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By Dr Toh Han Chong, Editor Interview with

Professor Peter Doherty, 1996 Winner of for or

Professor Peter C Doherty is the recipient of the Nobel Prize in Physiology or Medicine in 1996. With a research focus on the immune system, he and Professor Rolf M Zinkernagel, the co-recipient of the Nobel Prize in Physiology or Medicine in 1996, discovered how T cells recognise their target antigens in combination with major histocompatibility complex (MHC) proteins.

Professor Doherty currently spends three months of the year conducting research at St Jude Children’s Research Hospital in Memphis, Tennessee, where he is a faculty member at the University of Tennessee Health Science Centre. For the other nine months of the year, he resides at the , .

THC: What has life been like since you won the so forth – but I expected that. On top of that, I Nobel Prize for Physiology or Medicine in 1996? was at the St Jude Children’s Research Hospital in Memphis, Tennessee, which has an enormous PROF DOHERTY: The Nobel Prize puts you in fundraising corporation, and I did a lot of the public arena, and that is very unfamiliar for a publicity stuff with the actress Marlo Thomas. basic scientist like me. A medical doctor like you She was Jennifer Aniston’s mother in Friends, and would be used to dealing with the public, but we her father, the actor-comedian Danny Thomas scientists do not deal with them very much. The founded the hospital. also called me up year after the Nobel Prize was a very heavy year and made me in 1997 even with a lot of people wanting you to give talks and though I have been living in Memphis for years!

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Page 12 – Interview with Professor Peter Doherty THC: So everybody wants you after the Nobel PROF DOHERTY: We knew we hit something really Prize! big when we saw the results at the first experiment. That was totally unexpected. It was very clear and PROF DOHERTY: Yes, everybody loves you. we had a very good experimental system, and we Also, I was the first person with a veterinary were able to work it out really fast. What we really training who won the Nobel Prize. I spent a lot built on was the whole transplantation genetics that of time, particularly in Australia, talking to broad has been done by George Snell, and we were able to public audiences, giving talks in city halls. I made map it straightaway using their recombinant mice. a few mistakes, but I learnt, very quickly, about the media and public communication. I tried THC: In a nutshell, how would you explain the to convey to the public a sense of why science is significance of the Nobel-winning research? important and why we need to do it. Back then, there was a retreat from science and a poorer PROF DOHERTY: At the time we were doing public image of science in the United States, our research, people had just come to the Europe and Australia. So I was trying to talk very conclusion that there were actually separate T positively about science. cells. That was still controversial in some minds, I have been doing that for about 10 years now, but most scientists accepted it. So we had the which is why I eventually wrote The Beginner’s circulating white blood cells and we knew they Guide to Winning the Nobel Prize. Despite the had some specificity against foreign entities. title, it is a book about science and how it works, Other scientists had taken T cells and injected where it comes from, how we do it, and what the them into mice, and shown there was some opportunities are, and also about the history of the protection against infection. But we had no idea development of the science of immunity. There is how that worked. So what we discovered was some biography in it but it was never intended as that the T cells circulating in the blood were one. The book was written for a lay audience and very potent killer cells. They were not directly the people who have said they enjoyed it a lot are specific for the . But they are specific for people like high school kids, undergraduates and something to do with the virus. We did not people who have done science because it is familiar fully understand the virus-T cell interaction in to them. It was not written for a highly intellectual a molecular sense, but we did propose the idea audience but some of it may be a bit difficult, like of “altered self”, where parts of the virus (or the story of immunity. The book is meant for foreign protein) was combined with a self protein everyone, and it is easy to read. from the host presenting cell called the major histocompatibility complex (MHC). THC: Was there the proverbial phone call in the We showed that T cells used a T cell receptor middle of the night formally informing you that that targeted the virus-infected cells and did you had won the Nobel Prize? not directly attack the virus itself. That was enormously important because while the PROF DOHERTY: You get a phone call, which is recognises the virus, T cells do not about 10 o’clock, Stockholm time in the morning. directly interact with the virus; they ignore What happens is that they have (the Nobel the virus and go to the virus-infected cells that Committee) a very long process that goes through present parts of the virus in relation to a self- months. They look at about 300 candidates and protein MHC on the presenting host cell. get information on all of them, but they gradually For the first time, we also understood whittle it down, and finally choose who they think why we had a transplantation system – why are their leading candidates. Then they put that we need an immune system that understood to the full group of professors at the Karolinska how to recognise foreign proteins but not self- Institute. If they approve of the final candidates, proteins, and how T cells are able to achieve this. they go ahead and call the people, and tell them they have about 15 minutes to call friends and relatives THC: Was this landmark work done in Australia? because they are going to officially announce the Prize winners to the public. Once that happens, PROF DOHERTY: It was all done in Canberra your telephone goes crazy! It becomes a whole at the Australian National University’s John media event for October every year. Curtin School of Medical Research during 1973 and 1975. We then both went off in different THC: Was there a Eureka moment in your Nobel directions. In 1975, Rolf Zinkernagel went to discovery? the Scripps Institute in California, and I went

