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Medawar Prize Acceptance Speech

Morris, Peter J.

doi: 10.1097/01.tp.0000250734.54464.21
Article

Emeritus Nuffield Professor of Surgery, University of Oxford; Director of the Centre for Evidence in Transplantation, Royal College of Surgeons of England; and London School of Hygiene and Tropical Medicine, University of London.

Address correspondence to: Peter J. Morris, Centre for Evidence in Transplantation, Royal College of Surgeons, 35-43 Lincoln’s Inn Fields, London, WC2A 3PE. www.transplantevidence.com

E-mail: pmorris@rcseng.ac.uk

Received 25 September 2006.

Accepted 27 September 2006.

Ladies and gentlemen, firstly I must thank David Sutherland and his Medawar Prize Committee for selecting me and secondly thank my old friend Tony Monaco for his very gracious and flattering citation. I am truly delighted at receiving this prestigious honor from The Transplantation Society. Furthermore, as I got to know Peter Medawar well after I had moved to Oxford in 1974, it gives me added pleasure to receive this award.

I have had a good life and a good career but also one in which luck played a considerable part at all stages. I am a fourth generation Australian and was a medical student at the University of Melbourne. I was certainly not a Phi Beta Kappa student in American terms but I had a great time and I still feel that my six years as a medical student at the University of Melbourne were some of the best years of my life. I had many interests outside my medical studies, most of them in the sporting arena. I played both cricket and baseball for the University of Melbourne, which did consume a lot of my time (Figs. 1 and 2). My wife Jocelyn, better known as Joce, was also in the same year and she was indeed a Phi Beta Kappa student. Although she started at medical school at the same time as me, I only began to date her in my final year and married her three years after graduation. That was my first bit of luck!

FIGURE 1.

FIGURE 1.

FIGURE 2.

FIGURE 2.

After graduation, I became a medical officer at St. Vincent’s Hospital, one of the University of Melbourne teaching hospitals. Following two busy years as a resident medical officer and after I had been appointed as a Surgical Registrar, the first of such appointments made at St. Vincent’s Hospital, I had my next lucky break when Dr. Claude Welch, the senior surgeon at the Massachusetts General Hospital (MGH) came as a visiting professor (1). In those days, visiting professors came for a month and in fact operated while they were there. Claude Welch operated every day and I was fortunate enough to be selected to be his registrar and to take care of him virtually night and day. Every day, I assisted him as the first assistant in theater where he was operating on very complex cases that had been referred to him by consultant surgeons at the hospital. His behavior and overall performance in theater and in the ward made him the true role model of a surgeon as far as I was concerned. Everything he did was accompanied by “please” and “thank you” to his assistants and scrub nurses, which, in my limited experience at that time, was almost unheard of. Nevertheless, to everyone’s amazement the first case that he did, namely a subtotal gastrectomy for peptic ulcer, was completed in an hour and 20 minutes! As I mentioned above this was my next lucky break, as it was through Claude Welch that later on I came to the MGH in Boston to complete my surgical training and embark on a research career.

After three years at St. Vincent’s Hospital, I planned to go to the United Kingdom for further surgical experience, because in those days there was no complete surgical training program in Australia. All budding young surgeons headed off to the United Kingdom for what was known as “cutting experience.” I worked in general practice for a few months, as my wife was also doing by then, to save some money to live on when we first arrived in the United Kingdom. In October of 1961, we set sail on the Prince Alfred, a cargo passenger boat, where I was the ship’s doctor and Joce was a passenger (Fig. 3). After a long and tedious voyage, which was lightened to some extent by my need to study for the Fellowship of The Royal College of Surgeons exams, we arrived on an early winter’s day in a rather godforsaken port in the North of England, namely Hull. We then took the train down to London where fortunately I had a Dominion Fellowship at Guys with Professor Sir Hedley Atkins for three months. I then moved to the Royal Postgraduate Medical School at the Hammersmith Hospital where I was a resident surgical officer working with Professor Iain Aird and Mr. Dick Franklin. This was an entirely new experience in that it was truly an academic center, with medical and surgical grand rounds and with the Professors of Medicine and Surgery being chairmen of their respective divisions. Later, after I had gone to the United States, I realized that the school was modeled on those in the United States, but it was the first such institution in the United Kingdom.

FIGURE 3.

FIGURE 3.

Following my time at the Hammersmith, I was fortunate to spend a year as a surgical registrar with Mr. Tom Rowntree at Southampton, which was an incredible year. This was the first time I had worked outside a teaching hospital, for Southampton at that time was an extremely busy district general hospital and I gained enormous surgical experience there. I was supervised and trained meticulously by Tom Rowntree, and indeed this was competence-based training at the highest level well before the term had been invented.

