Peter Charles Doherty 1940-

Nobel Prize in Physiology or Medicine 1996

Shared with Rolf Martin Zinkernagel

Peter Doherty has always regarded himself as somewhat of a misfit; invariably out-of-sync with his circumstances. He has always loved the icons of Australian outdoor life, the sun and surf, yet as a boy he was invariably forced indoors by an Irish-inherited complexion that rapidly turned him lobster red in the sun. On leaving university he was a veterinarian when he wanted to be a researcher and, 40 years later, a Nobel Prize-winning scientist with no time to be the novelist that he had aspired to become. His academic interests at school had been literature and history, but he also excelled in physics and chemistry and he felt these were more likely to find him a good job. He was tempted by marine biology, but a visit to an open day at the University of Queensland's Veterinary School settled the matter. From an early age, this tendency to walk adjacent to, rather than on, the routine path occupied by his peers shaped him into an avid, liberal reader and observer to which was added a dash of Irish rebel- all handy ingredients for someone drawn to the allure of bold ideas and scientific discovery. .Peter Doherty is quite willing to use the clout that a Nobel Prize bestows to push the cause of science and education in the political arena and in the community generally. 

Doherty's story still has some distance to run. However, in the meantime, he is an intriguing living history; a person whose experiences are still touchable by aspiring young scientists looking for a role model. He did not follow the ordered career paths of predecessors like John Eccles and Frank Macfarlane Burnet, but he has triumphed as an individual who refused to be subdued by the jealousies of university politics. Peter Doherty was born on October 15 1940 in Brisbane as the eldest son of Eric Doherty, a telephone mechanic and administrator, and Linda Byford, a piano teacher. The family lived in a tough outer suburb of Brisbane where he went to the Indooroopilly State School. Near his home a cement works caked everyone and everything in grey dust, providing a reason to stay inside to read and soak up the sounds of his mother's passion for classical piano.

 

He recalls: "There was always music in the house including Chopin, Debussy and Beethoven, and books, so my early influences were classical composers, reading and the wireless. When I look back, the ABC had a very strong influence on me. I still remember being absolutely moved, listening to a program one day on Icelandic sagas. I think that's the key to education- being able to reach and intrigue a child."

At school Doherty says he was good at science, bored by maths, and passionate about history and ideas. These ideas came from books, people and exploring art galleries. His interest in artistic expression saw him buy a second-hand Leica camera and even build his own darkroom and enlarger. "I was interested in learning and creativity because I think I realised even then that education was a way up, and a way out." Even so, school life was tough. It was authoritarian and Doherty, then and still, had never been one to acquiesce to authority or dogma, which made his entry into university absolutely liberating. He says: "It was a transformation for me, a real freedom to learn and explore like never before." He was influenced by authors as diverse as Aldous Huxley, Jean Paul Sartre and Ernest Hemingway and it was reading Hemingway that resolved him to be "the man of action rather than the philosopher", which is why he decided to study veterinary science. "I was also going through a religious phase and captivated by the whole 'feeding the world' ideal, and veterinary science seemed one way to play a part. Of course, I was just 17 years old and would probably have made a very different decision had I been more mature." Doherty graduated with his BVSc in 1962 from the University of Queensland and because he had been supported by a bonded government scholarship, he was required to spend several years working as a rural veterinary officer. He was keen to do laboratory based research and made the mistake of saying so. His employer, the Queensland Department of Agriculture and Stock, promptly sent him to the country as a rural veterinary officer. It was reading Hemingway that resolved him to be "the man of action rather than the philosopher. "I spent some months driving large distances to perform post-mortems on 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. Realising 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) at Yeerongpilly." At the ARI he undertook an epidemiological study of the bacterial infection of livestock, bovine leptospirosis, and a thesis on this was later the basis for his masters degree. At the ARI was a young microbiologist-- Penelope Stephens -who had been contracted to develop a viral diagnostic service. They graduated about the same time and she was his first real girlfriend. They married in 1965.

