Paul Korner was born in 1925 in Moravská Ostrava in Czechoskovakia (now the Czech Republic). At age 13, Korner, along with his mother, father and brother, fled to England to escape the Nazis. After spending a year in England the family emigrated to the safety of Australia. Korner completed his secondary schooling at Barker College in Hornsby, NSW as dux of the school. He enrolled in a medical degree at the University of Sydney in 1943, which he finally completed in 1951, having taken some time out from his medical studies to finish a BSc (1946) and an MSc (1947). Korner went on to the Kanematsu Research Institute at Sydney Hospital in 1952, after spending a year as a medical resident at Royal Prince Alfred Hospital. During this time he was working on the link between hypoxia and pulmonary capillary permeability. From the Kanematsu Institute he travelled to the Royal Postgraduate Medical School, London, in 1954 and then on to Harvard where he developed his experimental skills further.
Upon return to Australia he took up a senior lecturer position at the University of Sydney (1956–60), followed by the offer of foundation chair in physiology at the University of New South Wales (1960–68), the foundation Scandrett professor of cardiology at the University of Sydney (1968–74) and then the director of the Baker Medical Research Institute in Melbourne (1975–90). During his career Korner tackled a number of scientific questions in the fields of exercise physiology, circulatory control and hypertension; about which he has written the definitive book, Essential Hypertension and Its Causes: Neural and Non-Neural Mechanisms.
Professor Paul Korner AO MD Hon DSc (UNSW) MD (hc) (Melb) FAA passed away on 3 October 2012.
Interviewed by Professor John Chalmers in 2008.
Hello, Paul. It’s great to be here with you today, and to be doing this interview of your life in science for the Academy, so I’m looking forward to it. I wonder if I could start by asking you about your early life in Czechoslovakia.
Yes. When we left Czechoslovakia, I was 13, so I remember quite a bit about it. I was born in a place called Moravska Ostrava, which is in north-eastern Moravia. It’s a town like Newcastle—a steel and coal town. Its other attribute was that it’s about 70 kilometres from the German border. It was largely a Czech town, about 20 per cent of its population was German; it was not like the Sudetenland. My father was an architect and he was Czech, and my mother was Hungarian. Neither spoke each other’s language, which is very understandable, and so the language that was spoken in the house was largely German. We used to have nannies who were all Czech, so thus we were all brought up bilingually.
That’s fascinating about the language, because I had the same, where my mother spoke French, because her mother was Italian, her father was English, and the language they had in common was French.
Good. Yes, well, it works out like that. And it, of course, worked out like that to a great degree in the Austro-Hungarian Empire, where these sorts of marriages were not uncommon. Anyway, we had quite a comfortable childhood. My father was quite a successful architect—at least successful in the 1920s, until the Great Depression came along. I went, first of all, to a primary school, which was largely Czech, and then I went to a high school, a Gymnasium, which was largely German, and I went up to about the third year of that before we left. My main memories of my early childhood were really our holidays, which were always very, very nice. We’d go skiing to a mountain range.
Was it in summer or winter?
Both winter and summer. We would go skiing in the winter and not skiing in the summer. Most of them were fairly close to where we lived. Up to 1933, the advent of Hitler, we would sometimes go in the summer holidays to a property owned by one of my uncles, who was the finance director of the big steel mill nearby, which was owned by the Rothschild family. The Austrian Rothschild family had a fair bit to do with the wellbeing of the Korners because my uncle, the eldest brother of my father, was their solicitor and my other uncle was their finance director, and my father, as an architect, got a lot of work through them. Anyway, we went to his property in Germany, in Saxony, not far from the Czech frontier, where he had a property and we used to meet the Korner cousins, which I very much liked. That all stopped in 1933, with the advent of Hitler, because the family was Jewish—very non-observant but Jewish enough for the Germans. And then we used to go on trips along the Danube and into Hungary or into Romania, where my mother had spent her youth. Anyway, they were lovely periods.
We were really not aware of what was happening in Germany with the Nazis. We were aware of the Great Depression in Czechoslovakia because my father’s busy office in the twenties had employed about 12 architects in it and, during the thirties, when the big depression came, it employed one architect because he didn’t have the heart to fire him, and he prepared a stamp collection for my father; there was absolutely no work at all then.
Paul, can you remember much about the time of Hitler, the start of the Second World War and leaving Czechoslovakia?
Yes. The first thing that happened, of course, was that Hitler marched into Austria, the so-called Anschluss, and one of my mother’s brothers, on about day three of the occupation of Austria, went into prison just as a cleanup of the Jews. My mother went by herself to Vienna by train to see if she could get him out and she was quite successful; all these things cost a fair bit of money in terms of bribing the right kind of Nazi officials. Anyway, he came to stay with us for a few weeks and then went to Hungary, where he was born, and later came to Australia. So that was that. That was March 1938.
And in May 1938, we suddenly woke up one day to find a partial mobilisation order of the Czech army, with tanks in the street and a lot of brouhaha, because the Czech government had misinterpreted some German troop movements near the frontier, which was close to where we lived, and thought they were about to be invaded. The Czech army was really quite strong in those days and the German generals were really not keen on a war with Czechoslovakia at the time that that happened.
Anyway, my mother at that stage said, ‘This is it,’ you know, ‘time to go,’ and my father said, ‘Oh, how can you say that? Haven’t we just shown them what we can do?’ My father was really always the charmer in the family and my mother always made the big decisions. So she said, ‘Well, you can stay, if you like, but I’m going with the children,’ and, as was his custom, he would always come along with us in the end. And so we left in 1938. It was really also very difficult to actually officially leave because you weren’t allowed to take any money out. Anyway, they managed all that through their Rothschild connection and we left in August ’38. It was the first time my younger brother and I had been in Prague. We then went by plane from there to Switzerland, to a place called Montreux, near the Lake of Geneva, and that was where I think most of the seven Korner uncles and three Korner aunts met for the last time together. All but two went either to the USA, England or Australia, and the two that remained finished in Auschwitz—and one of their children, fortunately, survived.
What was the pull to Australia? How did that happen?