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Page 13 – Interview with Professor Peter Doherty PROF DOHERTY: Well, it was just a to Wistar Institute in Philadelphia. We never beginning of the stage when they were starting worked together after that; we were in other to expand. Brisbane, like a lot of Australian communities. So it was about two and a half cities, had a system of private schools. So we years of work together. would all put our kids there. But my parents did not have much money and they just about THC: Going back to your PhD years in saved enough to send me to public school Edinburgh, were you not working on the – that is, a government school. The school I sheep virus? went to was in its first year, so we were the first graduating class. At that stage, I do not PROF DOHERTY: I was studying virus think they taught Biology to boys in any of the infections of the central nervous system of state high schools – of course, they do now. sheep. I was then really working as a paid But at that stage, it was physics and chemistry, diagnostic neuropathologist. I had a job and which actually, I think is not a bad thing. I I did my PhD part-time and just wrote up think we often start to learn biology too soon, a thesis. I used to see my supervisor once and we get stuck with a lot of details and stuff a year and tell him what I had been doing, that can best be understood with the basics of and he would only say, physics and chemistry, and “That’s very interesting.” maths. [Laughs] I graduated from And I think it is veterinary school when important, if you are going I was just 22, and I have to do things like science really been running my and medicine, to learn own research since then, language. And the other although I have never been thing, which is absolutely trained properly – I am essential, is they should very badly trained and I learn how to write clearly. would not recommend If you do not write well, that! I had scientific you do not make any sense training as a vet because even in science – unless the veterinary course was you employ someone to designed towards animal write for you. reproduction. So we learnt a lot of population THC: Were you a good genetics, , student? infectious diseases and control, breeding, and all that. PROF DOHERTY: I was not a straight C’s student, but I was not a straight A’s student THC: There is a picture of you as a young boy either. For many parts of the veterinary on the cover of your book. How old were you course, I just passed the courses and did not at the time? do really well at all because I was not really interested in sick cats and dogs. PROF DOHERTY: I think I was 3, maybe 4 years old at most. I was a kind of dreamy THC: Were you not an animal lover when you kid. And I was easily sunburnt. I was in were a young boy? Brisbane. I tended to read a lot; I was very imaginative. But I also did the things kids PROF DOHERTY: No, actually, I killed do. My dad had a workshop under the house, tons of mice! I mean, I got nothing against so I did a lot with tools. I also did a lot of animals – I think we have a very complex photography when I was younger, but all relationship with animals. That part I those photographs were unfortunately lost. I found very challenging and very interesting, did not really intend to go into science and and I could have gone on working with sort of just fell into it. live animals. It is quite exciting. Well, they can kill you – and horses kill vets all the THC: There is a fascinating piece of your time; they can kick you to death. They are biography which mentions that boys in the big, powerful animals, and you are trying school that you went to could not do biology. to do things to them that they do not want

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Page 14 – Interview with Professor Peter Doherty THC: In this world of economic bottomlines, done to them, like saw off their arms or cut there is a shift towards translational research off their teeth. because this is closer to the economic end point. What is your comment on that? THC: So you had no ambition of going on to become a vet? PROF DOHERTY: It is fine as long as you know what you are doing and why you PROF DOHERTY: Oh, no. When I went into are doing it, and you have a reasonable veterinary school, I went in with the idea likelihood that it will work. Unfortunately, of doing research on animal disease. I was with a lot of translational research, people very altruistic and I had a fairly religious have gone into big translational programmes upbringing in the Methodist church. And I without having a good scientific base, and very much had the idea that I wanted to do you have a disaster – look at the original something practical, and I thought I would field of gene therapy. You also need the basic do what I could to help global food discovery science to get a new aspect on it. production. I was 16 when I made that So I think you need both. On the one hand, decision, and well, you know how naïve you you need to go down the translational can be when you are 16. research road and try and seek solutions. And so I did research in the veterinary But one of the problems with translational field for nine years before I started basic research is you may do a lot of really bad . science just because it is translational. So you really have got to make sure that your THC: So it was at Edinburgh that your scientific base is good because human beings interest in immunology began? are not mice or monkeys.