I had no particular interest in transplantation at that time, but while I had been at the Hammersmith one of the first living unrelated kidney transplants was performed between two general practitioner partners in Newbury, about 30 miles from Oxford, by Professor Ralph Shackman, a urologist, and Mr. James Dempster, one of the pioneers in experimental kidney transplantation. Dr. Clarke was dying of renal failure and his partner had volunteered to donate one of his kidneys. This was done in 1962 and was technically successful but the recipient, Dr. Clarke, died some four months after the transplant procedure from infection because immunosuppression was total body irradiation and 6-mercaptopurine. After his death, his patients created a trust fund in his memory, which became quite sizeable and was used to fund research into renal disease mostly at the Royal Postgraduate Medical School. However, the Dr. Clarke Trust Fund was held at Reading and some 12 years later when I came to the Chair of Surgery in Oxford and set up a Transplant Unit for the Oxford region, the Trustees decided that as Reading and Newbury were in my region, to hand all the funds over to the University of Oxford for my use. However, I must confess that although I was not directly involved in that transplant at the Hammersmith in 1962, the organizational problems associated with it left me somewhat unimpressed with respect to renal transplantation being a clinically relevant procedure!

Towards the end of my year at Southampton, Claude Welch phoned to say that the U.S. Government had unexpectedly drafted one of their senior residents and would I like the job? He said that he was aware that I wanted to come to the United States to do research but felt that if I spent a year as a senior resident it would open up doors for me in the United States—and how right he was. After discussing this with Tom Rowntree, he agreed that I should move. So Joce and I, now with one child, our first son Peter, flew off to Boston on December 30 and I still vividly remember that on arrival the temperature was −13°F.

I had a hugely interesting year as a senior resident, for in those days the MGH had a huge surgical workload and the surgical staff was also very large (Fig. 4). I learnt virtually nine ways to skin a cat for most surgical conditions as I took the opportunity of being exposed to as many of the surgical visiting staff as possible, but of course, I did have to do my stint on the East Ward service.

FIGURE 4.

FIGURE 4.

At the end of that year, I was seeking a research fellowship and various people were keen to take me on board. I took up an offer from Jack Burke, whose laboratory was investigating defense mechanisms in models of surgical infection. Jack Burke, following his fellowship year with Sir Ashley Miles at the Lister Institute in London, had published the seminal paper on the rational use of preventive antibiotics in experimental models of infection in the guinea pig back in 1962 (2). This led to our present-day use of prophylactic antibiotics given before or during induction of anesthesia in patients at risk of infection following a surgical operation. He was also director of the Shriners’ Burns Unit, which looked after children with bad burns, and I was very much involved in studies of metabolism and the impact of silver nitrate therapy, which had just been introduced for the initial treatment of severe burns (3, 4). I also studied aspects of the immunological reactivity to infection and I guess the first paper I wrote in this area was involved with the impact of antilymphocyte serum on Staphylococcal infection, which was published in Nature (5).

I had a great two years in Jack Burke’s laboratory, but just across the hall was Paul Russell’s laboratory, which was entirely devoted to transplantation immunology and histocompatibility testing. And indeed this was where I first met Tony Monaco. In those days, histocompatibility testing was cellular, such as normal lymphocyte transfer testing and mixed lymphocyte cultures. I became increasingly interested in this area, for Paul Russell after he came to the MGH as the chairman of surgery two or three years earlier, had established an excellent renal transplant program, which finally impressed me as a truly viable management of end-stage renal failure.

Early in 1966, I had received a phone call from Professor Maurice Ewing, the first Professor of Surgery within the University of Melbourne, to ask me if I would join his Department and also would I consider bringing tissue matching back to the embryo renal transplant unit recently established at the Royal Melbourne Hospital. I went to discuss this with Paul Russell, who was very supportive, but I remember him saying that he thought that tissue typing was likely to become a serological exercise and this might be difficult for surgeons to embrace! However, he arranged for me to visit Bernard Amos at Duke University, Paul Terasaki at UCLA, and to meet Jon van Rood, who was about to visit to type the MGH living related donors and recipients. He felt that this would give me an opportunity to see the three technical approaches to serological tissue typing at first hand. To cut a long story short, after seeing these three pioneers in action, I decided that the cytotoxic technique and particularly the microcytotoxic technique developed by Terasaki and his senior technician, John McClelland, was the way to go (6). In fact, this led to a lifelong friendship and collaboration with Paul Terasaki (Fig. 5), and indeed I took part in the now famous International Histocompatibility Workshop in Torino in 1967 as part of his team. It was at this wet workshop where HLA was finally shown to comprise two genetic loci, and it also enabled me to meet and work with all the pioneers in HLA over the three weeks.