Well, again, we went from Montreux for a year to England first because, I mean, you couldn’t just travel to Australia or to anywhere without getting quite a lot of paperwork done. And my father was rather hoping to go to the USA, where his eldest brother, whom he really was very fond of, lived. And my mother thought Australia would be better because (a) it was very far away and (b) her brother lived there (that she had gone to rescue from Vienna). So we went to Australia, anyway, to cut a long story short.
We left England in August ’39, in the middle of August ‘39 and we arrived by a Dutch ship in Colombo on September the 3rd, which was a couple of days after the outbreak of World War II. The ship that we were meant to be changing to, a P&O liner, to come to Australia didn’t come, because it had been requisitioned to carry troops to the Middle East from India. So, from the point of view of my brother and myself, it was a wonderful six weeks in Colombo; from the point of view of my parents, it was more anxiety provoking.
But one of the strange things in relation to my life in science is that one of our fellow passengers was Bernard Katz, originally from Leipzig. He had escaped the Nazis, because he was Jewish, and had worked with AV Hill in London. He had not done much medicine, but what little skills he had were called upon in Colombo when various passengers got boils and carbuncles, and he did his best with those. We got to know him quite well and kept up. When he later heard that I was going into science, he really was always very interested in what I was doing and very nice to me.
So, Paul, you ended up arriving in Australia. Can you recall the difficulties, some of the cultural issues, in getting to a new country, coming out to Australia, and maybe some of the good things?
Yes. The problems for my parents were considerably greater than they were for me. We all spoke quite good English. I mean, my father was a fantastic linguist, really, and my mother spoke, in addition to Hungarian and German, she spoke quite good Italian and she spoke quite good French. And they all spoke quite good English. I had learned English in Czechoslovakia from the age of about nine or ten, from what I thought at the time was an old Scottish lady, but she was probably in her 40s. So I spoke some English and we’d been to school in England. And that was actually quite instrumental in our choice of school in Sydney. The headmaster of our English school was an Australian, and he had been a master at Barker and recommended that I go there. And it wasn’t a bad place to go to. It had people from the city, people from the country, and I got to know, I think, probably what Australians were like more quickly than certainly my parents did.
Looking back on your school days, would you like to tell us a little bit about that and playing rugby?
Well, let me start with the positives. I was quite good, of course, on the academic school work. And I was particularly good in English actually because we had an absolutely brilliant school teacher in English who taught me how to analyse Shakespeare, and I’ve never really looked back from that.
As regards my sporting activities, I did football and I did cricket, but I think my overall cricket score in my four years of school would have been under 20; but I tried. I was quite a good swimmer. My father, for a reason that I will never understand, thought I ought to learn boxing. Well, I went to class number one and I got absolutely macerated by a giant of about seven foot high. And I thought once was enough [laugh], so I never reappeared there again. I used to go to their nice school grounds, get books out of the library and read. I had forgotten that at the end of term reports were due and my master was kind enough to say that ‘This boy has absolutely no temperament for boxing,’ and that was very correct.
I like it. Looking back, when did you decide you were going to do medicine? Was it an easy decision?
No. It was really before I left Czechoslovakia, funnily enough. I used to read a lot as a child—I mean, more than current children tend to do—and I read a book by Paul De Kruif called Microbe Hunters, which was a novel around the discovery of yellow fever. I thought that was absolutely wonderful and I really wanted to be a doctor, and preferably one who did research. And somehow or other, that stayed with me all the time, and the only thing that I really was worried about once we came to Australia was, would I be able to do well enough at school to get into medicine, because in those days after war broke out there was a limit, just as there is now, on the number of people who can enter medical school.
Did Katz have an influence there?
No. Katz was at that time at the Kanematsu Institute that he had joined, where Sir John Eccles was the Director. That was the golden period of the Kanematsu Institute—Eccles, Katz and Stephen Kuffler. After about two years in that job, which in a sense started to convert Eccles from his view about chemical transmission—but only started—Katz then joined the RAAF and went into the radar division of that and then returned to the Kanematsu just after the end of the war and married an Australian. [brief laugh]
So you had decided that you were doing medicine, but you were already heading towards science and research?
No, at that stage I was just heading towards medicine. I liked the idea of research, but I didn’t really know enough about it, and I knew enough to know that these novels that I had read tended to romanticise it a little bit.
When did you know that you were heading for a life of science? Was it early or was it after you started medicine?
Again, medicine one and medicine two I quite liked, but there was no evidence that the people who were teaching us were doing much research. The only one that I’d heard about doing research was Frank Cotton, who taught us physiology. He had been basically the inventor, on the Allied side, of the antigravity suit, the so-called g suit, and was working on that at the University of Sydney. His prototypes were then being tizzed up by the RAAF, the RAF and the US Air Force and went into the Allied armamentarium as anti-gravity suits for fighter pilots, to prevent blackouts.
So at the end of year two I asked him, greatly daring, could I get a holiday job for his research— ‘I’d really like to find out a little bit more about it.’ So I couldn’t get a job with the g-suit, because there were too many other people involved in that, but he said he was interested in the physiology of exercise. He had got a drawing of a little device for recording blood pressure about four to six times a minute, or even more often if you were diligent, and asked whether I could see if I could get that going and, if that worked, we could start trying it out on people who were exercising on the stationary bicycle. So that’s how I got into the technology of research.
By the end of the holidays, when I went to go back to medicine, we had just got everything going and had got a few results but nothing definite. So at that stage I thought, ‘Well, maybe I ought to do a little bit more.’ My parents didn’t think it was a great idea to interrupt my medical course, but I did talk with the Dean and with Professor Hugh Ward, who was one of the wise old men of the faculty, ‘What it would be like to interrupt medicine?’ The long and the short of it was that, at the end of med three, I was allowed to interrupt it for a couple of years. In the first year, I did a BSc honours course—there wasn’t a BSc (Med) in those days—and then in the second year I really consolidated on that and did a masters course, where I basically wrote quite a good thesis on exercise. And then I resumed my medical course again.
