Gustav Nossal studied medicine at the University of Sydney from where he earned a BSc (Med) in 1953 and a B Medicine and Surgery in 1955. After a two-year residency at the Royal Prince Alfred Hospital, in Sydney, he moved to Melbourne to work as a Research Fellow at the Walter and Eliza Hall Institute of Medical Research (the Hall Institute) leading to his PhD from the University of Melbourne in 1960. From 1959 to 1961 he was Assistant Professor of Genetics at Stanford University. In 1968 he spent one year at the Pasteur Institute in Paris and in 1976 he was a Special Consultant to the World Health Organisation. Apart from these exceptions, Nossal's research career has all been at the Hall Institute. During his time there he concurrently served as Professor of Medical Biology at the University of Melbourne. He was Director of the Hall Institute from 1965 to 1996.
Interviewed by Dr Max Blythe in 1987.
A later interview with Sir Gustav Nossal was conducted by Dr Max Blythe in 1998.
Gus, I’d like to start by asking just why you chose a career in medicine.
Well, I’ve got a pretty precise answer to that. I was born in 1931 in Austria, where a Jewish medical man, a professor of paediatrics called Professor Knöpfelmacher, was paraded to us children as a hero, the model of what a person should be. So from as long ago as I can remember I wanted to be a doctor too.
Very unusually for those times, I had a father of Jewish extraction and a mother who, like most Austrians, was a true-blue Catholic. That created quite a dilemma for them at Anschluss in 1938. They did not realise that in the crazy logic of Hitler’s Austria, Mischlinge like me – children of partly non-Jewish parentage – conferred a degree of protection on the parents. Instead, it seemed imperative for them to migrate, and we came to Australia.
I then had nine very happy years being trained by the Jesuits in primary and secondary school in Sydney. (It’s interesting how often a child’s religion follows the mother’s.) The Jesuits were extremely supportive of me, perhaps because I was seen as a bright kid. Anyway, eventually the classical interview came, as I subsequently found it so often did with the bright kids, ‘Well, my son, do you want to be a priest? Would you too like to be a Jesuit?’ But they backed off when I revealed that no, it was my ambition to be a doctor.
Refining the ambition: medical research, not in biochemistry but in virology
How did you set about becoming a doctor?
At the ridiculously young age of 16 I went to medical school at the University of Sydney. And at about that time my elder brother moved to Adelaide as a lecturer in biochemistry, so I suppose a bit of hero-worship came into the situation. In fact, he did his PhD in Sheffield with Hans Krebs, who was famous at Oxford and a Nobel Laureate. What glamour to this 16-year-old lad: ‘My brother actually knows a Nobel Laureate!’ No-one had ever thought in those terms from Australia before. It seemed to me I might become very interested in biochemistry.
When I did my third-year med, the possibility arose of doing a Bachelor of Medical Science: taking a year off, working in a lab and getting some faint taste of what research life might be like. When I went up to see the Dean of the medical school, Professor Dewar, to ask what he would think if I took a year off to do biochemistry, this wise old man – who had seen so much more of the world than I had – said, ‘Plenty of good science students will be doing PhDs in biochemistry, and yes, it is an important discipline. But you really should do something that harnesses your medical knowledge a bit more.’
‘I have this colleague who is a virologist,’ he said, referring to Pat de Burgh, who was at that time a senior lecturer in microbiology. ‘Viruses are the simplest forms of life. Knowing about their reproduction will teach you a lot of biochemistry. Why not do that instead? Why not complete your fourth year, learn your pathology, learn your bacteriology, get into the wards a little bit? If you still want to do it, take your year then and do virology with de Burgh.’
That one conversation was, in a sense, the great moment – the beginning and the end in choosing my professional life, because the rest rolled forward very simply indeed. I had the good fortune of studying under this brilliant man Pat de Burgh, who became Professor of Bacteriology while I was finishing my time of working with him. I had this very wonderful entry point – at the low, low level of being a student for a year – into the world of medical research.
For any Australian working in virology and thinking back to the very early ’50s, only one name would spring to the foreground of your mind: Sir Macfarlane Burnet. And Pat de Burgh had this really smart idea. Each year he trotted his two or three students down to Melbourne for a week, to spend a few days with Burnet and one or two days at a couple of other institutions. So, as a 21-year-old, I had the good fortune of meeting this famous figure and actually joining him. You know, people are very impressionable at that age, and the ambition to work in virology at the Walter and Eliza Hall Institute was born at that moment.
How to work best with Sir Macfarlane Burnet
Macfarlane Burnet seems to have been an incredible man. Was that your impression?
Yes. In fact, my first impression of Burnet stays with me to this day. He came to Sydney towards the end of my fourth year, in 1951, and gave us a lecture on the poliomyelitis virus vaccine. (He had just been overseas and spoken to John Enders.) Here were we, each summer, frightened to death that we might catch polio, yet this man was telling us about a vaccine – and what’s more, one that was about to exist. In faraway Australia we’d never met anyone that had been an eyewitness to something as historic as that. It really fired my imagination, that someone could actually tell you about a discovery that was about to happen. And the impression grew in 1952, when I had those much more personal meetings with him!