PROF DOHERTY: Well, no, not really. I was THC: A lot of good scientific findings have always aware of immunology because I read been through serendipity? a lot of the work of , the great Australian immunologist. But I was not PROF DOHERTY: The discovery stuff has really doing immunology in Edinburgh. I was often been serendipitous, and some of it can working with another guy who was doing the also go down very logical lines that are likely immunology side; and I was doing mainly to lead to positive clinical outcomes, for pathology. instance, targeting molecular events in the It was only really when I went to Canberra cancer pathway. A lot of that will be done by that I started basic immunology. That was at drug companies. the end of 1971. I think scientific discovery is enormously important because we still do not understand THC: What advice would you give to a lot, especially in immunology. someone who wishes to do a PhD? THC: You are the eighth Nobel Prize winner PROF DOHERTY: I think if you are doing a from Australia. Who are the others? PhD, you want to have curiosity. If you are satisfied with the status quo, and you like PROF DOHERTY: You know, I am never to be told how things are, do not go into sure how many there are. The ones who research. Research is for people who ask did their Nobel work in Australia were questions. And to be good at it, you got to be Macfarlane Burnet, John Eccles, novelist obsessed by that. The other thing you got to , Rolf Zinkernagel, and more be really excited by is finding things out. So recently with . it is a good idea that if you are thinking of There is also at Oxford doing a PhD, to just spend a bit of time in the University, and at lab and really find out if you like getting new Cambridge University. Bragg was the results. And if you are scared, for instance youngest at 25 to ever win the Nobel Prize. by the fact that your results do not fit what And then the Australians claimed Aleksandr people say is supposed to happen, well, maybe Mikhaylovich Prokhorov who was born in think about why that is the case. We discover Australia. His family returned to the Soviet things by finding out things that are not Union when he was 11, in 1923. He won the supposed to happen. Nobel for Physics.

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Page 15 – Interview with Professor Peter Doherty bit dull for a couple of weeks. My friend Hugh THC: Australia is a small and young country. Reid, who was working with me and doing the Was it just by accident that there are so many immunology side, did the plaque assays and great Australian scientists, or was there a blood tests, and this was actually written up system and culture that encouraged this level in the Lancet. The virus has actually caused of creativity? some very severe infections in humans at about that time. They had a vaccine for a PROF DOHERTY: Well, I am not sure if it was number of years but it was not working, and more the British culture – the British have that was one of the reasons why I was working done rather well in Nobel Prizes. Australia on it. So there was a lot of concern about it. has two very strong areas in neuroscience But for a while, I was very reluctant to work and immunology. John Eccles was part of the with lymphochoriomeningitis virus (LCMV) neuroscience team, and there has not been because it could be fatal. another neurophysiology-based Nobel Prize but people have certainly been considered. THC: And studying the immune response to Then there was MacFarlane Burnet and he was LCMV was really the crucial experiment for a major figure in immunology. You can almost the Nobel Prize. say I am directly in his lineage because he was a virologist and PROF DOHERTY: an immunologist. Yes, because if we But Burnet was had used any other actually much more virus, it would not of a virologist. His have worked quite as contribution was well. It was just the theoretical, but it was perfect experimental a different era – you system. You know, could think about when I started science and come to out and came to conclusions. Now, Canberra, I did not it is very difficult want to work with to do that. It is very it but Cedric Mims complex today. who was a senior professor there THC: We always advised me that I thought that Barry should. Marshall was the first Nobelist THC: What areas to experiment of research are you on himself by doing in Memphis swallowing the right now? Helicobacter pylori bacterium, but I have heard that you once PROF DOHERTY: We are doing research injected flavivirus into yourself. on the H5N1 avian virus. And the reason I went to Memphis in the first place PROF DOHERTY: Oh, not on purpose! is because of Rob Webster, who has been [Laughs] That was purely an accident. I working there on avian influenza for probably was injecting these into sheep and 50 years. He is now 75. the guy who was helping me was in a rush. So we were rushing and one of the sheep THC: Can you tell us more about St Jude bumped my arm and the needle grazed my Children’s Research Hospital? It is a unique finger. I thought I was probably okay but I hospital and one of the world’s stellar took my temperature every eight hours and children’s hospitals, with seemingly endless had someone bleed me every day to test my funding. blood out. Then my temperature shot up, so I knew I had it. The blood tests demonstrated PROF DOHERTY: Early on, actor Danny the viraemia and then the specific antibody Thomas went into St Jude’s and decided that response. I did not get very sick but I was a this was a charitable thing that he would do,

