7 March 2008
Professor Judith Whitworth of the John Curtin School of Medical Research talks about her life’s work so far.
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Voice-over: Welcome to the National Health and Medical Research Council podcast series, a conversation with some of the great minds and leaders in Australian medical research. The NHMRC is Australia's leading funding body for health and medical research. We provide the government, health professionals and the community with expert and independent advice on a range of issues that directly affect the health and wellbeing of Australians.
Interviewer: Today's conversation is with Professor Judith Whitworth, who's the director of the John Curtin School of Medical Research and the Howard Florey Professor of Medical Research at the Australian National University in Canberra. In addition to that, she heads the High Blood Pressure Research Unit and she's got a very illustrious career. She's practised medicine and has conducted extensive research in Australia and overseas. She's chaired the Medical Research Committee of the National Health and Medical Research Council of Australia and is past president of the Australian Society for Medical Research and the High Blood Pressure Research Council of Australia. She's currently chair of WHO's Global Advisory Committee on Health Research. And she's also a fellow of the Royal Australian College of Physicians. Professor Whitworth's previous appointments included being the chief medical officer for the Australian Commonwealth Government. In 2001, she was made a Companion in the Order of Australia for service to the advancement of academic medicine and as a major contributor to research policy and medical research administration in Australia and internationally. Judith, welcome to this podcast.
Judith, I wonder if we could start our conversation today with you talking about your current role as the director of the John Curtin School of Medical Research. Tell us what the John Curtin School is doing and let's tease out some of the intriguing research that's going on there as well as a bit of history.
Prof. Whitworth: The John Curtin School is Australia's national medical research school. It was founded back in 1948 and it has a very distinguished history and many of the people who've worked there are household names in Australian science. Sir John Eccles, for example, who won the Nobel Prize in '63, Peter Doherty and Rolf Zinkernagel, who won in '96 for work that they did in the school back in the '70s, Frank Fenner, well known for his amazing work in the eradication of smallpox with the WHO ‑ the list goes on and on.
Interviewer: In looking at your website, you've got a very nice roll call there. There certainly has been a tremendous lot of output that's come out of the institution in all those years. Tell us what the current focus of the school is.
Prof. Whitworth: The school has three major divisions and the themes of our work are infection immunity and, I guess, genes and proteins, and the third major thrust is in neuroscience, particularly in synaptic transmission.
Interviewer: Let's take each of those three areas. Now, disease and immunity ‑ that's an area of strength that's been long held in the school. Who are some of the key players and what are some of the key projects that are currently being undertaken?
Prof. Whitworth: Chris Parish is very well known for his work on heparanase ‑ he's very well known for a range of things, but ‑‑
Interviewer: What is heparanase?
Prof. Whitworth: Heparanase is an enzyme that's important in breaking down the basement membrane and Chris has developed a new class of anti‑cancer drugs which are two‑hit drugs ‑ they both inhibit new blood formation or angiogenesis in tumours and inhibit the heparanase, which helps cells to get across the basement membrane and hence disseminate through the body. So we're very excited about that
Interviewer: Just on that point, he's a great example of a scientist who does brilliant basic research, but has been able to translate that right across into industry?
Prof. Whitworth: Yes, not everybody can do that, but Chris has managed to do it par excellence, and excitingly, his drug has been given orphan drug status by the FDA in the United States for the treatment of liver cancer and it's currently in phase 3 clinical trials. Professor Chris Goodenow and his team are doing extraordinarily exciting work in relation to immunological memory, which is a very big scientific question, but also very much in the field of autoimmune disease and what the particular pathways and genetic pathways are that predispose individuals to diseases like type 1 diabetes, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, vitiligo, a whole host of conditions. So their work is fundamental, but with a very, very direct clinical application
Interviewer: And what's the importance of immunological memory?
Prof. Whitworth: Immunological memory enables the body to remember when it's previously been exposed to a foreign invader and to ramp up a rapid response to repel it.
Interviewer: So it's really our basic immune response that's so primal that it's absolutely critical?
Prof. Whitworth: Fundamental, very fundamental.
Interviewer: And proteins and DNA?
Prof. Whitworth: This is a very substantial issue also. We've got work ranging from evolutionary genetics through to transcription factors, particularly those that are important in immunology and some structural biology and allergic disease, a team of people working on asthma. So the work varies, it's quite broad ranging.