Tell us about those years in the Masters of Science with Geoffrey Kellerman and whoever else?
Well, Geoffrey Kellerman was the only other person there. He was susceptible to chilblains and really felt very hurt about that. So he thought, once I had started stirring about whether one could interrupt their course, that he would also do that, and we were in it together. He worked on a completely different research problem, but he was a wonderful person to actually be there because he was very, very quick on the uptake—really one of the brightest people that I’ve come across, and the sorts of courses that we attended were largely do-it-yourself courses. We did a course in science mathematics, which wasn’t difficult, but I felt and he felt that we ought to learn a little bit more about data analysis as we were going to get data. So we did a course in statistics, which again was just very fortunate. It was an extension course, done by Dr Helen Newton Turner, who herself was an architect. But she had worked as an assistant to the great statistician and geneticist R. A. Fisher, Sir Ronald Fisher. Because there were just two of us, we got the courage to read his book called Statistical Methods for Research Workers and The Design of Experiments. Which would read as follows, it said, ‘It may easily be seen that X equals Y’—or something like that. Geoffrey could usually see it before I could, but it would take both of us about two or three weeks to work out these ‘easily be seen’ phrases, and we really learned a lot about statistics. And, it stood me in good stead for a long time.
It sure did. But I remember Geoffrey Kellerman particularly from when John Uther and I were doing our Bachelor of Medical Science review. We interrupted our course, and Geoffrey used to be one of our main torturers, because he would come in every two or three weeks to have a cup of coffee with you and have a chat and en passant would get the two students and ask them some question like, ‘If it is easy, how would you prove it?’
Yes, and he later became Professor of Biochemistry at Newcastle University. He was a very brilliant person, but he somehow knew too much to succeed in research.
Can you recall what made you choose to go into physiology?
Cotton was one of the very few people in the University of Sydney at that time who were really doing any research. He taught me quite a lot. He was not an imposing figure. He had been a champion swimmer in his youth, which is why he was interested in exercise, but he was really one of the main figures. I mean, there were people like Hugh Ward, who had been an associate professor at Harvard in Hans Zinsser’s Department of Microbiology. He, in an attack of patriotism, had returned to Australia. Really the funding of everything was just so deplorable in those days that they didn’t get much done, but they got a little bit done. Interestingly enough, the bacteriology department was also the department where Gus Nossal, Don Metcalf and Jacques Miller, who were also Sydney graduates, were inspired into their career in research.
But that inspiration was by Pat de Burgh. Was Pat de Burgh already around when you were there?
Pat de Burgh was Hugh Ward’s senior lecturer in those days. But Hugh Ward had a very considerable horizon. I got to know him later on because he, like I did, lived in Hunters Hill and we saw each other on the ferry. But, even long before that, he was a person you always wanted to consult on difficult problems, and then he would give you a pretty good resume of the pros and cons.
He seemed to have an influence on you in relation to doing the MSc, but you hadn’t done microbiology yet.
No. The person who sent me to him was the Dean, Sir Harold Dew, who said, ‘Well, you know, I don’t really know about all this, but talk to Hugh Ward.’ So I had to find out who Hugh Ward was and went on from there.
Let’s change tack. Maybe you can tell us about meeting Jennifer. How did that happen—getting married, having a family, and that sort of time?
That started off as what you might call a one-horse romance. I met her when I was about 19, a medical student, and she was a school girl of about 16. What happened was that I was in the Burragorang Valley, spending my summer holidays with two colleagues. I would never have met her but for the fact that, in the boarding house that she was staying at, a horse had died outside and was gradually decomposing, with the usual results. Her mother was in South Australia visiting her various sisters and Jennifer was meant to be chaperoned by her father and brother and his fiancée, who did a reasonable job of it.
Anyway, we met. She came from a very musical household and we had common interests in classical music and literature. And, the three of us all vied for her interest and favours for quite a while. Anyway, in the end, she ditched the other two and stayed with me. That went on through my medical course. She graduated; she went from school to arts and did very well there in anthropology. At the time I was doing my MSc, she was working in the anthropology museum and she came and occasionally was a subject in our blood pressure experiments.
Then, when I finally graduated in 1950, we married about three days later. At that stage that was very much frowned upon by the hospital authorities where I was about to become a resident, but I had fortunately not asked whether they approved of it or not and so we lived through our first year, me as a resident and she at home with her mother.
One of the things I recall from doing a Bachelor of Medical Science review was talk that, on some very critical occasion—it can’t have been just after you got married; maybe it was your honeymoon—you were writing your MD thesis. When did that happen?
Well, I hadn’t written up my MSc thesis as my work and I thought I’d really better do something about that. So I started writing a few sketches of it on my honeymoon, but I didn’t actually get very far in, you’ll be glad to know. I did my residency and then I went eventually to the Kanematsu Institute, which Eccles had long left and where now Colin Courtice had become the Director. He looked at my MSc thesis and said, ‘Why haven’t you written any of this up?’ So I muttered and said, ‘Well, I haven’t had time and I’ve got married and I’ve been a resident in the hospital’—and he said, ‘Oh, what’s that got to do with it?’ He gave me a job as a junior NHMRC Fellow and helped me write all of it up. Really, it was also a salutary throw-away remark that I’ve never forgotten, that really it is no use doing work unless you actually write it up.
Who have been some of the major figures to have influenced your life in science?
Well, at the University of Sydney, it was people like Frank Cotton and Hugh Ward. Then later on, Ruthven Blackburn who, at the time I was doing some of my postdoctoral work, had become the head of the clinical research unit at Prince Alfred. I then later met him as my boss, when he was Professor of Medicine and I became Professor of Cardiology. He was a very impressive figure, not so much for his research but for his grasp on clinical medicine and his capacity to teach clinical medicine in a really interesting way. Then, of course, there were my various overseas friends.
One of the people that have been both a model and an antagonist in a way is Arthur Guyton. You might like to talk a bit about that.
I got an invitation to go to the international physiological congress in Tokyo, to talk on some of our work in hypoxia that we had started to publish in decent journals, the Journal of Physiology and in Circulation Research. I even had to have voice tests, with these characters in the vanguard looking on, to get my talk prepared.
