Professor Peter Rathjen, biochemist

Professor Peter Rathjen. Interview sponsored by the Australian Research Council.

Peter Rathjen studied as an undergraduate in the Department of Biochemistry at Adelaide University, working in part as a member of the team that discovered RNA self-processing in viroids. As a 1985 Rhodes Scholar he undertook a DPhil at Oxford University, studying mobile genetic elements in yeast and mammals. He began investigating the molecular regulation of embryonic stem (ES) cell differentiation during a two-year postdoctoral position at Oxford.

He returned to the Department of Biochemistry at Adelaide University in 1990 as a lecturer. In 1995 he was promoted to the chair of this department and in 2000 he became head of the new Department of Molecular Biosciences at the University. His research interests include the molecular basis of mammalian development, the differentiation of ES cells, and the use of genetic and ES cell technologies for human therapy. His work has proven to be commercially valuable and forms a basis for the cell reprogramming division of BresaGen Ltd, an Adelaide-based biotechnology company.

Teachers' notes to accompany this transcript.
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Interviewed by Ms Marian Heard in 2001.

Contents


Gaining a broad interest base

Peter, where and when were you born?

I was born in the UK. My family had taken part in the Lutheran migration from Germany to Australia in the early 19th century. Afterwards, my father was the first to leave the family farm, getting a PhD scholarship to Cambridge. His stipend there was marginally less than his yearly living expenses and so I suspect the last thing my parents wanted was a child, but I was born in the very cold winter of 1964. We stayed in Cambridge for a year before returning to Australia for my father to take up a position at Adelaide University.

My early childhood memories are of a fairly suburban kind of a childhood, a lot of time fighting with the girl next door, and time spent (with my four brothers and sisters) on that family farm during most of our vacations and weekends.

You were good at most subjects in primary and secondary school?

That's correct. I had a very broad spectrum of interests and I don't recall any preference for science in the early years. I was not at all like some of the young people I now teach, who are set from an early age on wanting to be scientific, and who even at school may be undertaking quite sophisticated experiments. As late as matriculation I was still at least as interested in English as I was in maths or science. But I was particularly bad at art.

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The genes that make up the organism: a moment of revelation

You met a defining moment in your first year of science at the University of Adelaide. Tell us about it.

I had not really planned to enrol in science. That was almost a spontaneous decision because I was a bit young to settle into university and I thought a year of science would give me some value and I could then move on to something else if I wanted to. I selected maths and chemistry because I had done them at school and had enjoyed them, and then biology and geology because I had never studied them before and wondered whether they might be interesting.

A relatively short time into the year, however, Professor Elliott taught us about the early days of molecular biology. That was an epiphany for me, and set up what I would do for the rest of my life, because as of that single lecture – specifically, as of one single slide that was shown – I knew this was what I wanted to explore.

I was utterly fascinated that you could explain the properties of an organism in terms of the genes that made up the organism. The slide itself was very simple: a virus that infects bacteria had been damaged so that the DNA had come out, and you could just see this long strand of DNA floating around. Professor Elliott then showed the sequence of that DNA and said, 'That's all there is to it. That's what makes that organism.' I'm very proud that when he retired I got that slide from him – it's a very archaic, metal slide which weighs a ton – and was able to show it last year in a talk of my own at the Shine Dome, making the point that this was what had got me so interested in the area.

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A significant Honours project in viroid replication

You majored in biochemistry and genetics, and went on to do your Honours. What work did you do for that?

I was working with Professor Bob Symons, a member of this Academy, on a group of quite fascinating plant pathogens called viroids. They were not much understood at the time, and probably still aren't. They are tiny, they are made of RNA and they do not, as far as we can tell, encode any proteins. So it wasn't clear how these small infectious parasites could cause disease in plants, which they do, or even how they managed to replicate themselves when they infected plants. We were trying to determine how that replication takes place.