Interviewer: A lot of this work, I assume, is funded by the National Health and Medical Research Council?
Prof. Whitworth: Yes, the bulk of the work is funded by the NHMRC
Interviewer: Which is highly competitive and it shows that these people are collaborating both nationally and globally on all these projects?
Prof. Whitworth: It certainly does. So it's interesting that of our program grants ‑ and I think we've got six or seven ‑ but really all of these are held with people in other parts of the country, indicating the very collaborative nature of contemporary medical research.
Interviewer: We touched on Chris Parish's drug that's now got FDA approval for a particular application. What's been the general trend for commercialisation of various pieces of international property out of John Curtin over the last two decades?
Prof. Whitworth: One very exciting, I guess, success story was Axon Instruments. Alan Finkel came to the John Curtin School with Steve Redman from Monash ‑ Alan came as a post doc ‑ and with Steve he developed a new recording device for electrodes and then managed to parlay this into a $200 million business. Alan, as people will know, has gone on to bigger and better things. He's now the chancellor of Monash and he's been a great friend and donor of the John Curtin School.
Interviewer: In terms of your own research, you've been interested in hypertension and we spoke with Warwick Anderson yesterday, from NHMRC, and he has a similar interest. He made some comments about this particular area as well. I understand that you've been doing this for over 30 years. Maybe you could summarise what your work has been about and the current state of play in the clinical management of hypertension and how you've contributed to that.
Prof. Whitworth: My work's been in three areas, one a pretty fundamental interest in how glucocorticoid steroid hormones from the adrenal gland regulate blood pressure. Glucocorticoid is an adrenal steroid hormone produced from the adrenal gland that sits above the kidney and is very important in metabolism. So very important in how the body controls glucose, very important as a modulator of the immune system, protean effects and glucocorticoid receptors are found in virtually every cell in the body, so very fundamental to a whole range of life processes. But the effect I'm particularly interested in is that on blood pressure. I've got two other areas of interest in hypertension or high blood pressure and one is the development of clinical guidelines appropriate not just for Australia, but for all around the world. And the third area of interest is in research for better health policy, so the use of research to inform policy and to try to generate evidence‑informed policy for decision makers.
Interviewer: So going back to the lab bench, why don't you drill down and tell us some of the current things your laboratory or your group is working on in terms of this hypertension research.
Prof. Whitworth: When we started out in this area, the dogma was that glucocorticoids raised blood pressure by acting on the kidney to promote salt and water retention, and over a number of years we've shown that although they are associated with increased salt and water retention, that's clearly not responsible for the hypertension. It can exacerbate it, but it's not the underlying cause. So it was very important then to look at what exactly the cause was, because this is a very important clinical problem.
The naturally occurring glucocorticoid hypertension is quite rare, but we use glucocorticoid steroids a great deal in clinical practice because of their effects in suppressing immune responses, so we use them in transplantation, we use them in treatment of autoimmune diseases. And hypertension and cardiovascular disease are very important side effects. So it's an important clinical problem. So we then set out to say if it's not salt and water retention, what is it? We worked our way through a whole range of the systems that are known to impact blood pressure and for many years we came up with a whole lot of very negative results ‑ sympathetic nervous system clearly wasn't the cause, renin‑angiotensin system wasn't the cause, and so on. And finally the breakthrough came after the discovery of nitric oxide as a key regulator of blood vessel tone and a very important factor in dilating blood vessels in normal physiology in health and disease.
So we started to look then at the role of nitric oxide in the hypertension produced by glucocorticoids and were able to show that it does play an important role, not just in laboratory animals, but also in humans, in conjunction with collaborators in Sydney, at Saint George Hospital, and more recently we've also shown that another key element is increased oxidative stress, and the two are interrelated, so we think that, if you like, nitric oxide redox imbalance is a key factor in production of glucocorticoid hypertension in laboratory animals and in humans.
Interviewer: Now, this is very interesting. In very simple language, how does that actually work?
Prof. Whitworth: It works because normally there's nitric oxide in the body being released from the lining of blood vessels to help them relax. And what the steroids do is to inhibit the production of nitric oxide, so there's less relaxation in the blood vessels; it tips the balance towards constriction, blood vessel narrowing, high blood pressure.