Still determined to be a research experimentalist, Doherty responded one day to an advertisement in Nature magazine for a training post in experimental pathology at the Moredun Research Institute in Edinburgh. He got the job, which also allowed him to enrol as a part-time PhD student with the University of Edinburgh. While there, he helped to run a diagnostic neuropathology program for the Scottish Veterinary Investigation Service and undertook a research project on the tickborne, encephalomyelitis virus. The thesis earned him his Edinburgh PhD in 1970 - just three years before his historic work back in Australia that would lead to the Nobel Prize. While in Scotland, Penny worked at the Institute of Animal Genetics until they decided to start a family and, in a few years, they were the parents of two boys. Doherty and his family thoroughly enjoyed the life in Scotland. Doherty recalls: "For the first time, 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." 

 The family considered staying in Britain permanently but Doherty was keen to learn more about the developing field of immunology and the John Curtin School of Medical Research (JCSMR) in Canberra was the place to do it. "I was actually supposed to come back to work with the Commonwealth Scientific and Industrial Research Organisation (CSIRO) at Geelong (Australian Animal Health Laboratory) but decided to go to Canberra first to learn more about immunology, and then join the CSIRO. Well, of course, we made our great discovery and got stuck, otherwise I probably would have spent the rest of my career happily in Geelong." Instead, Doherty was awarded the Nobel Prize when in 1996 he and a former colleague, Rolf M Zinkernagel, were recognised in the category of Physiology or Medicine. The Prize was awarded for groundbreaking research, carried out in 1973-74, that fundamentally changed medical science's understanding of immune response. "It was a classic science story," Doherty says. "Both Rolf and I were interested in trying to see exactly how an infected micro-organism actually causes damage and disease, which meant finding out a way to quantitate the cellular invasion. "By chance, an American researcher, Richard Carp, was visiting as part of his research into scrapie (a sheep disease) and we got chatting. He explained how he collected cerebral spinal fluid (from mice) where it accumulated at the back of the brain. This provided us with a source of cells in which a viral invasion could be quantitated." Doherty and Zinkernagel discovered that white blood cells (lymphocytes) must recognise both an invading virus and certain "self" molecules - the so-called major histocompatibility (MHC) antigens - in order to kill the virus-infected cells. This concept of simultaneous recognition of both "self" and "foreign" molecules now forms the basis for a new understanding of the cellular immune system. At the time they began their research, it had already been discerned how antibodies, the circulating defence molecules, recognise and kill targets such as bacteria. It was far less well understood, however, how the white blood cells recognise and kill virus infected cells without destroying the normal uninfected cells. Another mystery was the reason behind nature's creation of immunological uniqueness, the small, but important differences that exist between molecules called transplantation antigens, which white blood cells recognise as "self" or "foreign". These differences were a major obstacle to organ transplants. In their research, the two scientists were able to use the mice to study how the immune system, and particularly T-lymphocytes (a sub-set of white blood cells), could protect animals against infection from a virus able to cause meningitis. Doherty calls T-lymphocytes the "hit men" of the immune system. The infected mice developed these 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 particular 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, which were published in Nature in 1974, demonstrated conclusively the need for the cellular immune system to recognise simultaneously both "foreign" molecules and "self" molecules. It became possible for the first time to understand that the true function of transplantation antigens was not to provide an obstacle to transplantation. Instead, their function is to bind and present molecules from viruses and other micro-organisms to white blood cells in such a way that the white blood cells understand whether they should become aggressive or stay calm. As a consequence it became obvious how each individual, thanks to his or her unique set of transplantation antigens, also carries his or her unique immune system. It also became possible to understand why evolution had created these large immunological differences between individuals within a species. Immunological diversity is advantageous for the individual and the species. Thus, there will always be some individuals who survive even the most severe epidemics. In return, individuals carrying a certain variant of transplantation antigens have an increased susceptibility to autoimmune diseases such as rheumatoid arthritis or multiple sclerosis and this is possibly the price they pay for their forefathers having survived a severe epidemic. Doherty and Zinkernagel's explanation of the self and not-self selectivity of the immune system advanced research in many clinical areas. It led to advances in therapeutic efforts to strengthen the immune response against invading micro-organisms and certain forms of cancer, and to efforts to diminish the effects of auto-immune reactions in inflammatory diseases, such as rheumatic conditions, multiple sclerosis and diabetes. It has also proved to be a great advance in the field of organ transplants. In an interview with science writer Roger Beckmann for the Australian Academy of Science, Doherty provided his own explanation of his research: "It shows us that the immune system can recognise a third state - an altered self - as well as self and non-self. When a virus had infected a cell and the cell is displaying viral antigens in addition to its own, it has become altered self. That's what's recognised and dealt with rather than the viral antigens per se. The point is that the body treats altered self in much the same way as non-self. A virally modified cell is destroyed in the same way that a transplanted cell from another individual would be. "People were wondering why the body should have a system for combating transplanted tissue when this state clearly never arises in nature. "We suggested that the recognition of alloantigens, that is MHC antigens differing from your own, was there not to frustrate transplant surgeons but to help the body 'see' altered self." The essential importance of the work is that it changed the entire direction of research into diseases such as cancer, multiple sclerosis, diabetes, and even AIDS - research that was going down the wrong path. It opened up crucial new fields of study that now occupy thousands of medical scientists around the world who are consequently getting much closer to understanding and combating some of humanity's most devastating diseases. The research gave medicine a crucial step forward, although it is not just the scientific advance that has made Doherty and Zinkernagel's collaboration folkloric in the annals of Australian science. The real reason they are said to have teamed up in the beginning was that Zinkernagelliked to sing arias from The Marriage of Figaro and Doherty, an aficionado of classical music, was said to be the only other person happy to share such an operatic workspace. Then, despite the significance of their research being quickly recognised around the world, the two scientists, Doherty in particular, found themselves unwanted in Australia.

