The Nobel Prize in Physiology or Medicine 1996
Peter C. Doherty, Rolf M. Zinkernagel
My childhood was spent on the outskirts of
the sub-tropical city of Brisbane. I have a younger brother, Ian,
and we grew up as part of a traditional, extended family that was
very much influenced by the values of our two grandmothers. The
one was a devout Methodist, the other a lapsed Quaker who was
born in England and embraced the informal Australian life style
with great enthusiasm. My parents (Linda and Eric) were first and
second generation Australians, the various elements of the family
coming from County Louth (in the 1840's), Lancashire and Essex.
Eric Doherty, a clever and entertaining man, trained initially as
a telephone mechanic and was an administrator involved in the
planning of telephone services. His mother had been left in
straitened financial circumstances when my grandfather succumbed
to pneumonia during the 1919 influenza epidemic. My father
communicated his frustration at not having received an adequate
formal education and, with his strong encouragement, the desire
to learn and understand became the major focus of my life. Linda
Byford was a piano teacher who, with her two brothers, spent much
of her youth on the tennis court. After marriage she cared for
her family, played Chopin, Debussy, and Beethoven and grew roses.
She gave me an appreciation, and emotional need for, classical
music, but did not pass on the genes for tennis. The Byfords were
devastated by the death of the eldest son, who was captured at
the fall of Singapore and lost in a Japanese transport torpedoed
by an American submarine. I remember my other Byford uncle
shivering with recurrent malaria that he contracted during the
fighting in New Guinea. I share Alfred Nobel's conviction that
war is the greatest of all human disasters. Infectious disease
runs a good second.
My Irish genetic heritage gave me a very fair skin, making me totally unsuited for life in a city that is known as the melanoma capital of the world. This limited my participation in the outdoor-oriented Australian way of life, and caused me to spend a great deal of time reading anything and everything. Even so, the Australian landscape was at our back door, there were adventures with home made canoes, I played tennis and Australian Rules football, and the extended family went to the beach for at least three weeks each year. The two things that I miss most when living out of Australia are the bush and the Pacific coast, especially fishing in the surf at night! My father had a workshop and I learned to be a carpenter, a skill that has resulted in the manufacture of some very substantial coffee tables and a fair amount of time working on houses. My most ambitious project as a teenager was the construction of a photographic enlarger and darkroom, but all the photographs that I took at that time seem to have been lost after my father's early death (in 1961) and the selling of the family house.
I went to the local public schools and Methodist church. The commute to the high school involved daily trips on a steam train. I played basketball, and was a sergeant in the army cadet corps. Physics and chemistry came easily, but my natural inclinations were towards literature and history. Growing up without much money, however, also left me with the conviction that I needed to get some sort of reasonable job. An older cousin, Ralph Doherty was a brilliant scholar who was in the process of establishing himself as a leading viral epidemiologist. What he was doing seemed fascinating, but my contacts with the local general practitioners left me with no great enthusiasm for the idea of following his path to medical school. A visit to an "open day" at the University Veterinary School was my first real contact with biology in the formal sense: the subject could only be studied by girls in the Queensland public schools of that era. Another major influence at the time of my matriculation, was that I was reading Aldous Huxley, Jean Paul Sartre and Ernest Hemingway simultaneously. I decided to be the man of action rather than the philosopher, and resolved to graduate in veterinary science and pursue a research career. At this stage I was just 17 years old, and would probably have made a very different decision if I had been more mature.
The then vice-chancellor of the University of Queensland pursued a policy of open admission, from the conviction that matriculation results bore little relationship to later academic performance. As a consequence, the veterinary school had a number of mature students who had worked in the bush, while more than 50% (mostly school leavers) did not make it past the examinations at the end of the first year. This was one of two veterinary schools in Australia, and the survivors were joined by a spectrum of students from other states, New Zealand and south-east Asia (under the Colombo plan) at the beginning of year two of the five year program. Being exposed in this milieu, together with spending the long vacations employed on sheep and cattle properties and seeing practice with rural veterinarians, caused me to grow up quickly. I soon discovered that I had little interest in small animal medicine or surgery, but retain a sense of nostalgia for the satisfaction and physical challenge of working with large domestic animals.