FIGURE 5.

FIGURE 5.

Now I come to another lucky break and that followed a phone call from Maurice Ewing to say that the University of Melbourne was in desperate financial straits and my job had been frozen and would I be able to stay on at the MGH while he sorted the finances out with Melbourne University? Both Paul Russell and Jack Burke said that there was no problem with this. However, Mel Williams, now at Johns Hopkins Hospital, who had been a surgical resident with me at the MGH, had gone to work at the Walter and Eliza Hall Institute of Medical Research in Melbourne with Professor Gus Nossal. He had heard from my mother about the disappearance of my job and as he was returning to the Medical College of Virginia to work in David Hume’s Department, he mentioned this to David Hume, who was anxious to get a tissue typing and transplantation immunology laboratory established at the Medical College of Virginia. Thus I had a phone call from David Hume asking me if I would visit to have a chat to him about this. This I did and the one thing that made me accept his very generous offer, which was not withdrawn when I made it clear that I was going back to Melbourne later in 1967, was a −120° freezer full of serum that he had taken before and after transplantation in all the patients that he had transplanted. By then he had established probably the largest renal transplant center in the world at the Medical College of Virginia. I remember asking him what he was going to do with the sera in this freezer and he informed me that they were waiting until someone came along who knew what to do with them. When I enquired as to whether I could have access to the sera and informed him that I did know what to do with them, he said yes I could and that clinched the deal.

I had a remarkably productive time at the Medical College of Virginia working with David Hume, H.M. Lee, Mel Williams, and many other equally enthusiastic colleagues. Using the sera from that precious freezer, I was able to show for the first time that cytotoxic antibodies did develop after renal transplantation and subsequently that they were donor specific (7–9). Furthermore, in those patients who developed cytotoxic antibodies the outcome was worse, leading me to suggest that these antibodies were either the cause of rejection or were a marker of prior sensitization. Another major event occurred over an extraordinary weekend, which led to the detailed description of the phenomenon of hyperacute rejection (10). David Hume had just returned from being a visiting professor in South America and was very anxious to operate himself, and as it happened we had the opportunity of doing four cadaver kidneys over that weekend. Following initial good reperfusion, three of these kidneys became dusky and blue within 20 min or so. Mel Williams beavered away in a laboratory doing frozen sections of the kidneys that had been implanted, and showed an intense polymorphonuclear leukocyte infiltration in the glomeruli and intertubular capillaries. Meanwhile, in my laboratory I had also been beavering away and showed, for example, that not only were there cytotoxic antibodies reacting with the donor lymphocytes but in one patient there was a high titer of antibody before transplantation, which fell after the kidney was in situ. In fact, this led David Hume—who had never seen anything like this before—to put the second kidney in from the same donor but the same thing happened! Several other cases were to occur after I left to return to Melbourne. This led to the very complete description of the phenomenon in the New England Journal of Medicine in 1968 (10).

I returned to the University of Melbourne at the end of 1967 to take up my now re-established position in the Department of Surgery of the University of Melbourne at the Royal Melbourne Hospital. Here again I was establishing a transplant immunology and histocompatibility laboratory, carrying out a general surgical clinical commitment and being heavily involved in the embryo renal transplant unit established by Vernon Marshall and Priscilla Kincaid-Smith. Due to my interest in cytotoxic antibodies I had felt that blood transfusions given to dialysis patients before transplantation would be a bad thing. I had tried to look at this retrospectively while I was in Richmond, Virginia but the records of blood transfusions in their patients were inadequate and I was not able to obtain sufficient robust data to make anything of it. However, on returning to Melbourne, the transfusion records of all their patients while on dialysis were excellent and here, much to my surprise, I found that patients who had received numerous transfusions did not do any worse than patients who had received very few transfusions. This led to the publication of what I consider one of my better papers entitled “The Paradox of Blood Transfusions in Renal Transplantation” (11), which in retrospect I wrongly published in the Medical Journal of Australia where very little notice of it was taken outside Australia. Indeed, in that paper I suggested that perhaps transfusions were inducing a degree of partial tolerance in the recipients. However, this did lead me to establish a research program on tolerance induction with prior antigen treatment in the form of blood transfusions, and tolerance was to remain a major interest throughout my professional life. The first model involved experimental skin grafting in rats but the skin graft proved to be too sensitive an assay to demonstrate any effect and hence, with John Fabre, my second Ph.D. student, we established a renal transplant model in the rat and this enabled us to show that blood transfusions could induce tolerance to a renal transplant in the rat (12, 13). We went on to use this model in studies of passive enhancement as well as a variety of antigen pretreatment protocols, which continued after I moved to Oxford (14, 15).