Interviewer: So these hormones ‑ is it just the glucocorticoid steroids that are doing this?
Prof. Whitworth: Nitric oxide may be involved in other forms of hypertension, but I think this is a pretty dramatic example. There's a lot of interest in whether so‑called essential hypertension ‑ which means we don't know what causes it ‑ might be due to relative nitric oxide deficiency as well. On the other hand, we're excited as well because there are also data suggesting that up to a third of all essential hypertension might reflect subtle abnormalities in glucocorticoid handling in the body. So we think that this is much more than a scientific curiosity.
Interviewer: So does elucidation of this particular mechanism point you to a potential treatment?
Prof. Whitworth: Yes, it does. We're currently spending quite a lot of time examining in the laboratory drugs that are already used in clinical practice, which we think, on the basis of a fundamental knowledge, might be effective and we're coming up with results from the lab which point us in directions to take in humans. And again we're doing that in association with our collaborators in Saint George, in Sydney, so we test it out in the lab and they're then able to take it into an experimental situation in humans.
Interviewer: We're seeing this quite often these days where you've got drugs that have been around a long time being revisited for some of the therapeutic benefits?
Prof. Whitworth: Yes, indeed. In fact, I think one could argue that a lot of the big advances in medicine in the last few decades haven't come from brand‑new therapies, they've come from the new applications of therapies that we already had. A good example in my own area is the use of beta blockers in heart failure. As a student I was taught that they were contraindicated. We now know that they're very valuable. Similarly with the angiotensin converting enzyme inhibitors, which are now very useful in cardiology, but they were developed simply to lower blood pressure. We've now found out that they've got other important actions. And I think this is a trend in medicine.
Interviewer: Yes, it does beg the question about whether we should be spending more money on looking at some of these existing drugs which form into sort of discrete classes actually, don't they, rather than going out there and doing a lot of very expensive reinventing the wheel.
Prof. Whitworth: I think that's exactly right. Another example is, I think, the great strides we've made in management of diabetic complications simply through lowering blood pressure, that we now understand much better through clinical trial, but not using new drugs, using old drugs. The same is true for prevention of secondary stroke. We now know that by lowering the blood pressure in people who've had a stroke, whether or not they were hypertensive to start with or are hypertensive now, that we can dramatically reduce the rate of stroke recurrence. So I think those new applications of existing therapies has become a very hot topic.
Interviewer: What I'm sensing from talking to you is the fact that you trained as a clinician and at the same time being on the research side of it is an incredibly important mix in the way that you've been able to go from almost the bench to the bedside in this whole cycle. Have you got any comments about clinical researchers versus pure researchers in biomedical sciences?
Prof. Whitworth: They both have a very important role. I think the advantage clinicians have is that they understand the questions. Sometimes they don't know how to find the answers. And the biomedical scientists tend to be really good at finding the answers, but they don't always know the questions. So as in so many things, I don't think it's either/or. They're really complementary roles. We need both.
Interviewer: Your career ‑ what inspired you to go down this path. I believe you actually have quite an interesting story around this question.
Prof. Whitworth: When I was a little kid, on my fifth birthday, actually, I got poliomyelitis, one of the last epidemics in Australia, and so I spent a great deal of my childhood in and out of hospitals and unable to walk. And so a lot of my early life, I was very exposed to medicine, and because I couldn't go out and play, I read all the time, and I read about people like Marie Curie and became very interested in science and research, and I guess that was why I went into medicine. But having done medicine, it really hadn't occurred to me to go into research. Again that was serendipitous. I was allocated a term in the clinical research unit at the Melbourne Hospital with a man called Ian Mackay, who really encouraged me to become interested in research and to develop it as a career. So like most things in life, I guess I fell into it a bit.
Interviewer: He was obviously your trigger mentor, but you've obviously had other people who've made an impact on the way.
Prof. Whitworth: I think John Coughlan was a very important mentor. He was my PhD supervisor.
Interviewer: Where was that ‑ at Melbourne?
