Henry George Burger was born in Vienna, Austria in 1933. Burger completed his secondary schooling at Xavier College in 1950. He then began his compulsory National Service in 1951 before beginning a medical degree. Burger graduated with an MBBS from the University of Melbourne (1956), winning eleven of the twelve prizes on offer. After graduation, Burger worked as a resident medical officer (1957-58) and then registrar (1959) at St Vincent's Hospital. In 1960 he completed a Doctor of Medicine at the University of Melbourne. He then went to the Diabetic and Metabolic Unit at the Alfred Hospital as a research fellow (1960-61).
In 1961, Burger was awarded a Nuffield Dominion travelling fellowship to the Middlesex Hospital in the UK. While in the UK, he worked on measuring testosterone in various disorders in women. Burger then moved to the USA to take up a United State Public Health Service International postdoctoral fellowship at the National Institutes of Health in Bethesda, Maryland (1962-65). Burger returned to Australia in 1965 as associate director of the Prince Henry's Hospital Medical Research Centre (1965-69). He was then promoted to executive director (1969-72) and director (1972-90) of the Medical Research Centre and the Department of Endocrinology and Diabetes at Prince Henry's Hospital. He also worked concurrently as senior lecturer at Monash University (1965-78). Prince Henry's became an Institute in 1990 and Burger continued as its director until 1992. He remained as unit head and director of Endocrinology at Prince Henry's Institute until his retirement in 1998, but has continued in endocrine practice since then.
Interviewed by Professor Rob McLachlan in 2010.
Contents
My name is Rob McLachlan. We are here today at Prince Henry’s Institute of Medical Research in Melbourne to talk with Professor Henry Burger.
Where and when were you born?
I was born in Vienna, Austria, in May 1933.
And your parents?
My father was an organic chemist in the Department of Chemistry at Vienna University. My mother met him when she was a student there. My mother was reasonably well to do and was a baroness appointed by Kaiser Franz Joseph. Her father was in the Austrian army. My father’s father was a GP. I was an only child.
Where did you grow up?
I grew up in Vienna for the first few years of my life but was sent to England in 1939. I spent a year there in boarding school before coming to Australia on the SS Oronsay. I arrived just at the outbreak of war, at the end of January 1940.
And your parents?
My father had preceded us. He had been in Australia for seven or eight months before my mother and I arrived. I had started on the ship in Southampton and my mother joined it in Naples, Italy. The rest of the journey we made together. She rather stymied my lifestyle on board the ship because I used to assist the stewards in distributing breakfast to other passengers and she disapproved of that activity.
They left everything they had in Europe?
Effectively. Although they subsequently managed to bring out some of their belongings in a very large packing case – not quite as big as a container but not far short. Curiously, many years later, my father took the packing case up to Mount Buller and built one of the very first ski huts for his company’s ski club.
Happy schooling and inspirational parents
What about your school life?
We spent the first three years after our arrival to Australia in Adelaide, so I went to school in Adelaide first. I went to three different schools, including being sent to a boarding school up in Mount Barker in 1942. My parents’ were concerned about the possibility of a Japanese invasion and bombing, so I was put out of harm’s way. We then moved to Melbourne in early 1943 and I went to a Jesuit school called Xavier College Preparatory School. I then moved on and spent the rest of my school life at Xavier College.
How do you reflect upon your schooling in that place?
My memory of school is really a very happy one. Having come from Austria to a country which was at war with Germany and, therefore, regarded German speech and German culture with considerable distaste, I found myself psychologically also developing anti-German attitudes. When my parents spoke German to each other in the street, I wouldn’t walk with them. I would walk behind or in front, as if to detach myself from that atmosphere. That was reflected in my last year at school, where I was doing German as a year 12 subject. I didn’t do very well in it. I was filled with pride when one of my oral examiners said that it was very surprising to learn that I was born in Vienna. Not a sentiment of which my mother approved at all, but of which I was quite proud.
Your parents were obviously well educated. Were they supportive of your schooling?
Very supportive. I think my time of schooling and early school life was happy. I remember pottering with test tubes, inspired by my father, who was a research scientist and who came to Melbourne as research director of Monsanto Chemicals. He made an important wartime contribution in developing a better method of synthesising sulphonamides. These were essential for Australian troops in New Guinea, particularly in the treatment of infections and malaria. He was an inspiration to me not only as a scientist but as a human being. He was somebody who was very popular with all around him and who related extremely well to all levels of Monsanto Chemicals in Braybrook, Melbourne. He was a very good sportsman. He had represented Austria in hockey. He played the equivalent of league football in soccer. He was a very good tennis player and skier. I very much looked up to him, even though I could not do any of the things in those areas nearly as well as he could. He taught me to ski and play tennis, and he was an inspiration. My mother meantime had decided that she had to contribute to the family income and she did a Bachelor of Arts. She became a senior lecturer in French at the University of Melbourne.
My schooling was happy. The school was supportive and open. It taught one to be self-critical. I made a lot of friends there and one of the influences that led me to do medicine, rather than anything else, was the group of friends whom I met and who were all determined to do medicine. I also enjoyed many aspects of school. I learnt about music from a school contemporary. Music has been a lifelong love, particularly baroque and classical music, but I also like popular music. I participated in sport but without a great deal of success, except for one sixwicket haul against Melbourne Grammar in the under15 B cricket team.
In my final years of school, I did the equivalent of year 12 twice, because I was too young to go to university after the first time. This gave me an opportunity to do subjects that I might not otherwise have been able to do. Amongst those, perhaps the most important was english literature, where I had a superb teacher. I thoroughly enjoyed my experience of that topic. I also enjoyed physics and chemistry.
The decision to do medicine was not too difficult. I was torn between doing organic chemistry, like my father, and doing medicine. It is hard to remember precisely what moved me in the direction of medicine. Certainly having a grandfather who was medical and having a close school friend whose elder brother was a doctor and whom I admired were influences that went towards that.
Catholic teachings: questions and answers
This was a Catholic school. Has Catholicism been an important part of your life?
Catholicism was a very important part of my life. As you said, Xavier College was a Catholic school. I think it would be fair to say that we were taught in a reasonably open manner, without having dogma thrust down our throats, one did develop a critical attitude at school. But I was what you would call quite a devout Catholic. When I was at university, I continued in that regard. And when I was a resident and registrar at St Vincent’s, I frequently used to go to Mass down the road at St Patrick’s Cathedral. At that time, I really followed church teaching quite closely and obediently. But, once I had met my wife, she used to challenge me and make me think. She always used to say, ‘They give you the questions and they give you the answers, and I want you to think about asking some of the questions yourself.’ That was a major influence that made me start to question some aspects of Catholicism.
There was a particular Jesuit priest who taught you mathematics and, indeed, went on to marry you and your wife, I understand.
There was a Jesuit priest called Father Walmsley J. Smith, who walked with a limp and a walking stick and who taught us mathematics and religious knowledge. He married us in 1959.
In your last year of schooling, you did very well in chemistry and got into medicine. Was it difficult to get into medicine in those days?
To my best memory, no. You could nominate and say that you wanted to do medicine. I can’t remember if there was any sort of a quota – perhaps there was – but I don’t think any of us from the school who wanted to do medicine failed to gain admission.
Teaching experience via national service
Before starting your undergraduate program, you had some interesting experiences serving your country in the national service. Can you talk about that?
Yes. At that time national service was a compulsory part of one’s late teens, particularly between school and tertiary education. That involved going to the army camp at Puckapunyal, near Seymour, for a period of 12 or 14 weeks. It was a curious experience for me, as somebody who had never been any part of military service at school. I had never been a cadet or anything of the sort. Hundreds of us were taken up to the railway siding outside Puckapunyal and our names were called as we were allocated to the various companies of which we were going to be members for the next 12 or 14 weeks. I remember standing the whole day on this siding and not having my name called. Finally, there were five of us left on the platform and we were informed that we were the forerunners of a company, the large part of which would be made up of boys coming from the country – from Cobram, Tocumwal, Shepparton and Echuca. I became the sole occupant of my platoon hut for one night before the rest of the fellows arrived from those country towns. To me, that was a very important education in human relationships, in learning to live with people who were of an entirely different upbringing and educational level.
I was sent immediately to a training course in order to become either a lance corporal or corporal. When my colleagues in the hut realised what I was doing, they made quite dire threats about my health, unless I came back with two stripes as a corporal – which, thank God, I duly did. At the time I don’t think I enjoyed national service at all but, in retrospect, found that it was very valuable. One of the things that was very valuable is that we were taught to teach. We had to give lessons to the rest of the platoon and we were taught the principles of good teaching. I think that stood me in tremendous stead which I later used to teach medical students, colleagues and graduates.
So you entered medicine with experience in teaching and human relations and with a commanding knowledge of English. It was a very powerful combination for you.
