Dr Hugh Tyndale-Biscoe, marsupial biologist
Hugh Tyndale-Biscoe was born in Kashmir, India in 1929. He attended the school his parents ran in Kashmir, then finished school in England. He was awarded a BSc from the University of New Zealand (then called Canterbury University College) in 1951. After a year of working at the Department of Scientific and Industrial Research, he returned to study at the University of New Zealand, receiving a MSc Hons.
In 1955 Tyndale-Biscoe moved to Pakistan where he taught biology in a college. Having decided that he wanted to do research, he returned to Australia to study marsupial reproduction at the University of Western Australia. He finished his PhD in 1962 and took up a lectureship at the Australian National University in Canberra. Tyndale-Biscoe moved to the CSIRO Division of Wildlife and Ecology in 1976 as the head of the marsupial biology group. His work on reproductive physiology of marsupials focused on the endocrine control of breeding. Later his research was directed towards looking for new methods of controlling rabbits and foxes, and he was director of the Cooperative Research Centre for Biological Control of Vertebrate Pest Populations.
Interviewed by Professor Frank Fenner in 1999.
Early stirrings of interest in biology
Hugh, you had an early life that looks unusual to people who have lived all their lives in Australia. You were born in Kashmir, I gather.
Yes. My parents and my grandfather were missionaries of the Church Missionary Society. My grandfather ran a school for 50 years in Srinagar city and my father joined him in 1928. So I was born there as the grandson of the principal of the school and was made a bit of a fuss of at the time. My grandfather thought that I would be the third in succession.
Kashmir was a wonderful place to grow up. Spring is a really remarkable time there. After a very hard winter, with about 300 or 400 millimetres of snow, in March and April the whole place comes alive with flowers and lots of birds that migrate in to breed. Some of the Kashmiri masters in the school that my father and grandfather ran were interested in the animals. One in particular, a dear man called Samsar Chand Kaul, who wrote several books on the birds and flowers of Kashmir, was like an uncle to me as a boy and I got my first interest in birds and plants and butterflies from him – and also from my father, who had done agriculture at Cambridge and talked with me about biology.
As a student I didn’t think of a career in biology. I was expected to follow my father and grandfather, going to Cambridge and then presumably back to Kashmir. It was only towards my last years at school that I found biology was more interesting than history, and then I took it up at university.
Learning through hypothetico-deduction and by discovery
How was it that you went to university in New Zealand?
For most of World War II I was at my parents’ school in Kashmir. When the European war finished, my sister and I were sent in a convoy of ships taking English children back to England, and we finished school there. Because it was clear that there was no longer any future in India for British people, my father got a job as a schoolteacher in New Zealand. I followed my parents there and went to university in Christchurch.
I came under the influence of Edward Percival, a wonderful teacher who was the Professor of Biology at what was then called Canterbury University College. He made a big impression on me, both in the way he taught biology and also in his scientific method. During the war Karl Popper had been on the staff of the Philosophy Department at the College – probably as a refugee from Hitler. He was a very influential man, whose ideas about scientific method made an enormous impact on the Professor of Geology, Allen, and on Percival. Ideas of the hypothetico-deductive method filtered down to us as students and I remember applying it in the first research project I had, trying to set up an hypothesis and to test and disprove it.
How unexpected, to be exposed in early life to somebody like Popper, even indirectly.
In 1996, at a reunion of our group in Christchurch, some of the people reminiscing about the 1940s talked about having lectures from Popper. A story that I heard then resonated with my experience. Very irritated by students writing notes while he was lecturing, he made a deal with the class: ‘If you stop writing, I will give you all the notes so that you don’t need to write them down. And now you listen to what I am saying.’ By the time I was a student there, Popper had gone – to London, I think – but the stencilled copies of his notes were still circulating around the university and I got hold of a set of them. Ever since that time I have had an interest in him.
I was influenced also by Percival’s technique of teaching. He did not believe in undergraduate students, particularly in first-year biology, being able to have in the lab any books which told them that they were going to see this or that. Everything had to be done by discovery. Those of us who acted as demonstrators for Percival could not tell the students what was there. We could ask them, but they had to discover it. So every practical class was an act of discovery by the students – the whole class gradually ‘discovered’ the amoeba, saw it and had a new experience. Later I found that method of teaching very effective in Pakistan (with students unfamiliar with the English language) and here at the Australian National University.
An introduction to rabbit ecology and reproductive biology
What did you do after you got your bachelor’s degree?
My father supported me through the first three years at university but at the end of that I had to find my own way. In New Zealand at that time you did a first degree and then a master’s degree with honours, the honours being done with a thesis. I wanted to do my honours with Percival, but he went on leave so I waited a while.
I found that the New Zealand Department of Scientific and Industrial Research (DSIR, rather similar to Australia’s CSIRO) had just started an animal ecology section. Kasimierz Wodzicki, a Polish emigrant, had been put in charge of a group to look at the biology of the rabbit, which had become – as in Australia – a major pest in New Zealand, probably because of the lack of control during the war years. He recruited a small team of parasitologists, reproductive biologists and ecologists to study the rabbit in the wild. Percival gave me a good reference and so I happened to become an assistant zoologist to the reproductive group. We used to dissect 150 rabbits every month of the year, working out the breeding season and so on.
There was a funny little story about that. We had a field station up in Hawkes Bay, with a rather tenuous telephone connection through a forestry camp. Kasimierz Wodzicki used to come up and visit us from time to time, and we got a telegram spoken through from the forestry camp: ‘Arriving Friday night. Please arrange for 50 females.’ He had some project for which he wanted to dissect rabbits the next day, but the message caused quite a hoot in the forestry camp.
A marsupial field study: the brush-tail possum
At the end of that year I went back to university to do an MSc. When it came time for me to do a research project, Percival said, ‘Well, are you a vertebrate man or an invertebrate man?’ I said, ‘Oh, I think vertebrates,’ so he told me he had a jar of pickled reproductive tracts of the brush-tail possum and would like a solution to an old problem about the shoulder girdle of the possum. When the newborn is climbing into the pouch, its shoulder girdle is seen to have an articulation of the coracoid to the sternum, as in reptiles. All marsupials have this, which had been seen in the early part of the century as being a throwback, a phylogenetic left-over. Percival was interested in whether the muscles were also reptilian or were eutherian, mammalian.
At that time, very little was being done in New Zealand on the brush-tail possum. There was still debate as to whether it was really valuable as a fur-bearing animal or was causing serious trouble in the forests, and it wasn’t yet considered an important pest. But by this stage I was very interested in ecology and reproduction, through my work on the rabbits, so I asked Percival if I could expand the study beyond the comparative anatomy to a field study. He said yes, and that was the first work on the ecology of the brush-tail possum published in New Zealand. (George Dunnett published a paper in Australia, in about the same year as mine.)
Actually, the comparative anatomy question was a bit out of date: it had been answered in about 1917 but had got lost in the literature. All marsupials that have been studied have mammalian muscles. The coracoid articulation is probably a functional thing to give strength to the glenoid articulation, because the forearms are very important in the travel of the young from the cloaca to the pouch, but it disappears within about a week after birth. So it may be a phylogenetic relic, but it actually has a function at the time of birth, which is lost shortly afterwards.
