

A conversation with Professor John Hopper

Vijaya Nagarajan

3 April 2008

Professor John Hopper is a mathematician and statistician who went on to become a world leading researcher in genetic epidemiology. Professor Hopper’s current population-based studies look at genes and the environment together in breast cancer, bowel cancer and prostate cancer. In this conversation, Professor Hopper talks about the power of statistics and letting the data speak for itself.


Interviewer: Professor John Hopper is a national health and medical research senior principal research fellow and a professorial fellow. He is the director of research at the Centre for Molecular, Environmental and Genetic and Analytic Epidemiology within the School of Population Health at the University of Melbourne. And in 2007 he was awarded an Australian fellowship. Professor Hopper is also the director of the Australian Twin Registry, which is a not-for-profit organisation which facilitates and supports medical and scientific studies involving the participation of twins. Professor Hopper has published more than 250 scientific papers on statistical methodology and its application for analysing twin and family data and addressing the genetic environmental causes of variation in health–related characteristics. John, thanks for joining us on this NHMRC podcast conversation today.

Prof. Hopper: Thank you for inviting me.

Interviewer: We're sitting here in your office in the School of Population Health Centre for Molecular, Environmental, Genetic and Analytic Epidemiology or, as it is often called, the MEGA epidemiology centre. I thought it might be useful for listeners to understand what is epidemiology.

Prof. Hopper: Epidemiology is the study of diseases and the determinants of disease at a population level that is distinct from clinical studies, which are looking at people with a disease, looking at individual characteristics. So we look at people, selected possibly from the population at large or selected because of a particular characteristic, and what we are interested in in the MEGA centre is to take this one step further. And mega epidemiology includes genetic epidemiology – and genetic epidemiology pays particular interest to the role of genes. The other aspect of our work is we do that by not only studying people from the population, but studying families.

Interviewer: As I said in the introduction, you trained as a mathematician, in fact in statistics, I understand. This brings a unique dimension to somebody who's studying biological phenomena on a population–type basis.

Prof. Hopper: I started as a mathematician, but it was very hard in mathematics, to do something new is not trivial. I got involved in statistics and probability theory. And that sort of led naturally then to an interest in medicine and epidemiology. It turns out that some of the leaders in epidemiology over the last 50 years have in fact taken that same route. They've come from a quantitative background, and I think we have a great advantage because not only do we know how to analyse the data that leads us to then understand the sort of data we need to collect, it also brings another dimension, that we don't necessarily know a lot about the diseases and the conditions that we set about studying, and that may seem to be a negative, but in fact when you're a statistician it's good that you don't have preconceived ideas. If you've done the study properly, the information is in the data. So my expertise is to be able to extract that information from the data.

Interviewer: So it's pure unblinded analysis?

Prof. Hopper: Well, we try and pretend that.

Interviewer: I was just waiting for you to come into the interview, and I was just looking at a display you've got in the hallway on the history, some of the artefacts from the smallpox vaccination area. Now clearly the containment of a global pandemic like that was very successful, but it took a very long time. But what has the study of the data that was derived from that worldwide activity provided us with in terms of going forward and looking at how we control major diseases, particularly infectious diseases, around the world.

Prof. Hopper: You mentioned the word epidemiology, and it is a strange word and people will immediately think of epidemics and so, you say, okay, let's go back and think about epidemics. Now the way to tackle epidemics isn't trying to treat everyone who gets infected. The reason why we've controlled major epidemics and have been able to damp down epidemics, such as recent outbreaks of SARS and things like that, is because we've learned to take a population perspective on the issue, to work out what are the factors going on, and not necessarily have to know exactly what's going on with every individual case, but to pick up the major issues.