Doherty's position at the university was only temporary and when he applied for a permanent job he was told quite bluntly that there was not one. Both men subsequently went to the United States-Zinkernagel because he had intended to move there anyway, but Doherty because he needed a job. For him, it was a move forced by institutional bloody mindedness and jealously. In a 2002 interview with journalist Luke Slattery for The Australian Magazine, Doherty recalled: "We made this big discovery. It was very exciting. And of course with a lot of very bright people who were a bit prima donna-ish really, there was a lot of resentment too. The difference between that institution and an American institution is that if you'd made a really big discovery like that they would have done everything possible to keep you. These guys were really glad to see us walk out the door." Doherty was 34 with a young family, and so he accepted an offer to work in Philadelphia as associate professor at the medical research and training Wistar Institute in Philadelphia. He quickly became involved with the highly regarded Immunology Graduate Group that worked closely with researchers at the University of Pennsylvania. After the disappointment of his rejection at home, the time in Philadelphia was fulfilling and rewarding. "The Wistar/Penn axis was a highly interactive, and very open, intellectual environment," he remembers. "I collaborated extensively ... and was part of a large, campus-wide multiple sclerosis research effort. 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 ascientist and academic. 

Buoyed by the direction his career had now taken, Doherty's confidence was up again, so much so that, "I made the major mistake of accepting an offer to return to the JCSMR as head of the Department of Experimental Pathology. However, my decision was made on emotional grounds rather than on the basis of what was actually being offered." Basically there was not enough money to go around and what funding there was, according to Doherty, was not distributed according to the quality of people's work, as it would have been in an American university, but to "local heroes" and favourites. 

Surprisingly, he was invited to join a group that was asked to review funding arrangements and the group recommended scrapping the existing tenure and funding system. The recommendation (which some time later was eventually adopted) was rejected vehemently by the university's hierarchy and Doherty and his associates were quickly ostracised. For the second time, he decided he was wasting his time in Australia and left. It was an emotionally tough period with Doherty, one of the most brilliant researchers in his field in the world, unable to work in the country he loved with a passion. "I was very angry for a long time, vowing never to return to Australia or go anywhere near a university. I was only interested from then on in working at a specialist research institution." The opportunity to rebuild his research career came with the resources offered to him by the St Jude Children's Research Hospital in Memphis. He was appointed as a professor of Biomedical Research and chair of the Immunology Department where he devoted himself to studying cancer-causing viruses, in particular the Epstein-Barr (EBV) thought to be responsible for a number of diseases including nasopharyngeal carcinoma-a tumour of the nasal passages and throat. EBV has also been cited as a possible link to Hodgkin's disease, a cancer affecting cells of lymph nodes. 