A Socratic approach to elementary biology
Perhaps because my family background was beginning to have an influence, I was uncertain whether I wanted to spend the rest of my life working in DSIR on rabbits or to do other things. I wrote to the man in Kashmir who had succeeded my father, asking if there was any chance of working with him, but the letter I got back from him came from Pakistan, not Kashmir. He had got involved in the politics of India and Pakistan, favouring Pakistan, and had become persona non grata in Kashmir. He didn’t know what I had done or what my training was, but he said he would really like me to go to Peshawar, to the Frontier, to help set up biology teaching in a college there – and I said okay. My job there was to establish a laboratory and start a course in elementary biology for the students from the North-West Frontier. That was a lot of fun, and quite an adventurous time, but not for a lifetime. I gave it three years and then decided to go back to research.
Those three years in Pakistan were very good. The Socratic discovery method of teaching worked very well with the students and I learnt that Pakistani students were no different from New Zealand students – given the same type of teaching. The traditional teaching in India and Pakistan, however, was all rote learning, fixed questions in exams and so on. Strange things were said: teachers would never go to the library because a student might see them in the library and realise they didn’t know everything! In the first year that I was there, my students were getting very worried that I was teaching them things which were not going to be useful for the exam. But when they all got through the first exams, they were willing to do these rather weird things and they learnt to think for themselves. In later years I kept up with some of those students as they went on to medicine in Britain and elsewhere.
Quokkas and Antarctic organisms: studies in suspended animation
Actually, I first met you on my way to Pakistan, when I talked to the people in Wildlife (at CSIRO, in Canberra) about the rabbit biology work we were doing. I also called in at Perth, where Harry Waring, Professor of Zoology at the University of Western Australia, invited me to go back if ever I wanted to do a PhD. I kept that in the back of my mind.
Harry was a very good influence in the early days of zoology in Australia.
He was the first person to make it respectable to study Australian marsupials. Before his time, to do a PhD in biology you really had to go and study problems in Britain – or perhaps America.
In fact, there weren’t any PhDs at all in Australia till 1947.
Or in New Zealand either. You had to go somewhere else to be polished.
From Pakistan I came back to do a PhD with Harry Waring. Geoff Sharman, before going on to Adelaide, had worked on reproduction in the quokka, the little wallaby that lives on Rottnest Island. The quokka had become the major experimental animal for everybody in the Zoology Department in Perth, so although I had worked on brush-tail possums in New Zealand, Harry Waring said, ‘Well, now you’re here you should build on our knowledge and work on the quokka.’
Geoff had discovered the extraordinary phenomenon of embryonic diapause, the fact that in the kangaroo group the embryo goes through to about 80 cells but, if the female is lactating with a previous young, it stalls at that stage and nothing further happens until the first young vacates the pouch. Then development starts up again. This was obviously very interesting. It does occur in other mammals, but we had an opportunity to start looking at the endocrine control of the process.
In my PhD project I used techniques of surgical removal of the corpus luteum at different stages of pregnancy and then eventually, through learning the techniques from Wes Whitten at the John Curtin School of Medical Research in Canberra, transferred blastocysts from one mother to another to identify the important factors in controlling this diapause and releasing the embryo from it. Actually, that has been a theme of my research almost to the present time and has proved that fascinating mechanisms are involved – and some unexpected ones.
During my three years there working on the PhD, I made a trip to the Antarctic in the summer of 1959-60. I was a member of the New Zealand Alpine Club, which had organised an expedition but found the Americans would accept it only if it had a scientific base. The club looked for people who had climbing experience but could contribute scientifically, and so I went as one of the biologists. The biology was quite different from wallabies in Perth, but it was interesting. We surveyed an area beside the Beardmore Glacier and discovered Collembola, springtails, and mites living there at 84 degrees south. It was at the time the most southerly record of living organisms, and made a little bit of a flurry. One of them was given my label, Biscoa sudpolaris.
Those animals must be frozen solid for probably eight months of the year. The rocks are very dark – black – and where they emerge through the ice, which they do on the mountains on the side of the Beardmore Glacier, you get meltwater forming because the absorption of radiant heat from the sun melts the snow just beside the rocks, forming little damp patches where lichens and mosses grow. And in these lichens and mosses are the little organisms, which must have a very short active period before going back into a frozen state – extraordinary.
The greater glider: impacts of forest clear-felling
By then the Canberra University College had just set up its Faculty of Science and you were offered a lectureship.
Yes, but by the time I took up that position – which was a year later, for a number of reasons – the College had been forcibly amalgamated with the Australian National University, much to the indignation of people at the ANU. I started a research project on marsupials and started getting PhD students. (They were assigned to an official supervisor in the Institute of Advanced Studies, though, because the Faculty was not allowed to have PhD students. That, of course, rankled a lot.)
So began the two projects on marsupial biology during my time there, both arising from projects of my students. First, Roger Smith – whom Geoff Sharman had sent to me from Adelaide – wanted to study reproductive biology in marsupials but didn’t really know what topic to take. When we asked John Calaby, who had all the wisdom about what was possible, what marsupial in this area would make a good research project, he said, ‘Well, the commonest animal in the forests around here is the greater glider, and there’s nothing known about it at all. Why not do that?’
Roger and I went out and looked for greater gliders in the forests near Tidbinbilla, but when we saw them about 60 feet up in the tops of the gum trees we said, ‘How the heck are we going to study these animals?’ We nailed cage traps about 30 feet up – as high as we could get – but they didn’t come into the traps and we were beginning to think that this wasn’t going to be a very suitable study. Then we heard that forests were being knocked down at Bondo, near Tumut, and lots of animals were coming out of the trees so we should be able to get all we wanted.
We drove over to Tumut to collect some animals and bring them back to the lab, but as soon as we saw the site I realised we had a wonderful opportunity to study the impact of forest clearance on animals in the forest. This was a patch of about 5000 acres of eucalypt forest, still standing. On one side of it was pine plantation from earlier clearing operations, and on the other side was farm land that had been cleared before. About a thousand acres a year were going to be felled for the next five to six years, and the only place for the animals from the felled area was to go into the forest which would be felled the next year.
We immediately changed Roger’s project to follow the felling for the next three years. We had two people out there with hard hats on, and as the bulldozers pushed the trees over we’d rush out and catch the animals, tag and measure them and so on, and let them go. So we got two studies in one. One study was the biology of the animals at the time that they were disturbed, in what we assumed was their normal place in the forest, and that gave us information about the distribution of the animals in the eucalypt forest and their biology. Then, from what happened to them afterwards, we got a measure of the impact of clear-felling on the population.
That showed very clearly that, although the animals were not damaged by the felling itself because they could glide out of trees, virtually 80 per cent were never seen again. Even though 20 per cent were recovered during that felling period, when we went back into the next bit of forest a year later we never got more than about 5 per cent of the ones from the year before. This was the first study in Australia to show the devastating impact of forest clearance on wildlife. Because all the animals that we were handling were protected fauna, we had to get a permit from New South Wales. But, in fact, at the end of three years we were able to tell the fauna authorities that virtually everything dies in this situation.
And that applied not only to the glider but to other animals as well?
We didn’t really look at that. That is a pity, but at the time the gliders were the most abundant and we just concentrated on them.