The veterinary school was staffed by a fairly young group of teachers, many of whom had strong research backgrounds. Courses in the physical sciences, zoology, botany and biochemistry were taught from the science faculty, and physiology in the medical school. I was introduced to the principles of ecology in first year zoology, with the commitment of my professor to marine biology almost causing me to switch to that discipline. Infectious disease was taught by John Francis, who communicated great enthusiasm for research, and immunology by the parasitologist, J. F. A. Sprent. Another course that influenced me strongly was population genetics given by Glenorchy MacBride. I also read F. M. Burnet and R. M. Stanley's books on viruses, some of Burnet's writings on immunology and cancer and wrote a final year thesis on the UV-induced squamous cell carcinoma (cancer eye) of Hereford cattle. Burnet's teleological Darwinism, the idea that the body is a set of ecosystems and the realisation that good science involves quantitation have stayed with me from those early days.
When I graduated, I was contracted (under the terms of a "bonded" scholarship) to work for several years in the Queensland Department of Agriculture and Stock. I expressed enthusiasm for laboratory-based research, so the Department immediately sent me to the country as a rural veterinary officer. I spent some months driving large distances to post-mortem cattle and pigs that had died of unknown causes, and to survey cattle for various venereal diseases. This resulted in the diagnosis of Trichomoniasis in an area where it was thought that complete eradication had been achieved. Realizing that I was a danger to their regulatory effort, the Department quickly brought me back to the state veterinary laboratory, the Animal Research Institute (ARI), Yeerongpilly. My task was to conduct a large-scale, externally-funded experiment on the epidemiology of bovine leptospirosis. This project involved injecting several cows with Leptospira pomona, then watching the spread of the disease throughout the herd. I became adept at dark-field microscopic analysis of urine for spirochetes, the histology of the bovine kidney and the serological test for the organism. This work was submitted for a master's thesis and published in local journals. I was also involved in the diagnostic veterinary pathology service.
The ARI was in the process of establishing a facility for diagnostic virology, and had employed a very attractive young microbiology graduate, Penny Stephens, to develop the laboratory. We married in 1965. Knowing of my interest in virology the ARI Director, Les Newton, sent me to Melbourne for six weeks to learn basic techniques. I worked with Toby St. George in the Commonwealth Scientific and Industrial Research Organization (CSIRO) laboratory of Dr. E. L. French, spent time in the virology group at the Commonwealth Serum Laboratories and (en route) visited F. J. Fenner's Department of Microbiology at the John Curtin School of Medical Research (JCSMR), Canberra The latter was motivated by the desire to meet C. A. Mims, whose work on viral pathogenesis had considerably influenced my thinking about disease processes. On returning to Brisbane, I realised fairly quickly that I am an experimentalist at heart. A career as a diagnostic virologist was not for me!
I tried for a Ph.D. scholarship to work with Cedric Mims, but was told to apply again later because he already had a "scholar" and would take only one student at a time. At about the same time I got to know J. A. Roberts, who had done an excellent series of experiments with Mims on the ectromelia model and had recently returned from Cornell to a position as a research parasitologist in the CSIRO laboratories on the Yeerongpilly site. John Roberts told me that he had been very impressed by a visit that he had made to the Moredun Research Institute in Edinburgh, where there was a major research effort on scrapie, the then enigmatic "slow virus" disease. The Moredun also trained graduate students, who were affiliated with the University of Edinburgh. The following week a job in the Department of Experimental Pathology at the Moredun was advertized in Nature. We sailed for Britain in early 1967, on a very slow and cheap ship.