So, for example, in understanding outbreaks of cholera, for example, in London several centuries ago, John Snow and the other epidemiologists used data to understand one of the key issues was where the water came from. Therefore they could then put in public health measures to improve the quality of water that people were drinking and that led to the control of the epidemic. It's a similar sort of thing in epidemiology, to try and see what are the major factors involved in the risk of the population. Smoking is a classic example of that. Not necessarily to stop everyone from smoking but then to try and put in place ways of lowering the impact of smoking on the health of the society. It's that broad scale view that differentiates epidemiology from other parts of medicine.

Interviewer: What over the last 10 or 15 years – because I guess these are long–term studies; they take a long time, because you're always looking back over the past —

Prof. Hopper: Yes.

Interviewer: So what are the other great health successes that have come out of these types of studies?

Prof. Hopper: Broader epidemiology studies?

Interviewer: Mmm.

Prof. Hopper: I think it's given us a much better understanding that our lifestyle is a major role – has a major role in our disease. The heart disease story is probably the classic – I mean, major, major changes in the impact of heart disease, cardiovascular disease, and it's going on, it's a linear trend. It's getting better all the time. It's been a lot harder to demonstrate that for cancers. Some cancers it's clearer; other cancers, it's not. So it's giving us a chance of seeing what we can do about the way we live in modern society to lower the impact. Now, how do we know lifestyle factors matter? Well, we just have to look across the world. There are enormous differences, for example, in the rates of common diseases like cancers across different populations. That has to be telling us something important.

Interviewer: And, of course, in a previous podcast we were talking with Warwick Anderson from NHMRC and we got on to the subject of obesity and diabetes. Now that's another good example, I would imagine, from data that's been collected that's starting to show the correlation between weight and the disease onset.

Prof. Hopper: One of the problems with epidemiology is you tend to be looking backwards, but you can pick up trends and then you can start to extrapolate what's going on. We know that we're facing major issues in terms of obesity, and it's preventable. I mean, we just have to think about how to change the structure of the way we live. One way of going about that is to tell people not to smoke, tell people not to eat so much. But I think we've also learnt, in terms of taking a population view on health, that it's structural changes that make a difference – increasing the cost of cigarettes, making cigarette smoking inside an unacceptable behaviour. Dealing with it at that sort of level has a much greater impact than wagging fingers at people. I think that's the issue now with obesity – we're going to have to take a structural view of it to make a change.

Interviewer: John, I thought it would be useful for us to understand what some of the key research projects in the centre for MEGA epidemiology are, and the sorts of activities that you're currently involved with.

Prof. Hopper: Well, the MEGA mentions it – it's got molecular, it's got environment and it's got genetics in there. I think epidemiology, especially over the last 50 years of the last century, we did a lot of good work, but it was using questionnaires – that was the tool; asking people how they lived was our major tool. The molecular aspect brings into account now that we can look at, for example, tissue or blood from people and pick up indicators of their environmental exposures. We can also look, for example, at cancer tissue and look at telltale signs and see how people with a particular cancer may have developed it. For example, we know there is a set of genes involved in colorectal cancer, and you can pick up from looking at the cancers those people who are likely to develop their cancer because they had a fault in one of those genes.

Interviewer: So it's a predictor?

Prof. Hopper: It's a predictor and it gives us a whole different way of now sub dividing diseases. So all breast cancers aren't breast cancers, all colorectal cancers aren't the same – they are subdivisions, there are various different pathways to disease, and now, by bringing in the molecular tools, we can subdivide the cancers, and then we bring into the role the genetics, the genetic susceptibility.

Interviewer: So your molecular colleagues come to you with these data sets, do they, the pathologists and other people?

Prof. Hopper: Well, a lot of very bright people across the world are putting together the bits and pieces of the jigsaw puzzle. What we do as epidemiologists is try and put it together and look at – our laboratory in fact is the population. So talking about the colorectal story, we looked at a series of people here in Melbourne who developed colorectal cancer at a young age, before the age of 45. We got their tumours and we looked for those telltale signs and we also did genetic testing for the genes we thought were implicated, and then we put the data together. And that suddenly showed us if we want to find people who carry genetic susceptibility to colorectal cancer, the best way is to look at the tumours of early onset cases and we will find those people very simply, and then we can look at them and their relatives and try to make a difference in terms of colorectal cancer.