A windfall for museum collections
After the first three years, when Roger Smith got his MSc and went off to Canada, I continued the study with other students. We started doing more manipulative things because we could show the fauna authorities that the animals were all going to die and so we could get permission to actually shoot animals before the forest was felled, in order to test our ideas about them. We wondered whether the reason why so few survived the clear-felling was that there was nowhere for them to go – the remaining forest was already occupied. So we started a number of experiments where we would shoot out the residents of the forest that was going to be felled in a future year, depleting it to see whether the displaced animals would be able to move in there. They didn’t, which means that they don’t move from their home territory. If their home territory goes, they die on the site. We now know from much later work on eucalypt forest that probably the fat reserves in these animals are so low that they are living on the edge, and if they do not get food for three or four nights they will die.
It was difficult to do anything rigorous in the forests. The forestry commission tolerated us but didn’t see us as being serious, and basically we had no rights at all. On a couple of occasions in the late 1960s, although the worth of having invested a whole year of preparation in selectively shooting out a forest depended on the forestry people telling us when they were going to fell, they didn’t do so. They would tell me after it had happened. Such a waste of time, to have a year’s work sabotaged because the forest was gone, shifted my main interest back to reproductive biology.
Disagreeable though it had been, however, to go through the forest shooting those beautiful animals, because I knew they were all going to die anyway I wrote to all the museums around Australia asking if they would like to take advantage of the chance to get really good series of animals from one locality. Most museums have one or two specimens, but when David Ride was director of the Western Australia Museum he had alerted me to the importance of having good series. Three museums took up the offer. The National Museum in Victoria sent up a team to collect 50 skins and skulls, all from one area in 1966, as did a team from South Australia, where Peter Crowcroft was the director. The West Australian Museum took 100 – from an adjacent area – asking us to send them in formalin. Also, quite a number of skulls went into the National Wildlife Collection in Canberra. And there they lay for 30 years.
The closing of a circle
Interestingly, David Lindenmayer, at the ANU's Centre for Resource and Environmental Studies, recently started a study of the survival of animals in relict patches of eucalypt forest buried in pine plantation. Quite serendipitously, without knowing where we had worked in the 1960s, about five years ago he chose the very same area for his study site and somebody recommended that he come out and see me. I was very interested to hear that he was finding gliders in those little patches, because I had assumed from our study that they would have died out forever. The density is about one animal per hectare, and if 20 hectares are left, theoretically the maximum population of 20 animals would hardly be viable.
I told David of the big series of animals taken from this area at the time when the forest was felled, and suggested that we could now do DNA analysis of the original population and the small populations in the present day relics to see whether they show genetic drift or founder effects, or whether they are animals coming in from 10 kilometres away – although our experience in the ’60s was that they couldn’t even move 2 kilometres across country which was not eucalypt forest. David is now the major leader of that big project and Andrea Taylor, from Monash, is the DNA expert. I am involved a little bit with David and we are about to look at a real test of population viability analysis. There is a lot of theoretical stuff on it, but hardly any actual tests.
Having that material from 30 years ago is strengthened tremendously by the ability now to do DNA analyses of it.
It is a vindication of museum collections, as had been argued by the Victorians and others. Dick Schodde, Director of the Australian National Wildlife Collection in CSIRO Wildlife and Ecology, argues that history is stored in the specimens. From skulls or skin apparently you can get quite good quality DNA. We have 400 specimens from that time – not counting the West Australian ones, which unfortunately we were asked to put into formalin. We can’t use them because, apparently, the formalin breaks up the DNA. But who knows, it may be possible in the future. The project is a wonderful closing of a circle, however, using the work which we did in the ’60s.
Returning to the embryonic diapause: lactational quiescence
What was your other project on marsupial biology during those years at ANU?
Ever since I came to Canberra I had been looking for a small wallaby or macropod which would make a good experimental animal to investigate the embryonic diapause – the state of quiescence in the kangaroo blastocyst, where no cell division occurs, no expansion of the embryo, while the mother is lactating a previous young.
I will explain later a complication with the tammar wallaby, but essentially what Geoff Sharman discovered was that pregnancy in kangaroos is equal in length to the oestrous cycle, whereas in all other marsupials it is much shorter than the cycle. In the brush-tail possum, pregnancy is 17 days but the oestrous cycle is 25. A female that becomes pregnant gives birth on day 17 and then suckling by that young in the pouch suppresses the ovary and there are no further oestrous cycles while lactation occurs. In kangaroos, the baby is born on the day that the female comes into oestrus. So she has what is called a post-partum oestrus: she mates a few hours after she has given birth. The egg fertilised at that time develops for about 6 days while she is suckling the newborn young, and then everything is suppressed. It just stays totally dormant while the baby is in the pouch, which in the case of both the red kangaroo and the tammar wallaby is about 7 months.
Geoff showed later, in CSIRO, that as the baby is growing up and about to leave the pouch, its suckling incidence declines as it eats grass. That diminished frequency of suckling releases the corpus luteum from its inhibition; it starts to grow and secretes progesterone; and that stimulates the embryo to start to grow again. Once that starts it can’t stop. Pregnancy then continues to completion and the female gives birth again, by which time the older baby is out of the pouch. Indeed, in some kangaroos the mother throws out the first one and won’t let it back in, on the day that she gives birth. A female kangaroo has four mammary glands and the older young has been feeding only off one of them, so the new baby attaches to one of the three unused mammary glands and that one starts to produce milk of an entirely different constitution, an extremely watery secretion that is appropriate to this newborn baby.
The very early milk contains galactose in the first day or two but then produces oligosaccharides based on galactose, instead. There is very little fat and very little protein in that early milk, but the milk slowly changes through lactation. The carbohydrate moiety goes down, the fat moiety goes up, protein goes up, and towards the end of lactation a very rich milk is being produced. A female red kangaroo can have one mammary gland producing rich milk for the baby that is out at her feet and also be making the watery milk for the newborn. And if conditions are good and the female has already weaned off another one, one of the other mammary glands is regressing from the earlier state. All four glands are in a different state of physiology.
This fascinating puzzle – it doesn’t fit the classical view of the endocrine control of lactation by prolactin – is one of the things we cracked later, at CSIRO. In a cow, for instance, if the calf suckles, the prolactin level goes up and that stimulates the mammary gland to produce more milk. So there is a simple feedback between sucking and milk production. But the kangaroos don’t change the concentration of prolactin. In the tammar wallaby there is no difference in prolactin from a lactating and a non-lactating female through the whole of the first few months of lactation. The sucking young stimulates an increase in the number of receptors for prolactin on the epithelium of the mammary gland, changing not the number of ‘arrows’ coming in but the size of the ‘target’. The level of prolactin stays the same but the mammary gland that the baby is attached to opens out, takes it all and is stimulated.
Seasonal quiescence: the tammar wallaby
You haven’t told me how you got onto the tammar wallaby.
We started off looking at the little rat-kangaroo, Bettongia lesueur, which lives on the islands of Western Australia. (It had been common right through continental Australia but had gone with the sweep of the rabbit.) The animals proved not to be amenable to close captivity. They weren’t docile enough – they fought.
Pat Berger, a Fulbright scholar from Louisiana, had come to do a PhD with Geoff Sharman, who put her onto studying the breeding of the tammar wallaby on Kangaroo Island. She discovered that although the tammar has a very strict seasonality to its breeding, the seasonality is not conventional. The female goes through the process of producing a blastocyst while it is suckling young, and that happens in February each year – the major time when the babies are born. If you take a baby off during the first half of the year, up to the winter solstice, the female will reactivate her blastocyst, give birth after a month, have a post-partum oestrus, produce another dormant blastocyst and now carry the new baby forward. But if you do that procedure after mid-winter, the blastocyst is not reactivated but continues to remain dormant in the uterus – in the absence of a young in the pouch. This seasonal quiescence, as distinct from lactational quiescence, is controlled not by sucking but by photoperiod.