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Page 16 – Interview with Professor Peter Doherty with the books that people are talking about. after he had made a lot of money – he was the I also read a lot of junk books on aeroplanes, person who produced Gilligan’s Island. And he murder mysteries and stuff. It depends on used his Hollywood contacts. Liz Taylor raised the mood I am in. I like books, particularly money for the hospital, and Frank Sinatra too, novels because they give you ideas and a and this has continued over the years. Robin different perspective. I recently finished the Williams and John Goodman have also helped autobiography of novelist Patrick White. And quite a bit. I have an autobiography of Aldous Huxley The other thing Danny Thomas did – he who interests me because he was a writer who was a Lebanese Catholic immigrant to the US used some of the science from his time in his – was that he organised the Arab-American book; and his brother Julian was a famous Christian community towards this altruistic scientist. focus. They raised funds for the treatment of children’s leukaemia at St Jude, and the THC: What do you think are some of the progress using aggressive therapy brought progress in science that will change the the death rate from over 90% down to 50% world in the next five to ten years? very fast. Now, it is below 20%. They use this success story of childhood leukaemia PROF DOHERTY: Well, clearly genomics is treatment as a tremendous publicity machine. having a substantial effect. A lot of things They raised US$350 million a year in the US, are just getting on the way, for instance, from general subscriptions, big stores like rational drug design and targeted therapies. Target and philanthropists. St Jude also brings The problem really has got to be cost; it is an in about US$80 to US$100 million in federal enormous problem. I just spoke recently at grants, and gets cost recovery where people do the Health Technology Assessment meeting have medical insurance – but otherwise, that was held in Australia. They are very good it treats the kids without cost. people – they are government people – who They also bring the kids and the parents are looking at the cost of drugs and how there, and they accommodate and feed governments are going to handle it. them. It is probably one of the biggest philanthropic corporations outside one THC: With the wider usage of such expensive of the major societies like the American drugs from pharmaceutical companies, will Cancer Society. it bring down costs?

THC: So research funding is also quite a PROF DOHERTY: I think we would have to luxury then for a top scientist who wants to work out something with Big Pharma. A lot go work at St Jude’s. of the basic science for drug development is done in the public sector anyway. Also, I PROF DOHERTY: Because they have so really wonder about the enormous cost of much money, they are already happy if you licensing of these drugs. We get a mistake raise 50% of your research funds. Whereas with something like Vioxx, and I mean, it was if you are at Harvard or Johns Hopkins, you overplayed and it is not a bad drug. We have raise 100%. to convince people that you cannot take these things without some risk. Certainly, we have THC: If you are on a desert island, what are to educate people a lot better about drugs, to the CDs and books you would bring along? be much more realistic. Of course, this does not really include newspapers who want to sell PROF DOHERTY: I would take classical their papers and want sensational news. music: Bach, Mozart, opera. I love opera, Italian, French, any opera. THC: A product that has really made a huge I would not want to read the books I impact in medicine is vaccines. already know quite well. But I would still bring the great books such as War and Peace PROF DOHERTY: There have been some and the Bible. I would like to read more about hostility towards vaccines though – people Buddhism. I have never read the Koran – I who would not vaccinate their children. There would like to read that. I think these books of have been problems in Japan, Australia and wisdom and history are interesting. I tend to California. There are people out there who read the fashionable writers. I try to keep up think that if they feed their children the right