I was very fortunate, because after my Honours year I spent another year in Bob's lab before going overseas to do a PhD. In that time the work had moved on, and we fell over something which turned out to be very exciting: one of the reasons these pathogens don't need proteins is that the RNA itself can act as an enzyme and help to replicate the viroid. In those days that was, to some extent, still heretical. In fact, when we submitted a paper to Nature we got a caustic set of comments from one of the referees who did not really believe what we thought was going on.

It turned out to be very important, providing the intellectual underpinning of what later became the gene shears technology. And in a nice historical accident, the intellectual leap from our basic research to the gene shears that CSIRO eventually commercialised was made by Jim Haseloff, an ex-student of Bob Symons who had kept working in the same area.

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Investigating jumping genes for a rewarding Oxford PhD

After your Honours you went to Oxford?

Yes. During my Honours year I applied for overseas scholarships, and I was awarded the Rhodes Scholarship. There is a bit of a story to that. I had to go to Government House to hear which of the eight finalists had won the Scholarship in South Australia. But that was the day of a very exciting test match. So there I was in Hindley Street, standing by a shop window where the match was being shown on television, when suddenly I realised that I was about 10 minutes late for the announcement. I went tearing through the gates of Government House – luckily, the policeman on the gates was an old school friend who recognised me and let me in – only to find I wasn't too late after all, because they'd had trouble reaching a decision. And straight after the announcement I was back in the department producing the photographs for my Honours thesis.

What work did you do in Oxford for your PhD?

I changed tack completely, away from working on plants to combining what I had always thought of as my two great loves – genetics and biochemistry, which I didn't think were very easy to combine in Adelaide at the time. I was particularly attracted to yeast, the organism on which you could best do biochemistry and genetics. Luckily, a lab in Oxford was working on the molecular genetics of yeast, and so I joined that.

The lab was working on a question which had sparked my curiosity as an undergraduate. We had known for some time that in the DNA of an organism there were 'jumping genes', small bits of DNA which could actually jump out of the chromosome and reinsert themselves at another place in it. They had been described genetically, and by the mid-1980s people were really starting to work out what they looked like – their DNA sequence – and how it was that they jumped out and what they did when they jumped out, what damage they caused to the organism.

We worked on these jumping genes in yeast, and in particular I worked on how they turn on genes when they jump next to them, which turns out to be very important as a mechanism which can cause cancer in cells. Then, in the last year of my PhD, we turned from yeast work to the first reported mammalian jumping genes (retro-transposons was the class I was working in) and characterised and sequenced some of them, showing that in fact they had very similar properties. It was quite rewarding.

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Oxford transitions: marriage and an enduring new field of research

While at Oxford you got married. Did this influence what you would do when you finished your PhD?

I think marriage always influences what a scientist is going to do! In those days, as a Rhodes Scholar you were not allowed to be married, but you were allowed to at least propose at the end of your first year's tenure. In fact, when I proposed to my wife, Joy, I didn't have to ask my parents or hers for permission to marry her (I did ask hers, though) but I had to ask official permission from the Warden of Rhodes House to get married. My wife was a year behind me, and had studied with me as an undergraduate and then as an Honours student in the Department of Biochemistry in Adelaide. She started a PhD one year behind me, working for a different supervisor but in the same laboratory, so when I finished my PhD – and in Oxford they are very rigorous about kicking you out after 3 years – I had a year to kill.

I had little idea of what I wanted to do with that year. I had found the PhD tough and wasn't even certain that I wanted to continue with science, and when John Heath, in the Department of Zoology, heard that I needed a position for a year and asked me to join his lab, I agreed without really understanding what he worked on. Within two or three months I decided that in fact I did not want to do the project he wanted to run. The work on embryonic stem cells that the guy on the next bench was doing, however, was quite fascinating. So I became personally friendly with that guy, Austin Smith, who is now a Professor in Edinburgh. We worked very closely together for the year, the work went exceptionally well so I stayed for a further year, and I have worked in that field ever since.

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The beauty of embryonic stem cells

Tell us about that postdoctoral work.

Embryonic stem cells are really quite fascinating. Perhaps the best way to describe them is to put them in their true biological context.