About 6 weeks after the summer solstice, all the females on Kangaroo Island give birth again. Ninety per cent give birth between 20 January and about 10 February, and the remainder a month later – the latter did not have a stored blastocyst but they went through the cycle and then became pregnant. There is a tremendous amount of sexual activity on Kangaroo Island between 20 January and the middle of February. Almost every female is giving birth and having a post-partum oestrus, so all over the paddocks there are females hopping around with a queue of about seven males hopping along behind.
For the rest of the year the males have very little to do, but we discovered that they are not seasonal. If you separate them from females, testosterone and luteinising hormone levels in males stay at a basal level all through the year. If they are with females from December through to February, their testosterone and LH levels go right up. So they are tracking the changes that are going on in the female. If they are excluded from females they don’t track that and they are not ready for the massive breeding in February.
We think that probably the tammar was a non-seasonal animal like the red kangaroo, which got isolated in the southern latitudes on Kangaroo Island and other parts of southern Australia and cobbled together a new kind of seasonality, which is dependent on keeping the corpus luteum in a state of suppression until the summer solstice and then letting it go. And the male just tracks the female.
The Bennett’s wallaby on Tasmania has done the same thing, but the red-necked wallaby, which is the mainland version of the Bennett’s, is like a red kangaroo. So in Tasmania it has probably evolved the same pattern independently.
In the southern areas, where the seasonal change is bigger?
Yes, where there is a selective advantage to having the babies all emerging from the pouch in the spring – whereas of course in Central Australia there is no such advantage. Reproduction is geared to the uncertainties of the climate.
Endocrine control of seasonal breeding: the pituitary
After discovering this extraordinary photoperiod-controlled embryonic diapause, Pat Berger went back to America. Among my students who were getting interested in this was Marilyn Renfree, whom I sent to Kangaroo Island to bring back some tammars for study here. From them we built up our nucleus of a breeding colony, kept at the CSIRO Division of Wildlife Research. The tammars have proved to be wonderful animals. They are very docile, they breed happily in open pens, and that colony has continued to be self-sustaining for 25 years with virtually no input from Kangaroo Island any more.
We started looking at the whole endocrine control of this process, from the environment through the brain to the pituitary gland, to the ovary, to the uterus, to the blastocyst. Various people took different parts of the program, but John Hearn and Marilyn probably contributed more initially than any others. Marilyn worked on the interaction between the uterine secretions and the embryo: what secretions are being produced by the uterus which switch on the embryo, and how are these being controlled by the ovary? I worked on the ovarian part of it and transferring blastocysts, as I had done for my PhD.
When John Hearn wanted to work in this program, I proposed that he tackle the pituitary – a really tough one. No-one had ever taken out a marsupial pituitary gland or measured pituitary hormones in a marsupial. And he did both, during the 3 years that he was here. He taught himself how to do the operation and his animals survived for up to 2 months after, with care. They had to have salt provided to them because their adrenals and their thyroids were all shot, as well as their gonads.
Our working hypothesis was that the corpus luteum is controlled by the pituitary gland withholding a luteotrophic stimulus, a stimulus to the corpus luteum. The conventional way the pituitary controls the ovary is by sending out stimulatory signals. If it withdraws the stimulatory signal, the ovary just stops – anoestrus. We thought that if John was able to take out the pituitary gland, the ovary would shut down and the blastocyst would not develop.
Eventually he could get out the pituitary gland. But, to our absolute amazement, when he opened up these animals two or three weeks later to see what was happening, they were all in late pregnancy. They shouldn’t be! This was completely contrary to conventional wisdom. It was saying that the pituitary is providing a tonic inhibition all the time, holding back the corpus luteum. If you remove the pituitary, you remove an inhibition and the corpus luteum is actually autonomous. There had never been any indication of that before. We had to completely rethink our ideas to ask what inhibitory substance the pituitary is producing.
John finished his PhD at that point and went to Edinburgh to work with Roger Short. I thought I had better get on and find out what this principle was. The first thing I found was that I didn’t know how to do the hypophysectomy! It took me 2 years to master what the PhD student had done. Then, having confirmed what he had found, we discovered that the principal hormone acting as an inhibitory substance was prolactin. That fits nicely with the fact that it is during lactation that this thing is suppressed, because during lactation prolactin is being secreted and is acting as a tonic inhibitor of the corpus luteum. When subsequently Francesca Stewart came to join the group at Wildlife, she showed that the concentration of specific receptors for prolactin in the corpus luteum was higher than in any other tissue in the body, even the mammary gland.
Photoperiod, clock information and seasonal breeding: the pineal gland
The model looked to be that the pituitary is inhibiting the corpus luteum through prolactin, but the question was what happens in the second half of the year, when the animal becomes sensitive to photoperiod. There is no suckling then. Is there still prolactin? At that time another PhD student, Steve McConnell, joined Richard Mark to work on the brain. Richard and I suggested that he might like to look at whether the pineal gland is involved – for which he managed to learn to do surgery from above the head to remove the pineal. We got some very paradoxical results with that.
The pineal is a very strange organ: although it is an endocrine organ it doesn’t work in the same way as others. Melatonin is not a simple hormone that affects a target and has a dose-response effect, but is much more like a neural messenger. The important information is usually the duration of the animal’s exposure to melatonin, rather than the concentration – as long as the concentration is above a minimum.
Steve found that the animal will remain in seasonal quiescence as long as the female is exposed to a summer-length photoperiod. A shortened photoperiod – increased night length and decreased day length – is a very potent signal to start everything up. And if you take out the pineal gland, you remove this reading of photoperiod.
He also adapted an assay for the hormone melatonin, which is secreted by the pineal. The secretion of melatonin, as is known in other animals, is high during the dark phase and low during the light phase. With the assay we could see that if you changed the night length, the melatonin changed on the very first night that the lights went out earlier but the response time for the animal was about 3 days longer than would be expected from other work. If you remove the pouch young, the baby is born 26 days later. If you start giving melatonin, the baby is born 30 to 32 days later. The question was: why those extra days?
Initially we thought that the melatonin level did not go up for the first two or three nights, and so it took that time for the animal to learn. But that wasn’t true. It goes up on the first night. The next argument, that it took the animal three nights to read the message before the process took off, did seem to be true. And if, instead of changing the photoperiod, we just gave an injection of melatonin at the time when the lights might go off, that was just as effective.
Then we found that you didn’t even need to have elevated melatonin between the beginning and the end, but just the punctuation mark. With a melatonin injection, 12 hours of light, and another melatonin injection, the animal thought it had had a 12-hour night – just amazing. That led to the idea that there has to be a centre somewhere in the brain which is computing this information about time. That is still an open issue: how do they read time, and how do they store that information for, say, three nights and then decide the signal is real and go to the next step?
Since I retired I have been hoping to do the experiment which would find and explain that centre in the brain – in the hypothalamus, probably. The tammar would be a very good animal for this because it has a response time that is much shorter than in the conventional animals that are used. The hamster takes 3 weeks to respond to a change in photoperiod and the sheep takes 6 weeks, but here is an animal which takes 3 days. So you actually should be able to find it.