The experimental pathology position at the Moredun required that I do research and help to run the diagnostic neuropathology program that the institute operated for the Scottish Veterinary Investigation Service. I learned neuropathology from the head of the department, R. M. Barlow, and from Hugh Fraser who was doing seminal studies with Alan Dickinson defining the genetics of the scrapie mouse model. Dick Barlow also taught me to write clear, concise English. My initial intention was to work on sheep scrapie, but I quickly realised that this was not a good project area for an experimentalist. My abiding interest in infectious disease caused me to focus on the tickborne flavivirus, louping-ill virus, which was then regarded as problematic because of concerns about the safety of the vaccine, first developed at the Moredun many years previously. I enroled as a part-time graduate student at the University of Edinburgh medical school and, after I had been working with the virus for some time, developed a collaboration with another young veterinary graduate, H.W. Reid. Hugh Reid did the virology and serology aspects of the ensuing sheep experiments, while I concentrated on light and ultrastructural pathology. Part of Hugh's role was to test my blood for the presence of virus and antibody when I injected myself in the finger, an inadvertent human experiment that I later wrote up for the Lancet.
We greatly enjoyed living in Edinburgh. Penny worked with E. C. R. Reeve at the Institute for Animal Genetics until the birth of our two sons, James and Michael. The Edinburgh Festival and the Traverse Theatre were high points and, for the first time in my life, I could spend the whole day outside without the penalty of sunburn. Our long vacations were used for camping holidays in Europe, including our first trip to Scandinavia and Stockholm with a young child in the back of a Volkswagen van. I went to veterinary research and neuropathology meetings, and we came very close to staying permanently in Britain.
Eric French visited the Moredun, and raised the possibility of a permanent appointment in the veterinary virology group at the CSIRO laboratories in Melbourne. At about this time I heard a seminar by Mel Greaves at the Metchnikoff Club, an Edinburgh group organized by Spedding Micklem and Angus Stewart, that convinced me I had no real understanding of contemporary immunology. Cedric Mims also came through and talked about the work that he and R.V. Blanden had been doing on T cell responses in virus infections. Shortly afterwards a junior academic appointment was advertised in the Department of Microbiology at the JCSMR, with a job description that seemed to fit me reasonably well. Fenner's successor as head of the department, G. L. Ada, had actually written it for Bob Blanden, but offered me the only other position that he had available, a postdoctoral fellowship to work with Cedric Mims. I left my permanent research position, and turned down the offer of another, to take this opportunity to learn basic immunology. My long-term intention was to return to veterinary research. My only formal involvement in the veterinary world since then has been to serve (1987-1992) on the board of the International Laboratory for Research In Animal Diseases, Nairobi, Kenya. This was an enormously broadening experience, and I learned a great deal from (in particular) my African colleagues.
We moved from Edinburgh to Canberra in December 1971. Cedric Mims had by then decided to take the Chair in Microbiology at Guy's Hospital Medical School so, though we overlapped by six months or so, we did not ever formally work together. At first I studied the pathogenesis of Semliki Forest virus infection in the mouse, then switched to the lymphocytic choriomeningitis virus (LCMV) model which was a much more powerful tool for immunological analysis. I first met Rolf Zinkernagel when he arrived to work with Bob Blanden in 1973, and Gordon Ada (for space reasons) moved him into the laboratory with me. We also lived in the same university housing complex, and shared rides to the JCSMR with a physicist from Trondheim, a Japanese pharmacologist, and a biochemist (Bob Gerdes) who is now working at the Karolinska Institute. The story of our scientific interaction through that time is told in the accompanying articles, and in an account that we wrote jointly some time back that is yet to appear in "Immunology Today". We were then (and have remained) good friends, though we don't always agree on everything.
The basis of the "single T cell receptor altered self" hypothesis was fairly much worked out by the time of the Second International Immunology Meeting in Brighton, England. I traveled through the United States and gave the same talk in about 20 institutions. Among my hosts were Alan Rosenthal at NIH, Bethesda, and David Katz at Harvard. I also met Gene Shearer, who had results comparable to ours with haptenated cells. This was probably the first time that the immunology establishment became fully aware of what we were saying. Our ideas both contradicted the accepted North American model for the role of immune response genes, and turned the perception of the transplantation system on its head. Many people have told me years later that they heard this seminar, came away with the sense that the findings were significant, but did not fully grasp the import. Evidently some were also infuriated by what we were saying. Rolf traveled more extensively through Europe, and I also visited a number of institutions in England and traveled to Stockholm to speak to Göran and Erna Möller's group at the Wallenberg Laboratory in Lilla Frescati.
