Interviews with Australian scientists

Professor Peter Doherty

Immunologist

Fellow of the Australian Academy of Science awarded Nobel prize in medicine
(Media release: 8 October 1996)

Transcript of Prime Minister's reception for Professor Doherty
(6 November 1996)

The Science of Immunisation: Questions and Answers
(26 November 2012)

Interviewed by Roger Beckman in 1996.

Contents

Introduction
Early life

The discovery
The significance of the discovery
Science in general
The present and the future

The Australian Academy of Science interviews Nobel Laureate, Professor Peter Doherty

Imagine going to a school where you're not allowed to do biology because you happen to be a boy; and now imagine that, despite that restriction, you decide to study Veterinary Sciences at the University of Queensland because you reckon it's doing something useful; and suppose that just eleven years after leaving University you make a more-or-less accidental discovery of such importance to medicine that you go on, years later, to receive the highest honour in all science – the Nobel Prize.

Too good to be true? Not at all. Meet Professor Peter Doherty, a fellow of the Australian Academy of Science, who did just that and became Australia's eighth Nobel Laureate in science.

The Nobel Committee in Stockholm recently announced that he and Dr Rolf Zinkernagel, from Switzerland, had won the 1996 Nobel Prize in medicine and physiology for work that they did together 23 years ago in Canberra. Although Professor Doherty now works at the St Jude Children's Research Hospital in the USA, the prize-winning discovery was made in 1973 at the John Curtin School of Medical Research at the Australian National University, showing that Australian scientific research can rank with the best in the world.

A completely down-to-earth, unassuming Australian, Peter Doherty was instrumental in making one of the most profound discoveries of the last 50 years in the burgeoning field of immunology. It has given us a clearer understanding of the intricate mechanisms at work in our bodies and its massive implications extend to the treatment of many terrible diseases. It's no exaggeration to say that a whole new field of science has extended from this one discovery. No wonder many are hailing Doherty's Nobel Prize as one of the greatest days in Australian science for decades.

In a recent visit to Australia shortly after the announcement of the award, Roger Beckmann spoke to Peter Doherty on behalf of the Australian Academy of Science about his early life, the process of scientific research and the nature of his own discovery.

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Early life

It all started in the suburbs of Brisbane, where the young Doherty attended the local government schools.

AAS: What were you like at school?

PD: Looking back on it, I think I was a dreamy kind of kid and perhaps a bit quiet – my head was always in a book. I had no particular feeling for science; in fact, I was quite inclined towards literary pursuits, although I also did the standard physics and chemistry courses – biology was forbidden for boys. Although I enjoyed reading, I knew I wanted to do something more practical with my life. I didn't want to spend hours analysing poetry at University, although it might be fun, when there were more important issues to think about – like feeding the world.

AAS: You were accelerated by a year at school, weren't you?

PD: Yes, and as a result I ended up going to University at 17. It was quite a shock.

AAS: How did you get interested in biological sciences?

PD: I became interested in disease partly through talking with my elder cousin, Ralph Doherty, who was working as a virologist. And then when I went to an Open Day at the Vet School at the University of Queensland I decided that I'd like to be a vet.

AAS: Not a Nobel Laureate?

PD: Not at all! Far from it, in fact. I was going to save the world by helping to produce more food by being an agricultural vet.

AAS: So what happened?

PD: By the time I had qualified as a vet I realised that food production was more a matter of agricultural economics and politics than of cows and sheep. I had to work for the Queensland Government for a few years. I was 'bonded' to them in return for my time at University. And then I became interested in virology and immunology through reading the books of Sir Macfarlane Burnet [another Australian Nobel Laureate in Medicine and Physiology]. And I knew by then that 'cat and dog' vetting was not really for me.

AAS: So generations of sick blue heelers or galahs with injured wings have had to manage without you. What did you do instead?

PD: I went to Edinburgh University to do a PhD on virus infection of sheep brains. When I'd completed that, I came back to Australia where I was offered a job with CSIRO. But instead I decided to take up a post-doctoral position with the John Curtin School of Medical Research because there was interesting work there on immunity to virus infections. And the dogs and galahs probably did better without me!

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The discovery

AAS: So what exactly was the discovery that you and Rolf Zinkernagel made back in 1973-4 and how did you go about it?