I had hoped, when I joined the ANU's Research School of Biological Science 4 years ago, that I would be able to use PET scan (positron emission tomography) to see hot spots in the brain. That may well be true in the future, but at that time there were no PET scanners in Canberra – it is extremely expensive to get onto one, anyway – and also the people running those machines reckoned that the site I am looking at in the brain would be too small for them to detect it. But things are changing so fast in this field that this is probably the way it will go. It would be a big advantage over what we are trying to do, which is to infuse radio-labelled 2-deoxyglucose and see where it gets sequestered in the brain.
While we know that in mammals there is a so-called clock in the suprachiasmatic nucleus, near the optic nerves, this is not the clock. I am interested in where the clock information is read. I may have a clock in my hand but unless I read it, it is no use. Somewhere there has to be a place where the information is being read and interpreted, and then a response made. I think if we could find it in the tammar, it would point to where it probably is in other mammals, including ourselves. So it might have some use.
The move to full-time research: setting up in CSIRO
You carried that sequence of research through from the Department of Zoology in ANU to CSIRO and, more recently, to RSBS. What made you move on to CSIRO?
At the end of 1972, when John Hearn and Marilyn Renfree finished their PhDs, there looked to be a really exciting prospect coming up. A lot of nice stuff was opening out, with people joining the group such as Phil Moore, who had worked on RNA activity in early embryos – the initial awakening of the blastocyst – during a QEII (Queen Elizabeth II) Fellowship. I really wanted to get into this research as a full-time commitment rather than alongside undergraduate teaching, even though I had enjoyed the teaching. I approached Rutherford Robertson about joining RSBS but that didn’t come to anything. I was invited to go to the London Zoo and went to look at working there, but I really wanted to work on marsupials and doing that from London seemed a bit silly.
Having heard of a feeling that there ought to be more physiology in the Division of Wildlife Research at CSIRO, I approached Alan Pierce (the biological member of the Executive of CSIRO) and gave him a three-page outline of what I had in mind. It was based on this work on the endocrine control of breeding in kangaroos and on growth of pouch young, development of physiological function in the pouch young, and digestive physiology – various aspects of physiology – and it was taken up. Harry Frith, the Chief of the Division, had been very supportive of me all along while I was at ANU and he was supportive of this idea.
CSIRO decided to create a new Marsupial Biology Group, and transferred three scientists from Animal Production in Sydney who had had an interest in marsupials but then had been working on wool. The wool money was collapsing and they were looking for something else. The job of leader was advertised and I was appointed to it, moving to Wildlife at the beginning of 1976.
It was a bad time to move, because the Whitlam government had been brought down in November 1975, the 'Razor Gang' had come in and the funds were all going to be cut. I wondered whether I had made a very foolish decision. However, the cuts did not immediately affect CSIRO and Harry Frith gave me some very good support, including a building to turn into an animal house and surgery and so on, and salaries for four people – two scientists and two technicians – on top of those who had been transferred. It was wonderful. I had a budget which was very expandable – there was no question about not having any money – and I didn’t have to do any teaching.
I was able to recruit some really good people. Rob Sutherland, who is now the Director of the Garvan Institute in Sydney, came from the John Curtin School and got the assays for the pituitary hormones up and running. Francesca Stewart was enrolled for a PhD in Cambridge but her husband was in CSIRO, so she came and did her research on the mammary gland with us, developing all the new techniques for receptor assays and receptors for hormones.
Several people who were already in the Division came into the group. Brian Green took on work on the lactation of kangaroos, opening up the whole field of the milk composition and how it changes through lactation. And Lyn Hinds was appointed as an experimental officer but eventually did her PhD, becoming the expert on the prolactin and progesterone hormone assays. So we had a real ferment of research going on, looking at not only the control of the reproductive cycle/embryonic diapause but also lactation and the growth of the young.
Competing to develop hormone assays
That was a great, productive time. We solved a number of questions which had been around for a while and got the assay systems going – in fruitful but quite intense competition with a similar lab which Marilyn Renfree had set up at Murdoch University, in Western Australia. We learnt that the level of hormone that is important in the wallaby is far lower – maybe a hundred-fold less – than in the conventional laboratory and farm animals. The normal levels of, say, progesterone in the blood of human beings or sheep, for example, are about 10 to 40 nanograms. In the wallaby, the normal level is 100 picograms and 200 to 250 picograms is actually a peak – if you use conventional progesterone assays there seems to be nothing there. With oestrogen the important level is under 20 picograms, and again you miss it with standard assays.
The two groups, in the west and the east, were striving to find out how we could measure this accurately. And in competing we would always be challenging each other. If the others said they had measured progesterone, we’d say, ‘Oh no, come on, you haven’t measured progesterone. What’s the sensitivity of your assay?’ We were both being pushed, pushed down until we got something which we all agreed on. All macropods seem to have this very low level of hormone, but it is still very important.
One spin-off has been that elephants also have extremely low levels of progesterone, which can’t be measured by standard methods. So Lyn Hinds has become the expert on measuring progesterone in the elephants at the Melbourne Zoo, because our assay will measure real levels.
Marsupial studies coming to fruition
There was also some very nice work done by Peter Janssens and his students from the Zoology Department, ANU. Because of all our studies a lot of pouch young were available, and so that they would not be wasted, Peter used to put honours students onto different projects. One student, for example, would study the development of the adrenal gland right through pouch life; another, the thyroid gland; another, the liver function; another, kidney function. One by one, all the systems in the tammar were being worked out.
Richard Mark, when he started work at RSBS on the development of the brain, asked me to suggest an experimental marsupial. ‘Why not use the tammar?’ I said. ‘It’s a really good animal and we can let you have as many pouch young as you like.’ And so they started with the tammar, as did several other groups around the country. Because we had this big breeding colony – 700 animals at its peak – and in those days CSIRO didn’t have to get money back for everything, I would just tell anybody who said they wanted to work on a problem in kangaroo biology to come and collect them. That is, in a way, why the tammar has become the favoured experimental animal. Now there are colonies in many universities around the country.
Originating from the group you brought in?
Not all. A number of people have gone back to get the animals from Kangaroo Island. But the strength is that we know that everybody’s results are useful to everybody else, because they are in the same species of animal.
A tremendous strength, just as the hamster has been so fantastically useful, and of course the lab mouse.
When I first got involved with marsupial biology, in the Waring days, everybody would take a different species. If somebody said that cortisol levels were very low in the brush-tail possum, you didn’t know whether that was a peculiarity of marsupials or of that animal or of that laboratory. Nobody could ever really challenge anybody else. When a lot of different people worked on the same species, the same wallaby, you could challenge them. If you didn’t agree with them, they couldn’t get away by saying, ‘Oh well, my species is different.’ We started to get much harder data.
A much better way of getting principles, rather than just detailed, fragmentary stuff.
It was really important to get the basic knowledge of marsupial biology. Now we are moving into a later phase: people are picking other species and asking whether, say, the Tasmanian pademelon or the parma wallaby is different from the tammar wallaby. We have got our core species; now the others are compared against it.
And you have developed your accurate assay methods.
