was widely in demand as a lecturer (his lectures, always carefully prepared, were invariably brilliant, and his BBC Reith Lectures on The Future of Man in 1959 aroused a great deal of interest), and he published several books in which he established his reputation as a writer and thinker with a wider public. These included: Uniqueness of the individual, London, Methuen, 1957, The Art of the soluble..., London, Methuen & Co., 1967, and Induction and intuition in scientific thought... Philadelphia, American Philosophical Society, 1969. His analytical ability as well as a certain streak of intellectual ruthlessness were well demonstrated in his devastating critique of the work of Teilhard de Chardin.

Although, following the disastrous brain haemorrhage in 1969, which happened when he was reading the lesson in Exeter Cathedral in his capacity as president of the British Association for the Advancement of Science, his research never again reached the heights recorded in the previous quarter century, he was now able to devote more time to writing. Apart from the two books written with his wife, and his final autobiographical volume, he published Advice to a young scientist, New York:London, Harper & Row, 1979, Pluto's republic, Oxford, Oxford University Press, 1985 (the title with a typical Medawarian touch), and The Limits of science, Oxford, OUP, 1985, originally published in New York by Harper & Row in 1984. The elegance or his prose and his perceptive analysis, linked to a self-deprecating humour, won him a wide readership and gave much pleasure to many, scientists and nonscientists alike.

All this time he was battling, together with his wife, children and friends, against the cruel fate of becoming increasingly handicapped, and his resilience and sense of humour, even in his darkest days, were both touching and exhilarating. He continued to preside over the transplantation biology section of the Clinical Research Centre, where he was strongly supported by the director and his staff, and where he was surrounded by loyal colleagues who regarded him with great affection and respect. His celebrated forays in his battery-powered wheelchair frequently caused hilarity both to him and to others.

What kind of man was Peter Medawar, apart from being a great scientist, thinker and writer? He had a tall, imposing presence and his handsome, dark features, his joie de vivre, boyish charm and self-evident intelligence, won him instant admirers. He enjoyed life to the full: good companionship, music, and sporting activities such as cricket and squash, provided him with the emotional and physical outlets that were essential to him in a life packed with intellectual activity. He had a passion for opera and knew the works of Verdi and Wagner intimately. He enjoyed chess, but did not mind losing. He was loyal to his colleagues and friends - a loyalty that was mutual - and he was generous to other scientists, especially those who were still making their way. His mind was wide open to new ideas and he made his own thoughts freely available to others. Medawar in his prime did not suffer fools; small talk was not for him, though he was not averse to hearing about minor scandals. He felt protective to those working in subordinate positions, such as his secretaries and technicians. Characteristically, it was under his directorship that the NIMR had its dilapidated sports pavilion restored and a common room, with a bar, established.

With such a busy and creative life it was perhaps not altogether surprising that he found it difficult to devote enough time and attention to his four children, Caroline, Charles, Louise and Alexander, a fact to which he referred with regret in his memoirs. He was nevertheless much loved and admired by them.

Peter Medawar was buried in Alfriston, Sussex, and a memorable Service of Thanksgiving was later held at Westminster Abbey. With his death there closed an important chapter in the history of immunology.

L Brent

[, 1987,295,1072-73; Lancet, 1987,2,923; The Times, 5 Oct & 8 Dec 1987; The Daily Telegraph, 5 Oct 1987; Roy.Soc.News, June 1985 7; New Scientist, 1975,27 Feb; Med. News-Tribune, 20 Aug 1971; Mayo Clinic Proc., 39,Sept 1964]

(Volume VIII, page 330)

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