That was a fortunate attribute that I had, that I could speak quite well and could write well. Education in Latin and Greek were important contributors to that ability. But it was a natural ability. My mother was a very good linguist. Whether there are some genes for that, I don’t know. I think that has been something that has been very helpful at all points of my career.
What about your undergraduate medical training at Melbourne University?
I did the classic sixyear medical course. Three preclinical years, a year of pathology and introductory medical studies and then two full-time clinical years, where I was a student at St Vincent’s Hospital – an institution about which I have very warm feelings. It was a great teaching hospital, a classic clinical school with excellent clinical teaching and wonderful pathology teaching in the autopsy room. One great character, a pathologist called Alex Tait-Smith, used to rivet us with his post-mortem demonstrations. But I very much enjoyed my clinical teaching in medicine and surgery. At the end of the medical course, I was extraordinarily fortunate in that I topped the year and got firstclass honours in all the three major subjects. I also won most of the clinical prizes that were on offer at the end of that year. Some of it was quite fortuitous, but it was something which certainly allowed me to make fairly free choices about the terms I would then serve as a junior intern, a resident and registrar. I effectively had free and first choice at what I wanted to do.
Can you recall any individuals who made a special contribution to your medical education and in what areas?
There was a group of us who formed an extra curricular tutorial group. One could make a private arrangement with appropriate people to be tutored. And we had made an arrangement with John Cahill, a medical tutor who was one of the senior physicians at St Vincent’s; John Connell, a surgical tutor; and Maurice Barrett, an obstetric and gynaecological tutor. We met with these individuals very regularly. They were very helpful in teaching us how to learn clinical medicine, surgery and obstetrics and gynaecology. But, apart from that, I was certainly impressed particularly with my physician teachers. I remember the physician teachers much better than the surgical teachers. All the senior clinicians at St Vincent’s were very good teachers, as were the specialists. I particularly remember the late John Billings in neurology, I very much enjoyed that as a subject and his teaching of it.
You also tutored the medical students one year below you. Why did you do that and what did that give you?
I think I was asked by colleagues both at my contemporary level and also a year or two behind me to give tutes on topics as we went through. I have always loved teaching and it was something that I enjoyed doing. It gave me quite a charge. If you have to teach it to somebody else it is also a way of reinforcing one’s knowledge of the topic.
The final medical exams in those days were fairly rigorous. What were they like?
The final exams were a real test of one’s stamina. We had to do a straight three and a half days of seven written papers, morning and afternoon. Then the clinical exam extended over another five weeks, where you had to do long cases, short cases, interviews and specialty areas like paediatrics and gynaecology. My preparation was perhaps a little unorthodox. For the two weeks before our final exams started, I skied at Mount Hotham, without any textbooks with me. I found that was fantastic preparation in terms of fitness and energy.
Your examiners presumably didn’t know that you had been skiing for the last two weeks.
I suspect that my examiners didn’t.
‘Where did the tan come from, Burger?’ They didn’t ask you that.
I certainly was much more tanned than most of my colleagues.
You obviously got most of the questions right, given that you got 10 of the 11 prizes on offer. There was one circumstance where you were correct and the examiner was wrong. Tell us about that.
After I had spent 25 years as director of the Medical Research Centre at Prince Henry’s, Harry Garlick, one of the senior physicians who had been involved in establishing that centre, told a story about me. He was one of the examiners, in conjunction with a well-known physician, William McIntosh Rose, for one of the written papers in medicine. After Harry Garlick had marked the papers, he said to Rose or Rose said to him, ‘Were there any outstanding papers?’ He said, ‘Yes, one.’ So they compared notes about that candidate. Harry Garlick had given that candidate 90 per cent for one of the questions and Bill Rose had only given him 70 per cent. The difference in mark was not a matter of style, it was a matter of medical fact in the subject of the question. They went back to the textbooks and the final mark that was resolved was the 90 per cent – and that candidate was me.
Immediately after your medical course, you had an experience, which many would be jealous of, at the 1956 Olympic Games in Melbourne. It was an extraordinary experience.
One of the best jobs that I ever had I got by courtesy of John Connell, the surgeon who had been our surgical tutor. The 1956 Olympic Games occurred immediately after our final exams and Connell knew the head of the photo-finish team which was to cover the Olympics. They were looking for one extra assistant to help them whilst they were in Melbourne, and Connell very kindly nominated me for that position. So I was the photo-finish extra. The highlight was the athletics at the Melbourne Cricket Ground. A special little shed was set up opposite the finish line for all the major sprints and long-distance runs. The photo-finish camera was up on the roof of the members’ stand and this shed was in the members’ stand. The film would be sent down a chute and I had to collect it and then go and develop it in the dark room in this shed. I was the first person to see who had won any of the close races. I worked there at the MCG for most of the Olympics. I also worked at the swimming and at the cycling, and it gave me my first exposure to competitive Olympic-standard cycling – a wonderful experience and something I would never forget.
What were your early experiences that led to your passion for endocrinology? How did that evolve?
That evolved significantly later. I went from the examinations to take up a standard ‘junior resident post’ at St Vincent’s. We did the standard twomonth terms in various aspects of medicine and surgery and the emergency department. Then, in second year, I did a sixmonth stint as medical registrar with Professor John Hayden, who was the first Professor of Medicine appointed to St Vincent’s Hospital, he was also the second University of Melbourne professor. I spent a twomonth term with a thoracic surgeon, John Clarebrough, who was one of my real role models and pin-up boys at the time. The experience of working with him almost made me do thoracic surgery. I found him an inspiration. But John Hayden was also an inspiration and I went back in my third year and spent the whole year as his registrar – a very interesting and informative experience. I started a little bit of research at that time. I wrote my first paper when I was in my third year there, with one of the members of the Department of Medicine. Hayden was an inspiring teacher. His ward rounds used to be populated by a significant number of people, particularly postgraduate students. He was very clever in the way that he would deal with a question to which he clearly didn’t know the answer. He usually handballed it to me and said, ‘Burger will tell you the answer to that,’ and Burger would never know the answer either. So we had to go off and look it up or admit that we didn’t know the answer.
You needed to make a decision whether to pursue a surgical career or one in internal medicine and endocrinology.
That was a decision that I had to clearly make in that third year, as to where I would go. It was clear that endocrinology was one specialty which was not well covered at St Vincent’s. There was one man, Bill Hamilton Smith, who was the endocrinologist and diabetologist at St Vincent’s. Somehow I started to get attracted to that area. I talked to him and was encouraged by him to do endocrinology and to then look at having a career at St Vincent’s, once I had been trained. He suggested that I would be free to take over endocrinology and develop it as a specialty at St Vincent’s. I was then directed to go and work at the Alfred Hospital, where the Ewen Downie Metabolic Unit was situated and where the late Bryan Hudson was endocrinologist. Joe Bornstein, an expert biochemist, was also part of the Metabolic Unit. So that appeared to be the optimal place in Melbourne for me to start training in endocrinology. I had hoped to spend most of the time with Bryan Hudson, but he spent a sabbatical year for most of the time I was there, and I only joined with him for a few months before leaving to go overseas. The experience was interesting. The laboratory side of it was rather frustrating and not very beneficial for me, except that it taught me patience and the need to be very careful in setting up experiments.
I was then awarded a Nuffield Foundation Dominion Travelling Fellowship and went to work with the late Sir John Nabarro in London at the Middlesex hospital. From a clinical standpoint that was an excellent experience. Again I was given a rather unsatisfactory laboratory project, on which I think I wasted quite a lot of time. That is, until I was directed to go and work in the laboratory of Dr Alex Kellie, an expert steroid biochemist and assayist. That was a very productive and fruitful few months, where I learnt the elements of measuring steroid hormones by the double isotope dilution derivative assay technique – almost as long-winded a technique as the name indicates. That led to my being able to measure testosterone in various disorders in women. And those results with Alex Kellie and under John Nabarro’s overall supervision led to my first paper in the Journal of Clinical Endocrinology and Metabolism.
Clearly you had developed an interest in endocrinology. What was it about that subject that really triggered your interest and passion?
I was attracted to endocrinology, in part, because of my father’s background as a chemist. He was somebody who worked in the laboratory and used laboratory techniques in his profession, and I saw endocrinology as a specialty which would allow me to combine clinical medicine with laboratory technology. That is, the need to learn and execute assays for hormones in the lab. The possibility of that combination was one that I very much valued and that attracted me. I think that is probably why I went in that direction. I never had any cause to regret that. I also found myself with the opportunity to visit institutions like the Royal Postgraduate Medical School at Hammersmith, where I used to go out to their grand rounds and occasionally on ward rounds. It was here that I was exposed to the upper echelons of English endocrinology and English general medicine at that time. That was the kind of thing that attracted me.