Anyway, I went to Tokyo and I decided then that, after I really got the course going at the University of New South Wales in physiology, I would take three months’ sabbatical; I felt I could take that much time off. So I went, first of all, to visit Björn Folkow, about whom I had read a lot, in Sweden, in Göteborg, and then Arthur Guyton who was already then making waves as the coming man in circulatory control. Arthur was professor of physiology in Jackson, Mississippi and had written a very interesting article on how cardiac output was regulated—was it by the heart; was it by the peripheral circulation—and I thought I would learn something from him. After being in Sweden, in London and after visiting my old mentor Cliff Barger in Boston, I went to Jackson, Mississippi, for six weeks, and what a culture shock that was. That was in 1965 and there was still very much a racial divide. It was just changing slightly, but it hadn’t yet changed in the Guyton household. So that was one aspect of him that was really quite extraordinary.
But he really was one of those people who had thought like an engineer. He wanted originally to become a neurosurgeon but he had been damaged and paralysed in the last big polio epidemic and he had to give that up and become a physiologist. He had started to think about how the system worked as a whole. At that stage he had really only thought about cardiac output. Where he was interested in our work and I was interested in what he was doing, because one of the things that regulates the peripheral circulation a lot is hypoxia, which we were all working on at that time.
He also gave me a preview of his next big opus on how blood pressure was controlled and especially how hypertension developed I was terribly impressed with all that. It was basically that all longterm blood pressure regulation happened through the kidney. That the fundamental cause of hypertension was a salt overload in a defective kidney. He’d worked out how this affected the whole circulatory control system and built a computer model of that. I returned very convinced of the rightness of his cause, and we had Guyton morning, noon and night for several years, before I actually started trying to verify some of his hypotheses and found that, like so many hypotheses on hypertension, that one too had feet of clay.
What happened in terms of your relationship with him?
We got on very well during my first visit. When I started finding faults with his idea, we had a long correspondence and I sent him all our exact data. He put it through his computer and he said, ‘Yes, well, this one isn’t behaving like the theory says it should, so there must be something wrong with your experiments rather than with the theory.’ We had this discussion also at meetings of the International Society of Hypertension. The one that sticks most in my mind was one we had in Göteborg, where I had a fairly sympathetic audience to my cause. At the end, Guyton said, ‘Well, it must be the rabbit in your work that really behaves quite abnormally.’ Franz Gross, one of the other big figures in the hypertension field, who was chairing that session, said, ‘Well, in clinical hypertension we often do get people who do not really behave like they should. How do you explain that?’
That is quite an episode in your scientific life.
It was a negative episode in some ways, because Guyton’s theory, once you thought about it, didn’t even really work for renal hypertension, because it is much more complicated than his theory allowed. His other big error in that theory is that it put an almost negligible role in the autonomic nervous system for longterm control; though in his books he did allow that it might play a role, but he was very opposed to it.
How about Cliff Barger? I know that you spent seven months with him at Harvard.
He had a very big role, he taught me how to handle conscious animals to a better degree than I had known before—though I had been working on conscious animals before that but—that they really had to be pain free and that one had to be very careful of how one handled them. But what I most got out of Harvard was the fantastic teaching courses they were running, which were something that was absolutely unknown in Australia. In my first job as the first Professor of Physiology at the University of New South Wales, they were keen to have me there and one of the carrots that they dangled was that there would be enough money available to introduce this kind of course in Australia. We did these courses and the reason why they worked was that all of us, (the entire staff and all the people who were there for research purposes—research students and higher degree students), they all helped in the practical classes. As a result there were very few failures in the preparations and the students got an enormous amount out of it. It was Harvard and Cliff Barger specifically who really was responsible for all of that.
Tell me, Paul, what do you think of the modern courses which are evolving around Australia with the graduate medical programs and mature age students? Might you have liked to have put such a course in at UNSW?
Well, my life hasn’t really been all in research. At Sydney University, after New South Wales, I was Professor of Cardiology and I was considered one of those professors who had a lot of spare time because I wasn’t the head of a department, other than in cardiology at Prince Alfred. I was chairman of the curriculum committee for a few years, and we tried to make the sixyear medical course into a fiveyear medical course. We did that, and it didn’t really work, because people didn’t really like the idea of having to drop things from their subjects. It worked in Newcastle, where my colleague, the then Dean of [Medicine at] Sydney, David Maddison, had gone and he managed to sell it to them. But I personally think that the course that is in now—that threeyear general science or arts course, followed by a fouryear graduate medical program, which is the American style course—is a much better idea. If I were to have my time all over again, I would have liked to have done a really proper science course rather than the two years research that I had, and learned some proper chemistry and learned some proper physics. I might have then become quite a good physiologist.
How about Horace Smirk from Otago?
Yes. In my exercise days, I rediscovered a reflex that is actually very important in regulating the circulation in exercise arising from the metabolising active muscle, and it’s called the muscle chemoreflex. I hadn’t known about Horace at all. He was at that stage actually Professor of Pharmacology in Egypt, because the London establishment didn’t really like him; he was an Englishman. Then he went to become Professor of Medicine at Dunedin, and he was the first one who really treated patients with very severe hypertension with these ganglion blocking drugs. Anyway, Horace was very interested in what we had done, and he and I had a good relationship all his life. He was really one of the big figures in hypertension and probably has never been recognised sufficiently.
I’m not sure. I would have thought that he is seen as one of the giants. Sure, there are others, but—
He was never seen as one of the giants by people like George Pickering, [Sir George Pickering, Professor of Medicine, Oxford] which kind of hurt Horace.
Because he was in the colonies, so you wouldn't expect Pickering to. But I think an awful lot did see him as that.
I agree. I saw him as one of the giants
It is interesting that you have interacted with some of the giants of the last 50 years. Horace Smirk is one in the clinical field; Arthur Guyton is another; Folkow himself. Tell us about Björn, you had a long relationship with Björn Folkow over the years.