All these things came to fruition in two books. The book that I co-authored with Marilyn Renfree, Reproductive Physiology of Marsupials, was written in 1985 and published in 1987, and in 1988 we published a volume I had edited with Peter Janssens called The Developing Marsupial, in which we looked at all the work that was being done on the way in which the physiological function of the young develops through pouch life. It is a wonderful model for the development of physiological systems.
That would be the first – and still the only – comprehensive book in the field.
Yes. It arose from a conference in 1986. Rather than compiling the proceedings of the conference, Peter and I agreed to invite chapters on the different systems. That allowed a different style of writing.
Times of change
By then things in CSIRO were changing very drastically. The Division had changed its name to Wildlife and Ecology and had changed its focus to become a much broader ecological division, with plant ecology, rainforests, rangelands and all sorts of other things – much bigger and stronger, with a Chief whose vision was of that kind of work and who really didn’t understand the kind of physiology that my group was doing. We came under considerable threat from the others in the Division, particularly because funds were no longer so easy to get and everybody was having to fight much harder to justify the money they had. Our group’s presence there at all was under question: perhaps, because this was not applied work, we should be at the university. We were more and more on the outers of the Division, without quite knowing how to respond because it didn’t seem that any of the arguments we put up were going to work. The moment of truth came in 1987.
Dealing with the rabbit: to kill or to control fertility?
How did that come about?
Some years earlier the work on rabbits, which had been a key area in the Division, was winding down with the retirement of Bill Sobie, who was a virologist, though not a molecular biologist. It seemed from his work and your earlier work that the interaction between rabbits and the myxoma virus had pretty well stabilised and there was no benefit in trying to get a better myxomatosis, because it would just get selected out. By then I was Assistant Chief. My feeling was that we should drop all the work on myxomatosis, that it had run out of steam and there was no benefit in continuing it. The Chief agreed with me, and we gave notice to the Wool Corporation and the Meat Research Corporation that we were going to discontinue the project. They wouldn’t have a bar of it, saying that we must recruit a new scientist to take Bill Sobie’s place and if we had problems with money they would provide, between them, a whopping grant of $500,000 a year to continue work on myxomatosis. That was too good to pass up.
About then I was given control of the group and we advertised for a scientist to do the work. Steve Robbins applied – a good virologist who had modern techniques and knew molecular biology, which then was just coming in. The interview was quite extraordinary: he talked about what he would do and he started asking some questions, such as whether anybody there knew the genomic structure of the virus. To all these questions the answer was no, and you could see him expanding as he realised what a goldmine he had. These people were going to give him all this money, and they didn’t know anything about it! He accepted, recruited two or three other people and set up a team.
For the next 2 years they did some really good, important work, finding that the myxoma virus had a lot of homology with vaccinia. Steve’s remit was to look at the molecular structure of the virus in order to make a more virulent virus that would kill more rabbits. They were thinking of putting in genes which would kill rabbits more quickly, but it all seemed to me pretty futile because from your work it seemed that that would all be very quickly selected against in the field.
Steve was very independent and pretty well worked on his own. I didn’t have much to do with him directly, although I was his program leader. Then one morning when I opened The Canberra Times, there in the last paragraph of an article by Graham O’Neill was a throwaway line quoting Steve as saying, ‘Yes, we are going to try and put in these genes which will make the virus more virulent – or we could put in genes which make the rabbit infertile.’ I just thought, ‘What? There is something.’ Ever since joining the Division I had wondered if there was any way in which the work we were doing on reproduction could help to control the rabbit. The big problem with rabbits is that they breed so fast. If you kill even 99 per cent of them, they just come straight back. You need something which stops them breeding, but how could you ever find such a thing? That throwaway line made me see that there was a possibility.
Applying kangaroo experience to the rabbit: a frustrated approach
I realised that from the work we had been doing on the tammar wallaby we had the background to know what gene could be put into the virus, which might affect reproduction. I raced in to work that morning with the newspaper and suggested to Steve that we could put in the gene for gonadotrophic releasing hormone, because I knew there were a number of antagonists of GNRH which block its function, and that would effectively make the animal castrated – it couldn’t breed – but would not kill it. It seemed to be something which his group and mine could do together, and he was quite interested.
Immediately, in 1987, we put in a couple of grant applications but both were knocked back. The first was to the Rural Credits Development Fund, who I thought were sure to give us the money. But they didn’t. Don Drover, the scientist in charge, said they thought it was too innovative!
The second application was to the Wool Corporation, saying that this was a better way of going with the myxoma virus than killing. In the presentation I said we would use GNRH, because it is a very small molecule – only eight or nine aminoacids – so the gene would be easy to put in. The head of the Wool Corp at that time was a scientist who saw the problem straight away: all mammals have the same GNRH. He said, ‘Hang on. You want to put something in here. What if it gets into my sheep? Is it going to make them sterile too? Or into my daughters – even worse! We’re not touching this one.’
Then, at a workshop in the Division, I presented our ideas to Alan Newsome’s group working on rabbits. Ian Parer, a very good critic, said it would not work: ‘A castrated rabbit just loses its position in the hierarchy and another rabbit will take its place. You won’t have gained anything.’ That seemed a fair criticism. Since we couldn’t get money and the ecologists were saying it wouldn’t work anyway, it stalled.
Financial salvation, clinched by the foxes
In July 1988 I went to a conference in Kyoto on the embryonic work for delayed implantation. Jurien Deane from the US National Institutes for Health gave a paper reporting that NIH had just cloned the gene of the zona pellucida (the outer coat of the egg) of the mouse, and describing the genome for it. I thought, ‘Ah! Here we have something. Rather than GNRH, let’s go for zona pellucida. The Wool Corp can’t be worried about this, nor can Ian Parer because the animal will be infertile but will still have its ovaries functioning, so it will retain its dominance in the group.’ Over lunch I asked Deane if it was feasible that we could put the gene he had into the myxoma virus. He called it a great idea, generously offered to let us have the gene, and has been a very good supporter ever since. I came back all enthusiastic, thinking I could now bowl over the Wool Corp, but they weren’t listening. The shutters just came down: they would not accept that the new proposal was different from the previous one. So that was out.
At that time, however, Bob Hawke as Prime Minister provided extra money to CSIRO – as a result, actually, of Max Whitten’s intervention.
Probably Ralph Slatyer had something to do with it. He was Chief Scientist then.
Anyway, CSIRO had had a cut but Max Whitten, Chief of the Division of Entomology, who was very politically adept, told Bob Hawke, ‘Look, if you keep cutting CSIRO like this, we’re just going to give up: we’re going to have to stop doing our work in Tasmania and here and there. You should be putting more money in, not taking it away. What it really needs is $60 million extra.’ Evidently Bob Hawke agreed, and so $60 million over 3 years came to CSIRO. In the sudden scurry to find a new, modern project I put up this one, it went in on Jim Peacock’s budget for gene shears – it was considered to be molecular biology – and we got money.
Also, John Stocker, Chief Executive of CSIRO, was very good. Being persuaded that this was worth funding, he gave a continuing grant to the Division for the work. So with John Stocker’s money and then gene shears money, finally we were able to start the rabbit work.