Despite the fact that we had made a major
breakthrough, the rigidities imposed by the excessive use of
tenured contracts through the earlier years at the JCSMR had made
any prospects of long-term appointments there fairly remote. Rolf
accepted a faculty position at the Scripps Institute, and Hilary
Koprowski called on my 34th birthday to offer me an Associate
Professorship at the Wistar Institute. I had visited Hilary, who was
a good friend of Cedric Mims, during my publicity tour en route
to Brighton earlier that year. We moved to Philadelphia in 1975,
and I quickly became involved with the outstanding Immunology
Graduate Group headed by Darcy Wilson and Norman Klinman at the
Pennsylvania. The Wistar/Penn axis was a highly interactive,
and very open, intellectual environment. I collaborated
extensively with Walter Gerhard on the influenza model, did some
experiments with the late Tad Wiktor in Hilary Koprowski's rabies
program and was part of a large, campus-wide multiple sclerosis
research effort. I talked a lot with John Sprent, the son of my
parasitology professor in Brisbane, who taught me how to do lymph
duct cannulation in mice. Penny went back to school, and
developed a new career in the area of drug information. I wrote
grants, was a member of the immunology circuit, worked with
outstanding graduate students and became an established scientist
My self confidence was such that I made the major mistake of accepting an offer to return to the JCSMR as Head of the Department of Experimental Pathology, intending to build a vital program comparable to that Gordon Ada had been able to create in the early 1970's. However, the era that this was possible had passed, and my decision was made on emotional grounds rather than on the basis of what was actually being offered. The less said about this time (1982-1988) the better, as I am still trying to get the overall experience in perspective. The most positive aspect was my interactions with some excellent colleagues, particularly Jane Allan and Rhodri Ceredig. With the passage of the years, the retirement of many of the tenured staff, the adoption of a more flexible appointment structure, and the return from Denver of Kevin Lafferty as Director, things at the JCSMR are now greatly improved. At the stage that I was there the situation looked hopeless. I decided to move back to a scientific world that I knew I could handle.
The opportunity to rebuild my research career came with the resources offered to me by J. V. Simone, then the Director of St. Jude Children's Research Hospital (SJCRH). I had first visited SJCRH during my swing through the USA in 1974. At that stage it was still a small institution, with a strong virology department headed by Alan Granoff. My contact was via Rob Webster, who had trained with Stephen Fazekas de St. Groth in Frank Fenner's program at the JCSMR and remains a close colleague of the JCSMR virologist, Graeme Laver. Alan and Rob engineered my move to Memphis, and Rob has been an outstanding friend and collaborator. This is a superb, open, research environment, that is extremely well funded. The two problems are that there is too much sunshine, and that we are too far from the Pacific Ocean. Such is life!
My characteristics as a scientist stem from a non-conformist upbringing, a sense of being something of an outsider, and looking for different perceptions in everything from novels, to art to experimental results. I like complexity, and am delighted by the unexpected. Ideas interest me. I was influened early on by reading Arthur Koestler and Edward de Bono, and more recently by the writings of Karl Popper and Thomas Kuhn. My research career has been highly unconventional, and I have not been a full-time student in the academic sense since I was 22 years old. I have never had a powerful mentor who saw me as the product (or continuation) of his program, a situation that probably helped to determine the outcome of my two attempts to return to Australia. Intellectually, I march to the beat of my own drum and have little interest in competing in "races". There are too few people working in the area of viral pathogenesis and immunity, too little funding, too many problems and too little time.
From Les Prix Nobel. The Nobel Prizes 1996, Editor Tore Frängsmyr, [Nobel Foundation], Stockholm, 1997
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.
Copyright © The Nobel Foundation 1996
Try to save some patients and learn about human blood types!
All you want to know about the Medicine Prize!
Read more about the Medicine Prize during the past century