Let me tell you about Burnet as a person. He was a very shy man, who in his autobiography actually described himself – with considerable exaggeration, I think – as a bit ‘autistic’. He was awkward with his fellow human beings, and he expressed that awkwardness by a certain sternness. So he was actually quite a stern boss, bordering on formidable. But I very soon realised that if you met this sternness by a respectful address, almost a respectful veneer, you could quickly access his mind. Supposing Burnet said something that I thought was nonsense, whereas another person might say, ‘Sir Mac, this is nonsense,’ I would say, ‘Sir Mac, what a very interesting idea. But do you happen to have read this recent paper by So-and-So, and have you considered the vague possibility of such-and-such and such-and-such, and if you look at it in that light, might not the conclusion be slightly different?’ You might almost think this is a bit hypocritical, but he responded to that form of intellectual interaction. It didn’t threaten his acknowledged primacy, which in some curious way needed constant reinforcing.
Was that one of the keys to your collaboration and your long-term friendship?
Absolutely. Do you know, to the day of his death we always called him Sir Mac; he never once asked me to call him Mac. He and I were comfortable and were good friends – as much as anyone could be with such an aloof and introverted person – and had a great deal of respect for each other. But it was a relationship based on the continued protection of his primacy.
Learning how to deal with patients
What did you do about that ambition to work in virology?
Well, after my Bachelor of Medical Science year I went back to medical school like a good little boy and did my two years as a resident at the Royal Prince Alfred Hospital. That was very good for me, because I learnt how to deal with patients. I love medicine – I always think of myself as a doctor first – and I like people. I loved all of the work with the patients in a predominantly rather poor area of Sydney, where you were in fact the interface between that impersonal hospital system and the ‘honorary’, the visiting specialist. He was far too busy to talk to the relatives. If someone died, it was my job to explain to the relatives why, and if someone got better, it was my job to say, ‘Just watch them do this and that over the next little period.’ I loved that.
But when the second year of that was over, I came to a decision fork: I could either go ahead and complete my ‘membership’ of the College of Physicians, my MRACP as it then was – we’ve since changed to a longer degree, for a ‘Fellowship’ – which would have taken me a further two years, or I could embark on what all of my colleagues thought was a stupid dream, to become a virologist. Apart from anything else, where would a virologist get a job? One lectureship might come vacant every now and then, but there weren’t jobs for virologists growing on trees in the 1950s. It seemed to me that I would have to move down to Melbourne for a while.
New directions: not virology, but immunology
By that time you were married, weren’t you? Tell me about your wife, Lyn, and what she thought about moving.
I got married in my year of being an intern. Interestingly enough, I always prided myself in the fact that while most of my colleagues married nurses, I married a speech therapist – but I didn’t meet my wife through the Royal Children’s Hospital, where she worked. I met her because we lived in adjoining suburbs and we had mutual friends. We were, oh, a happy, up-and-coming young couple. I suppose it would be fair to say that in a sense we had Sydney at our feet: she was (and is) very beautiful, and for better or for worse I was the dux of my medical school class and president of the medical students’ society, that sort of thing. You might say that we were what would be called in today’s world medical ‘yuppies’.
When I said to my wife, ‘Well look, this is what I want to do, but it’ll mean moving down to Melbourne,’ she said, ‘Give it a go. What have we got to lose for two years?’ You see, our thought in moving down to Melbourne in 1957, after my senior residency year, was that we would do a two-year stint with Burnet and then I would just trot back to Sydney and maybe Pat de Burgh, my mentor, could have organised a senior lectureship for me by then. And I would have been happy as a bird, to have that kind of a career. So although we weren’t too pleased in one sense about going down to Melbourne where we knew no-one, this two-year compact idea sustained us: we’d get back to all our friends and the lovely life we knew in Sydney before too much time was over.
But that was not to be.
That was not to be. First, there was a big disappointment in store for me. I wrote in late 1956 explaining my wishes and my hopes. I said, ‘Dear Sir Macfarlane, You will remember meeting me on the such-and-such, and I now want to become your student,’ and he said, ‘Nossal, we’ll fit you in somewhere. We’ll find you a fellowship’ – I think he mentioned the sum of £700 a year – but I have one thing to tell you: I am switching my whole interest from virology to immunology.’ And for a moment the bottom dropped out of my world.
We had had a few lectures in immunology, but (difficult as it must be for today’s student to believe, 30 years on) really immunology was a dead subject. It was a thing that Pasteur had invented and a few odd Germans had done something with, and then these here Yanks called Cabot and Heidelberger had turned it into something biochemical. I wondered what in the hell Burnet was on about. But this man had actually seen a wave that was about to crest and break, the immunology boom that really hasn’t yet receded. And so – by happenchance, by the sheerest accident, because I wanted to work with Burnet – I had the incredible experience of joining that wave before it had crested and of being brought along by it, like an inept surfer that can’t do anything other than be there in the foam. I consider that very good fortune.
Immunology concepts, from Pasteur to the direct template hypothesis
Is that why you didn’t go back to Sydney after two years?
Yes. And now I’ll explain to you how I have been doubly blessed and doubly fortunate in my early life in the lab – which is why it’s my abiding desire to create the same kind of opportunity, the same kind of chance, for all of my lovely students and postdocs as Burnet prepared for me at the Hall Institute.
Burnet’s passion was to understand how cells made antibodies. I ascribe the discovery of our immune system to Louis Pasteur because even though Edward Jenner had vaccinated his milkmaids – they had told him that cowpox would be a good vaccine for smallpox – that was really entirely empirical. It was Pasteur who understood the microbial nature of infectious disease, and the process of attenuation. He didn’t know it was due to mutation, but he understood that if you attenuated germs they could still make you specifically immune. And in 1901 Emil von Behring discovered that this immunity was due to substances called ‘antibodies’. That began the great saga of the puzzle of antibodies.