Other interests in the HLA area involved extensive studies of HLA and disease, particularly autoimmune disease and two such studies which have stood the test of time involve the first description of the association of HLA with autoimmune active chronic hepatitis and an association between HLA and pancreatic islet cell antibodies (16, 17). I was also very much involved in anthropological studies using HLA as genetic markers around the Pacific Rim. One of the more exciting findings in our studies of HLA in New Guinea Highlanders (Fig. 6), who had been isolated from other genetic exposure for some 10,000 years, was that they had an extraordinarily limited polymorphism of HLA Class 1 antigens (HLA Class 2 antigens had not been described at the time) (18).

FIGURE 6.

FIGURE 6.

The application of tissue typing to renal transplantation was being developed and Alan Ting, my first Ph.D. student, and I continued to study the role of antibodies. One significant contribution, also involving Ian McKenzie, an M.D. graduate student, was the first description of natural cytotoxic antibodies in man against pig and sheep lymphocytes, these experiments being triggered by the attempt of Denton Cooley to implant hearts from these animals in two patients dying of heart failure in Houston and which from the media reports sounded to me like another example of hyperacute rejection (19). We also showed also that there was some impact of matching for HLA on the outcome of cadaver transplantation, modest as it was (20).

Then in 1973, I was invited to take the Nuffield Chair of Surgery at the University of Oxford, and so in August 1974 with Joce and now five children I moved to Oxford. Here I began what was a long and exciting career in surgery and transplantation at the University of Oxford. As several of my technicians from Melbourne moved with me to Oxford, I was able to rapidly establish working laboratories, including yet another tissue typing laboratory. I was also fortunate in obtaining a Medical Research Council Programme Grant in transplantation immunology, which I held for the next 20 years. Later John Fabre joined me in Oxford as did Alan Ting, and over the succeeding years a whole succession of first-class young scientists with a wide variety of immunological interests joined the Nuffield Department of Surgery (NDS), which became a powerhouse of experimental immunology. The scientists were recruited as young postdocs or in their first appointments after postdoc positions and were grown, so to speak, in the NDS. These included such people as Andrew McMichael, Keryn Williams, Ian Hutchinson, Phillipa Cullen, Sue Fuggle, Jon Austyn, Maggie Dallman, Alain Townsend, John Bell, Andrew Bushell, John Todd, and of course, Kathryn Wood. Kathryn joined me in 1982 as a young biochemist, which we required at the time for our tolerance studies, and here she is now as an internationally renowned figure in transplant immunology and presiding over this World Congress as an outstanding president of The Transplantation Society. The clinical staff were of the highest order and included a succession of Australian and New Zealand transplant fellows such as John Thompson, Richard Allen, Bob Jones, and Justin Roake. Numerous research fellows and graduate students have passed through the department from almost every country in the world and nearly all have gone on to great things. The department’s research activities needless to say included a major interest in histocompatibility and immunological tolerance but also had major research programs in type 1 diabetes, viral infections, tumor immunology, and pancreatic islet transplantation. On the clinical side, a renal transplant unit was established and specialization was introduced into the clinical surgical services as we had all been true general surgeons in the early years. The Oxford years have been an exciting and productive time and space does not allow more detail to be given or individuals to be singled out, but you can see why I started this address by saying that I have had a marvelous career with a large element of luck all along the line, not the least of which is the people I have been fortunate to work with.

Finally let me come back to Peter Medawar, whom this prize is named after. I first met Medawar a few years after he had his major stroke in 1970. He visited the department on several occasions after I came to Oxford and what impressed me was his enormous intelligence—I couldn’t help but think that if this is how he could perform with half a brain what must he have been like with two intact hemispheres! In 1978, he opened the first of our new transplant units at the Churchill Hospital (the second transplant unit opened in 1992) and I thought it would be appropriate to finish by reading an extract from his opening speech, in which he recounts how he became interested in transplantation (21) (Fig. 7). Of course, later he was to become the first president of The Transplantation Society after it was founded in 1966.

FIGURE 7.

FIGURE 7.