Interviewer: So it means that there is a certain cohort of the population that has some sort of genetic susceptibility. That's the point that's come out of the study.

Prof. Hopper: Yes. The big thing about genetics, of course, is why would you want to know. Why would you know you're at a very high lifetime risk of a disease that's got high mortality. In my mind the only reason you'd want to know is if you could do something about it. And in terms of breast cancer, that's problematic, because for a young woman to know she's at high risk of breast cancer, mammography is not very effective; MRI scanning is more effective. It's not a good situation to be in. Later in life when she's had her children, then there are some options that may be more acceptable. But at the moment they're not very nice options. They generally involve surgery, not just of the breast, but ovarian surgery is very good as well.

When it comes to colorectal cancer, knowing you're at high risk can really make a difference, because surveillance can really save you from developing bad cancers, and that can therefore, because it's effective, for your relatives to know is also important for them. So we think we can make a big impact in lowering the mortality and morbidity associated with one form of inherited colorectal cancer, by targeting people with colorectal cancer at a young age, looking at their tumours, working out those who are most likely to be mutation carriers, doing the testing and then dealing with it.

Interviewer: Of course, getting the Joe Bloggs citizen to participate in these regular screening processes or monitoring processes is probably difficult because it's all bottled up with sort of an education program and a compliance program. I seem to remember a number of years ago there was a biotech company in Sydney that developed a quite rapid screening technique that could be used in the home for colorectal cancer and I think it found great difficulty actually in getting market traction for that product, which tended to say that the general public don't really want to know, as you were indicating earlier on.

Prof. Hopper: There's another aspect to genetic epidemiology that's coming through, and it's sort of anti–democratic that what we know about common diseases like colorectal cancer, breast cancer, heart disease, almost every common disease, having a first degree relative with the disease increases your risk, and it probably doubles your risk, which doesn't sound like a lot, but that could not occur without there being major underlying familial and most likely genetic factors operating.

So for any disease where we have this twofold increased risk to relatives, 25 per cent of the population are at about five times population risk, and at the other end of the spectrum 25 per cent of people are at about a quarter of population risk. There's a 20–fold difference between the top and bottom quarter of people. So instead of treating everyone democratically and trying to get everyone to do surveillance for every disease there is, the real future will be to identify people and say, 'Okay, in your situation, based on your genes, the diseases you need to worry about are X, Y and maybe Z', and then put in appropriate measures. That will be much more cost effective. That's a bit down the track, maybe 50 or 100 years, but that I think will be the way we redefine public health in the next century.

Interviewer: There are a lot of ethical questions around that, though, that data – access, use. People will have raised the issue for many years about insurance companies, which I think are already starting to tap into some of this data – increasing or having an effect on premiums or no premiums whatsoever. So it's a difficult one, isn't it?

Prof. Hopper: Well, the insurance industry is very interesting because the bottom line for insurance companies is they don't want people who know they're at high risk to then go, in a sense, and up grade their premiums so they'll make a profit. That's not fair – it's not fair on the insurance company, but the insurance companies point out very rightly it's not fair on the rest of the people who are paying insurance. But with colorectal cancer, for example, knowing you're at high risk actually will lead to you being at a lower risk of mortality and bad consequences. So it comes back to why would you want to know. If having that genetic information can improve your situation, it's worth knowing.

Interviewer: That's right.

Prof. Hopper: There is this sort of dogma, this sort of genetic determinism that people talk about, as if, if you have a genetic risk for something, that's it, mate, you've got it; there's nothing you can do about it. The talk about immutable risks is in fact wrong. Our challenge as genetic epidemiologists is to work out, if you have a genetic risk, how you can lower your risk, and then insurance becomes not an issue.

Interviewer: You're also director of the Australian Twin Registry?