Yes. My first relationship with him was when I went to Göteborg, Sweden, and I was very impressed with his work on neural control – all in anaesthetised preparations – including these diving ducks that got a bit like seals; they can redistribute all of their blood flow to the brain and heart and cut it off everywhere else. He learned to use our thermodilution method for measuring their cardiac output. I saw the human side of Björn when he said, ‘we’ll go up here on the rocks near Göteborg.’ We went up the rocks and he knew where he was going and I slipped into this icy water in the North Sea. So he took me out, wrapped me in something that was in the boot of his car, drove me home and poured an aquavit and a beer, and I said, ‘What do I want the beer for?’ and he said, ‘Drink this and you’ll find out.’ And I drank that and I thought I was going to start burning. And then the beer chaser was absolutely de rigueur. So we’ve been friends ever since.
We will come back to maybe talk about the book, Björn Folkow was going to do the book with you. So you obviously did an awful lot together.
Björn was a wonderful person to know. In the sixties and seventies he was absolutely on top of the autonomic nervous system control field and he started his very interesting work on structural changes in the blood vessels in response to hypertension, which I then took up. I thought we had so many things in common that, when I started writing this book, we would get on quite well together.
What was a problem was that Björn is about four or five years older than I am, and he really thought that physiology had reached its peak in the seventies, and that it was downhill all the way, all this modern biology was not really his scene. It is a pity because, if you really look at the history of physiology, people have said this from about 1850 onward. First, when biochemistry came along, everybody shouted, ‘Wally, wally’ [‘Woe, woe’]; then, when pharmacology came along, it was the end of civilisation as we know it! It is a great pity, because he still is a very bright guy; he just cannot bear the thought of having to say, ‘Well, maybe we if go a bit further this way some of the conclusions we drew were a bit simplistic’. His other great attribute was that he was the last surviving person in Sweden—and, I think, in the whole of Europe—who actually used the golf-ball typewriter. He used it single space, writing in between the spaces for his corrections, and you couldn’t really work with him on that kind of basis. So we agreed, reasonably amicably, to part and I finished the book.
Looking back, Paul, what are two or three of the decisions that have been the most critical in your scientific life?
I think the first one was when I had graduated in medicine and had done just one year as a junior hospital resident and I thought, ‘Should I or shouldn’t I do a second year?’—and in some ways it would have been good if I had done a second year. I’ve never been very pleased with that decision. But the really good decision I made at that time was about not going back to the physiology department to do more work on exercise. Ruthven Blackburn thought I might go to the clinical research unit and work with him. But at that stage Colin Courtice offered me this position down at Sydney Hospital, at the Kanematsu Institute. It was a good thing for me to have gotten away from the University of Sydney. At the Kanematsu Institute Colin had been at Oxford for several years (he was reader of physiology in Oxford) and that had rubbed off on him and it rubbed off on all of us. We had a lot of freedom there to design our own experiments. But he really also taught us a lot about how to have good laboratory order.
So that is one critically important one.
That was one. The other one was, as TS Eliot once said in his Murder in the Cathedral, ‘The greatest treason is to do the right thing for the wrong reason.’ I did that when I got very disappointed with the University of New South Wales. I had a problem with them over a famous examination—their examination system in physiology—and I resigned in a huff. Out of the kindness of the Australian scientific community, they found a job for me as Professor of Cardiology at the University of Sydney. That was an enormous milestone in my career, to actually have the opportunity to do some clinical research and to translate some of my earlier, rather esoteric work into patients.
Paul, we were talking earlier about the University of New South Wales. Would you like to think back and tell us a little more about that and maybe how you would handle it now?
We had a very good department at New South Wales. There was a final exam and you either passed or you didn’t. Not just in the final exam, but the whole course. In one year, we failed about 30 per cent of the students, normally we had failed about 25 per cent of the students, and they deserved it. But at that stage the university was a bit embarrassed because they had said, ‘There’s such a huge number of people coming in, we can’t cope with it in our teaching hospital at Prince Henry; we need another hospital,’ and they had their eyes on St Vincents. But by this rather large failure rate, that argument fell apart, because there weren’t so many students coming through. Anyway they said, ‘You must let more people through.’ We looked at it all fairly carefully and we said, ‘Well, no, we aren’t going to. The committee is not going to tell us what to do.’ Ian Darian-Smith was the other professor in the department, of course, and he also agreed with all that. We both resigned. No sooner had we resigned than the university caved in and said, ‘Oh, yes; you were right all the time.’
At that stage I really had had enough of it. The foolishness of it was that I hadn’t looked for another job at that stage. I didn’t think it would be all that difficult to find one, not in Australia, because there just weren’t any at that time, but in the USA. However, Jennifer didn’t want to go to the USA and I didn’t really want to go there either. Half of me didn’t want to go there because of the Vietnam War and our children were becoming,..
You had two teenage boys who would have been drafted.
Yes, two boys who would have probably been drafted. So that was against that.
I could have probably gone to Canada. But, just when everything really looked at its blackest, there came this job of Professor of Cardiology at Sydney, due to philanthropists Mr and Mr Scandrett, who gave money for that chair. Ruthven Blackburn and I had known each other quite well for years, but he thought this was really an opportunity to get research into cardiology. Very few people of that time would have taken that kind of decision. It was, in a sense, the furthest I had ever travelled. If I had gone to America to another physiology department, it would have been child’s play compared with the amount of work I had to do to look like a cardiologist, as your wife, Alexandra, my registrar, found out. Anyway, she was very nice about it, Alexandra.
She recalls, with great fondness, having to show you an electrocardiogram and, when you looked at it upside down, she wasn’t sure whether that it was because you were just so brilliant that you could read it upside down or whether you didn’t know the difference!
I am not going to comment on that now. Anyway, it was a wonderful opportunity. I think the department became an absolute buzz of research activity. One of my biggest surprises was that no sooner had I arrived, you wanted to come back (I think you were at that stage in the USA doing your post-graduate work). And the number of really bright registrars from Prince Alfred who queued up to come was far beyond anything that I had expected. Even people like Peter Sleight, from Oxford, were interested in coming there. So that was good. I think it really started my work on the clinical physiology of hypertension, which hasn’t really looked back since then.