There you were in England – and you experienced the very highest level of academic environment.
A very important event then occurred while we were in England. I was visited by the late Bryan Hudson, who had been appointed foundation Professor of Medicine at Monash University at the old Prince Henry’s Hospital, which no longer exists. Bryan came to London in 1962, telling me that he had been asked to look after a new initiative at Prince Henry’s which was to establish a Medical Research Centre. It was the only hospital, of the teaching hospitals in Melbourne, that didn’t have an institution or research laboratory. He asked me whether I would consider being the Associate Director of this Research Centre. I thought all my Christmases had come at once. This was an unbelievable opportunity – a very precocious one, when I was still very much in the raw stages of learning endocrinology. But he clearly had some sort of faith in my abilities and possibilities. So I accepted that with alacrity, much to the chagrin of my St Vincent’s colleagues, who had fully expected me to come back there.
I remember, before leaving for London, I went to see the Mother Rectress, who held all the power at St Vincent’s, but it was a new Mother Rectress whom I had not previously known. I asked her whether I could have any assurance that I might have a future in endocrinology at St Vincent’s, as it had been, in a sense, promised to me. She said, ‘No, I’m not going to give you that sort of assurance before I see how you get on overseas.’ I bottled that piece of information and, when I was offered the Prince Henry’s job, I accepted it with great enthusiasm.
Protein hormones by radioimmunoassay
Bryan was immensely helpful in suggesting to me that the future of research in endocrinology would be in the protein hormone field, not in steroid hormones. He had been an expert in measuring testosterone, but he was also interested in other aspects of steroid endocrinology. But he said, ‘The future is in protein hormones.’ I had originally planned to go and work with the late Dr Fred Bartter, who was an eminent American steroid endocrinologist in the aldosterone field, and I had to make very last-minute arrangements not to go and work in his laboratory but to go and be trained in protein hormones. I had a US Public Health Service International Postdoctoral Fellowship, so when we went from London to the States, I went to work in a protein hormone laboratory rather than the steroid hormone laboratory.
That was a very critical decision, wasn’t it?
It was a hugely important decision and Bryan gave me absolutely the right advice. I went to work at the National Institutes of Health, and the advice to do protein hormones and protein chemistry was very important advice. It also gave me the opportunity to learn the relatively new technique of radio immunoassay. Radio immunoassay was a technique developed in order to be able to measure the very tiny circulating concentrations of protein hormones. It was subsequently applied to other molecules circulating in very low concentrations. But the initial developments were particularly for insulin – a protein hormone.
The radioimmunoassay technique relied for its sensitivity on the employment of a radioactive label which allowed detection of very small amounts of radioactivity. Its specificity was conveyed by the immuno part – namely, the use of an antibody to the hormone of interest. You had to have specificity to be able to measure a protein in amongst thousands of other proteins. One of the big advances was a technique of labelling protein hormones without destroying their tertiary structure, usually with radioactive iodine – a technique what was introduced by two Englishmen called Hunter and Greenwood. One was able to label a purified form of the hormone with radioactivity, purify it so that you just had the labelled hormone and then incubate the hormone with a limiting concentration of a specific and high-affinity antibody. You then added known amounts of unlabelled hormone to construct a standard curve where the unlabelled hormone would displace the radioactivity from the antibody. After that incubation, you separated the radioactively bound hormone from the free or unbound, which had been displaced. By measuring the ratio between bound and free as a function of the addition of increasing quantities of the unlabelled hormone, you constructed a standard curve. You then incubated a serum specimen, read the bound-to-free ratio and worked out what concentration of unlabelled hormone that was equivalent to.
That technology was introduced in about 1959-60, not long before I went to the States. Ultimately, it resulted in the development of an immunoassay for insulin. My memory is that the first insulin assays were published in about 1960 or 1961, and it was then applied to growth hormone. One of the laboratories or the laboratory that first developed a growth hormone assay was the laboratory of Sol Berson and Ros Yalow in New York. I had an opportunity to go and visit them. They worked in a cellar in the Bronx. I was amazed when I got there to find the two of them sitting, surrounded by thousands of little tubes, pipetting the reagents, doing the separations and measuring growth hormone.
Berson was an extraordinary man, probably one of the most extraordinary individuals I ever met anywhere in endocrinology. He was a genius. He should have won the Nobel Prize but, unfortunately, died before that opportunity arose. His colleague Ros Yalow did win the Nobel Prize. The other two people who worked on the growth hormone assay with them were Jesse Roth and Seymour Glick. Jesse Roth went on to a very distinguished career at the National Institutes of Health. He is still active in research and in teaching. He was in the laboratory next to me when I worked at the National Institutes of Health in Bethesda and I learnt the growth hormone immunoassay directly from him. That was invaluable to me when I came back to Australia to develop the new Medical Research Centre at Prince Henry’s. I subsequently encountered Berson again in 1968, on the first major overseas trip I made after my return to Australia, and I found that he was not only a superb biochemist and endocrinologist but also a superb historian, art appreciator, chess player and violin player. At that time, I was at a meeting in Liege, Belgium, when the book called The Double Helix had just been published, describing the structure of DNA. He spoke about that book as though he had been in the laboratory involved in all the work. He was just a most extraordinary individual.
The young Turks, bovine growth hormone and giants at NIH
Tell me about the young Turks.
One of the encounters with Berson that I observed from a distance was his participation in the annual meeting of the American Society for Clinical Investigation, which was often called the ‘young Turks meeting’. The radioimmunoassay field and the assay of insulin was a highly competitive area where more than one group was involved in the development. There was another team in San Francisco, Gerald Grodsky and Peter Forsham, who were also right at the very beginning of the ‘immunoassay for insulin’ story. I was at a young Turks meeting where Grodsky was presenting their findings on immunoassay and claiming priority, and Berson got up from the floor and attacked him in the most incredibly vitriolic terms. I could not believe my eyes and ears as I sat there, watching the interchange between the two of them. It exposed me to what is very much an American tradition of standing up and expressing your views and not being frightened and not being embarrassed to do so, which I think here in Australia we were much more anxious about.
Tell me more about your NIH experience.
As I have indicated, the advice Bryan Hudson had given me was to learn about protein hormones and protein chemistry. I went to the laboratory of Peter Condliffe, who was an expert in protein hormone purification. His particular area of interest was thyroid-stimulating hormone, but he also was expert across the board in protein hormone chemistry. He, in turn, recommended that I work with a physical biochemist, Harold Edelhoch, who was a student of protein structure, ultracentrifugation, fluorescence polarisation and other techniques which one could use to study the behaviour of proteins in solution. The protein that we decided to study was bovine growth hormone. So I spent essentially two years in his laboratory, learning and doing physical biochemistry. Bovine growth hormone turned out to be quite an inspired choice because it underwent spectacular changes in its fluorescence properties when it was acidified. We made studies of all sorts of aspects of the structure and function of bovine growth hormone and, as a result of my studies there, we published three papers in the prestigious Journal of Biological Chemistry and another one in the leading endocrine journal, Endocrinology.
One of the things that I should have considered at the NIH was to do a PhD. But I would have had to spend a lot of time doing course work as part of a PhD at any of the universities closely associated with the NIH in Bethesda, Maryland. I chose not to do that, because I wanted to maximise my laboratory training and some clinical training.
At the NIH at that time were a number of giants of endocrinology. Including Martin Rodbell, who went on to win a Nobel Prize for his studies of second messenger signalling; Gerry Aurbach, a pioneer in the parathyroid hormone field; Ira Pastan and Bob Bates – all big names in endocrinology. The rest of the unit had people like Ed Rall, Jack Robbins and Jan Wolff, who were experts in the thyroid hormone field, in which I didn’t have a great deal of interest, but I admired them and watched them.
I didn’t entirely sever my contacts with Fred Bartter, who was in the building several floors below. I used to attend his laboratory meetings, listen to how he planned his clinical research and learned from him the importance of what many of us called the ‘dry run’. The dry run was a practice for presenting at meetings or for being interviewed for grants. He was ruthless about the importance of adequate preparation, criticism by your peers, going back to the beginning and preparing it again and, finally, being able to give a polished rendition of your research, your ideas and what your laboratory was doing. That was something which I brought back with me and put into practice right from the very beginning when I worked in Melbourne.
A new Medical Research Centre with plenty of talent
You moved back to Australia in 1965 to take up that position that had been offered you by Bryan Hudson several years previously.
Correct. I came back to the Medical Research Centre at Prince Henry’s Hospital and was placed on the eleventh floor of the hospital, which had a great view over the city of Melbourne and the Victorian College of the Arts. It was in St Kilda Road. The hospital has now long been torn down and has been replaced by an upmarket apartment building called the Melburnian. I was placed up on the eleventh floor with some laboratory and office facilities, and the staff included a secretary and two laboratory technicians. I found the initial few months of being back in Melbourne quite challenging, having been in an environment where everything that you could possibly think of in research techniques and research facilities was available. Here I was really responsible for getting the place equipped and started.