Prof. Whitworth: That was back at the Howard Florey Institute in Melbourne. Not only was John a scientific mentor, but he encouraged me to become involved in the affairs of the Australian Society for Medical Research and I guess that's then very much shaped my career, because by becoming active in ASMR, I went on to become active and involved in the MRC. When I was at the Howard Florey, I'd been an NHMRC scholar, and it was because of being involved with the MRC I think that I was recruited to Canberra to be chief medical officer. And that in turn has led to my activities with WHO. So very much one thing has led to another and I've got a lot to thank John for.
Interviewer: It also illustrates the power of networks, effectively. You build networks through these associations and being involved in these activities outside your normal clinical or research hours. I think scientists have to recognise that, don't they, if they contribute to their local environment or even national environment they're going to benefit from it?
Prof. Whitworth: Absolutely. Certainly I've always felt that it was a fantastic thing for young scientists and medical researchers to do, to become involved in activities like those of the Australian Society for Medical Research, and absolutely fundamental that people who are publicly funded by the Australian community to enjoy research and science give back by contributing to professional bodies to the granting agencies and to the broader community.
Interviewer: And, of course, as we mentioned in the introduction, you're now chair and I understand recently appointed as chair of WHO's global advisory committee on health research. Congratulations. That's quite an accolade. What is the role of this advisory committee? That must be fairly exciting.
Prof. Whitworth: I've actually chaired it for the last three years, but I've just been reappointed by the Director‑General for another four‑year term, which I'm excited about. The role of the committee is to advise the Director‑General of WHO on all research matters that may be relevant to the organisation. Our particular thrust is to ensure that WHO is a steward for global health research, sets standards, sets agendas, and assists member states in developing their own research efforts, and very much with a view to using research and its benefits to inform policy for health.
Interviewer: And you have also contributed, as you indicated, substantially to the National Health and Medical Research Council over the years. Tell us how important that's been as part of your sort of career mix overall and what you've been involved in doing within this particular organisation.
Prof. Whitworth: It's been extraordinarily important for me. I was an NHMRC scholar when I did my PhD at the Howard Florey. And after my involvement in ASMR, I became involved with a whole range of NHMRC activities. I think I've probably been on just about every committee or panel, one way and another, that the NHMRC has had. So I've been on training awards and fellowships, I've chaired the NHMRC, I've been on discipline panels and grant interviewing panels and special reviews. Indeed, when I was Commonwealth chief medical officer I had executive responsibility for the NHMRC within the department and I've served on the council as well. So it's just been a very, very major part of my life and I've been very grateful too for the support I've had through projects and now we have a health services program looking at chronic disease. So the NHMRC has been extraordinarily important for me.
Interviewer: And a venerable institution it is becoming, because I understand that it's over 70 years old now.
Prof. Whitworth: It is. I can remember when we did the 60th birthday celebrations, that was a great occasion, and I look forward to the 70th birthday.
Interviewer: Fantastic. One of the big issues, I guess, that we often talk about is how we inspire young people to take off and go down the track of becoming a scientist, a research scientist or a biomedical researcher. What advice would you give to parents or young people who might be listening to this about how they could embark on that particular pathway and why would they embark on it?
Prof. Whitworth: I think they'd embark on it because it's such fun, and there's no doubt that doing research is a very fulfilling, very stimulating and indeed in many ways despite the lack of financial reward a very privileged life, because you get to do things that very much interest you, you get to travel and meet interesting, bright, creative people. I think the life of researcher is really a very, very enjoyable and privileged one.
Interviewer: Of course, these days it can become quite varied. It's not just a career at the bench if people don't want to do that all their lives. They can go off and do other things, or they can maintain their clinical interests or their basic research interests and still be involved with industry or whatever.
Prof. Whitworth: Certainly. That's extraordinarily important. The John Curtin School, as Australia's national medical research school, has a pivotal role to play in training the next generation of researchers, but, as you say, we're not simply training people for a career in research. We're training people who are going to be academics, who are going to work in industry, who are going to be in the patent office ‑ maybe we're even training politicians and journalists. I think the careers that are open to people with a research training are pretty well unlimited.
Interviewer: Medical research in this country has received significant boosting and funding over the last couple of years. Are you optimistic about the future for medical research?
