The Nobel Prize in Physiology or Medicine 1996
Peter C. Doherty, Rolf M. Zinkernagel
Rolf M. Zinkernagel
Born: 6 January 1944, Basel, Switzerland
Affiliation at the time of the award: University of Zurich, Institute of Experimental Immunology, Zurich, Switzerland
Prize motivation: "for their discoveries concerning the specificity of the cell mediated immune defence"
I was born in 1944 in Riehen, a village
near Basel, and spent almost all of my first twenty-five years
with my family in the same house. My grandfather on my father's
side had bought this house in 1918 after moving with his family
from Tübingen to Basel to become Professor of German
Literature at the University of Basel. My father grew up in Basel,
went through the schools there, and studied biology, finishing
with a thesis under the guidance of Prof. A. Portmann. Portmann
was an outstanding zoologist-palaeontologist, with a very broad
perspective on human development seen in an evolutionary context,
not only anatomically, but also psychologically. With this
training my father became the first PhD to be employed by the JR
Geigy AG - one of the former four big pharmaceutical companies in
Basel - not as a chemist, but as a biologist. This in a way
heralded a new era of biologically oriented pharmaceutical
research and development.
My mother grew up in La Chaux-de-Fonds, in the French-speaking Jura mountains, raised by parents whose family was in the watch-making business and in banking. After moving to Basel, my mother became a lab technician and met my father at work. I was the middle child of three, my brother Peter, born in 1942, became an architect and my younger sister Anne-Marie, born in 1945, became a lab technician.
I went through public school in Riehen, then in Basel, to the Mathematisch-Naturwissenschaftliches Gymnasium, the same school attended by both my father and father-in-law. Since this school didn't teach Latin as a compulsory subject, which was at the time still necessary for several disciplines, such as medicine or law, I took four years of voluntary Latin as well as the school's more mathematically and science-oriented subjects. During that time I had a great number of hobbies: I was introduced by a chemist and collaborator of my father's - who is also a gifted painter - to the prehistory of the Basel region. This was extremely interesting, because during the last glacial period this area was not covered with ice, so that many sites of the previous inter-glacial period have survived. At the same time I also attended several handicraft courses, learning cabinet-making and smithing, as well as enjoying dancing and going to the mountains with the Swiss Alpine Club. My father sent my brother and me on a holiday exchange program to England to learn English. I read a lot and was allowed to do a fair amount of travelling through England, France and the Scandinavian countries, between the ages of twelve to sixteen. When I obtained my matura in 1962, I was uncertain as to what to study. The two areas I favoured were either medicine or chemistry and, because of the greater range of choices the medical profession could offer, i.e. research, clinical activity, or private practice in the mountains, medicine was my target for the next 6 years. I first had to acquire my matura in Latin, however, and in parallel with the medical studies I also had to do my military service. I somehow managed all this by working hard during the first two or three years of medical school. During that time I met my wife, Kathrin, who was studying in the same class, also at the university of Basel. We took our final exams together, which we had prepared with a very nice group of four medical students. In November of 1968, two weeks after the final board exams, we got married. We had originally wanted to go to Africa, where I would have liked to work and learn about leprosy. We applied to the WHO in Geneva and other international organisations, but we were not accepted because of our lack of experience. On the first of January 1969 I began to work at the surgery department at one of the hospitals in Basel, and Kathrin started at the University of Basel Eye Clinic. However, within that first year I somehow became aware that surgery might not be the career l should pursue for the rest of my life and I started to look around for alternatives. After many discussions about my career with several researchers (including A. Pletscher, J. Lindenman and many others), to find another goal, I applied to the postgraduate course in Experimental Medicine at the University of Zurich. To fill in the time between surgery and this course, I did some studies on capillary growth in the epiphysis of the long bones in the Institute of Anatomy at the University of Basel, under the direction of R. Schenk and U. Riede. The course in Zurich is a unique institution that is financed by the Swiss National Science Foundation and the state of Zurich, it gave some ten medical students from all over Switzerland the opportunity to learn more about modern science, in particular molecular biology, biochemistry, genetics, neurobiology and immunology, and to catch up with what had been missed during medical school. Starting in October 1970, I spent two years in the Department of Biochemistry at the University of Lausanne, under the direction of H. Isliker, learning about immunology, immuno-chemistry and the frustrations of experimental lab work. In Lausanne, I was asked to apply to bacteria a technique that had been made popular by T. Brunner and then by J. C. Cerottini, the 51Cr release assay to monitor the destruction of the immunological effector functions of host cells. This test involved the labelling of cells with a radioactive isotope, to monitor the immune mechanism destruction of host cells. The process was measured by determining the relative amount of radioactivity released from the dying cells. This project proved very difficult and did not produce any conclusive result: The chromium was not properly absorbed by the bacteria and this release assay was therefore not easily feasible. Nevertheless some work was accomplished on the role of IgA, which was obtained from hyperimmunised cows that release a significant amount of IgA into the colostral milk. I was evaluating whether such hyperimmune milk products were able to protect in an ileal loop model against the entrotoxin-releasing entropathogenic E. coli. This confrontation with an infectious disease and the potential of immune responses to protect against it, motivated me to look for a second postdoc position in the same field. Together, Kathrin and I sent about fifty applications to various labs throughout the world, including ones in the UK, the USA, and in Australia, but we either got no answer back or only negative ones. At that time we already had two children and my wife was also trying to find a position to pursue her own career as an eye doctor.