Prof. Hopper: Yes, the Australian Twin Registry was established over 25 years ago by some very forward–thinking people, Professor John Mathews, John Gibson and Nick Martin. It now consists of over 30,000 pairs of Australian twins who put their name on the registry to be available and to consider participation in studies.

Interviewer: Everybody is fascinated by twins – twin behaviour, twin biology – so tell us how the centre works.

Prof. Hopper: Researchers wanting to study a particular issue can approach the twin registry and with proper funding and proper approved study, and then we invite twins to participate in that study. And we don't pass names to researchers. The twins know they're special. Those on the registry understand the role that they can play. We have about 10 per cent of all twins in Australia on the registry and the key issue is not just what people – when you say twins, people think of identical twins. But the key issue is to also study what we call non–identical, fraternal, dizygotic twins, including twins who are male–female pairs, boy–girl pairs. And there are two major issues about how to use twin studies. The first is to look and see are the identical pairs more similar for the condition or the trait or the characteristic you're looking at than the non–identical pairs, and if so that tells us that genetic factors may be important, and that's very important if we're then going to spend a lot of money on trying to find the genes involved. And the other way is simply the comparison of twins. For example, one study I did with a colleague, Professor Seaman, we found twins, they were very rare, we had to search through thousands of pairs of twins to find them, but twins where one smoked for 20 years or more and the other didn't. And these women came into our study, we measured their bone density.

Interviewer: How many would you get in a study like that?

Prof. Hopper: Well, we looked at over 2,000 pairs across Australia and we ended up with 40 pairs who came in from Victoria and New South Wales, and we found a striking difference in the bone density of the twin who smoked compared to the twin who didn't smoke. That's a way of getting really strong, definitive information from a relatively few individuals. But it took a lot of hard work to find that gold.

Interviewer: With non–identical twins, what sort of information can you derive?

Prof. Hopper: Well, studying non–identical twins and identical twins gives us information about the possible role of genetics. But what's become of great value now for the non–identical twins on their own is we now have these possibilities of doing genome wide association studies and measuring up to 500,000 genetic markers across the genome on individuals. That's where the dizygotic pairs come in. They are the very best people for those studies, because you can do comparisons with each other.

Interviewer: Just explain dizygotic?

Prof. Hopper: Dizygotic is the non–identical twins, the fraternal ones. So they share, on average, half their genes, just like brothers and sisters. So we have comparisons of them. They're very well matched for age, of course, and they can be chosen to be perfectly matched for sex. And they're also matched for their upbringing and a whole lot of other factors. So any differences between them are very important. So we can start by measuring hundreds of thousands of genetic markers to try and find the genetic markers that differ between those pairs, especially if we start to choose one who is high on a characteristic, the other low on a characteristic. So dizygotic pairs have really come into the forefront in the last few years with this new technology.

Interviewer: So are there any really – other than the one you talked to us about, smoking – are there any other really significant findings that have come out of these twin studies?

Prof. Hopper: Well, coming back to the idea of looking at identical pairs and seeing how similar they are and comparing them with non–identical pairs, so this was a wonderful study done by Professor Martin in Queensland. They looked at schoolkids around Brisbane and the Gold Coast and counted the number of moles they had on their back, what we call dysplastic naevi. And this is important because they're a risk factor for melanoma. Now you would have thought that sunlight was the most important thing and that it was all environmental. But lo and behold, the genetically identical pairs were very similar in their mole count and the non–identical pairs were about half as similar, which is exactly what you'd predict if it was due to genetic factors. So this was a bit of a shock. So colleagues then, Tim Bishop and his wife, did a wonderful study of it in Leeds, which had a completely different environment in respect of sunlight.

Interviewer: Did you say Leeds?

Prof. Hopper: Leeds in the United Kingdom. And a similar age group and a similar twin study. What they found was that the average number of naevi was 25 per cent lower for these twins in the United Kingdom, but when you looked at the differences, the variation, you got exactly the same pattern as you got in the genetically related relatives from long past out living in southern Queensland.