We start life as a single cell, a fertilised egg. And nothing much happens for a little while. Yet our bodies consist of several trillion cells, of several hundred different kinds, and all of those cells are organised into a structure that looks human. Where they came from in the first place is a very small group of about 10 to 20 cells called embryonic stem cells, which existed in the embryo at about the time it implanted into the mother's uterus. The whole story of embryogenesis is of how those 10 cells turned into trillions of cells, how that one kind of cell turned into several hundred kinds of cells. The beauty of embryonic stem cells is that they are the true founder cells of the entire mammal. Those cells can turn into any other kind of cell.

When I was in Oxford we were working on how we might stop that, how we might keep them as embryonic stem cells and stop them from differentiating, from turning into any other kind of cell.

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Returning to do something in Australia for Australia

After those postdoc years in Oxford, you had a number of options. What made you choose to return and take up a lectureship at the University of Adelaide?

The reasons were entirely personal. My family was in Adelaide but I had never ever expected to be able to return there. I have always had a very deep sense of being an Australian, though, and never intended at all to stay overseas for any protracted period. Returning to try and do something of importance in Australia for Australia has always been a deep philosophy of mine. Probably, I spent about 2 years longer in Oxford than I would have by choice; by 3 years I had had about enough and could have gone somewhere else with profit.

Actually, careerwise I doubt that it was the right thing to return at that stage. I would have been better off staying overseas and working as a postdoc for another 2 to 3 years, building scientific networks and building a track record before I undertook the very pressurised job of starting off as a young lecturer. But the opportunity to work in a university, which had always attracted me, and to come back to Australia – in particular, to come back to a really strong department – was just overwhelmingly attractive to me.

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Understanding embryonic stem cells

You mentioned that since Oxford you have continued with embryonic stem cells. What specifically are you working on now?

When we came back here I decided to start working on how to control the differentiation of those cells. What signals – and they are usually protein signals – do you have to give to the cells to instruct them to become a new kind of cell? How do you tell them to become blood, or skin, or bone?

We undertook that work for the specific reason that no-one knows just how the embryo itself does that. We know that this one kind of cell turns into several hundred kinds of cells, but not really why or how it does so, or even why, for example, the cells in one part of your body become brain cells and the cells elsewhere in your body don't. What controls it all? We wanted to understand that basic science.

We reasoned that if we could take our embryonic stem cells and tell them to become newer cells, we would probably be copying what goes on in the embryo. And our first 10 years' work suggests that that is the case. We are starting to learn very valuable things about how the embryo itself came into being.

Secondly, we recognised very early on that if we could learn to produce particular kinds of cells there might be commercial opportunities – and more importantly, I suspect, therapeutic opportunities. If you can make cells, you can transplant them into people who need them for some reason. For example, a stroke results in death of neural cells, and there is already evidence to suggest that if you could transplant replacement neural cells, you could alleviate stroke. Again, many diseases result in damage of bone marrow. If you could learn how to produce bone marrow in the laboratory by differentiating these stem cells, perhaps that could give you a therapeutic intervention for treatment of bone marrow disease.

The particular advantage of using these stem cells is that they are immortal. You can quite easily grow as many of them as you like, and you can also differentiate them into as many cells as you like, producing an unlimited number of any kind of cell to transplant. In addition, it turns out to be possible to modify the genes in embryonic stem cells better than in just about any other kind of cell we know. So you can start with an embryonic stem cell population and, through knowing what you are doing, turn it into any kind of cell, in any kind of number, with any kind of gene in it. What a formidable opportunity to then start trying to correct disease!

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An interesting game: international competition in biochemistry

Where does your group stand internationally in this research?

I think we are up with the game. It has been an interesting time for us, because for the first 6 or 7 years we were almost the only group thinking along these lines. Our world changed almost overnight when America reported the isolation of human embryonic stem cells, which suddenly made people aware that experiments in the mouse might be transferable to the human. That prompted enormous worldwide interest: what are these cells, how do you grow them, how do you control their differentiation? I would say that intellectually we had got a long way ahead of the rest of the world during those years when other people weren't thinking much about these things, but in the last few years the rest of the world has substantially caught up.