In 1972, while I was looking around for positions, H. Isliker discussed my plans with Professor G. Ada, Head of Department of Microbiology of the John Curtin School of Medical Research in Canberra at the Australian National University, and with Robert Blanden, a professorial fellow at the same institution. G. Ada and H. Isliker were working together at the International Union Against Cancer in Lyon, and R. Blanden came by to teach at the WHO course on immunology at our institution, which was hosting the WHO training lab in Lausanne. This juxtaposition opened up the possibility that I could join the Department of Microbiology in Canberra with the condition that I brought my own salary. The post-doctoral fellowship from the Swiss Foundation for Biomedical Fellowships granted me 32'000 SFr. per year for two years to go to Australia. Fortunately Kathrin did not object to such a drastic move with our two small children Christine, 2 1/2 years, and Annelies 11 months old. We flew to Canberra in January of 1973. My plan was to work with R. Blanden on cell-mediated immunity against Salmonella and Listeria to learn more about the role of cell-mediated versus antibody-dependent immune effector mechanisms in these infectious disease models. When we arrived in Canberra we were very lucky and happy to find a generous infrastructure offered by the Australian National University, which provided us with a detached four-room family house within a group of some thirty houses lovingly called the "University ghetto", in Hughes. It provided an extremely nice and congenial environment for students, young and middle-aged post-doctoral, pre-doctoral and professorial visitors from all over the world. Kathrin soon found a position as a part-time physician at the emergency room of the Woden Valley Hospital, the kids found access to play-groups and kindergarten, I spent all day in the lab studying immunity to infectious diseases and we made many friends amongst the Hughes community.
Within the department, the only empty space in the small labs at the John Curtin School, was in the lab occupied by Peter Doherty. He had arrived as a post-doc from Edinburgh at the end of 1971, his interests being mostly in inflammatory processes in the brain, particularly in mice with the Semliki Forest virus or with lymphocytic choriomeningitis virus (LCMV). We started to cooperate on immune responses against the LCMV virus; he was tapping the cerebral spine fluid and doing the inflammatory and immunopathological analyses in the brains, while I was doing the cytotoxicity assays, since I had become familiar with them in Lausanne. This collaboration resulted not only in the discovery of the MHC restriction, as will be detailed in our lectures, but also encouraged me to eventually enrol at the age of 28 as a PhD student at ANU. I had two reasons: one, obviously, was to add a PhD to the doctorate that I had earned with a thesis on the clinical problems of neuritis of the plexus brachialis at the University of Basel. The second motivation was that the exchange rate of 5.2 Swiss Francs for 1 Australian dollar made life rather difficult at the time. The PhD scholarship added a welcome 2000 Australian dollars to our budget.
The two-and-a-half years in Canberra were particularly successful because the group of people that had come together in G. Ada's department (including R. Blanden, K. Lafferty, A. Cunningham, P. Pletscher, P. McCullagh and many others), was just the right mix of investigative, critical if not aggressive, intelligent if not inquisitive, humorous if not bitter, and enjoyable minds working together and making sure that one's feeling of being right was constantly questioned and challenged. Of course, the fact that all these people - or at least most - worked with biological model situations, either involving infectious diseases or the transplantation of organs, made all of us very aware that immunology really had to deal with defence in vivo and not with artificial antigens in an in vitro setting.