But one of the first things I did was to establish the growth hormone immunoassay. We went along swimmingly for a short time and then the assay stopped working. It took us six months to work out that, in purifying the labelled growth hormone and collecting the purified fractions into tubes containing fairly concentrated albumin solution, we were failing to properly agitate the fraction tubes, so the hormone was not protected from degradation. That took six months to find out.
Once we had that solved, we ran the immunoassay very heavily and received samples from many different laboratories because it was the first immunoassay for growth hormone in Australia. I fairly quickly established a collaboration with the late Norman Wettenhall. He was a paediatric endocrinologist and there were very few in the world at that time. He had a big population of children with short stature and the assay technique enabled us to determine who was truly growth hormone deficient, and therefore who might be expected to benefit from therapeutic growth hormone preparations. These preparations were just starting to become available at that time, particularly through the offices of Kevin Catt, one of my colleagues at Prince Henry’s. Kevin was a skilled protein chemist/clinician scientist. With his efforts and those of a few others, we started to develop growth hormone for therapeutic use, and the assay clearly provided a way of making an appropriate diagnosis in those short children. Growth hormone therapy for them was a huge boon and produced some quite spectacular improvements in their growth velocity and final height.
You were Chairman of the Human Growth Hormone Subcommittee for fifteen years. Tell me about that.
Yes. At that time it was decided that the Department of Health in Canberra would establish a pituitary hormone committee to guide the therapeutic use of protein hormones in Australia. It was called the Human Pituitary Advisory Committee and it was officially a committee advising the Minister for Health. It established three subcommittees: a purification subcommittee, which was charged with overseeing the purification both of growth hormone and of gonadotrophins for use in the treatment of infertility; a follicle stimulating hormone (FSH) committee, that being the main therapeutic gonadotrophin, which was established to supervise the therapeutic use of FSH in hormone deficient men and women; and then a growth hormone committee to supervise the therapeutic use of growth hormone for children with short stature. I became chair of the growth hormone subcommittee and a member of the Human Pituitary Advisory Committee and served in that capacity for about 20 years. I worked with the two leading paediatric endocrinologists in Australia at the time and learnt an enormous amount from them. I practised in paediatric endocrinology for a time, until that specialty became better established, and I used to see children with short and with tall stature and used my laboratory technology to assist that at the same time.
That perhaps illustrated a very important principle for me: (a) I had to be familiar with assay techniques by doing them myself and knowing what could go wrong. For example, what the interpretive difficulties might be and what limitations there might be to the interpretation of assay results. And (b) seeing the clinical problems to which those assays could be applied and having a kind of bench-to-bedside approach to the clinical practice of endocrinology.
Going back to those days, Bryan Hudson was the chairman of the Department of Medicine, but there were many other important figures at Prince Henry’s at that time.
Bryan was the foundation Professor of Medicine and he quickly established a very vigorous, talented Department of Medicine at the old Prince Henry’s Hospital. He was situated on the sixth floor of the outpatient block, whereas I came back to the eleventh floor of the main block. There was a physical separation, but that didn’t prevent a very close collaboration. In his department, Ken McLean was the associate professor, a cardiologist and an inspiring individual. He had people like Kevin Catt, as mentioned, Hugh Niall of distinguished endocrine career, Jeff Tregear and Jim Stockigt, who became a leading thyroid endocrinologist. Then, in other related fields, people like Jack Hansky in gastroenterology – Jack was also somebody who developed assay methods for gastrointestinal peptides; Blair Ritchie, who was a respiratory physician and physiologist of distinction; and Mel Korman, a registrar who subsequently moved into the gastroenterology field. It was a distinguished and very active group, and we did a lot of collaborative research and prospered the Department and the Medical Research Centre at the same time.
When you look back on the achievements at the Prince Henry’s Institute in those days, what do you reflect on?
A very important milestone for me was the recruitment of my first medical postgraduate scholar, a man called Don Cameron. He came down from Queensland and enrolled to do a MD. He decided that he would work on human growth hormone to determine how growth hormone was handled in the body, that is, the metabolic clearance of growth hormone, its secretion rate and its disposal in the circulation. Don enrolled and joined me in 1967. That was really when the Medical Research Centre took off.
A couple of years later, the late Yogesh Patel, a Fijian Indian who was a New Zealand medical graduate, came to join us. Yogesh was an extraordinarily brilliant individual. He decided that he wanted to work in the thyroid field, so he made an existing assay for thyroid stimulating hormone much more sensitive. At the time he joined us that assay could not distinguish the lower limit of normal from a suppressed value. In thyroid disease, it was very important to be able to make a diagnosis of hyperthyroidism or thyrotoxicosis. One of the ways to do that, in principle, was to be able to show that a patient had suppressed thyroid stimulating hormone (TSH) because of the autonomous activity of the thyroid gland, over secreting and suppressing the pituitary. Yogesh made the existing TSH assay much more sensitive and enabled us to measure suppressed levels of TSH and distinguish them from the lower limits of normal. He also developed one of the first assays for the second thyroid hormone, tri-iodothyronine or T3. With the combination of standard T4 assay, T3 assay and TSH, we did a lot of studies of thyroid physiology and thyroid pathophysiology.
Yogesh went on to have a distinguished career overseas. He went to work in Geneva with Lelio Orci, who was a pioneer of the cellular localisation of hormones and their transport intracellularly. Ultimately, Yogesh went to Montreal to become Professor of Medicine and become the world expert on somatostatin, the hormone which inhibited the release of growth hormone. He died very young at the age of 61 or 62 – a very sad occurrence.
From there on, a number of other people joined the Research Centre, including Frank Alford, who became the main endocrinologist at St Vincent’s and who also joined us to do studies of growth hormone. Gordon Baker, who became a distinguished Professor of Andrology, was my first endocrine registrar. Fairly early after my return, not only was I charged with running the Medical Research Centre but I also became head of the hospital Department of Endocrinology. We were allowed to appoint our first endocrinology registrar in 1970, and that was Gordon. Gordon subsequently stayed at Prince Henry’s and became a PhD student. He did a masterly PhD on the endocrinology of liver disease, under the joint supervision of Bryan Hudson, David de Kretser and me. He was another distinguished member of the team who contributed enormously to our studies of pituitary hormone secretion. We studied the 24hour patterns of secretion and looked at the pulsatility of pituitary hormone secretion. Yogesh’s assay allowed us to show that thyroid stimulating hormone had a circadian rhythm, as did some of the other pituitary hormones. Other members of the laboratory at that time included a biochemist, Terry Bellair and subsequently, Adrian Herington, who studied all sorts of aspects of the mechanism of action of growth hormone and its binding to a growth hormone receptor.
In turn, after that, I was joined by David Healy, who became Professor of Obstetrics and Gynaecology at Monash. He came to do a PhD on prolactin, so my interests diverted to that. All that, in a sense, represented the fact that my philosophy in running the Medical Research Centre, fortunately backed up by the fact that people expressed a wish to come and work with us, was to use the talents of people to the maximum and to allow them to decide which hormone and which direction they thought was appropriate. That resulted in us ultimately becoming a highly productive research institute in quite a number of aspects of endocrinology. In the meantime, I was joined in 1974 by David de Kretser, who spent several years on our staff as a senior research fellow. That continued a collaboration I had begun with David before he really joined us and of which the pinnacle was the isolation and purification of the hormone inhibin.
The story of inhibin is a fascinating one and a major component of both your life and mine. It is really a triumph for basic science and clinical connection, what we now call translational research. Perhaps you should tell the story.
David had, as his special area of interest, the structure and function of the testis. He had undertaken postgraduate training in Seattle at the direction of Bryan Hudson, who was our mutual endocrine ‘father’. David had come back. In the interim, I had established, among other things, immunoassays for the two pituitary gonadotrophins: follicle stimulating hormone (FSH) and luteinizing hormone (LH). We applied those assays to the study of men with infertility and found that men with some forms of male infertility had a hormonal pattern with an elevation of FSH but normal levels of testosterone and normal levels of the other pituitary hormone that controlled the testis, luteinizing hormone. The fact that there was an isolated elevation of FSH indicated that there must be another factor produced by the testis which was lacking in men with some forms of testicular disease.