And that of course is the problem we always deal with in Australia. We are quite good at taking the early steps in research, but when the Americans and the Europeans really start to build the huge teams and move fast, when they throw in the big funding schemes, we struggle to compete.

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Juggling multiple roles while maximising teamwork

You were appointed to the Chair of Biochemistry at Adelaide University in 1995, and as head of the newly merged Department of Molecular Biosciences in 2000. Are there challenges in juggling your research, teaching and administrative roles?

It is an extremely difficult job, the only job I know where you are expected to perform with excellence at so many levels. As a head of department you are like a CEO: you must have a strategic vision for where your discipline is going and you must be able to manage people. Our budget is probably about $15 million a year and we have about 270 people in the building.

At the same time, you must deliver excellent quality courses to your undergraduate students and you must be able to talk to your postgraduates with conviction – they need to respect you, which means you need to be close enough to the research that you can talk to them day to day about the experiments that they're doing. And you are going to be judged in international terms on your research output, so you must perform at an internationally excellent level in research.

So in a single job you are moving from the big-picture stuff right through to the highly scrutinised detail. It's very difficult to do that, and in my case I am quite sure it would not have been possible except that the senior postdoc within my group has been my wife. Because we have managed to some extent to live the science and live the job together, she has been able to take a lot of the load, particularly on the purely scientific side, from me.

Is science no longer an individual pursuit, but one that requires a group, a team?

My team is essential; it is critically important to acknowledge that. We tend to see scientists as individuals who make discoveries that are personal in some way. Even if that was true 50 or 100 years ago, science now is done by often quite large teams of very dedicated people. In South Australia I have been extraordinarily fortunate with, particularly, the group of PhD students I have managed to work with. Starting at probably five or six people, at different times over the past 10 years or so the group has been as large as 35. My role in that is very much to set broad direction. I am utterly dependent on their ability to work hard, to assimilate scientific information I can't necessarily provide them with, and to produce scientific information as well as people do anywhere else in the world.

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Wanted: excited, hard-working, analytical, creative scientists

Besides the ability to work as a team, what skills are needed in science today?

It is vital to have curiosity, together with a genuine excitement when you see the result. I can tell usually within about three months of someone commencing Honours whether they are going to be a scientist, because that is when they get their first result. Normally that result is not very spectacular and doesn't matter much, but if they have a sense of excitement when they see it, they will succeed. If you have that sense of excitement, you almost can't help yourself from doing the rest of it right. You're going to get stimulated; you're going to think about it; you're going to work hard.

Indeed, you must have a capacity for very hard work. This is an international game. You are competing with the best people in the world, who all work very hard, and you've got to be prepared to do that as well.

Most of all, you need the ability to analyse data crisply, accurately and with rigour – for which a scientific degree prepares people extremely well – and you also need something which is much rarer in good scientists, I think: a genuine creative flair. That is not just doing what other people have done and tweaking it slightly, but having the insight and the courage to try something new, to see if you can't create something that is really a bit different.

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Stimulation and satisfactions in a science career

What are the most rewarding or exciting aspects of a career in science?

For me it is the sheer excitement of seeing new information, seeing the result of an experiment that tells you either that you are right about something and your predictions are borne out, or, just as often, that you are wrong about what you were thinking and there is a new model to explain what you are trying to investigate. There is almost a moment of epiphany when you hold in your hand a piece of information that no-one has seen before, when you have thoughts that other people haven't thought before. Intellectually, I find it enormously stimulating.

Last night I needed to get a paper draft from some PhD students who were working late in the lab, and when the email came through – at about 11 o'clock – I saw that it had a quick note appended, 'By the way, we got an exciting result tonight.' So there was a great sense of satisfaction: 'In this case, we're right. What we thought was going on, is going on.'