How could a human being, or an experimental animal, make antibodies against virtually everything in that microbial world – even, as the great Karl Landsteiner discovered, against substances manufactured in the test tube, that had never existed in nature before? And how many bugs are there? Would there be a million different bacteria? I don’t know how many would exist, but each of those bacteria has many foreign substances on its surface, many ‘antigens’, which unfailingly cause antibody formation unless a person has an immunodeficiency of some sort. That was the puzzle that Burnet set himself to solve.
It was believed that the antibody fitted so beautifully, so precisely, into the antibody combining site – antigen and antibody like a hand in a glove – that the antigen had to act as a sort of a template. Although Landsteiner’s discoveries guided this belief, he didn’t actually coin the term ‘template’; that distinction belongs to Felix Haurowitz (a scientist still living today), who with Mudd and more or less also with Linus Pauling created the ‘direct template hypothesis’ of antibody formation. The concept was very simple: when antigen comes into the body, protein synthetic machinery sees something interesting and new, and begins to create a protein on the template of the antigen. So, in fact, rather than a hand in a glove it is like a plastic being moulded against a template, or a piece of hot metal being forged against a hot template. And that theory of antibody formation held sway for many decades.
Burnet's insight into clonal selection
Burnet, however, had read the beginnings of what is now called the Crick dogma. He had realised something big was going on in molecular biology, but didn’t have it absolutely straight. But then he also read a paper by Niels K Jerne, who was subsequently to win a Nobel Prize for immunology, in which Jerne had put together a totally different, shocking view of antibody formation. He said, ‘In our total blood we have 1017 molecules of antibody per millilitre. We could afford to have in existence 1011 different sorts of antibody, and there’d still be a million of each. You would have a million molecules of 1011 species – a very, very big number – and that surely should be enough to recognise any antigen that could exist in nature or could be synthesised.’ Jerne didn’t specify at all how these antibodies would be made, or why there should be 1011 different antibodies, but he did introduce the incredibly important notion that the immune response was not going to be ‘instructive’, with an antigen instructing the body how to make these antibodies; it was going to be a ‘selective’ immune response. The antigen would fossick around in the body and find those rare molecules which would attach to it, and then, he said – but this is where his theory went a bit wrong – macrophages or scavenger cells would eat up this complex that was formed and somehow the antibody molecule would perpetuate itself, would act as a template for its own production. That turns out to be incorrect. It contravenes every rule of the Crick dogma.
But in 1957 Burnet twisted it around to say, ‘The selection notion is going to be right; there are going to be a large number of antibody molecules. But they’ve got to be seen as receptors on lymphocyte cells, so that the role of the antigen is to select a lymphocyte with a receptor molecule on it that fits the antigen, and then to cause that lymphocyte (but no other) to multiply, to differentiate, and perhaps’ to mutate further, to give better and better antibodies as more and more antigenic molecules hit that cell.’ And that turned out to be essentially correct.
What impact did that great insight by Burnet have on your research?
I must admit that at first, halfway into my first year in the lab, I thought it was pretty crazy. Burnet had shown me Jerne’s paper and asked what I thought about it, but let’s be frank, he’d also showed me many, many other papers. Perhaps as a reflection of my lack of imagination, I didn’t warm to this Jerne thing at all. I didn’t hear any more for a few weeks, but then one weekend Burnet wrote his ‘clonal selection theory’ and said, ‘What do you think of that?’ I took it away and read it, and a few days later I came back and said, ‘Well, Sir Mac, I can’t really tell you what I think of the theory. I’d like to think about that some more. But, with respect, I think I have a way that I could disprove it.’
I happened to have been reading the virus literature – some part of my mind still wanted to be a virologist – and so I explained, ‘Well, viruses can be grown in single cells, and there are very tricky ways now of culturing single cells in little capillary tubes and having one virus turn into 100 viruses by living inside a single cell. I don’t see why we couldn’t immunise an animal with three or four different vaccines, and then take out the single cells. We know that the animal as a whole would be making three or four different antibodies. Would one cell always be making one antibody, or would it be making two or three? Why shouldn’t we do such an experiment?’ I was so steeped in this direct template business that I was pretty confident we would find the cell was making two or three. Why shouldn’t I drop what I’m doing – which was good, steady, beginning work in immunology, nothing very fancy – and instead do this? ‘Why not?’ he replied. ‘Furthermore, I know who can help you.’
Working with Lederberg for a golden three months
So now comes the second really big event in my life. Through the Fulbright Scheme, which brought visiting professors to Australia from the United States – and which still exists, as the Fogarty International Center Fellowship – Burnet was expecting the three-month visit in his lab of a truly fine geneticist, Joshua Lederberg. As a student of Beadle and Tatum’s he had worked on the genetics of the yeast Neurospora. But because bacteria multiply even faster than Neurospora he set out to develop bacterial genetics, and he and his wife Esther more or less created this science. Josh had become a very famous man in 10 years as the father of bacterial genetics, winning the Nobel Prize at the amazing age of 33. And this was the great man who Burnet was saying could help teach me micromanipulation.
What happened was that Lederberg – having come to work with Burnet on influenza virus genetics, in which Burnet was now no longer interested – totally changed his mini-sabbatical of three months to teach this 26-year-old upstart from Sydney, who was wanting to do something with single cells and antibody formation, how to micromanipulate cells. One of the little sadnesses of this very happy story, however, is that just when it looked as though the first results might be coming in, it was time for Lederberg to leave. He never did participate in the critical experiments which I did in late ’57 and early ’58, proving that, after all, one cell always did make only one antibody.