That factor had been postulated as a hormone forty years earlier by workers in the United States. Various groups had made sporadic attempts to purify that substance which had been called inhibin. The original introducer of that was McCullagh. The term ‘inhibin’ was really a concept rather than an actual entity, because nobody had been able to purify it. From our radioimmunoassay studies and the studies of other laboratories around the world we were convinced that such a hormone must exist. So we set out to explore whether we might be able to isolate this hormone because it was one of the big unanswered questions in reproductive endocrinology. Victor Lee and Ted Keogh, who was one of my early registrars, extracted bovine testis and infused those testicular extracts into castrate sheep. They showed that those sheep, which initially had elevated FSH levels, had their FSH levels suppressed by the infused testicular extracts, but their LH levels were not suppressed.
Our research was also supported by observations from a Belgian endocrinologist called Paul Franchimont. He was another individual who was very influential on me as an endocrinologist. In 1968, Paul ran a protein and polypeptide hormone conference in Liege, Belgium and invited me to participate. I met him and was immediately struck by his abilities in endocrinology and his enormous charism. I would become due two or three years later for a sabbatical, so I was starting to consider where I might take it. I decided that, if he would have me, I would go and spend a year in his laboratory in 197273.
Paul was somebody else who was interested in the inhibin concept and whose laboratory was also very early in establishing an FSH assay. He, too, had made the observation about infertile men in papers that were published almost simultaneously by him and from our group in Melbourne. He was an extraordinarily innovative endocrinologist who asked the simplest of questions and used the simplest of technologies to answer them. He took castrate rats, injected them with seminal plasma from normal individuals and showed that the seminal plasma suppressed FSH. He then took seminal plasma from men with infertility and azoospermia and showed that their plasma didn’t suppress it. So he was also very convinced that there was an inhibin and that it would be possible to isolate it perhaps from seminal plasma. Regrettably from his point of view, he didn’t finally succeed in what then became a competitive race to be the first to isolate inhibin. But this sabbatical provided me with a year of exposure to his thinking and his technologies and additional material, which I found invaluable.
Having come back from that sabbatical and having shown that these testicular extracts would suppress FSH, we went on to try to purify the activity, in continuing collaboration with David. An important next step was to find a simpler way of assaying the extracts than infusing them into castrate sheep. An important person in that was Larry Eddie. He worked at the Howard Florey Institute, going up as a senior research fellow, where he was joined by Hugh Niall and Geoff Tregear, both eminent protein chemists. Bryan Hudson had gone to the Howard Florey in 1972, having resigned the chair of Medicine at Prince Henry’s. Larry Eddie developed a cultured pituitary cell assay in which, putatively inhibin-containing extracts would suppress the stimulation of gonadotrophin secretion by the cultured cells. This stimulation occurred when they were exposed to the fairly newly discovered luteinizing hormone or gonadotrophin-releasing hormone, GnRH.
Late in the 1970s, I was joined by Russell Scott, a research fellow from New Zealand. Russell Scott established a cultured pituitary cell assay which worked even better than the Eddie assay. He did this in conjunction with Helen Quigg, one of our technicians at the Medical Research Centre, and me as supervisor. We applied this cultured pituitary cell assay to monitoring the purification of inhibin. At that stage, we were using what was called ‘rete testis fluid’ as a better source than whole testicular extracts, which were very messy. The rete testis fluid was collected from the lymphatics which trained the testicle. In the attempt to purify inhibin, David de Kretser and I worked at Prince Henry’s in collaboration with Bryan Hudson and his team at the Florey. The collaboration worked, in the sense that the protein chemistry was done at the Howard Florey and the assays were done by us with Russell Scott and his cultured pituitary cell assay.
Late in 1978, when that collaboration appeared to be going quite well, David and I received a visit from Bryan Hudson, who said that the Florey group felt that they weren’t progressing as fast as they would like to. He said that some of that delay was due to the fact that we were taking longer to do the assays than they were happy about. They had, therefore, made the decision that they would terminate the collaboration amicably, that we would continue to use the same extracts from rete testis fluid as a biological standard but they would proceed alone with the purification technique.
How did that make you feel?
David de Kretser and I couldn’t believe this discussion, at first. But, in the wake of Bryan’s leaving my office at Prince Henry’s, we looked at each other and said, ‘We’ll beat them.’ So together, David and I pursued the purification. We decided that it would not be appropriate to use the same starting material as Bryan. It had become clear that there was a similar activity in follicular fluid from the ovary and, therefore we used bovine follicular fluid, which could be readily collected at the abattoir. The other crucial aspect was that we were joined by David Robertson. David had had an extensive training at the Karolinska Institutet in Stockholm, Sweden. David was a rigorous, careful and dedicated protein chemist and assayist and he was crucial in the progress we made in purifying inhibin from follicular fluid. It was a very difficult protein to purify. It kept on disappearing from column chromatography attempts at separating it from other proteins.
Marian Dobos worked with us in the early 1980s and applied reverse-phase column chromatography to the purification and succeeded in partial purification of what was, in fact, ovarine follicular fluid inhibin. We were assisted by Milton Hearn, who was an expert in protein chromatography, and also by Frank Morgan at St Vincent’s, who was a protein chemistry expert. This illustrates the fact that we had a wide collaboration in this attempt to purify inhibin. David and I led the team from Prince Henry’s and David, subsequently, from the Department of Anatomy at Monash, to which he moved in 1978. We had regular team meetings with all the main players, we kept rigorous accounts of what we were doing and the project proceeded slowly but in a generally successful direction. Until 1984, when we felt we had succeeded in our mission.
Do you remember a Eureka moment with inhibin, where you knew you ‘had it’?
I don’t remember a Eureka moment. There must have been one.
I can. I can remember a silver stained gel showing a homogeneous band, and David Robertson was uncontrollably excited.
Certainly we reached electrophoretic purity of a molecule which had the inhibin properties. We first submitted our work to the American journal Science, because we thought this was a very important breakthrough discovery. The isolation of a new hormone in reproductive endocrinology was a pretty major achievement. Science held on and held on, and we didn’t get an answer. We started to become a little suspicious that one of the referees for the paper might have decided that this was a real plum and they might quickly see whether they couldn’t duplicate the technology which we had submitted. We weren’t very used to dealing with prestigious American journals, but after Science had had the paper for about four or five months I finally plucked up courage and I rang the editor of Science. He said, ‘No, we still haven’t made a decision,’ and I said, ‘I’m sorry. I wish to withdraw the paper. We cannot hang on for ever and ever to have this published.’ We then made a decision to go for a much quicker, less prestigious journal, Biochemical and Biophysical Research Communications. We submitted it there, it was accepted within a few weeks and we published about three weeks ahead of the main Japanese competitors, who had isolated inhibin more or less at the same time. But we had the science prize, we had got there first.
We also should have got to the cloning of inhibin first, which turned out to have two subunits, but one of our collaborators in amino acid sequence analysis had made an error in the sequence of one of the two subunits. That meant that we were frustrated and we were beaten to the cloning by Hugh Niall, who was working in the United States at that time.
But we also went on to generate antibodies with the purified hormone. I think David Robertson was crucial in that and you were also crucial in that. You and David developed a radioimmunoassay for inhibin. In retrospect, we realised that that was a radioimmunoassay which generically recognised inhibin, which was subsequently shown to exist in two forms, and the assay probably mainly reflected inhibin A. But you had joined us as a PhD student and the world was at your feet because you had a new hormone, a new assay – which you had participated in the development of – and now you could go out and apply it to almost all areas of reproductive endocrinology, male and female. You indeed did this with great distinction. So we were able to publish jointly a whole series of papers on the physiology and the pathophysiology of inhibin.
Inhibin – granulosa cell tumours and ovarian tumours
Perhaps the next big step that occurred was that in the interim several people had joined the lab to study inhibin control and the control of the inhibin genes in the test tube. Including people like Susan Davis, who did her PhD in that area and went on to a distinguished career in female reproductive endocrinology. A crucial meeting occurred, when I met a Dutch gynaecologist at an international congress in about 1987 or 1988 and he said, ‘You guys are publishing measurements of inhibin. I have a series of patients who have a rather uncommon ovarian tumour called a granulosa cell tumour but, as you have now shown that granulosa cells are the source of inhibin, my prediction would be that patients with granulosa cell tumours (GCTs) would have high inhibin concentrations. I’ve got a whole lot of sera in my freezer, would you be willing to assay them?’ I very enthusiastically agreed to do that, and he was absolutely correct. The patients with GCTs had very high inhibin levels. He had collected serum from patients whose tumours recurred only a year or two later, and we showed that the inhibin assay would predict tumour recurrence up to 18 months or two years ahead of the actual recurrence being clinically detectable. We published a paper, in the New England Journal of Medicine,on the elevated inhibin levels of patients with granulosa cell tumours.
How has that area now progressed?