Paul, when you were at RPA, the coronary care unit got going. Tell us about that, because you were head of department and had to make those decisions.
Yes. Well, the question was should we or should we not build a coronary care unit. I asked my very supportive clinical colleagues should we or should we not, and they said, ‘Oh no, it’s a bit of a waste of money. We really do treat these patients pretty well.’ Fortunately, I really did look up the literature on that. The introduction of coronary care units had been one of the great revolutions in cardiology because all that happened in a coronary care unit is that you monitored people’s electrocardiograms after they had had a heart attack and, if any rhythm disturbance looked like it had happened or was about to happen, the coronary care sisters could actually give some anti-arrhythmic agents, and they had saved enormous numbers of lives. So I showed them all that and they said, ‘Oh well, maybe we ought to have one.’
Anyway, we got one, and the most dramatic thing I have ever seen in my life was the in-hospital mortality after heart attacks dropped from double figures to about two or three per cent in the first year of its operation. I was pleased that I had made the right decision there, my clinical colleagues were pleased that I had made the right decision there, and it really was great. It just shows that you need to read the literature.
Paul, you’ve had a fascinating time heading three very different organisations over your career. One was as foundation Professor of Physiology at the University of New South Wales, another was the Scandrett Professor of Cardiology at the Hallstrom at RPA, the first Professor of Cardiology at the University of Sydney, and then finally moving to Melbourne to head the Baker Medical Research Institute. Would you like to maybe talk about those different experiences and a little bit about the way the different contexts shaped the science that you were doing?
It’s not an easy question to answer because so much depends on the person who goes into these jobs. But, in general, if you are in a university department, you’ve got teaching commitments and you’ve got research commitments. If you’re in a clinical department, you’ve got all that and on top of it, is the fact that you are the role model for patient care in the hospital and, therefore, your time for doing research is even less than in a basic science department.
Now, if you are in a research institute, your whole reason for being there is to do research. If you want to do other things, that’s your privilege or misfortune, but you’ve got to do good research. In a university department, you really have to tackle problems that can be tackled within the time constraints and even if you do have good research assistants and higher degree students, you can’t run programs that go for five or 10 years. In a research institute, you probably ought to be doing some of that; but you should also be looking at broad problems in science. For example, what are the causes of hypertension, and what are the mechanisms. That creates a problem there because you have probably more senior researchers than you would ever have in a clinical department, but each researcher wants to be recognised for his/her own individual work.
We sometimes accentuate this through our grant giving bodies. But, on top of that, if you are the institute’s director and want to tackle these broad problems in science, you’ve got to get people interested in doing some collaborative kind of work and they’ve got to feel that there’s something in it for them. That’s really a juggling act and quite an art, and I tried to have it both ways at the Baker Institute, where, on the whole, it did work. Many of our researchers are now recognised in their own right and we did manage to do collaborative programs, especially in the hypertension field.
Do you think you would ever have got to working on hypertension if you hadn’t moved to the Hallstrom and RPA?
I very much doubt it, in the sense that at the Hallstrom we actually did clinical physiological experiments on humans, which I couldn’t have done in a physiology department, and people hadn’t done them and it again set the fashion of how you approach this kind of problem.
Then we became slightly more courageous at the Baker Institute, where one of the real pieces of luck that I had was that one of the young persons who wanted to come at the end of his postdoctoral period was Murray Esler. He came and said, ‘I’ve had an idea about trying to work out a method for measuring sympathetic activity in humans’ which is basically similar to assaying plasma hormone production, and I said, ‘Oh, that sounds good.’ Then Murray came along and he did not write new papers for about two or three years. He collaborated on a few things that another person there, Garry Jennings, and I were doing together, but I did manage to see that it really had to work in the end. We were not putting any pressure on him to write papers; we were just putting pressure on him to get the best possible opportunities for actually demonstrating his method, and he did demonstrate it, and it has been an absolute winner ever since.
That spill-over technique in humans, looking at regional sympathetic activity, has really been the hallmark at the Baker.
Yes. Murray did the theoretical part of it. But, again, he and Garry Jennings, who was the person who had green fingers on all these things and could pass catheters into the most unlikely places, were an absolutely terrific team.
Do you think that is one of the things about the research institute: that you can scale things up and get teams with multiple skills in a way which you can’t dream of in a basic department or even a clinical department?
Yes, that is absolutely correct. The other person along those lines that came to the Baker, and we all benefited from that, was Julie Campbell and her husband Gordon. Julie is now in Queensland. She really has green fingers, and not only in growing cabbages, which she is very good at, but in growing cells. She really put that on to the map at the Baker Institute. One of the areas where it really benefited the sorts of things that Jim Angus, our pharmacologist, and I were interested in was how to grow endothelial cells so that one could try to find out what was this endothelium dependent relaxing factor. Anyway, Jim was hoping he would discover that and win the Nobel Prize, but he didn’t. But the method that he used for growing cells was actually used by Moncada, the final discoverer that this was nitric oxide, and it is really entirely to Julie Campbell’s credit.
It is fascinating; as we go through discussing your life in science, an awful lot of people who have been through your hands being mentored by you have ended up as Fellows of the Academy. I am thinking of Murray, Julie, Jim, etc. Looking back, what are two or three of the scientific achievements that you value most?
I think I ran three quite good departments, but what I think is the best thing that I have ever done is my book on the causes of essential hypertension.
I am not sure if we should call it ‘the book’ or ‘the Bible’, but still.
I would like to call it the Bible, John; thank you for that. The sad thing about all this is that when I was Director of the Baker Institute I had been saying to myself, ‘I really must get all this together. We are again working as though we were in a university, little bits at a time. It’s not coming together enough.’