But the association with Lederberg was to continue and to be quite important to you.
Indeed it was. You see, as far as I was concerned, Burnet and Lederberg were quite different people. Burnet was 32 years older than I was, and when I first met him he had a monumental record of achievement already. Lederberg was only about six years older than I was, and from that point of view it was much easier to identify with him, even though he was far more achieved in science than I was. And secondly, I suppose I would describe myself as a fairly verbal person. I love debating; I think on my feet reasonably quickly. Burnet wasn’t at all like that, but Lederberg is the most brilliant person in the thrust and parry of scientific debate that I have ever known. He has an extraordinarily verbal, lightning-fast brain. Altogether, he made a massive impression on me.
You mentioned my wife. I can remember us sitting with Esther Lederberg and Josh on the floor of our little flat in Melbourne, getting stuck into debates that were mainly about science, but ranged over just everything in the world. Then they would go home to their rather ritzier flat (the visiting professor could afford it, you see) and I’d say to Lyn, ‘What an extraordinary thing that this chap has befriended me in the way that he has. I really think I’d like to go and work for him when we’re finished here.’
The Stanford years: opportunity, challenges and inspiration
The next phase of this association was for me quite pivotal, centrally important. Lederberg was in the process of moving from a good but somewhat low-key university in Madison, Wisconsin, to a brand-new medical school in Palo Alto, California, the Stanford University Medical School – which previously had been a small annex to Stanford University based in San Francisco, in the city. The importance of this for me was, firstly, that Lederberg asked me to come and be a young assistant professor in his department. Secondly, Stanford University set out to create, in this wonderful and brilliantly designed new medical school, an absolute paragon of excellence in medical education, with a panoply of foundation professors who were historic figures. Think, for example, of the Department of Biochemistry, headed by Arthur Kornberg and containing Paul Berg, Dave Hogness, Dale Kaiser, Buzz Baldwin, Bob Lehmann – all figures to reach the US National Academy of Science in their own right, and both Paul Berg and Kornberg winning Nobel Prizes. A wonderful department. Think of the Department of Radiology, with Henry Kaplan (dead now) and George Klein, probably the world’s best-known cancer researchers. A magnificent opportunity for a young man. And as an assistant professor only 27 or 28 years old, I had to teach the freshman medical students: 64 selected out of 6000. So, a tremendous challenge, a wonderful thing to happen in a young life.
During those Stanford years, unfortunately, Lederberg was so preoccupied with the building up of his department and of the medical school that we never collaborated again. Those golden three months in Melbourne, I now recognise in hindsight, had been golden for him too, because he could work in the lab eight or nine hours a day. What chairman of a department can do that? I missed very much that closer, more personal contact with him, but as well as being always wonderful to debate things with, he gave me that opportunity and those years 1959 to 1961 were absolutely crucial to my formation.
In what way?
It predominantly has to do with the inadequacy that many people from Australia feel when they contemplate the international scene. The Australian community of scholars is very small, and before you’ve moved out you don’t know whether you can stack up. You may be the brightest medical student in your class, but do you really believe that you can mix it with those people in the US, the UK, the Scandinavian countries and so forth who write the textbooks, who win the Nobel Prizes and who, essentially, make world medical science? The answer is, ‘Of course you can.’ But you have to find that out. One of the happiest things in my life is now to see student after student, postdoc after postdoc, go through the same heady experience. We train our people well at the Walter and Eliza Hall Institute, and they go off to the National Institutes of Health (NIH) or to Oxford or wherever, they succeed and they see that they can compete. But you know, you have to live through that. There’s no way anyone can explain it to you.
Your pioneering presence there must have conferred something on Australian scholars of this generation.
Indeed it did, because it would be fair to say, I think, that Lyn and I were very popular at Stanford. A lot of that I ascribe to her. People liked to ask us to dinner parties, and we met all of these great and famous people – and they became my colleagues. I was only an assistant professor but in California that doesn’t matter. It was refreshing to learn that whereas here in Melbourne things were rather hierarchical (they’re a bit less so now) you were on first-name terms quite quickly with all of these people. In some ways we think of those two and a half years as the happiest of our lives, because there’s something wonderful about being so free. You know that nothing that goes on in the politics will ever really touch you, so you can get stuck into the political debates and it doesn’t go as close to the heart as if someone is taking Australia to pieces. And you’re beginning to put the little planks in the career platform you’re building. You’re in that lovely stage of just being young.
The dawn of a new age in immunology
I suppose you took with you to Stanford the Burnet problem that you had said that you would handle. If so, then apart from this being the happiest period of a lifetime, it must have been one of the most fruitful.
Yes, it was. We built on the one-cell one-antibody proposition, saw that it was absolutely correct, and began to apply it in various situations, such as considering its implications for immunological tolerance – this very big puzzle of how the body knows not to form antibodies against itself. We developed certain ideas about how that might work.
This is an excellent point at which to introduce a second major topic: what was happening to immunology generally at about that time. I mentioned a wave that was cresting, but Burnet was far from being the total wave. I was a happy and conscious eye-witness to a very drastic change in a discipline, the birth of what some have called a second golden age of immunology.