PD: Well, of course, you don't set out to make a discovery. What you are doing is checking a hypothesis – strictly speaking, you try to falsify a hypothesis. In our case, there was a certain amount of serendipity involved. We started out looking at ways of assaying [measuring the activity of] killer T-cells. We wanted to know how T-cells recognise and respond to viruses in mice. Bob Blanden at the School was then working on the cytotoxic T-cell response to the ectromelia virus in mice. Rolf Zinkernagel worked with him, learning several techniques, including T-cell assays. As Bob's lab got a bit crowded, Rolf moved into my lab. Rolf loved to sing grand opera, and I was the only guy with sufficient musical taste to have him in the lab!

AAS: And then?

PD: Well, sure enough, we found killer T-cells in mice infected with a lymphocytic choriomeningitis virus called LCMV. And, in the lab, we could get these T-cells to kill the virus-infected cells. But then we connected this work up with the system of transplantation antigens – something which hadn't really been done before.

AAS: In what way?

PD: Other people had suggested that there was some kind of relationship between the immune response genes, which map in the region of the major histocompatibility [transplantation] antigens and the susceptibility of mice to LCMV. Certain mouse strains, carrying particular histocompatibility antigens, were more susceptible to the virus, others less so. We did experiments to see whether the activity of the killer T-cells correlated in any way with the type of major histocompatibility antigens (MHC) in the mouse from which the T-cells came.

AAS: And did it?

PD: Well, yes, but not as we had supposed. It turned out, quite unexpectedly, that killer T-cells from one mouse were not active against virus-infected cells from another mouse – which of course, would have a different class of MHC antigens. In other words, the MHC antigens were certainly having an effect. In fact, the killer T-cells were not doing any killing of virus-infected cells unless the infected cells were showing the 'right' MHC antigens that the killer T-cells expected.

AAS: So the thing that decides whether or not a virus-infected cell is eliminated by these T-cells is not only the fact of having virus antigens on the outside, but also the possession of the 'correct' variant of the MHC antigens?

PD: Exactly. The MHC antigens have to be of the same sort as the individual that the T-cells come from. This means that what the killer T-cells are recognising is two things – virus antigens and MHC antigens. Virus antigen by itself is 'invisible' unless it is there with the MHC antigens; and it can't be with any old MHC antigens, it has to be with the MHC type of that individual (or inbred strain of mouse in the case of our work).

And incidentally all this work was only possible because the inbred mouse strains with different but consistent MHC types already existed.

AAS: So one piece of research always builds on what's gone before...

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The significance of the discovery

AAS: After grappling with immunology enough to appreciate your discovery in simple form, people may now cry 'so what – what's the big deal?' So can you tell us the significance of all this?

PD: I'll try....The fact that cytotoxic T-lymphocytes – the killer T-cells – cannot usually recognise foreign antigens unless these antigens are paired with MHC antigens is pretty fundamental.

AAS: That's what you called MHC restriction, isn't it? It's in every textbook now...

PD: It shows us that the immune system can recognise a third state – altered self – as well as self and non-self. When a virus has 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.

AAS: And what does that tell us?

PD: It gives us a biological role for the MHC system. 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 – MHC antigens differing from your own – was there not to frustrate transplant surgeons but to help the body 'see' altered self.

AAS: But wouldn't it be easier just to see the viral antigen on an infected cell, rather than recognise the virus antigen in combination with the MHC antigens as an altered self?

PD: But altered self recognition allows the body to conduct surveillance on its own cells. A cell's antigens can be changed not just in virus infections but in certain cancers, for instance.

AAS: And such cells could be destroyed before they spread and threaten the whole organism?

PD: If all is working well, yes.

AAS: So you found a biological role for the MHC antigens....

In fact, Doherty and Zinkernagel had opened up a whole new highway that led to major advances of great significance to clinical medicine. Many common and severe diseases depend on the function of the cellular immune system and thus on the mechanisms for specific recognition. Viral disease is only one part of the story; various long-term inflammatory illnesses such as rheumatism, rheumatoid arthritis, multiple sclerosis and even diabetes involve damage caused by the cellular immune system, probably as a result of altered self. Certain forms of cancer, where the body's cells escape the controls on their multiplication, are also a form of altered self. And we are now in a position to explain better the associations between tissue types (ie, HLA) and susceptibility to various diseases. Knowing a person's HLA-type it is possible to give a statistical likelihood of their developing certain diseases, based on the observed correlations between HLA-type and disease. Why particular tissue types are associated with a greater propensity towards certain conditions is under investigation.