I didn’t have time to do it then and I probably should have done it. But when I retired 18 years ago, at the end of 1990, as happens to retirees, people say, ‘Oh, you’ve got a lot of spare time; you can go on this, that and the other committee.’ I did a bit of that for about three years and I finished some experiments that I wanted to finish at the Baker by travelling down to Melbourne. But then I said, ‘Well, this is it. You’re getting on.’ I tried to write this book with Björn, and that was about three or four years down the gurgler because it wasn’t really getting the right vibes. Then in the end I did it. I took about 12 years over it, mainly because I had to learn so much myself.
Tell us, what it was about the book or what was the essence of your having to go and learn new stuff? You weren’t just writing your own stuff up?
One of the things that I learned from Arthur Guyton, even though I disagreed with his specific interpretation of the theory, was that you had to look at the whole system; that was undoubtedly correct. I then went along to my various engineering friends and said, ‘What is the simplest kind of thing that is not a linear system like Arthur Guyton used, because that obviously doesn’t work’.
Can you explain what you mean by a ‘linear system’?
A linear system is just a simple feedback system, where the properties of the controller never change. That is basically what Arthur Guyton used by insisting that the kidney was the cause of hypertension. Anyway, I talked to people like Brian Anderson, the former President of the Academy, who was quite helpful. Then I found one in my suburb in Hunters Hill. Everything happens in Hunters Hill. Barry Thornton, who is Professor of Applied Mathematics at UTS, really helped me to work out, not a system as complicated as some of these nonlinear systems are, but what is called an adaptive control system. This takes into account that, in hypertension, the environment as well as the genetic factors are very important in its development. So I had to learn about control theory.
Then, notwithstanding that Björn didn’t like it, I had to learn a fair bit of molecular biology because, even at the simple level that I used, you really needed to know some of it. But I then went through the various components of the system, of which the initiator is basically the nervous system. In the process, I not only dealt with hypertension but I also dealt with several important aspects of normal circulatory control, and it’s got a new few ideas on that. So, at the end of it, I had really put all of that together. I must say that it’s been quite well reviewed and I’m quite pleased with it.
You asked me, ‘What would you do if you had your time all over again?’ What I probably should have done, we got our block grant institute funding, which started in 1983. I probably should have taken off a year in about 198485 and actually drafted out some of this. Whether I could have done it is another matter. But it would have been very good if I had, because then we could have actually tested some of these things out experimentally.
In retrospect, you probably couldn’t. Given the amount of time that you spent doing research into areas where you weren’t expert, to do that while you were in that post would have been very near impossible.
But summarise, if you can: what is the essence that comes out of the book?
The essence of it is that mental stress is one of the really important drivers of essential hypertension. The three important things are mental stress, high-salt intake and obesity. But stress is often the initiator. It works through the central nervous system initially. The cortex perceives, ‘Is it stress, is it severe stress? Can I do something about it?’ If there is a lot of doubt and uncertainty in the system, you get what is called the defence response. That basically gets you ready to kick somebody into the moosh, or run away, whichever is the wisest thing to do.
Everybody gets stress and everybody gets this kind of response, so what is different about hypertension? In hypertension, what happens is that the stress behaves like a memory neurone. The brain somehow remembers the stress and it sensitises some of the connections between the cortex and the hypothalamus so that very low levels of stress, levels that most people wouldn’t regard as stressful, actually give you this response. Once you’ve got that, it stays with you for a long time because there are changes in your synaptic structure. The person, who discovered this, was the Nobel Prize winner in the year 2000, Eric Kandel. I had been reading some of his work before he received the Nobel Prize and thought ‘this must really about be it’. There is not much evidence in the literature, but there is quite compelling evidence in the literature that that is how it really works, that gives you permanent hypertension.
Thanks to Murray, we found out that in people with mild hypertension you get your maximum neural activity at that point of time. So, as blood pressure keeps going up in the course of a normal untreated hypertensive’s life span, there must be other things in the system that give an additional rise in blood pressure. The other things are really quite complex systems. They include Björn Folkow’s structural changes, which we of course also worked on quite a lot ourselves. They include things like these endothelial factors, like nitric oxide, that diminish, and other local factors that cause constriction. In the end, having triggered these other factors into operation, you gradually destroy a lot of the peripheral organs, including the kidney, the brain and the myocardium. So, in other words, what triggers hypertension is the nervous system, and what kills you is the periphery.
Tell me: the obesity story, how do you weave that in?
I think obesity is one of the really overdone things in the press. It doesn’t really cause a huge rise in blood pressure, but it causes some very nasty complications. It gives you, in the end, type 2 diabetes. If you get diabetes plus hypertension, you get slightly different complications to the ones that I have just been talking about, but you get very serious diabetic complications added to hypertension, which is also a deadly mix. So it is the combination of diabetes plus hypertension that accounts for the adverse effects of obesity.
An interesting question about obesity is: how is it linked to hypertension? Long before obesity become fashionable, one of the things you couldn’t help noticing is that, in any series of hypertension, the people were always, even the so-called lean hypertensives, up to two, three or five kilos heavier than the normal-tensive age-matched controls. What I think happens is that people, when they get stressed, start eating too much. In most people, the system that regulates energy balance keeps that in check and their weight doesn’t really go up. But in about 40 per cent of people the cortex manages to ignore this, for reasons that are not well understood.
Mine certainly does!
Well, it does. You keep yourself in check now, thanks to your wife, Alexandra.
Where do the genes fit into all of this? You said that you had to do a lot on the molecular biological and genetic side of it.
There is absolutely no doubt that, roughly speaking, if you look at the blood pressure variation in the population, about 30 per cent is due to genetic factors and about 60 to 70 per cent to environmental factors, yet the genes are absolutely critical in the whole story. So the question really is: what do they do? Again, I wish I knew the answer to that. One possibility is: why are these neurones that sensitise the response to stress between the cortex and the hypothalamus, why are these synapses sensitisable? Normally, the autonomic nervous system can be conditioned to do things, but they don’t even behave like memory neurones, where the stimulus can become smaller and smaller to elicit the response. So, possibly, it must be a developmental set of genes that do this. There may also be genes, in relation to what you mentioned about obesity, that allow you to ignore the messages from your energy balance. These are examples of these nonlinear systems that I was talking about earlier.