There are two parts to that change, a fundamental science part and a slightly more applied part. Since I’m a doctor first and a scientist only second, I will deal first with the applied, medical part. Three areas of medical science that don’t have much to do with vaccines were beginning to burgeon out at that time: the fields of auto-immune disease, organ transplantation and cancer.
I’m speaking now about the late 1950s, early 1960s, when people in various parts of the world – Melbourne, yes, but also London and New York and Stockholm – were just beginning to ask very deep questions about the involvement of this immune system which heretofore had been thought of only as a defence against infectious diseases. They were beginning to ask themselves, ‘Might this system be the total answer to some of the great problems of auto-immunity, organ transplantation and cancer?’ Do we have time for me to say a little bit about each of these three in turn?
Yes, please, if you would.
The deep problem of auto-immunity
First, the deep problem of auto-immunity. If you, Max Blythe, were to donate a pint of your blood to me, Gus Nossal, something very bad might or might not happen. But if you were to donate your kidney to me, something very bad would certainly happen unless we did something about it, because my immune system has a vigorous capacity to react to, and reject, your kidney. It was beginning to be found out at that time, especially by people like Medawar and Gorer and James Gowans, in Oxford, that the rejection of foreign tissue is an immunological event. Medawar won the Nobel Prize for this insight that the cells which have the task of making antibodies, of guarding us through inflammatory responses against tuberculosis – a more cell-mediated style of immunity – are the same cells that will possibly reject the blood, if the blood groups are wrong. They will most certainly reject the kidney, because there is a thousand million to one chance that your kidney is identical to my constitution in all its blood groupings, all its tissue–histocompatibility types. And that leads to problems in transplantation, to which I will return.
Auto-immunity presents another puzzle. Why don’t we form antibodies to ourselves? Unprotected, Gus will form antibodies to Max. Why doesn’t Gus form antibodies to Gus? And then we have nature’s experiments. Robert Goode has termed disease ‘the great experiment of nature’. Diseases tell us so much about the normal. In some diseases we make antibodies, for example, to the red cells. Let’s ponder for a second what happens when I make antibodies to my own red blood cells. Instead of having their normal life span of 100 days, pumping the oxygen around the body to allow me to live, those antibody-coated red cells now live two or three days. I’ll have a vicious, haemolytic anaemia, where the red cells in my blood are dissolving inside my body. It’s very simple: with an untreated haemolytic anaemia, I’ll die.
So we have a progressive recognition of these auto-immune diseases, of which systemic lupus erythematosus and acquired haemolytic anaemia were like prototypes – one organ-specific, one more generalised – coming into the orbit of immunology. And lo and behold, everything that you learn by studying antibody formation, by studying organ transplants, suddenly fertilises, in a very particular way, this new area of medicine. We were, with Ian Mackay in the Hall Institute and Mac Burnet, amongst the very first to popularise this concept of the auto-immune diseases. At about the same time, in the late 1950s, Henry Kunkel was doing the same in New York and so was Peter Miesche (who was briefly at New York University but then went back to Switzerland). So a few hardy souls were daring to say that what we had in these diseases was auto-immunity.
In 1987, of course, that is now commonplace, even trite. But it was very unpopular at that time to say a disease might actually be due to antibodies gone wrong. In the intervening decades, diseases as common and as important as insulin-dependent diabetes and multiple sclerosis, possibly also rheumatoid arthritis, have somehow fallen into this auto-immune camp. It has been wonderful to see that evolve.
Persuading the immune system to tolerate organ transplantation
You foreshadowed that the second developing area was organ transplantation.
Yes, the fact that the aggression of my lymphocytes against your kidney has to be combatted. I can remember, as if it were yesterday, a surgical professor of nephrology at Stanford University called Roy Cohn coming to me and saying, ‘Gus, you’re supposed to be an immunologist. Please explain to me why I can’t just wrap this kidney in plastic and prevent those lymphocyte cells that you speak about from getting in. Why doesn’t such a kidney graft work?’ You see, that is how primitive the understanding in 1959 was of how the immune system worked. I remember Norman Shumway, a wonderful man, doing heart transplants in dogs and brilliantly succeeding in allowing the heart to pump, until the total rejection by the lymphocyte cells of the body. And I remember Rose Payne working on the histocompatibility system, because Gorer and Snell had found that there were certain antigens that we call histocompatibility antigens, tissue type antigens, that you could match for. She was one of the real pioneers of that matching. All of that was happening there at Stanford University.
Of course, we now know that Norman Shumway stuck with it, and we do have heart transplants now. Sure, they work better because of cyclosporin, but he was able to make them work reasonably well with less elaborate immunosuppressant treatment.
Search and/or destroy? The immune system’s role against cancer
That’s more controversial, and has been less spectacularly successful. But I must say that in my time at Stanford, to my great good fortune, my colleagues included George Klein, one of the great fathers of tumour immunology. He spent a six-month mini-sabbatical with Lederberg, who had the power to draw these great people to him. (Avrion Mitchison, one of Britain’s most famous immunologists, also came and spent time in the lab while I was there.)
Why is the cancer side of it more controversial? There is no doubt at all that lymphocytes and macrophages, the intelligent cells and the scavenger cells, have the potential to kill cancer cells. There is the potential of the immune system to kill cells that are cancerous – under some circumstances. Where there is grave doubt is whether the potential exists to kill the very last cancer cell. Debulking of a tumour we can achieve already; through radiation, cytotoxic chemotherapy and, for that matter, surgery, we can remove the great mass of tumorous tissue. The trick in cancer treatment is to remove that last malignant cell. And as we sit here it is still not given, with a few exceptional situations like chorionic carcinoma, that the immune system really has the potential to remove that last cancer cell. But the field has not gone away. It has progressed: there are still people such as Stephen Rosenberg, of the NIH, who are acting on the belief that the lymphocyte cells, if properly trained, properly schooled, properly helped by soluble molecules like interleukin-2, can do the job.
