Rolf M. Zinkernagel Biography (1944-)

immunologist, virologist

Rolf M. Zinkernagel was born on January 6, 1944, in Basel, Switzerland. In 1962, he attended the University of Basel, deciding to study medicine rather than chemistry--his other great interest--because the former profession offeredthe possibility of clinical or private practice as well as research. He passed his final boards in 1968 and in 1970, the university accepted his M.D. dissertation.

In 1969, Zinkernagel's work in the surgery department of a hospital in Baselfailed to spark his interest. He began looking around for other possible career paths. From 1970 to 1973 he worked as a postdoctoral fellow at the University of Lausanne, Switzerland, in a laboratory studying the process by which the immune system kills virus-infected cells. Zinkernagel's project, trying to monitor the destruction of bacterial cells preloaded with radioactivechromium-51, was frustrating because the method never worked properly on thebacteria--but it gave him experience with a number of experimental techniques that were to prove crucial for his Nobel-winning research.

In 1972 Robert Blanden of the John Curtin School of Medical Research, Canberra, Australia, came to the Swiss university to teach a World Health Organization course on immunology. Intrigued by the course and encouraged by senior researchers at Lausanne, Zinkernagel applied for a fellowship with Blanden at the Curtin school. Thanks to a two-year Swiss Foundation for BiomedicalFellowships grant, Zinkernagel and his young family moved to Australia in 1973. While at the Curtin school, Zinkernagel earned a Ph.D. in immunology, finishing his dissertation in 1975.

A fortuitous accident led Zinkernagel to team up with another young postdoctoral fellow at the Curtin school, Peter Doherty. While the Blanden laboratory was cramped for space, Doherty had room in his assigned lab. Thanks inpart to their shared love of operatic music--and Zinkernagel's penchant forsinging it aloud while working--Zinkernagel began to work with Doherty on howwhite blood cells called killer T cells identify virus-infected host cells to attack. "He was tolerable, but loud," according to Doherty.

At the time, immunologists were very interested in a group of genes collectively called the major histocompatibility complex, or MHC. These genes, clustered together in the DNA sequence, encode a series of proteins called the MHC antigens, which determine whether a transplanted organ will be accepted or rejected by a recipient. If the MHC genes of the donor and the recipient match,the organ survives; if they do not, the organ is attacked by the recipient'simmune system and dies.

A number of researchers had guessed that the rejection of MHC-mismatched organs was essentially the same process as the killing of virus-infected cells bykiller T cells. Zinkernagel and Doherty demonstrated that this was true, andthat the MHC antigens were necessary for killer T cells to tell friend fromfoe. But when they investigated further, they found something very unexpected; most immunologists had expected that when virus-infected cells and killer cells were poorly MHC matched, the immune cells' killing response would be strongest, much as in badly matched transplants. But the opposite was true. In order to get proper T-cell killing of the virus-infected cells, Zinkernagel and Doherty discovered, the cells' MHC regions had to match.

The two had discovered that T cells--indeed, the immune response in general--can only recognize viral proteins when they are displayed in the context of properly matched MHC antigens. The immune system, which had evolved to recognize "self" from "other" did not react most strongly to "other," but to a thirdstate, "altered self." This discovery finally put transplant rejection intobiological context. The body does not purposely reject mismatched organs because they are different, it rejects them because it mistakenly identifies themismatched MHC antigens as "self" antigens that have been altered by interaction with viral proteins. The finding also opened the way to better methods for heading off transplant rejection, for creating vaccines, and for further unraveling the workings of immunity; as well as understanding vulnerability tocertain infections and autoimmune disease, where the body mistakenly attacksits own tissues.

Zinkernagel's and Doherty's work together took place in a fairly short amountof time between 1973 and 1974. By 1976, both were moving on, with Zinkernagel going to the Scripps Clinic Research Institute in La Jolla, California, asan associate--a rank roughly equal to an assistant professor at a university.There he studied whether or not the thymus gland--long known to play a rolein the "maturation" of infection-fighting white blood cells--used MHC antigens to select which white blood cells would mature and which would die before being released to the bloodstream. The work once again proved seminal, providing the first evidence that the thymus only allows killer cells that react against slightly altered self MHC antigens to survive. This helped explain how and why killer T cells recognize altered-self antigens most strongly. The thymus prevents autoimmune disease by killing off killer cells that would otherwise attack healthy tissues and prevents a too-weak immune response by destroying those that would fail to attack any but the most profoundly changed self antigens.

Zinkernagel became a member--the equivalent of a full professor--at Scripps in 1979. But later that year he returned to Switzerland to take an associate professorship at the University of Zurich, followed by a full professorship in1988. During that period, his work with Doherty began to receive growing international recognition, with an Ehrlich Prize in Germany in 1983 and a Gairdner Foundation International Award in Canada in 1986. In 1992 Zinkernagel wasnamed head of the Institute of Experimental Immunology in Zurich and also received the Christoforo Colombo Award in Italy, to be followed by an Albert Lasker Medical Research Award--often a prelude to a Nobel--in 1995.

In 1996, Zinkernagel joined the ranks of the Nobel laureates because of his relatively early work with Doherty defining the system by which the immune system identifies friend and foe. His work since then has built upon this discovery, revealing how the thymus gland selects only white blood cells that reactproperly to virus-infected cells and investigating the complex interplay bywhich viruses and their hosts co-evolve.

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