The other thing is salt. If you eat too much salt, according to the Guyton theory, blood pressure is meant to be going up through the kidney, and it will do that in people with renal impairment. But in people with normal kidneys, which most of the initial hypertensives are, it doesn’t do that; it goes through the brain. The permeability of the blood-brain barrier to salt increases so that, in the end, the question is: what genetic factors are involved in making the blood-brain barrier leak here? Again, these are the sorts of things that are not known. One reason why I would have liked to have started this book earlier is that we could have probably found some of these things out by now.
We might have got to it. Apart from putting it together in the book, what are three or four of the individual components, in terms of scientific discovery and achievement, which you think you look back on with the greatest pleasure?
One is the work that you were initially involved in; on how the autonomic nervous system is controlled in oxygen lack. I started it because it appeared a soluble problem. It would give you a definite answer. There weren’t too many factors involved in it, and we worked through a lot of them at the University of New South Wales and then back at Sydney. That, I think, still stands today as a very interesting piece of work. It even has clinical applications in relation to obstructive sleep apnoea. The theory that I developed about how it all worked, in the years before I even knew how to spell ‘obstructive sleep apnoea’, has in fact given probably the best explanation of obstructive sleep apnoea that there is. One of the people again who helped me in this was an English physiologist, Michael Daly, who came out to Melbourne to help us put the final touches on some of that work.
Did that hypoxia stuff originate in the Cotton days, with g-suits?
No, that initiated in the Colin Courtice era, when I was meant to be working out what oxygen lack does to pulmonary oedema. It makes animals more susceptible to pulmonary oedema because they get an acute cardiac failure response, and I worked all that out. That’s one of the things.
The other thing on which I did a lot over the years, and which still is probably amongst the best things, is how baroreflexes work in the whole intact organism. They are actually incredibly important in analysing this kind of complex system, because they are connected to so many regulatory areas in the brain that, whenever some of these parameters of the control system alter, you find it out in the changes in baroreflexes.
Perhaps one of the other things that I discovered was that a lot of the operations of the brain are comparing one thing with another thing, and that it simply can’t just work through straight synaptic connections. Probably one of the important areas in that is the cerebellum, which has more nerve cells in it than the rest of the brain put together. It is very stereotyped. I still remember Sir John Eccles coming to me once. He was one of my great supporters when I became Professor of Physiology at a very young age. He said, ‘Paul, I’ve worked out all of the connections in the cerebellum; there is nothing more to be said about it.’ Well, we are still wondering what’s to be said about it. But it is very stereotyped in its action and it is an ideal organ for comparing A with B. It does that in relation to exercise. It says, ‘Are the commands we are telling the muscles about how quickly to exercise, are they being carried out?’ If not, we will try to bring them around. That is all done through the cerebellum, and not only through the cerebellum, but that is one of the organs. It does things like, in hypoxia, ‘Is the respiration doing enough to keep the oxygen just up a bit, or do we have to whack it up a bit more?’
Interesting. I wonder if you could relive it, would you do anything differently?
Well, that would have been the most useful. But I don’t know. After all, in one's lifetime one can’t do things differently once they are done. But what I would have done, is in my last three years as director of the Baker Institute I had a double job, I was also chairman of the board of the Alfred Hospital. That was probably one of the most stupid things I’ve done. Everybody said to me, ‘Don’t do it, Paul.’ Somehow out of, I don’t know, feeblemindedness or vanity or whatever, I did it. I mean, I managed. We didn’t go backwards, we went slightly forward. But it really wasn’t worth the effort and my time would have been much better spent if I had said no to that.
Going back to that University of New South Wales episode, if you were advising the young professor of physiology who was contemplating a similar action today and he said, ‘You’ve been through it,’ what advice would you give him?
In a sense, this is the ‘blind watchmaker’. I did the thing that one shouldn’t have done, because, on the whole, with a young family, as we had, it really took a terrible risk for them. I probably could have done quite a reasonable stint as a general practitioner if everything else had failed. Anyway, it didn’t come to that, thank God. So there is an element of chance and certainly it’s been that in my career.
It led to you becoming Professor of Cardiology, which then set you off.
Yes. It really opened up a new world for me.
But it was traumatic.
It was traumatic, hence the role of stress—and you really know what you’re talking about.
Paul, I wonder also, if you had a young scientist who had just finished their doctoral phase and was embarking on a postdoctoral phase and a life in science, what advice might you give that young man or woman?
That is a difficult question. What I would really probably advise is, first of all, ‘Is there anything you really want to find out?’ A lot of them, of course, don’t know what they want to find out, and that’s a pity, because it often helps. At least if you know that you want to find out something in the cardiovascular field it is something. The other thing to do is to actually shop around for a good mentor. In Australia I think it’s beginning to happen, but it hasn’t happened yet. You were one of the great shoppers-around in your young days and I think to beneficial effect, and it illustrates that point.
But one of the real problems I think is that, at the stage young people are making their most critical decision, which is who to work with for that doctorate, they do not have the equipment to make a good decision. It’s luck.
Yes.
You don’t know enough about the process of science, nor can you find out enough about your proposed supervisor to know if that person is a good scientist. That is difficult enough, but to know if they are going to be a good supervisor is very difficult.
It is.
And it is the most critical decision you make, because that first supervisor has such a huge influence. In my case, it was you; in your case, maybe Courtice. It’s interesting.
I knew that Frank Cotton at Sydney was the only person I could see who did any research, but I didn’t want to go back to him because he just didn’t have that charisma. So I tried the next-best in Sydney, and it worked out very well for me.
One of the other things might be: during the course of a career, what would you stress, beyond having made the right decision and got started, what would you tell the young scientist?
A lot of young scientists that I know do research because it helps them to get a career job, and that’s not a good approach. On the whole, even if it works out that way, you really want to have something that interests you burningly, and that never should stop. It hasn’t quite yet stopped with me yet, anyway.
That’s for sure. Paul, thank you so much for joining in this interview. It’s been great fun discussing your life with you. It’s always fun having a talk with you. I would like to thank you very much.
I’ve enjoyed it too. Many thanks.
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