Is it possible, in fact, that they would do the job on certain slow-developing cancers?
That is exactly what I was coming to next. During those years I also met the wonderful Lewis Thomas, who was then at New York University as the Chairman of the Department of Medicine. He was keen on the immunological surveillance notion. He asked how we knew that this immune system didn’t actually evolve to constantly patrol the body, find cells that were a bit aberrant, and knock ’em off. Perhaps we were only seeing the organ transplantation/nuisance value of the immune system as a side function of the cancers that have got away, the few that remain after the immune surveillance has done a good job polishing off most of the precancerous centres.
Burnet took up this view of immunological surveillance very actively and wrote some brilliant papers about it, but I believe the primacy of the notion is Lewis Thomas’s. It hasn’t quite survived as a clear-cut notion, however. For example, we now know that immunosuppressed people who have had too much therapy for their kidney or liver grafts don’t really come down with a bewildering variety of cancers. They do get an excessive number of lymphoid malignancies – lymphomas and leukaemias – but in point of fact it would be pretty doubtful as to whether cancer of the stomach, of the cervix/uterus, of the lung, has much to do with immunological surveillance.
In any event, those were the three big disease areas that came into the orbit of immunology as I was a young man growing up, and it has been very heady to watch their separate, parallel, strong evolutions as subdisciplines.
Developments in the underlying science
You would find the changes in the basic science quite exciting too, I imagine.
Well, don’t forget that in 1957, when I started, really all we knew about antibodies was that they were proteins that could be separated electrophoretically, and then we used to talk about big antibodies, the 19S, with the macroglobulins and small antibodies being 7S. All of the beautiful work on the structure of the antibody molecule – which we can now, with X-ray crystallographic precision, see at 1.5-Ǻngstrom resolution – was still in the future. And even further in the future was the knowledge of the genetics of the immunoglobulin genes, this extraordinary system that indeed allows us to create inside our own bodies, through genetic translocations, genes for millions and millions of antibodies.
True, I have never, despite my ambitions as a 16-year-old, done any biochemistry myself. Yet as a cellular immunologist (of, shall we say, some note) I have had a box seat to watch people like Rodney Porter, Gerald Edelmann, Lee Hood progressively uncover the secrets of the structure of the antibody molecule. And then I have been able to gain a still better perspective, as it were, as the director of a large immunology research institute, to watch the likes of Tonegawa and Phil Leaver come in and dissect for me, display for me the genetics of the immune system. I’ve been terribly lucky, Max, in the colleagues that I’ve had over the years.
You’ve talked of a seemingly golden period of immunology, and of three massive areas of change, from that early defence and immunisation field to one that is much more ambitious in terms of wider body defences. Let’s look now at the next 10 years. Where’s the future?
Well yes, I will speculate with you on the future, but as a real disciple of Louis Pasteur I’ll go right back and start with him. Pasteur saw no discrepancy between pure science and applied science. In fact, the man who did these wonderful pure science things – discovering the true nature of microbial life, the fundamental principles of immunology – was also a consultant to the wine industry of France, and (though many people don’t know it) an expert on the restoration of Old Master paintings through applied chemistry. There’s still a laboratory in the Louvre where he did that work. So he was both a pure and an applied scientist.
In the applied science of immunology in the Pasteurian sense, I see a great future for the development of new and improved vaccines. We do not yet have a vaccine for any parasitic disease of man, including malaria. And the only vaccines we have for the great diarrhoeal-disease producers like cholera and typhoid are still unsatisfactory. We do not have a vaccine for AIDS or for hepatitis A, some of these very important diseases. I see a great future – impelled, I believe, by the genetic engineering revolution and by the fact that we can now manipulate these microbes so much more cleverly than Pasteur could – for vaccine development, not only molecular vaccines created through recombinant DNA but also live attenuated vaccines through the more planned attenuation of microbes than Pasteur could do.
So the vaccinology is where I’d like to begin. I have a very great interest in the diseases of the Third World, which desperately needs new vaccines and improved vaccines. That’s not terribly glamorous, you know. It might be more glamorous to think about cures for cancer, but there’s an enormous field here.
The continuing fight against cancer
We’re facing an extremely interesting future in regard to the cancer problem too, because we are learning more about the lymphoid and scavenger cells, and how to make them dance to our tunes. I’m thinking very particularly of a new research area, lymphokine research. We have a lot still to learn about the pure molecules, again made available through recombinant DNA technology, that act as ‘whips’ for the immune system: they act as strong triggers for the individual cells. There are quite a few of them, perhaps as many as nine or 10 different molecules. Some affect the scavenger cells, some affect the lymphocyte cells, some affect the so-called B cells more than the T cells and so forth. As we learn all about all of that, I believe, with the intelligent harnessing of these cells in the fight against cancer we will find there are particular cancers which immunotherapy will cure.