Doherty remained at St Jude's (where Penny worked as a hospital volunteer) until their final return to Australia more than a decade later in 2001. By this time Doherty was an acclaimed Nobel Laureate and had been named Australian of the Year in 1997. "I had gradually reconciled myself because I did come into contact with Australians who were working hard to try and make a difference; to make the country work. Also Australia is small enough to be able to do things differently if it chooses, and it occasionally does this very well." There were also family ties. His youngest son was by now a Melbourne barrister, although the eldest had settled in Seattle as a neurologist. In reflecting on his career, Doherty felt his characteristics as a scientist stemmed from a non-conformist upbringing, a sense of being something of an outsider, and looking for different perceptions in everything from novels, art and experimental results. . In his Australian Academy of Science interview with Beckmann, he said he loved immunology because he loved puzzling out complex, intricate systems. He also made the case for scientists to be free to be able to pursue conceptually driven research, rather than be locked solely into end-use driven research. This is an issue that has been dividing scientists and science policy-makers in Australia in recent years. 

"Conceptually driven research is what is likely to yield some of the biggest benefits," Doherty says. "But with this stuff you can't be sure where it will end up. Real curiosity led work cannot be confined by a short-time horizon and it doesn't guarantee an outcome. Plenty of research leads up blind alleys. Bur you have to know that those blind alleys are there in order to find the right pathway. "Of course, that doesn't mean you don't need applied research - it's essential- but you need to get the balance right between the two. Many governments, with their short time horizons, tend to favour the applied side too much." When asked about the qualities needed to be a successful researcher, Doherty listed persistence and the need to be totally absorbed in what you do. "You also need to have an open mind, and be prepared to drop one line of inquiry and follow another if it looks interesting." He adds: "We never set out to make our discovery -we weren't aiming in that direction at all. Bur when we found something unexpected we followed it." In summarising his own approach he said he liked complexity, and was always delighted by the unexpected. "Ideas interest me. 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."

Doherty founded the Peter Doherty Institute for Infection and Immunity, a joint venture between the University of Melbourne and The Royal Melbourne Hospital in 2014. Guided by Doherty and University of Melbourne’s Professor Sharon Lewin, some 700 staff work on discovering, preventing, treating, and eliminating infectious diseases.

Name: Peter Charles Doherty

Born: Brisbane, Queensland

Birthdate: October 15, 1940

School: Indooroopilly State School

University: University of Queensland; University of Edinburgh

Married: Penelope Stephens in 1965

Children: Two sons, James and Michael

Lives: Melbourne

1983: Paul Ehrlich Prize for Immunology; Fellow, Australian Academy of Science

1986: Gairdner Prize 

1987: Fellow, Royal Society

1993: Alumnus of the Year, University of Queensland Alumni Association

1995: Albert Lasker Basic Medical Research Award

1996: Nobel Prize in Physiology or Medicine

1997: Australian of the Year

2001: Melbourne University’s Laureate Professor

2015: Honorary Fellow of The Academy of Medical Sciences

2017: Fellow of the Royal Society of Victoria

Peter Doherty was awarded the Nobel Prize for his work on immune responses. He and his solleague Rolf Zikernagel, with whom he shared the prize, were trying to see how infection micro-organisms causes damage and disease. The two scientists discovered that white blood cells must recognise both an invading virus and certain “self” molecules in order to kill the virus instead of cells. The concept of simultaneous recognition of both “self” and “foreign” molecules now forms the basis for a new understanding of the cellular immune system. Doherty and Zinkernagel’s explanation of the self/non-self selectivity of the immune system advanced research in many clinical areas. It lead to advances in therapeutic efforts to strengthen the immune response against invading micro-organisms and certain forms of cancer, and to efforts to diminish the effects of autoimmune reactionism in inflammatory diseases, such as rheumatic conditions, multiple sclerosis and diabetes. It has also proved to be a great advance in the field of organ transplants.