As soon as our first papers were published in Nature I had to look around for the next post-doctoral or professional situation and was contacted by F. Dixon of the Scripps clinic in La Jolla, who was looking for an assistant professor to join Scripps to work on cell-mediated immunity of auto-immune mice; he had heard from J.C. Cerottini in Lausanne about our work in Canberra. I had also approached B. Benacerraf at Harvard to find out whether there would be any chance of working in his Department of Pathology to continue studying infectious disease immunology. At the second International Congress of Immunology in Brighton in 1974 P. Doherty and I had various opportunities to report on our findings of MHC restriction. I met with F. Dixon and B. Benacerraf. After several discussions and because I could no longer continue to work with the virus in the Boston lab, but also because California, the sea and sun seemed attractive, the decision to join the lab of F. Dixon in La Jolla was easy.
Our two children were very happy in Canberra and they both spoke the most beautiful Australian English. Our second daughter, Annelies, however, went through repeated colds and middle ear infections, one of them causing a near-lethal Haemophilus influenza meningitis, signalling a selected IgA defect (that turned out to be transient). On December 9th, 1974 Kathrin gave birth to our Australian son, Martin, at Woden Valley Hospital, while I was summarising our experiments on MHC-restricted T cell recognition during the annual meeting of the Australian Society for Immunology assembled in Canberra.
Kathrin moved back to Switzerland in early January 1975 to spend a few months with our parents and to get another 6 month's training in ophthalmology, while I had to write up my PhD thesis and Peter Doherty was sweating to correct my offences to the English language. So for another 3 months I finished up several studies in the lab in Canberra and then travelled through Australia by train and bus. The two following months in Switzerland were spent by renovating a 16th century house in the Jura mountains with my brother Peter. In early July 1975, we all moved to La Jolla with a green card, i.e. as US-immigrants, to join the Scripps Clinic of Medical Research. The decision to apply for a green card was suggested by F. Dixon not only to avoid time restrictions during my stay in the USA but also because the prospects for finding an interesting job in Switzerland were virtually nil. Work at Scripps started well, not least because Alana Althage, one of F. Dixon's technicians, was assigned to me. She has been helping me ever since by preparing much of the experimental work and by keeping the lab running for the past 20 years. I continued studying cell-mediated immunity and LCMV. This virus had also been studied for several years at Scripps by M.B.A. Oldstone and F. Dixon. We were using experimental surgical techniques to evaluate whether or not the MHC of the thymus played a role or not in the selection and expression of the T cell specificity for self. A series of similar data was obtained by experiments done in parallel by M. Bevan at the MIT. They resulted in the discovery that the MHC-molecules of the thymus dictated the restriction specificity of T cells for self-MHC. These results caused major excitement in the immunological community because they fitted in nicely with what one knew about the role of thymus in T cell maturation as originally described by J.F.A.P. Miller in England and in Australia.
My wife worked as a voluntary collaborator at the ophthalmology clinic at Scripps for about 10 to 20% of her time; she kept her medical skills alive, particularly in 1978, when she decided to study for - and successfully passed - the US-medical board exams.
The University of Zurich had approached me in 1976 to look into the possibility of taking over a position that had been freed in 1975 by Professor G. Zbinden, Head of Toxicology of the University and the ETH. This division of Experimental Pathology within the Department of Pathology was an attractive chance to go back to Switzerland and to start a larger group. Although the Medical Faculty of the University of Zurich had voted on a finalist for this position sometime in 1977 and had put me in first position, it took another two years of tough negotiations with the government before we could move in the fall of 1979. This required a lot of patience from Kathrin, F. Dixon and all of us; the signed contract only arrived about 10 days before the planned starting date in Zurich!
For the past 17 years we have lived near Zurich, first in Zollikon, and now in Zumikon, in a cosy old house with huge woodstoves, a beautiful flower garden and a handy vegetable plot, chickens, and an Appenzeller dog. Kathrin finished her ophthalmology specialisation in the first few years, then started up her own practice. The children adapted reasonably well to schools here and are just about to finish medical school.
Work in the lab was difficult at first because we had to organise all installations, equipment and animal quarters for infectious experiments. This was made much easier when Hans Hengartner, a molecular biologist from the ETH, joined the lab; he had spent 4 years at the Basel Institute of Immunology. In 1978, he approached me to plan a possible move together to Zurich. This was another lucky event in my life, comparable to the moves to Australia and to Scripps; the collaboration with Hans, first in the division of Experimental Pathology and subsequently in our Institute of Experimental Immunology, as associate - and eventually as full professor of both the University and the ETH - has been extremely productive, exciting, stimulating, straightforward and mutually complementary. Joining our molecular, immunological and physiological capabilities and expertise has helped to achieve far more than either of us could have done alone. Together, we continue to follow viruses in infected hosts to find out more about how the host immune system functions and how viruses and immune system have co-evolved.
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
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