The big question is whether this will include the common cancers. Most of the triumphs in cancer therapy in the recent past have been in malignancies like leukaemia, lymphoma, chorionic carcinoma, seminoma of the testis – rather unusual tumours. Will we be able to cure metastatic cancers of the breast, the colon, the lung, by immunotherapy? The jury isn’t yet in on this one, I think, but I would look more to a future which combines cellular therapy with monoclonal antibodies, the targeted missiles homing in on the cancer through an antibody vehicle acting as a magic bullet, and which builds on our knowledge of these lymphokine factors. By the way, I’m not telling you anything very new here, because in fact the DNA ‘industry’ – the Genentechs and the Thetises of this world – is investing many millions of dollars into the search for the various factors I have mentioned, in the hope that, inter alia, a cancer therapy modality will come forward.
Everything we’ve learnt about cancer in these last 50 years of very frontal study points to the need for a multipronged attack. The cancer cell is not really just like the parasite or the influenza virus, which mutates away exclusively to avoid the immune system. This cell does indeed have a fantastic capacity to mutate and change and foil the immune attack, because it can easily spare a few antigens and change its spots, but it is also mutating and changing to avoid every other defence of the body – and it has been a successful parasite too, because of its adaptability. It’s amazing to look down the microscope at a cancer cell that has gone completely wild. You and I have 46 chromosomes, but this cancer cell can have any number of chromosomes, up to twice as many as the normal cell or even more, and it chucks out chromosomes willy-nilly. Please have great respect for the cancer cell’s capacity to foil what human intelligence can do.
I’m not pessimistic in the long run, but society is going to have to give us time.
Moving inevitably towards medical–political science
You mentioned diseases in the Third World as long-lasting problems that might be solved in the next decade or so. Would you say you have an opportunity now, from a high-ranking position in science, to influence future developments?
Once again I can really thank fate and fortune, in that I’ve had a very lucky association with what might be called the political and the international-political aspect of medical science. Of course you would want to change a lot of things if you could rerun the tape of your life. And then there are other things which you say you would change, but in your heart of hearts you wouldn’t.
If I kid myself and listen to the part of my mind that says, ‘Nossal, you really could have done better in the lab if you’d had a longer time exclusively for lab work,’ I may think that I’d have been much better off being made the director of an institute at the age of 44, not 34. Part of my mind does believe that. It says, ‘Gosh, on top of the relatively short time of only eight years of full-time lab work, wouldn’t it have been lovely to have another 10 with no administration and no other thoughts?’
But that didn’t happen. I became Burnet’s successor in 1965, some three years or so after returning from the Stanford years. And so another part of me says, ‘Because you were indoctrinated into the wider world of medical research at 34 and could make a lot of your mistakes and do a lot of your learning while you were still very young, you’ve had a bigger window and a longer and, in some ways, deeper perspective onto the wider thing than if you’d only become a senior professor in your late 40s.’
Becoming the Director of the Walter and Eliza Hall Institute meant fairly naturally that you were fed bumph from the World Health Organization and things like that. And because I began so early in my life, by about 1970 I was already – probably as no great surprise for anyone – being regarded as a fairly senior adviser to WHO. Indeed, in 1973 I was asked to join WHO’s Global Advisory Committee on Medical Research, its central policy committee for such matters. I served on it for eight years.
True partnerships to promote tropical disease research
My interest in Third World diseases began even earlier, though. In about 1970, essentially through my friendship with Howard Goodman, an immunologist who had given up his career in research to work full time with the World Health Organization, I became closely involved as an informal adviser to WHO in the planning of research aimed at Third World diseases. And I have had two sabbaticals in my period as Director of the Hall Institute: one in 1968 as a scientific experience at the Pasteur Institute, and one in 1976 which I chose to devote entirely to thinking about and planning for a bigger research thrust on Third World diseases.
At that time I had very great good fortune in being associated first with Howard Goodman and then with a Nigerian, Adetokunbo Lucas, who came as Howard Goodman’s successor to head what we were calling by the end of the year the Special Program for Research and Training in Tropical Diseases – which has become a $25 million to $30 million a year research program, targeted against six of the major tropical parasitic diseases, with malaria at their head. I spent the year planning, thinking, proselytising, travelling, promoting the view (which Joshua Lederberg, by the way, also forcefully shared) that more of Western science should be devoted towards these tropical problems. This could be seen as a little bit of the ‘white man’s burden’, a little bit of the Albert Schweitzer coming out, but we were absolutely determined that it wouldn’t fail for the same reasons as Schweitzerism.
Schweitzerism failed because it was paternalistic. It was the ‘white man’ telling the ‘black man’ what to do and how to lead his life. We were determined from the beginning to make it a true partnership, with responsibility and planning truly shared between developed and developing countries. And that is indeed how this WHO program has evolved.
As a direct result of this program we have many new drugs already in place for the treatment of parasitic disease. Mefloquine is one example, for malaria. Ivermectin is a new treatment for African sleeping sickness. In the short time since 1976, great things have already happened. And we are well down the track of experimental vaccines for diseases such as malaria. But these things too have to be construed in the long term.
How well has the malaria vaccine program gone?
Frankly, had you asked me that question six months ago I would have said, ‘Very well.’ Over these last six months we’ve become more aware of some of the roadblocks. For example, we have to do some of this research in monkeys, but monkey availability is a very big roadblock. We are gaining a great respect for applied research and developmental research as, in some ways, even more difficult than basic research. So I would now answer your question by saying, ‘Fairly well, and as well as it is going anywhere in the world.’ But no-one in the world has yet produced a malaria vaccine, I regret to say. I hope that a decade from now you and I will be able to reconsider this interview and say, ‘Gosh, they did it!’ – whether at New York University or at the Hall Institute or in Stockholm at the Karolinska Institute doesn’t really matter very much, so long as someone does it.