At about the same time, Bob Hawke got concerned about the extinction of native fauna. In a document called Our Country, Our Future, the fox had been identified as a big factor in that extinction – the sheep should have been identified, of course, but instead the fox was. The Division then got called on by the government to come up with a way of controlling foxes. It was in my program, so I put up a paper stating a number of options and saying, ‘It is going to be very difficult, and you can go from the simplest and possibly least effective through to the most complex and most expensive.’ The cheapest would have been putting out baits of stilboestrol, which was known to affect breeding in coyotes in America; that could be done almost straight away. Then it went through several other options to the most difficult – viral-vectored immuno-contraception – where we didn’t have a virus, we didn’t know anything about the reproduction and we didn’t know anything about the immunology. I said, ‘This is really very risky and probably shouldn’t be tried at this stage.’ However, of course, they said they wanted the best for the least cost.
We had said that for the immuno-contraception we would need $300,000 a year for 5 years, but we were offered only $120,000 so I said no, we were not going to take it. I said to Brian Walker, ‘There’s no point. We haven’t got the resources. If we have to do this with underfunding, it will draw money away from the rabbit work, which has much more prospect of success.’ I was told that if a minister offers you money, you never refuse it. But we did. So they had a big workshop which convinced them that they should support us properly, and we eventually got the money. We could now recruit scientists to work on the fox and some to work on the rabbit, all under the one roof and interacting.
The crossroads: ceasing marsupial studies
About then we had to stop the work on marsupials, because everybody in the Division saw this concept of immunising animals against their own reproductive proteins and using a virus as the agent to carry the immunogen to the animals as something with great promise for future control. Many of the people who had been very critical of my group were now very generous in their tremendously strong support within the Division. I tried at that point to say that we should have new money for the new project so that we could continue the marsupial work, but the Chief and the program leaders just said no, we would have to choose which to do. So we were really stymied.
We had a meeting of the whole group to weigh the increasing difficulty in studying marsupials without support from the Division against the need to be wholehearted about the new project if it was to work at all. I thought we really should go with the fertility control and say that we could not continue to compete in marsupial work. Lyn Hinds and I and some others decided to drop marsupial studies but Kevin Nicholas decided to stay with lactation and Brian Green with marsupial physiology. (They did that, but their resources dwindled and inevitably they became vulnerable to cutbacks in the Division.) So then all the other resources of our group and whatever we could get went into the new work.
Tapping into the Cooperative Research Centres program
Then in 1990 the CRC program was introduced by Ralph Slatyer. We put in a bid for the first round but we were not successful because at that stage we didn’t have any results, just a promise. Most of the referees who read it said it was a brilliant idea but very risky, and we hadn’t demonstrated that we were capable of actually doing it. They would not give us 7 years’ money for a proposal which they considered premature.
I felt disappointed, but I was encouraged by Ralph Slatyer and then by Gus Nossal, at the AGM of the Academy, to resubmit the proposal in the second round because Gus and several others thought it would turn out to be great. By the time we applied on the second round, we had some good runs on the board. We had recruited two good scientists (and support staff) who were working so fast that they had already isolated a whole lot of antibodies from fox and rabbit sperm; they were beginning to purify the zona pellucida; and we were looking for viruses for foxes and had identified two or three. Everything was burning along. In the myxoma work, Ron Jackson was finding sites where you could insert a gene and he had actually made the first recombinant using a marker gene, influenza HA, and had shown that the virus was still effective.
We had some strong support by then from Wollongong University and from Conservation and Land Management in Western Australia. And we obviously had a selection committee who were prejudiced in favour of us: Nancy Millis, coming in for the big interview, said, ‘Oh, this is such an exciting project!’ So we were almost a shoe-in, I think, on the second time. That gave us 7 years’ security, with $2 million a year, plus the fox money and the other sums – but we never really got the Wool Corporation on side. They were on the Board of the CRC but they remained very anti, thinking we were using their money for a concept that they had never really approved. In retrospect I think we have been vindicated – recombinant viruses that make mice and rabbits sterile have been constructed and the original CRC has been renewed for a further 7 years as the Pest Animal CRC.
A new turn of events: rabbit calicivirus
When the rabbit calicivirus emerged from Italy, the Wool Corporation decided that there was much more mileage in it than in fertility control. I was involved in it, in the sense that I was chairman of the RCD Subcommittee of ANZECC (the Australian and New Zealand Environment and Conservation Council, previously called CONCOM). Our job initially, with a very small amount of money, was to send people to England to find out what this virus was and to import it to AAHL for trials there, and Brian Cook was sent to Spain to see how it was performing in the field.
That was going along concurrently with the CRC program but never as part of the CRC, although some of the people in ANZECC were really keen that I should take it on as an activity of the CRC. Brian Walker told me he would be quite happy for that, but I feared that we could end up losing all the impetus for fertility control: the Wool Corporation, Meat Research and New Zealand Ministry of Agriculture and Fisheries who jointly funded the first phase of rabbit calicivirus disease research would say, ‘Why should we be giving you more money? You’ve already got all these millions for rabbit control.’ And so it was developed as a separate activity.
When the Australian Animal Health Laboratory reckoned that they had done all the tests to show that the virus didn’t affect other, native animals and that it was very effective in rabbits, they said we should be now moving to trials for release. So we organised a meeting at AAHL in September 1993, at which you gave the opening address. That was to be a public forum at which all views would be expressed, including the government view as to what hurdles had to be jumped before this could be released, and on the basis of that we would design the research to be done.
Unfortunately, the so-called facilitator of the meeting didn’t really know enough about it and we didn’t get any resolutions before everybody ran off to catch their planes. I circulated what I thought were the conclusions of the meeting and there was general agreement, so we operated off that, but it wasn’t very satisfactory for planning. And then there had to be negotiations for the next few months before ANZECC and ARMCANZ funded it.
The sense at that meeting was very much, ‘We must push on and get this thing out as soon as possible. We don’t really need to do any more trials. What we need to do is to help the farmers.’ That was certainly the feeling of the Meat Corporation at that time. Kent Williams from CSIRO Wildlife and Ecology, who is a very thoughtful person, gave a paper there pointing out the risks and the need for much more care before it was released, and he was scarified by people who really took to him as being just an academic who doesn’t understand the real world and so on. So then the program of trials on Wardang Island was driven by a feeling, ‘We’ve got to do this, but let’s get on quickly and get it out.’ I think we should have taken that more slowly.
I gather there was a lot of difficulty in finding a suitable place. Wardang wasn’t regarded as the ideal place.
There aren’t many islands that have got wild rabbits on them, genetically similar, which are in the right climatic zone and where the logistics of getting on the island are reasonably good. I was advocating a small island in Spencers Gulf, about 30 kilometres offshore, but I was not at the meeting of the committee at which the choice of island was made. Basically Wardang was chosen because AAHL saw it as much easier to load and unload stuff there. I think the other island would have been much safer and would not have needed fencing because it is so far away.
Considering the meteorological conditions that apparently took the calicivirus from Wardang Island to Blinman, even 30 kilometres is not very far if there are a lot of flies about.
No, but there was still some question as to whether that first jump was natural or whether journalists took it.
Anyway, it was not an easy arrangement to manage, in that the experiments were run by two different groups with two different cultures. Fortunately, we had Brian Cook on the island, but he had a very hard job to do because AAHL didn’t appreciate field conditions at all, yet they had the major responsibility. So when it went wrong, the situation was pretty difficult. And then all the people who had been so enthusiastic suddenly became remarkably silent. There were plenty of critics, and people who asked why the public was never involved in making the decision. But the public had been involved. We had every colour of opinion at that meeting at AAHL. The animal welfare people were even taken right in to have a look at the animals dying.