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Science in general

AAS: You have obviously been successful in science. Can I ask what qualities are necessary?

PD: You've got to be very persistent and totally absorbed in what you do. You need to have an open mind, and be prepared to drop one line of inquiry and follow another if it looks interesting. We never set out to make our discovery – we weren't aiming in that direction at all. But when we found something unexpected we followed it.

AAS: Would you recommend science as a career?

PD: You're certainly not likely to make a fortune doing it. There are easier ways to make a living. But it has to be one of the most interesting pursuits. I love immunology because I love puzzling out complex, intricate systems.

AAS: Professor Kevin Lafferty, the Director of the John Curtin School, has described your prize as 'a triumph for curiosity-led research.' I take it you'd agree with that?

PD: Absolutely. Conceptually-driven research, as opposed to end-use driven research, is what is likely to yield some of the biggest benefits. 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 doesn't guarantee an outcome. Plenty of research leads up blind alleys. But 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.

AAS: How do we keep basic research going?

PD: It's probably best funded through peer-reviewed grants from funding agencies. There is also a need for block grants to research institutes, though these must be subject to careful scrutiny by scientific peers. Of course, the funding must be regularly reviewed. But privately-funded basic research is also very strong. St Jude has a budget of about $150 million a year, much of which comes through private fund-raising.

AAS: Your prize-winning work was done fairly quickly and cheaply, wasn't it?

PD: In a sense, yes. Today everything is much more sophisticated and expensive. The main thrust of our prize-winning work was done in about 6 months, but we needed the strains of inbred mice that had been developed over many years. Had those not been available we couldn't have done our work.

AAS: You did the research in 1973, and it's taken 23 years for all this to be rewarded, although the research was already being used by many other scientists within a few years and you have won other prizes before this.

PD: I think it shows that the benefits of basic research can sometimes take a while to be recognised. Also, the molecular basis of the 'altered self' model took another 10-15 years to work out.

AAS: But the benefits are no less real for all that.

PD: Exactly.

AAS: And you can't always tell which bit of basic research will turn out to be of fundamental significance for application in the future?

PD: Yes.

AAS: How does Australian science rate in world terms?

PD: It has a good reputation, but obviously we're not a large country in terms of wealth and population. We can't keep up with the United States. But certain institutions and individuals in Australia are among the best in the world at what they do. And if you've come through an Australian PhD you can probably cope with anything.... There is a real need to spend more money on basic science. That is, research aimed at understanding mechanisms rather than developing technological applications.

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The present and the future

AAS: On this brief visit you've already been the guest of honour at a reception by the Prime Minister at Parliament Houseand you've had a one-on-one meeting with the Minister for Science. Professor Gustav Nossal, the President of the Academy, has said that your life will never be the same again now that you have won the Nobel. You'll be invited to every conference, your volume of mail will expand tenfold. How do you feel about that?

PD: It's a good point – if somewhat frightening. I don't want to turn into a talking head and an A-grade waffler....

AAS: But naturally your opinion will be sought on many things, just as we are doing now.

PD: I shall have to watch what I say.

AAS: Your prize is worth a lot of money, but I gather that a fair whack goes straight to the US tax department?

PD: Yes, but that's fine by me. Taxes help pay for research, after all.

AAS: You've got plenty of your own research still going. Will there be any more major breakthroughs?

PD: Well, it would be nice to make another big hit, but very few people actually do.

AAS: What is your current research at St Jude concentrating on?

PD: We're looking at certain cancer-causing viruses. We're also studying a model of a human virus – the Epstein-Barr virus or EBV – which can infect anyone but is a particular problem in people with AIDS because of their compromised immune system. A particular mouse virus has many characteristics in common with EBV and we're seeing how the immune system deals with it.

I'm also interested in cell-mediated immunity to respiratory viruses - particularly influenza and parainfluenza.

AAS: The chances of making major breakthroughs are still as high as ever?

PD: Well, there's still plenty we don't know that's waiting to be unravelled. There's an awful lot to be done in terms of understanding human disease

AAS: And there are few aims worthier than that.

The Academy would like to thank Professor Doherty for his time and help in the preparation of this article.

November 1996

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