It's even better than that, because the experiment which showed that we're right – and which for 2 years we've had trouble doing – turns out to have been very clever, and it was done by a new PhD student who had the strength of her convictions to go about doing it in a different way. It has taken her probably a year to show that her way is better than the way I suggested or the way we tried to do it before. For me it was doubly rewarding. Firstly, I had the excitement of knowing the result was there, and secondly, I could see that a young student who was prepared to take a scientific risk was validated in her approach.

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Keeping things in perspective: an ongoing range of interests

Peter, what have been your main interests besides science?

Sport has always been a dominant theme in my life. At university I was an orienteer, competing at national and international level for a long time. I backed out of it a little bit, though, when I got to the truly elite competition. To perform at elite level in orienteering, as with anything else, you need to be more or less full-time, and that is not consistent with being a very serious scientist. But I spent a lot of time in the Australian bush producing maps, and racing.

I also played a lot of soccer, and captained the university soccer team for a while. That I found extremely rewarding. I have continued in soccer, but the lesson I learnt this year is that I am just about becoming too old to play serious soccer. I am still playing in the 1st Division amateur competition in South Australia, though.

In summer I used to play tennis, but although I had always thought I was all right at tennis I gave it up when I went to Oxford. I happened to attend a very small university college where the tennis team contained six men of whom two had played at international standard (in fact, one of them supported himself through university by competing in tournaments) and another had been selected as the only junior from America for an exhibition match against Björn Borg. So I went out and played against the sixth best man, who I assumed would be about my standard. It turned out that he played No. 1 for his county, and he beat me 6-0. That was the last serious tennis I ever played. I converted to cricket at that stage.

I have a great love of classical music, and when I was younger I was fortunate enough to learn piano from the Conservatorium at Adelaide University. That has stayed with me; although I had 5 years off when we were in England and couldn't afford a piano, I got back to it when we came back here and still play a great deal.

And the interests at the top of my list are my family and my love for Australia. I have recently taken up bushwalking as something I can share with the family and the children, and we walk quite a lot. In Adelaide we are very lucky in having the Flinders Ranges so close. They are stupendously beautiful. They are also, in some ways, like science. Just as you feel humble when you see great experimental results and read about great scientists, when you're up in that timeless, ancient landscape you realise how small is your own place in the grand scheme of things.

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The really exciting days of biochemistry continue to dawn

I believe that at one stage you were advised not to pursue biochemistry, as it had 'had its day'. You appear to have proved that advice wrong.

It is a matter of personal perception. When I was tossing up between chemical engineering and biology at university, one of South Australia's most prominent biochemists advised me that while this might be a good career for a young man to pursue, I needed to understand that the really exciting days of biochemistry were over. He was referring to the discovery of DNA, of genes and working out how proteins are made, when it must have been an extraordinarily exhilarating time to be a biochemist.

To my mind, though, it can't have been more fascinating than my 20 years of research, and I can't believe that the future could look any more exciting. To me personally, the relatively chemical side of working out that DNA was the important molecule has been less interesting than working out how human biology works at a molecular level. In my lifetime already we have gone a long way towards understanding why cells become cancerous, and in clinical trials we are seeing the first generations of drugs that ought to be able to tackle the defects that we have identified. We are starting to understand how you bolt an organism together, starting with one cell and finishing up with enormous numbers of cells and complex kinds of structures. In the future we are probably going to understand things like the biochemistry of memory – and even get at the biochemistry of imagination. To understand that would be extraordinary indeed.

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Taking the future as it comes

Where, then, do you see yourself in 10 years' time?

Actually, I don't. I have never had a life plan or a career plan, and I've very rarely applied for jobs. I've normally been offered positions and then had a look and taken them if they looked exciting or challenging at the time.

Within the next 5 years I really want to get to grips with the research and see if the things we've been doing in the past 10 years are as important as we expect. I want to see whether we can turn these basic ideas about science into things that matter for human medical outcomes. That would be immensely exciting to me. Within 5 years it should be apparent either that we're right or that we have done something which is valuable but not as important as it might be in those contexts. But 5 years beyond that – I have absolutely no idea.

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