“Early in the war, an RAF Whitley bomber crashed into a house in North Oxford with much serious injury and loss of life. Among the injured was a young man with a third-degree burn extending over about 60% of his body. People burned as severely as this never raised a medical problem before: they always died; but the blood transfusion services and the control of infection made possible by the topical use of sulfonamide drugs now made it possible for them to stay alive. Dr. John F. Barnes, a colleague of mine in Professor H. W. Florey’s School of Pathology, asked me to see this patient in the hope that being an experimental biologist I might have some ideas for treatment. With more than half his body surface quite raw, this poor young man was a deeply shocking sight; I thought of and tried out a number of ingenious methods, none of which worked, for eking out his own skin for grafting, trying to make one piece of skin do the work of ten or more. The obvious solution was to use skin grafts from a relative or voluntary donor, but this was not possible then and it is not possible now.”

“I believe I saw it as my metier to find out why it was not possible to graft skin from one human being to another, and what could be done about it. I accordingly began research on the subject with the Burns Unit of the Glasgow Royal Infirmary, and subsequently in the Zoology Department in Oxford. If anybody had then told me that one day, in Oxford, kidneys would be transplanted from one human being to another, not as a perilous surgical venture, but as something more in the common run of things, I should have dismissed it as science fiction; yet it is just this that has come about, thanks to the enterprise of Professor Morris and his colleagues.”

Thus, in conclusion, you can see why I am so thrilled to have received this prestigious Medawar Prize of The Transplantation Society and again I thank the Society for the honor they have bestowed on me.

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REFERENCES

1. Welch CE. A Twentieth-century Surgeon: My Life in the Massachusetts General Hospital. Boston: Watson Publishing International, 1992.
2. Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery 1961; 50: 161.
3. Burke JF, Bondoc CC, Morris PJ. Metabolic effects of topical silver nitrate therapy in burn covering more than fifteen percent of the body surface. Ann N Y Acad Sci. 1968; 14: 674.
4. Morris PJ, Bondoc CC, Burke JF. The control of burn wound sepsis with 0.5 per cent silver nitrate. Aust N Z J Surg 1968; 38: 108.
5. Morris PJ, Burke JF. Antilymphocyte serum and staphylococcal infection. Nature 1967; 214: 1138.
6. Terasaki PI, McClelland JD. Microdroplet assay of human serum cytotoxins. Nature 1964; 204: 998.
7. Morris PJ, Hume DM, Terasaki PI. The development of cytotoxic antibodies in renal transplantion. In Curtoni ES, Mattiuz PZ, Tosi RM, eds. Histocompatability Testing 1967. Copenhagen: Munksgaard, 1967.
8. Morris PJ, Williams GM, Hume DM, et al. Serotyping for homotransplantation. XII. Occurrence of cytotoxic antibodies following kidney transplantation in man. Transplantation 1968; 6: 392.
9. Morris PJ, Mickey MR, Singal DP, Terasaki PI. Serotyping for homotransplantation. XXII. Specificity of cytotoxic antibodies developing after renal transplantation. BMJ 1969; 1: 758.
10. Williams GM, Hume DM, Hudson RP Jr, et al. “Hyperacute” renal-homograft rejection in man. N Engl J Med 1968; 279: 611.
11. Morris PJ, Ting A, Stocker J. Leukocyte antigens in renal transplantation. 1. The paradox of blood transfusions in renal transplantation. Med J Aust 1968; 2: 1088.
12. Fabre JW, Morris PJ. The effect of donor strain blood pretreatment on renal allograft rejection in rats. Transplantation 1972; 14: 608.
13. Fabre JW, Morris PJ. The mechanism of specific immunosuppression of renal allograft reject donor strain blood. Transplantation 1972; 14: 634.
14. Fabre JW, Morris PJ. Dose response studies in passive enhancement on rat renal allografts. Transplantation 1973; 15: 397.
15. Fabre JW, Morris PJ. Passive enhancement of renal allografts with only partial cover of the incompatible Ag-B specificities. Transplantation 1974; 18: 436.
16. McKay IR, Morris PJ. Association of autoimmune active chronic hepatitis with HL-A1,8. Lancet 1972; 2: 793.
17. Morris PJ, Irvine WJ, Gray RS, et al. HLA and pancreatic islet cell antibodies in diabetes Lancet 1976; 2: 652.
18. Morris PJ, Ting A, Alpers MP, Simons M. Leucocyte antigens in a New Guinea population. Tissue Antigens 1971; 1: 49.
19. McKenzie IF, Stocker J, Ting A, Morris PJ. Human lymphocytotoxic and haemagglutinating activity against sheep and pig cells. Lancet 1968; 2: 386.
20. Morris PJ, Kincaid-Smith P, Ting A, et al. Prospective leucocyte typing in cadaver renal transplantation. Lancet 1968; 2: 803.
21. Morris PJ. Preface. In Kidney Transplantation: Principles and Practice. 1st Ed. New York: Academic Press, 1978.
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