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Peter Doherty

Second Nobel Prize for John Curtin School of Medical Research

‘A triumph for curiosity-led experimental research’

See also The Australian Academy of Science
Interview with Professor Peter Doherty

by LIZ TYNAN

The ANU’s world renowned John Curtin School of Medical Research (JCSMR) has again been recognised by the highest award in science, with the announcement earlier this month that research on the immune system carried out at the School during the 1970s had led to the award of Nobel Prizes for Physiology or Medicine to the two researchers involved.

• Photos of the Nobel Prize award ceremony

 

Peter Doherty and Rolf Zinkernagel carried out the work jointly between 1973 and 1975, partly in association with present School Director Professor Kevin Lafferty and head of Immunology, Professor Bob Blanden, on basic understanding of how the immune system recognises virus-infected cells. This work, described by a spokesman for JCSMR as “a triumph for curiosity-led experimental research” gave scientists a way to investigate the body’s immune defence system, paving the way for organ transplantation and effective anti-cancer agents.

At the time that research was undertaken, Professor Doherty was a Research Fellow in the Department of Microbiology and Professor Zinkernagel was a postgraduate student from Switzerland. Professor Doherty later became Head of the Department of Experimental Pathology at JCSMR (between 1982 and 1988). Currently, he is an Adjunct Professor in the Department of Pathology and Pediatrics at the University of Tennessee in Memphis. Professor Zinkernagel is now Head of the Institute of Experimental Immunology in Zürich.

In August this year, both scientists were awarded Honorary Doctorates of Science at the 50th Anniversary Congregation at ANU.

Work at JCSMR had first been honoured with a Nobel Prize when neuroscientist Professor Sir John Eccles received the accolade in 1963.

When the news of the Doherty/Zinkernagel Nobel Prize broke, a congratulatory statement was released by Dr Peter Pockley, Australian Correspondent for Nature, the international weekly journal of science in which the papers written by the two researchers were published.

“The singular achievements” of Professors Peter Doherty and Rolf Zinkernagel in research they began together at the ANU were first published in two papers in Nature in 1974, said Dr Pockley. The Editor of Nature, Dr Philip Campbell, said from London “I am delighted that Peter Doherty and Rolf Zinkernagel’s work on the immune system has achieved this recognition. The fact that it appeared in Nature is a bonus, giving me and my colleagues tremendous pleasure”.

The two papers, available on request from Nature, are “Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis with a syngenic and semiallogeneic system” and “Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis”. (See the item by Bob Blanden outlining the scientific significance of the research.)

The scientists carried out the experiments using mice to study how the immune system, and particularly T-lymphocytes, could protect animals against infection from a virus able to cause the deadly brain disease meningitis.

According to a statement from the Nobel Assembly in Sweden, “infected mice developed killer t-lymphocytes, which in a test tube could kill virus-infected cells. But there was an unexpected discovery: the T-lymphocytes, even though they were reactive against that very virus, were not able to kill virus-infected cells from another strain of mice.

“What decided whether or not a cell was eliminated by these killer lymphocytes was not only if they were infected with the virus, but also if they carried the ‘correct’ variant of histocompatibility antigens, those of the infected mouse itself.

“Zinkernagel’s and Doherty’s findings...demonstrated conclusively the requirement for the cellular immune system to recognise simultaneously both ‘foreign’ molecules (in the present case from a virus) and self molecules (major histocompatibility antigens)

“What also became obvious was the important function of the major histocompatibility antigens (in humans, called HLA antigens) in the individual’s normal immune response and not only in conjunction with transplantation.”

The phenomenon they had uncovered came to be known as “MCH restriction”. Their findings revolutionised immunology, transforming scientists’ understanding of the way the immune systems of mammals control and eliminate many viral, bacterial and parasitic infections.

At the time of the research, Professor Doherty was 34 years old and newly-graduated with a PhD (from the Moredun Research Institute in Edinburgh). Professor Zinkernagel was just 29 years old and had arrived from Switzerland on a Swiss scholarship, travelling with funds provided by the ANU. After publication of the first paper in Nature, Zinkernagel was enrolled as a PhD student under Professor Blanden. Their work stimulated research by so many others that a review written by them only five years later on this topic contained over 550 references.

According to the citation for their ANU Honorary Doctorates, “these days it is hard to overestimate the impact of their original discovery. The phenomenon of MHC restriction is now a fundamental principle in immunology. ”

In September last year, both researchers received the 1995 Albert Lasker Basic Medical Research Award for this work. The figure describes how a killer T lymphocyte must recognise both the virus antigen and the self histocompatibility antigen molecule in order to kill a virus infected target cell. The figure is a modification of the figure published by Zinkernagel and Doherty in 1974 (Nature 251, p.547).

The significance of the discovery of ‘MHC restriction’

by Bob Blanden*

In 1973 it was known that the major histocompability gene complex (MHC) encoded the antigens responsible for stimulating a response by T lymphocytes that led to the rejection of tissue grafts exchanged between incompatible individuals. However, since grafting was an artificial event performed by transplantation surgeons and experimental immunologists, the real biological function of the MHC was a mystery. Rolf Zinkernagel and Peter Doherty solved the mystery. The experiments that they performed from October 1973 to 1975 made it clear that when T lymphocytes recognised and killed a virus-infected cell, they recognised not only a component of the virus but also a major histocompatibility molecule on the surface of the infected cell. Thus, the major histocompability antigen molecules were a means of focusing T cell recognition on cell surfaces so that they could perform the essential functions leading to elimination of infected cells and recovery from viral infection. Following the precedent set by Rolf and Peter, other workers showed that the basic principles discovered by them also applied to the mechanisms by which a subset of T lymphocytes helped B lymphocytes to produce antibodies. The new paradigm of T lymphocyte recognition set an agenda for cellular immunology which has dominated the field ever since.

Over two decades later, much of the molecular detail of T cell recognition and the cell biology connected with immune responses mediated by T lymphocytes has been worked out, but these aspects of immunology still constitute an enormous proportion of current immunological research.

*Professor R V Blanden was then Head of Immunology and Cell Biology at the John Curtin School.