Prof. Whitworth: Oh, yes, I am. I think that we've moved from a view of medical research as being an endeavour where we really confine ourselves to trying to understand the biological causes of disease and develop new compounds to deal with those to a much broader understanding of the really key role of population health and the enormous role that that plays in improving the health of the nation, and with understanding more about the need for appropriate research into health systems, because the nature of the health system can be really important in determining the nation's health, and now in the area that I've become involved with recently, research for health policy. So I think that on the one hand the new biological advances are enormously exciting, but on the other, we're understanding far more about a holistic research approach that I think is likely to pay off very substantially in both short and long term. So I think overall the future is incredibly exciting.
Interviewer: So what sorts of things are you looking at in terms of research activities around health policy in this country?
Prof. Whitworth: We're particularly interested in how policy is determined and clearly evidence will always be only one factor in the genesis of health policy. One might like to think it's everything, but that's just unrealistic, because a whole lot of other factors will come into play. They might be pragmatic factors like the interests of particular lobby groups or the needs of a particular electorate. They might be more altruistic, like the importance of equity. They might be financial imperatives. They might relate to the culture and history and geography of the people making the decisions. So I think it's very important to recognise that evidence is only one factor.
That being said, any investment by government is an opportunity cost, and so if we build a new road in New South Wales, there's going to be a new road or school somewhere else in the country that won't be built. So the more limited one's resources, the more important it is to use the best available evidence to guide the application of those resources. And so the questions here come round, well, how then do you develop evidence that's relevant to the needs of policy makers, given all their other imperatives, and how do researchers, who've got a very different time frame and different set of imperatives, communicate the importance of what they do.
An anecdote, but I think a very important one and a very Australian one is the story of analgesic nephropathy. Back in the '50s, a condition was recognised of kidney failure due to abuse of compound analgesic preparations ‑ in Australia things like Bex and Vincent's, which were freely available in corner stores and widely used and very widely abused. And the common constituent of all of those preparations was phenacetin. And so based on that evidence that this was the common constituent in association with the condition, the phenacetin was removed from the preparations.
Interviewer: And what is phenacetin?
Prof. Whitworth: Phenacetin is a minor analgesic that was one of the substances in these particular compounds. And that had absolutely no effect whatsoever, despite the effect that it was called phenacetin nephropathy in Britain ‑ it had no effect. And so researchers in Australia looked at animal studies and were able to show in animals that virtually all of the constituents were toxic to the kidney and they were particularly toxic when they were all put together.
So education programs were tried and they didn't do anything. So based on the evidence that it was due to a combination of all of the constituents in these drugs, the compounds were taken away from over the counter and put into pharmacies. They were available only on prescription. You could only buy single analgesics in supermarkets or corner shops and they were in foil wrapper, which made it harder to take a lot of them. And that legislation that was introduced around the same time in virtually all the states and territories has led to the disease which was extraordinarily common when I was a young doctor now being really a curiosity. It was over 30 per cent of end‑stage renal failure in this country; it cost millions and millions of dollars. We've got rid of it and we've got rid of it because to start with we had a policy that was made on inadequate and incomplete evidence and then we had policies that were made on solid evidence and they were very effective. There are similar stories around tobacco usage. And there are now some really exciting stories about blood pressure control coming out of the United Kingdom in relation to reduction of salt in processed foods. So here we're talking about things that have the potential to save millions and millions of lives.
Interviewer: And we were talking with Warwick Anderson briefly about type 2 diabetes and obesity. That's a huge challenge globally, but it's going to, I would assume, the same sorts of basically of evidence‑based studies will eventually help develop policies and processes and then ultimately clinical, I don't know, treatments to try to address this issue, because it is a multifactorial condition.
Prof. Whitworth: Indeed it is. And we really have to do far more on the side of prevention, because otherwise we simply won't be able to deal with the epidemic.
Interviewer: As you said, education isn't always enough.
Prof. Whitworth: Education often isn't enough. Education is essential, but it needs to be education in association with other factors. For example, most people in Australia know that smoking is bad for you. It's not enough to make people change their behaviours. We've needed very strong government intervention through legislation, regulation, excises, and so on. So education is important, but we need a lot more than education.
Interviewer: Well, on that good note, I think, Judith, thank you very much for making the time to talk to us. And I wish you well with your endeavours.
Prof. Whitworth: It's a pleasure. Thank you very much.
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