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Page 17 – Interview with Professor Peter Doherty within three months – it was really very good food, they do not need vaccines, and nobody science – that this new virus had come from was going to tell them what to do with their Himalayan civet cats who were being sold child! China has a real problem and there as food in live animal markets in southern are a lot of people not vaccinated. We even China. It is now known that the virus came had the United States Congress opposing to the civet cats from bats, and then from it because the period after you vaccinate these civet cats to humans. That has probably hundreds of thousands of children, some been happening over the years because many of them will coincidentally develop various of the people in the market were found to be other conditions, and people would blame the antibody-positive to the SARS coronavirus. vaccine. So what happened back then was that it was the Chinese New THC: The bird Year period, flu pandemic and people went concern is a big home and so issue in Asia. Do it spread more you think there quickly. One is going to be an person took it effective vaccine to Hong Kong against bird flu? and another to Toronto. PROF Once we DOHERTY: understood what There is a the virus was, we vaccine now. It also understood is not a great it was not like vaccine but it flu. We also probably would understood that protect people if it survives well it is exactly the on a surface. And right one. The it was because problem is that the medical it is not very professionals did immunogenic. not understand Vaccines are that initially, being produced that some of and being them got sick stockpiled in the – they did not US, Australia, expect it to be all and elsewhere. that infectious. President Bush just gave US$1 billion to the But once we understood that, we stopped the vaccine companies to produce vaccines and spread pretty much in its tracks. another US$1 billion to develop research into vaccines. President Bush has been very THC: There were a few observations from proactive on this. the Singapore experience which were pretty unusual, like the whole concept of THC: We were hit by SARS a couple of years “Super-spreader”. There were people who ago and it was quite a mysterious virus. never died but they were “Super-spreaders”, Any comments on such pandemics coming like the Singaporean air stewardess who through Asia? contracted SARS.

PROF DOHERTY: We did not know what PROF DOHERTY: I do not think we SARS was initially because it was a completely understand the whole “Super-spreader” new virus. The people who worked it out thing. We really do not know. thought initially that it was the H5N1 avian flu virus because we already had a bird flu THC: Any views about the evolving dynamics outbreak in 1997. Eventually, they worked out between viruses and human beings?

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Page 18 – Interview with Professor Peter Doherty really bright people. Some of them are PROF DOHERTY: Since 1979, 30 new going to be very good at passing infections have come into humans, and one of examinations but they are not going to them is AIDS which comes from chimpanzees. be all that innovative in science. So you They developed the serology, so they carry the also got to have a mechanism that says: virus but do not get sick. “We love you, you are very bright, but you are not the world’s greatest scientist.” THC: The question is why, before the , we did not hear about HIV and AIDS? THC: How do the big American institutes sustain such a high level of successful PROF DOHERTY: I think it was because research and development activity? Is it it did not get across in humans in a big just getting good people? way. It could be possible that it was coming across in humans occasionally PROF DOHERTY: Very good people and over the years, but then you know, if the from all over the world. And very generous whole African village died, who would funding. The National Institutes of Health notice – especially under colonial rule. (NIH) offers competitive grants. The Then of course, the health authorities standard NIH grant does not ask for the and the US government did not get onto tangible outcome. All it asks are: Is it it as quickly as they should have. The then good science? Can the person do it? Is it US President Ronald Reagan did not even worth asking those questions? want to know about it. It was politically explosive but a lot of activists acknowledge THC: Perhaps you could share something now that they have made a serious mistake interesting about yourself not very many of not being more proactive then and people know about? they are now being much more aggressive about it. You need the government to be PROF DOHERTY: There is nothing interesting open about it. about me. [Laughs] Well, I guess I have had But the HIV infection rates are going a lot of fun doing science and that is a pretty up again. demanding activity. None of my children have gone into science as such – my neurology son THC: What do you think are some of writes clinical papers; he does clinical research the features that will make Singapore and sees patients and is based in Seattle. The progressive in R&D? other is a lawyer. Like a lot of scientists, I am still a bit PROF DOHERTY: The fact that you are of an outsider. Because of the way we are really focusing on science education is trained, we always look at everything from very impressive. If you read my book the point of view of “What is the evidence?” for instance, you will find that one high Of course that is not the way politicians school produced seven Nobel Prize think. The ‘evidence’ they look at is the winners: The Bronx High School of Science evidence of the latest opinion polls. But I in New York City. What goes into making think most people do not look at world in that is basically the Jewish immigration a very evidence-based way. culture – they are very focused culturally on education; and a very good school THC: Any hobbies outside work? which is teaching science and offering opportunities to the kids to go on to PROF DOHERTY: In Australia, I used to pursue science seriously. play a lot of squash. But coming to US, it Singapore, from what I understand, is has been racquet ball. I enjoy playing sports putting those sets of conditions together. but I am not really interested in watching it. They are streaming kids into science. I get very bored very quickly. So I rather They are picking the very bright ones and read a book or even watch a mystery movie. giving them very good opportunities. I do A good movie which I have seen recently is not think you can do better than that The Constant Gardener. because if you really want to do well in science, you have to provide the resources, THC: Thank you for giving us a good but you really want the bright people – interview. ■

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