That clearly provided a very important practical application of the inhibin assay. I should say, parenthetically, that our group in Melbourne – Hudson, de Kretser and myself as the main investigators in the midseventies–had been awarded a big Ford Foundation grant for our work directed towards the possibility of a new male contraceptive. The theory was that, if one could isolate a hormone like inhibin, which was a selective suppressor of FSH, you might be able to selectively suppress spermatogenesis, for which FSH was crucial, without interfering with the male hormone function of the testis. So the testosterone producing function which gave a man his virility rather than his fertility would be unaffected. Of course, it turned out that inhibin was far too complex a protein to make it a practical male contraceptive. But suddenly, with the advent of the granulosa cell tumour finding, here was the possibility of a new diagnostic in ovarian tumours.
David Healy then collected material from a lot of other patients with ovarian tumours and showed that some patients with serous epithelial tumour, the most common form of ovarian tumour, had raised inhibin levels. He also showed that most patients with the mucinous tumour, the second most common tumour, also had raised inhibin levels. The common marker for ovarian cancers at that time, and still now, is an antigen called CA125. It looked as though in samples from patients with ovarian tumours, suspected ovarian tumours or even in screening for ovarian tumours, CA125 and inhibin, measured together, might be an excellent combination because inhibin picked up the tumours that CA125 didn’t. David Robertson, in particular, was the person who moved that field along and was able to show that that complementary assay was very helpful in the diagnosis and monitoring of patients with ovarian tumours.
We now know that hormones are secreted across the day and moment to moment in different ways and with different patterns. Can you remember an important development at Prince Henry’s in this particular area of physiology?
One of the very important members of staff of the research centre at this stage was Iain Clarke. Iain Clarke had been an associate of Professor Jock Findlay, who was also a very important contributor to reproductive physiology, particularly using sheep as a model. We had collaborated much earlier in developing an immunoassay for FSH in the sheep. For some reason, that had proved to be a very difficult nut to crack. But finally, with the collaboration of Lois Salamonsen and Helen Jonas, we did establish a good immunoassay for FSH, which allowed Jock to pursue a lot of physiological studies in the sheep.
More or less at the same time, Iain Clarke had established a collaboration with a neurosurgeon from St Vincent’s, Jim Cummins, because Iain wanted to be able to access the portal circulation. He wanted to access the blood supply coming from the hypothalamus at the base of the brain to the pituitary, using the sheep model. Between Jim and Iain, a method was established for directly sampling portal blood coming from the hypothalamus. Iain had established an assay for GnRH, the small peptide which stimulated FSH and LH secretion, particularly LH, from the pituitary. In fact, it was an assay which I think I had originally established in Paul Franchimont’s lab, when I had done my sabbatical and we established an ongoing immunoassay for GnRH. Iain took frequent samples from the portal blood and, at the same time, measured peripheral blood LH secretion in the sheep. Iain showed that GnRH secretion was pulsatile, with pulses occurring about every 30 minutes. Each pulse was followed by a pulse of luteinizing hormone in the peripheral blood. So here we had a demonstration that hypothalamic hormone secretion, at least as far as gonadotrophins were concerned, was a pulsatile secretion.
The ramifications of that observation are profound in reproductive systems.
The ramifications are indeed profound. A similar demonstration had been made almost simultaneously by a group in the United States with a different approach to the problem. Nevertheless, Iain’s was the pioneering observation. We decided that treatment with pulsatile GnRH, if we could find some way of giving it to them, might be a method of treating women who had stopped cycling because of functional hypothalamic amenorrhoea. So we established a collaboration with Charles Hackman, who was an anaesthetist. He helped us to design an infusion pump which would give pulses of GnRH. David Hurley was a postgraduate student who had joined me to do his MD or PhD – I have forgotten which – and he took on this project with Charles Hackman. For quite a long time, we had been running a program to induce ovulation in women who weren’t ovulating. It was one of the projects in which I was very enthusiastically involved at the clinical level. I supervised the treatment of a lot of these women. Using Iain’s data, David, Charles Hackman and I set up a program in which women would wear this infusion pump with a needle placed subcutaneously into their tummy and where the infusion pump gave them pulses of GnRH. They appeared to be able to wear this pump without too much difficulty and they had to wear it for days at a time. We followed, with daily or second-daily hormone measurements, the evolution of a perfectly normal menstrual cycle of hormone secretion in response to this and we had a number of successes in inducing ovulation and causing pregnancies in such individuals.
We had one very famous or notorious patient under our care. She was treated with what was then the common way of inducing ovulation, which was to use FSH as the gonadotrophin to induce ovulation. She had had what, on all reviews, was an impeccable and appropriate dosage of FSH and she conceived quintuplets. That became very rapidly widespread daily news, and she lost the quintuplets one by one in the succeeding weeks after they were born. Very courageously, she came back to me and said, ‘I still want to get pregnant. Are you willing to treat me again?’ We decided that we would give her the pulsatile GnRH therapy rather than trying gonadotrophins again, and she conceived a singleton pregnancy and very happily went away to motherhood. So that was another aspect of our bench-to-bedside research and clinical application in employing the pulsatile GnRH technique.
The menopause has been a major focus for you for decades. How did that initiate?
My interest in the menopause was stimulated originally by a visit from the late Dr Jean Hailes, who was the pioneer of menopause management in Australia. She was a general practitioner. She asked the advice of Bryan Hudson and then me about how she could improve the lot of women suffering menopausal symptoms. At the time, this was in 1971, there was no accepted treatment in Australia which was specific to treat hot flushes and sweats, which troubled so many women at that time. The general attitude was paternalistic and dismissive by the medical profession. Recently she had been to the United States and had seen the benefits of hormone replacement therapy in the States. We set her up in a room in the endocrine unit where she could see patients. She saw very few for the initial weeks, until she gave an interview to a reporter for the Melbourne Argus, one of our daily papers. From there, she was flooded with inquiries and interest, and we very rapidly established a menopause clinic. She worked in it and she recruited several of her colleagues. I never physically worked in the clinic with her, but she came to me as a mentor and adviser. She wanted to introduce research from the beginning. She did one of the earliest controlled trials of menopausal hormone therapy in the 1970s and published in the Medical Journal of Australia. That is what really stimulated my interest, her continued discussion of issues and problems related to it.
Then I had the benefit of another sabbatical leave, which I chose to take at the World Health Organisation in Geneva. I had worked with the Human Reproduction Program at the WHO, so I knew the organisation a little bit. One of my reasons for going was to explore whether I might want to have a late career change and go and work in a place like that. I had always enjoyed my contacts with international colleagues when working in international programs. When I got to the unit where I was going to spend six months, I was asked whether I would work on a Scientific Group on the Menopause, which the Program was going to conduct. That meant that they invited a number of experts from around the world to prepare position papers on various aspects of the topic and who then came to Geneva for a meeting to discuss all aspects. At the meeting they are supposed to reach agreed positions and decide what sort of research needed to be done in the future. So I spent most of that six months in the library at WHO, reading almost everything that had ever been written on the menopause and becoming reasonably knowledgeable in the process. I then acted as the rapporteur for the Scientific Group meeting. It was a very revealing and interesting experience. I met my first real live epidemiologist at that meeting. We agreed about a position paper and I wrote the final report. That was quite an influential document worldwide because it summarised almost everything we knew about the menopause and pointed out the directions for research. Interestingly, even in early 1981, the two key issues were: did hormone replacement therapy prevent heart disease in menopausal women and did it increase the risk of breast cancer? They were the two key issues of that Scientific Group.
I came back and Jean Hailes involved me in more discussions on aspects of menopausal practice. I started to go around and give lectures about the menopause, because it was something I had ready-made and was able to present. That then stimulated my interest in doing some more research. I realised that we didn’t know a lot about the endocrinology of the menopause and that, with the availability of the inhibin assay, we might have an opportunity to see whether inhibin played a role, which one forecast that it would.
We started some early studies, to study the pattern of hormone evolution, we took blood samples from women who had just started to have irregular periods and also from normally cycling women aged between 20 and 50. We realised fairly quickly that particularly over age 40, inhibin levels dropped as FSH levels started to rise. We also demonstrated that, in the initial long cycles of women starting their transition through menopause, hormone levels were unpredictable and were clearly of no value from a diagnostic point of view. This was because they would change from one week to the next in the same individual. So we started to teach that diagnostic hormone assays were not of much value in that situation.
That research continued into the early 1990s and, in 1991, Professor Lorraine Dennerstein invited me to join her in a prospective study that she planned to look at how women transited the menopause. At that time she was head of a centre of excellence for women’s health in Melbourne. She did a cross-sectional survey of about 2,000 Melbourne women and then initiated a longitudinal study of over 400 women who were still cycling and who were aged between 45 and 55 at the time they were first recruited. We took annual blood samples from them and they completed questionnaires. That turned out to be an enormously fruitful collaboration because I was able to study, at least once a year, hormone levels collected, where possible, in the earlier part of the menstrual cycle. That started to build a picture of what sort of hormonal changes were occurring. That completely confirmed the likely uselessness of hormone assays, which up to that time had been widely used in women to diagnose whether they were menopausal or not. I finally wrote and published a paper which said that these hormone assays have very little diagnostic value.