I remember the demonstration: ‘This really is a very peaceful death. The rabbits don’t even scratch the sand as they die.’
The virus jumped off the island on Friday, 15 October 1995, my last official day in CSIRO before I retired. On Monday morning, when I was no longer a member of CSIRO, all hell broke loose, with the Minister calling up and demanding an explanation. Brian Walker rang and said, ‘Hugh, please, please, can you come in, even though I know you don’t have to.’ So I spent the next two days introducing everybody to the files. I was a bit nervous about that, because all sorts of people were threatening to sue CSIRO and I had no protection now. When they wanted me to continue but would not give me any protection, I decided I’d better not be involved any more.
There certainly was a lot of talk. Even in Western Australia, people who were just setting up rabbit farms were going to sue.
Actually, I did make some comment about that suggestion, because it seemed totally illogical. In the early days with myxomatosis, a law had been passed that no-one could immunise a rabbit against myxomatosis. So anybody who wanted to farm rabbits in Australia over the last 50 years, and protect them from myxomatosis, had to put them behind flyscreen wire. What’s the difference with rabbit calicivirus? Presumably, people farming them have already got them behind wire, in which case they are safe. But that argument didn’t seem to carry any weight at all.
The rabbits probably weren’t behind wire. The risk of myxo was very great in the early days: even in the centre of Melbourne the Baker Institute lab colony got myxo. It was astonishing how it got round. But the risk became much less when the rabbit numbers were down, and farmers probably took a chance on it.
I suppose so, when not so many mosquitoes carried the infection.
Well, that’s an interesting career. Thank you very much for telling us about it.
It started with myxo and finished with rabbit calicivirus disease.
Yes, it did – and you’re not a virologist.
No, never. I had difficulty while I was director of the CRC knowing whether I was actually talking sense or nonsense!
I suppose it would be a bit hard! Well, thank you again.
Well, Hugh, when we spoke – a few months ago, it is now – we were beginning to talk about the work of the Vertebrate Biocontrol Centre, with which you were very deeply involved. You were also involved in the use of the rabbit calicivirus for rabbit control, and we got deflected onto the calicivirus work. You remarked that you retired on the day that the calicivirus escaped from Wardang Island, and thus escaped from the calumny that accompanied that, and we forgot to get back onto the Vertebrate Biocontrol Centre. So I wonder if you could outline that, since it was a very important initiative and well worth talking about.
Well, we talked about the genesis of it, and the idea that we would try to develop a way of immunising wild pest animals so that their fertility would be compromised. I think I described the initial stages of that, which were supported by CSIRO and later Environment Australia for fox control. I also said that we had made an application at the first round of the CRCs and we were not successful, and then we had applied again at the second round, encouraged by Gus Nossal, and we were successful in the second round. So the CRC, which was called the Vertebrate Biocontrol Centre, started in January 1992.
The partners in that were the CSIRO Division of Wildlife and Ecology as the major partner, the ANU was also involved through the John Curtin School on the immunological side, and we had two government instrumentalities in Western Australia who were very interested in the control of pest animals. This was the Department of Agriculture, which was responsible for rabbit control in Western Australia, and the Department of Conservation and Land Management, which was responsible for fox control. And so those two partners were very keen, very supportive in getting it going and were very important for us to get support for a cooperative research centre, because if you recall, Ralph Slatyer’s original idea for the cooperative research centres was that they must be a cooperation of institutions, both government and private, and universities and CSIRO. In order to get up, you had to have partners representing different interests within the community.
The other challenge for us in this CRC was that it wasn’t a single-discipline CRC. It really was quite a challenge to not only get different institutions cooperating but also scientists with very different disciplinary backgrounds, because we needed to have immunologists, virologists and molecular biologists who could use the new techniques to make a recombinant virus which would express a reproductive antigen, and at the same time we needed to have ecologists who could answer the questions of what proportion of a population would have to be sterile in order for it to have any effect on controlling that population.
In fact, it was an interesting exercise, because each group obviously felt that they were the people who had the real running on the board, and it took quite a lot of time to get people to respect the contributions of the other discipline, so that the molecular biologists would recognise that ecologists actually had something to contribute, and ecologists would attempt to understand what the molecular biologists were trying to do. One of the ways we tried to achieve that was that once a year we gathered all the scientists involved, from right around the country, for a three‑day meeting and deliberately chose a place for that meeting away from the territory of any of the groups. I think you attended a couple of those.
Yes, I came to at least one, down at Braidwood.
We thought, well, we ought to go to a pleasant place, where we were away from everybody’s home territory, and try to get people to see and appreciate what the other members of the group were doing. And I think that was quite successful.
I think in some senses that bringing those people together was perhaps one of the biggest achievements of that CRC. Of course, we had a number of goals. The key questions for the first 7 years of the Centre were: Can you make a recombinant virus which will express the genes which have been inserted into it, and will the products of those genes provoke a strong immune response in the target? (That was to be either the sperm or the coatings around the egg.) That in itself was a major challenge. And the second one, of course, was the ecological one: What proportion would you have to sterilise to have an effect on the population? So with the resources that we received through the CRC we tackled both those.
By the time I retired, which was at the end of the third year of the CRC, neither of those questions had been yet answered, although we were very close to… No, I’m wrong. By the end of the third year, Ron Jackson had in fact made a recombinant ectromelia virus which expressed mouse reproductive protein, but that was in an inbred strain of mice and those female mice remained sterile for several months after the infection with ectromelia. That was a really important step because it showed that it was possible to do it, although with a number of reservations. Actually, that success encouraged the Grain Research and Development Corporation to join the CRC as a major partner, so that we were then working with three species – the fox, the rabbit and the mouse. And that has continued to the present day.
We set up two very big ecological experiments, one in Western Australia and one near Canberra. They were ground-breaking experiments in ecology because we were answering ecological questions but with a very tight experimental design, which is very rare in ecological research.
What exactly were you doing?
Well, we used surgical sterilisation by tubal ligation of the oviducts of females to represent immunocontraception. That is to say, the females would have their ovaries intact but they would be sterile, which is what we were hoping to achieve with the virus. And we set up four treatments: a control treatment and then three levels of sterilisation – 40 per cent, 60 per cent and 80 per cent. And we argued that if you had to go to 80 per cent, well it probably wasn’t going to work. So that was the highest treatment. Each of those treatments was triplicated. We had three separate populations of about 100 rabbits, out in the wild, for each of those treatments.
So that meant there were 12 populations in New South Wales, and 12 populations in Western Australia, and in each of those populations the field team had to catch every rabbit. Then the females were assigned to the treatment according to the protocol and then they were all released back into the paddocks, and then they were followed regularly through the year. And each year the new recruits, the new females that were recruited into the population, were treated on the same schedule as the first year. It was a huge job. But because it was so well done, with such good replication, it stood up to very rigorous statistical analysis.
Unfortunately, because it was so good the outcome is quite incontrovertible, and the consequence is that you need more than 80 per cent sterilisation to have any long‑term effect on the rabbit population. So that was in a sense a disappointment, though I think that it was a very fine experiment in ecology.
Well, after I retired, Bob Seamark became the Director – he was a reproductive biologist from Adelaide – and he led it through the reviews, which were successful, and then established a second bid with slightly different objectives and it was renewed for another 7 years. So it is still continuing.