Worldwide endeavours for Third World health
Don’t think that WHO was the only organ beginning to think about more first-class, high-powered research for tropical diseases. Some of the foundations, in parallel, were thinking similarly – the Edna McConnell Clark Foundation in schistosomiasis, the Rockefeller Foundation with its charismatic director of medical science, Dr Ken Warren, in the parasitic disease area, and most recently the MacArthur Foundation in Chicago ploughing $20 million a year into this style of very important research.
So we’ve been lucky at the Hall Institute. Having come in on the ground floor, we now have a very big position in tropical diseases – first-class science, and great younger scientists like Graham Mitchell, Dave Kemp, Robin Anders standing shoulder to shoulder with me pursuing these goals right here in Melbourne, even though we don’t have any tropical problems. But that was my first blooding, you might say, in medical–political science. And it’s ongoing: in just a few days I am off to one of WHO’s big committee meetings about this tropical disease research program.
Shedding light on society’s questions
Having looked at the minutiae of the biochemical spectrum and at immunological mechanisms, and at ways in which they might help to rid a very wide section of the world of the suffering it has endured for so long, through your publishing you have also helped other people to look at these things. This is an enormous breakaway from all your other responsibilities. How did it come about?
Well, I do fancy that I have a certain role to play in communication with the layman – the lay person. (I’m trying very hard, as an old-style ‘male chauvinist pig’, to get with this nonsexist language. It is important, actually.) So why am I so interested in such communication?
I was very interested in debating at school: one of the things that the Jesuits did for me was that they spotted what I suppose you might call my verbal skill, and one of my big turn-ons at school was being captain of the debating team. On becoming a medical student, then, I parlayed this skill into quite an activity in student politics, and after some years I ended up as president of the medical students’ society.
When I got into science, however, other than giving technical lectures – which obviously every lecturer and professor had to do – I wasn’t using these skills very much, until one fine day in about 1963 or ’64 Scientific American asked me to write an article on how cells make antibodies. (That would have been when the work I was doing on antibody formation by single cells reached its flowering.) I enjoyed doing that article, and immediately after its successful publication someone wrote to me saying, ‘There’s enough in this for a book.’ So Antibodies and Immunity was my first book. It gave me great pleasure to put together words from which regular students and maybe school-leavers and maybe even – with a very big effort – an unbiological lay person could get some glimmering of an answer to questions such as: What’s this immune system all about? How do the cells make antibodies? Why it is important? Over the years I’ve had a chance to do five books of that general ilk, all probing some different aspect of popular science or of the science–society interface.
Scientific credibility and communication
Here I’d like to bring in another angle. As the director of a medical research institute these days you can’t just lead your life with other scientists. That’s still the most important part: you’ve still got to have scientific credibility, to try to exercise scientific leadership, to have the respect of your own colleagues in our own discipline, otherwise you certainly won’t be a successful director. Ask Sir Walter Bodmer, for example, how he leads ICRF, in London – one of those two great cancer institutes. Ask Robin Weiss, who runs the Chester Beatty. They’ll both tell you that they’ve got to have their credibility in science.
But you’ve also got to be a communicator. You must understand the political sector and the private donors that make it possible to continue your work. You must welcome into the laboratories all kinds of people – those interested in animal ethics or in the ethics of medical research, community leaders of a wide variety of types. I think that having a prior interest in communication, with the debating and that quasi-political-animal side of me that got into student politics, has made it much easier for me to do that part of the job, let’s say, moderately well.
Similarly, the types of things that allowed me when I was 20 to influence other medical students in the arrangement of the medical students’ ball, or in the production of the yearbook at the end of the year, now allow me – having been director under conservative and Labor governments – to count as dear friends and valued colleagues Cabinet ministers from both sides of the political fence and to have some small role in advising them about Australian science and technology and this biotechnology revolution that we’re in the midst of. I have tremendously enjoyed that. I’ve rather valued the fact that if I take off, temporarily, my hat of thinking about antibodies and B cell growth factors and immunological tolerance and the immune system and cancer, I can put on another hat and say, ‘Well, how does Australia build a biotechnology industry, from a standing start?’ – not an easy thing to do, but very worthwhile to ponder. I suppose I spend now 10 or 20 per cent of my time on this really quite political-style consideration of ‘science in society’, ‘science in politics’, ‘science in business’.
Gus, I am indescribably grateful for this talk about a career that has spanned so much and has broadcast such enlightenment. Are there any particular thoughts you’d like to leave with us this afternoon?
Just this: I’ve been very happy and fortunate in my life, and I suppose some would say I have been successful to a degree. But I am so much more impressed with what remains to be done, with the ineffable challenges and joys of a life in medical research. I often say that the happiest thing that happens to me is when one of my students is so much brighter than I am (and believe me, the good ones mainly are) and becomes my teacher within six months.
There is so much to be done in this wider world of medical research, so much good to be done for humanity, so many challenges, such a rich way of leading a life with many facets, that if this interview influences even one person towards thinking about medical research as a career for their life, then the work that you and I have done here today, Max, will have been worth while.
And I hope that in 10 years’ time we can extend the range of this interview by talking about 10 more years of work on your part.
Absolutely fabulous, because believe me, by then I’ll be retired. And although I can’t really have any more grey hairs, you will certainly have a few more.
Probably lost altogether! I look forward to our next talk, and thank you again.
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