However, we measured inhibin in these women as well as the gonadotrophins and oestrogen. That allowed me to incorporate studies of inhibin into studies of transition through the menopause. We recognised that probably the very first clearly detectable event was a drop in the levels of inhibin B right at the beginning, when women were starting to go through the transition. So again, for me, that was a sort of bench-to-bedside ability to apply an assay to the clinical study of women transiting the menopause.
More or less in parallel with all that, I developed an active interest in menopause management and in the role of menopausal hormone therapy. That has been an abiding interest ever since. One of the major areas in which I have been active, not as successfully as I might have liked, was in the reaction to the American Women’s Health Initiative study. It caused a total explosion in the hormone replacement therapy field in 2002 and resulted in an up-to-80 per cent drop in the use of menopausal hormone therapy. In my opinion, this reaction was for what were totally specious reasons. The data were not fairly and appropriately presented, in my opinion. From the day that study was published, I have been one amongst many who have spoken out against the applicability of those findings. That is a standpoint that has been taken by the International Menopause Society, the American one, the Australasian one and, most recently, in a scientific statement published by the American Endocrine Society, called A Scientific Statement on Post-menopausal Hormone Therapy. This statement also came to the same sorts of conclusions that I had been defending.
Do you see an important role for scientists and clinicians to engage in the public arena in discourse about matters such as the menopause?
I think it is an essential role. One must be there to comment. Unfortunately, given the nature of the press, they will often single out people who are of a diametrically opposite view and perhaps a view that one would not regard as very fairly presented. So you often end up in a position where completely conflicting statements are made to the media, and it becomes very difficult to persuade people of a particular point of view. But I think it is absolutely essential to do that.
The name of Jean Hailes continues to this day in the form of the Foundation. Can you tell us a little about the early history and your involvement in that?
Jean Hailes died a premature death of lung cancer in 1988. A group of us who were closely associated with her felt that we must do something to perpetuate and honour her name. Ultimately, we founded the Jean Hailes Foundation for Women’s Health. We developed a clinical service, a research arm and an educational arm, which has become very well known nationally and is funded significantly by the federal government. The Jean Hailes Foundation has really become the reference point for all questions relating to women’s health, particularly menopausal women’s health. Its present director, Helena Teede, who was one of my last registrars, is interested in the very topical area of lifestyle influences on women’s health. She is especially interested in the commonest reproductive-aged women’s health disorder, polycystic ovary syndrome. Helena is leading the research arm in producing an excellent set of guidelines for how women should regard their health, their weight and their exercise patterns, in order to prevent future disease. She is also leading diabetes at Southern Health.
I would like to turn to other aspects of your life now. What other hobbies and interests do you have?
I mentioned earlier that I was very interested in music. That has been an abiding interest. I love to listen to music at home and we love to go to concerts. I mentioned particularly my interest in baroque and classical music. I have always loved to ski and that has given me an opportunity to see some wonderful and picturesque parts of the world. I play tennis regularly and I am an avid watcher of cricket, football and other competitive sports, mainly on the television but sometimes at the Melbourne Cricket Ground, which is near where we live.
I believe that you also have a four-wheel drive in the family and you like to get around in the outback.
Yes, and we have made several trips up to the Kimberley region, which we love. We feel very fortunate in that we have now managed to see a fair part of Australia rather than just confining our visits to overseas, of which we have made very many.
I think it is important to recognise the significant others in your life: your wife and your family. How have they impacted on your life at home and, indeed, at work?
Absolutely essentially. Jenny was a student of my mother’s at Melbourne University in the French Department. We met at a Bastille Day celebration in 1957 and we were married in 1959. She was a teacher of French and German for very much of her professional career but then changed fields completely in 1987. She did a Master’s degree and went to work in the field of mental health, particularly as a carer consultant, meaning that she looks after the families of people where there is a member with a serious mental illness. That is something to which she is devoted and which, as far as I can see at least, she does superbly. She has been a wonderful wife, a wonderful mother. She’s a superb cook. She’s my best friend. I couldn’t speak highly enough of her.
It struck me, in thinking about your travels overseas, in particular with your wife and young family, it must have been challenging for you and particularly for her.
Certainly it was. We went to England on our first overseas trip with our first child about to turn one and the second child in utero. He was born in London. The third one was born in the United States, and the fourth and fifth were born back in Australia. I think Jenny found life very difficult, as a young mother without much in the way of a support network particularly in the United States, things were a bit better in London. In the Unites States we lived in a little house off the campus of the NIH. That was a tough life for her. Jenny single handedly, effectively, brought up the five children. She stopped working almost entirely and I am afraid that I probably fell short as a father who worked long hours and was persuaded for quite a long time that he should spend at least one day of his weekend playing golf. I ultimately realised this was not a profitable thing to do and then returned to the fold a bit more.
Yet, we had some marvellous trips. Our sabbatical in Belgium in 197273 included the company of the youngest daughter of my mentor, Bryan Hudson. Leigh lived with us as a kind of younger sister to Jenny and then stayed in Belgium as a secretary to Paul Franchimont after the rest of us returned to Australia. We had camping and caravaning trips through Europe with all five children. When we first arrived, the French used to look at us and say, ‘cette famille enorme.’
And now you have twelve grandchildren.
Yes. Three of them live in Germany, one of them lives in Canberra and the other eight live here in Melbourne. They are a great joy.
And you still have a very close family. I understand that recently all five children came back from around the globe to celebrate Jenny’s birthday.
All five children planned a surprise for their mother, including the German and the Canberran residents, who both came to Melbourne for the weekend. We had a most wonderful family reunion just with them and the two of us. We also celebrated our 50th anniversary of marriage late last year.
Your Catholic faith and your life in medicine, particularly reproductive medicine, must have presented opportunities and also some conflicts over time.
I mentioned earlier that I was brought up as a Catholic. During my time, possibly even as a medical student but certainly as a resident, I got to know John and Lyn Billings. They were teaching a method of fertility regulation which conformed to the Catholic orthodox teaching of the time, they called it the ‘ovulation method’. I was involved in teaching in a marriage preparation course, which was a course for engaged couples. I used to give a lecture on reproductive anatomy, physiology and the basis of the ovulation method. Not with any injunction that couples should use that, but to inform them about its nature. In fact, I got involved in a very interesting study with the late Jim Brown and the Billings which was able to show that the ovulation method, as taught by the Billings, was extraordinarily accurate in picking the likely day of ovulation and the likely day of maximum fertility in the cycle. It basically taught women that a pattern of mucus secretion, which could be recognised in the vulva, would guide them as to when in the month they were fertile or not fertile. Jim Brown and myself did the relevant hormone assays and the Billings taught the fertility observations to a group of twenty women. That was a landmark publication in the Lancet in 1972.
I went on to join the Human Reproduction Program as a consultant in Geneva and was asked to coordinate a fivecountry study of that method to determine whether women of all backgrounds and educational levels could learn the method. And how well or otherwise it would work when put into practice. What we found was that more than 90 per cent of women were able to produce a chart which was interpretable as indicative. That they knew what they were looking for and what they were observing and that, if the method was applied strictly according to the rules taught by the Billings, the pregnancy rate was extremely low. As one would expect with a method that requires periodic abstinence, in practice many pregnancies occurred. It is still a method which the Billings promote and teach. They have programs particularly in China and Africa. But I have no good appreciation of how widely the method is used now.
You are also a part of a group of other Catholics who gave a great deal of thought to the teachings of the church, particularly the Papal Encyclical of 1968. Can you talk about that group?
We are part of two discussion groups. One of them is particularly concerned in the area that you have mentioned – a group of what could be called ‘Catholic intellectuals’. This group included my former deputy director at the institute, Professor John Funder, who is a widely educated man, and his wife, Kathleen, who has since died and who was also extremely well informed; a professor of philosophy at Melbourne University and his wife; a psychologist married to an urologist; an American historian; two senior teachers and a lawyer. We meet regularly. Also, there were two or three priests who used to join the group regularly and there was one who was an ex-priest who became Professor of History at Melbourne University.
But, when the Papal Encyclical on artificial contraception was issued, which reaffirmed the Church’s position that this was contrary to moral teaching, one of the priests in the group made a public statement. It was published on the front page of the newspaper, saying that neither as a moral theologian nor as a priest nor as a man could he give either internal or external assent to the papal statement. He lost his priestly job in the blink of an eye. Another man who was of similar views and who had been director of Catholic Education was also a part of that group and also was a dissenter. I think all of us in the group were dissenters and felt that we could not accept any longer that sort of teaching. It has to be remembered that Paul VI, who promulgated that encyclical, had been advised almost unanimously by a special papal commission that the church’s ban on contraception should be lifted but was persuaded by a very small number of conservatives at the very end not to do so.
Since that time, there have been other controversies in reproductive medicine, particularly IVF and donor insemination. How have you dealt with that personally and also professionally in terms of what the institute was researching?
It has always been my view that my personal attitudes or my personal morality should not influence what was done at the Research Centre or the Research Institute, unless there really were a gross conflict – and that there has never been. But, for areas like donor insemination and IVF, the Institute itself has not been directly involved but certainly it has been involved indirectly and I acted as an adviser to the early weeks or months of the establishment of IVF in Melbourne. My personal attitudes were that I was in a pluralist society, that I respected the views of others and that I was certainly not going to impose my views on them.
What you think were the most important and significant overseas experiences that you have had.
I would have to go back and say that the early experiences of postgraduate training were significant, but I won’t go back over those. The experience of the Ovulation Method survey in the five countries, which included countries like the Philippines, South India and El Salvador, was a wonderfully enlightening one and opened my eyes to what poverty in other parts of the world really meant. It also always seemed delightful to be to work with overseas colleagues. In 198485, I was appointed a Sims Commonwealth travelling professor and that involved visiting Zimbabwe, South Africa and the United Kingdom. Apartheid was very much alive and well in 1984, when we visited South Africa. I enormously enjoyed the experience of seeing and working with South African colleagues, and most of those that I encountered were seriously anti-apartheid. The man who mostly looked after us in Cape Town was somebody who had vigorously fought apartheid in his own hospital to the extent that he could do it. Many of his colleagues had left South Africa because of that problem. He had chosen to stay and fight and I had enormous admiration for him. His name was Solly Benetar. That trip was one that was highly significant.
I made many trips overseas to attend and speak at international conferences and to serve on advisory boards. I suppose that, for a number of years, I was travelling overseas between five and eight times a year. All of which I enjoyed and all of which I found to be a great privilege, to be able to interact with colleagues overseas who were inevitably hospitable, generous and a delight to work with.
You also visited China in 1983, I recall.
I went to China in 1983 for the World Health Organisation to teach a course in andrology. It is a specialty that we haven’t talked about today but in which I was very active with David de Kretser and others in the early 1970s and 1980s. I went to teach a course in andrology in Beijing, at a time when there were very few cars on the road and everybody still wore a Mao suit and road a bicycle. That was a very interesting experience.
You also had some extraordinary experiences travelling and teaching in eastern Europe. Would you like to talk about those?
One of the aspects of my involvement in the menopause that I didn’t mention was an involvement with the International Menopause Society, with which I became associated probably in the mid-1980s. I became president of that society in 1996 and decided that, in 1998, we would make a visit to Eastern Europe. I was very concerned that there was very little connection between the Western European based International Menopause Society and its Eastern European counterparts. So we made a trip which began in Yugoslavia and included Romania, Bulgaria, Hungary, Poland, the Czech Republic and Russia, a trip which was marked by enormous hospitality, enormous warmth and a successful outcome. From there on, Eastern European representatives started to play a much bigger role in the International Menopause Society.
International and national recognition
Over your career, you have received many awards and invited speakerships, but there must be some that stand out in your memory as being particularly significant. What are they and what was it about them that made such an impact on you?
Important to me was the promulgation of the name of Prince Henry’s Medical Research Centre and the making known to colleagues overseas that we were doing worthwhile work. In part, that is achieved by publishing in internationally recognised journals, and our staff were successfully in doing that. But there was also the aspect of being recognised by awards from international colleagues. I suppose the first significant one of those was in 1981, when I was asked to give a state-of-the-art lecture on testicular inhibin at the American Endocrine Society, which didn’t invite too many foreigners to speak. That was one of the initial big events for me. Subsequently, I was also asked by the American Endocrine Society to give a plenary lecture at one of its meetings in the late 1990s, where I talked about our work on the endocrinology of the menopause.
I was recognised by the British Endocrine Society with the awarding of its Dale Medal, which is its highest accolade. I was recognised by the American Endocrine Society with the Distinguished Physician Award. I was given two awards about six years apart by the North American Menopause Society, one for the work on perimenopause and the other for work that we haven’t talked about today: the use of androgens in women with disordered sexual function.
Also, in Australia, you were awarded the Harrison Lectureship of the Endocrine Society of Australia.
That also meant a lot in terms of being recognised locally. I was thrilled to be elected to Fellowship of the Australian Academy of Science and I was also thrilled to be given an award in the Australian Honours list as AO.
Granted that your publication record has been extraordinary – you have over 580 manuscripts – what else do you regard as being your major achievements in science?
Probably the most enduring achievement, if I set aside family life, has been what I would humbly call the successful leadership of Prince Henry’s Medical Research Centre and Prince Henry’s Institute, as it became in 1990. I had the privilege of leading the Institute essentially from 1965 to 1998 and was able to build, by virtue of the excellence of the people who came to join us, a firstclass productive Institute. I would like to think of it as being Australia’s leading endocrine research Institute. I led it with values of the absolute importance of integrity and honesty, of collaboration and cooperation and of joint leadership. I always had all the senior scientists of the institute as members of a senior advisory group and took no decisions for the Institute without consultation with them. I attempted to ensure that the working environment was conducive to work satisfaction and good relationships. I must say that occasionally I exercised my discretion in not appointing people who I thought would not work in accordance with that sort of principle. I was very strong in encouraging young people and, particularly in my later years, encouraging women in endocrinology. I was fortunate enough to train a substantial number of endocrine registrars and PhD and MD students, many of whom have gone on to leadership positions in endocrinology.
What was your approach to the direction of the Institute and the work that was undertaken?
My philosophy was always to attract firstrate people who would work in the broad area of endocrinology, to foster their research and to rely on the fact that they were people of excellence, who would be productive and would make significant contributions. In the early years, after Bryan Hudson had left to go to the Florey, a major individual to join the institute was Professor John Funder. Funder was an expert in salt-retaining hormones and had been crucial to the identification of the cellular receptor for aldosterone. He continued his work in that field, served as deputy director of the Centre for many years, was a major contributor to scientific dialogue in the public domain, a brilliant speaker and served the Centre with great distinction. He subsequently became director of the Baker Institute. But, after stepping down from that, he rejoined Prince Henry’s Institute and is now working at the Institute in a part-time capacity.
Other significant people who were members of staff included Lois Salamonsen. She was one of our original graduate research assistants who came back to do a late PhD, in career terms, and subsequently headed a Uterine Biology group. This group has made superb contributions in the whole area of menstrual bleeding disorders, implantation of the embryo and new approaches to contraception. She has really had a star-studded career in contributing in that area. Harry Majewski, a pharmacologist, joined the Institute in 1990 and was with us for 10 years. He was interested in cardiovascular pharmacology. Helena Teede, whom I mentioned, did some postgraduate work under his guidance. He provided a new opportunity in the Institute and brought new research students and again made a highly significant contribution. Evan Simpson joined the institute and eventually became its director. His work in breast cancer research was pivotal and resulted in the Institute becoming a member of the Breast Cancer Research Consortium in the state of Victoria. This research consortium made important contributions to knowledge and led to the establishment of a collaborative group of people who regularly talk to each other about breast cancer research.
Sir Henry, you are now 77 years old and it has been twelve years since you retired as director of the Institute. But, in those twelve years, you have had 120 papers, you continue to see patients, every Monday morning you come to journal club at eight o’clock and every lunchtime you contribute to the clinical discussions of the unit in a very active way. The resident staff also value your insights enormously. So, with that in mind, can you talk about what the word ‘retirement’ might mean?
I think the word ‘retirement’ for me is a difficult word to understand. I would say that I regard myself as being in the extraordinarily fortunate position of being able to do the things that you have just mentioned. My successors as directors of the institute, Evan Simpson first and then Mathew Gillespie, were both very welcoming to me to stay. They gave me access to an office and secretarial help and the privileges of library communication. They could easily have said, ‘You’ve been here so long; we would rather not have anybody peering over our shoulder.’ I accepted that hospitality on the condition that I would have absolutely no involvement whatever in the administration of the Institute, once I had stepped down.
Retirement has certainly meant an easier pace of lifestyle. I do two half days of clinical work, I keep my hand in a few research projects, I still referee quite a lot of papers for learned journals and I act in a consultative capacity to various bodies who seek review of statements and advice. But I do it in a fairly leisurely fashion. I spend probably three days a week still in front of my computer at home. But weekends are longer. I am able to relax a bit more and read a bit more widely. So retirement so far has meant a gentle modification of what I did before, and that is the way I see it rolling out from here on.
Henry, thank you for being here today and sharing with us your life history and your insights into science, clinical medicine and, indeed, life in general.
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