Interviewer: So you've delineated that, but you've also found that if you live in Queensland you're going to have a higher level —

Prof. Hopper: That's right. It had two stories.

Interviewer: Very interesting stuff. And I understand that the Australian Twin Registry is actually funded by the Federal Government through the National Health and Medical Research Council?

Prof. Hopper: Yes, the twin registry came together as the Australian Twin Registry way back in 1980, and had been funded by NHMRC through a variety of mechanisms and grants for many, many years. In the last few years NHMRC have introduced what they call an enabling grant scheme. This is a recognition that there are resources such as the Twin Registry which are there for everyone to use that need to be supported long term. So we were grateful to be one of the first recipients of that through that scheme, and that has given us the confidence now to build the registry and to make it widely available to researchers.

Interviewer: From what you are saying there are clearly other twin registries around the world, so you must collaborate and link and probably use data from different sources, do you?

Prof. Hopper: Well, it's very important that people replicate findings in different studies. There are some registries in the United States, none of them quite as big as ours, and none of them except one, which uses veterans from the Vietnam War, are supported as a resource for researchers, such as the Australian registry, which is supported by NHMRC. So it's a very unique model in that respect. The other registries which are in effect our envy from Australia are in Scandinavia, where they can identify twins from birth by birth records, because everyone has an ID number, and they can do studies where they're actually matching against other registries, such as hospital databases. They also have national registries there. They're not quite as big as ours, but they have the great value of being population complete. We're trying to develop something similar in Western Australia and have set up what we call a population–based twin registry of young twins and we're now trying to extend that to older adult twins.

Interviewer: This is not really twins, but I'm aware around the world of a number of longitudinal studies that have occurred where people have followed a whole range of parameters, health parameters, in young people from birth right through to – in many cases adults or even now they're probably getting on, in their 50s and so. Tell us what you think about those types of studies and how powerful they can be.

Prof. Hopper: Well, they're the sort of – we think they're very important. We only wish that our ancestors had set them up in the past for us to make use of now. The Busselton study in Western Australia is probably the most famous Australian one. But one that we're involved in, which I think is going to become famous as the Boston studies, the Tasmanian asthma study. So in 1968, some very forward thinking researchers in Tasmania studied all 7,000 schoolchildren who were born in 1961, so this was their first year of school. So they not only studied the children; they also got information from their parents and their brothers and sisters. So we have this extraordinary cohort of families from Tasmania. We've now been following them up. They're now in their late 40s. We've identified where over 70 per cent of these people live in Australia – still a large percentage back in Tasmania, but, of course, all around the world – and we're doing follow–up studies of those families.

Interviewer: That's amazing.

Prof. Hopper: That is really a wonderful resource for us to have in Australia.

Interviewer: John, what inspired you to embark on a career in research?

Prof. Hopper: Well, my father was a physicist and he was a professor of physics at university. He had a wonderful time. He set up what started out as weather balloons, with packets on the end of them to measure cosmic rays. He ended up with giant helium balloons and other balloons which flew around the world and he had to chase after them in aeroplanes to try and get them to come down.

Interviewer: Was he trying to look at the universe as it began?

Prof. Hopper: He was looking at where gamma rays came from and cosmic rays. It was an excuse to travel around central Australia. His brother, my uncle, said to him once, I remember him saying, 'You're so lucky, Victor, that your job is your hobby.' And I thought that was a very important message in that statement. As I say, I started off doing mathematics and statistics, fairly dry stuff, and I ended up in medical research because I'd rather have put my talents to that use than go and help some company make bigger profits. Because I think the point is that as statisticians, who are incredibly powerful people, especially now with computers the way they are, understanding data is a tremendously powerful quality, and unfortunately it doesn't seem to be recognised in our schooling system and in our universities. It's extraordinary – the faster computers got, the less students went into statistics; the more they went into commerce and learning how to be a croupier at a casino, that seemed to be a sexy thing to do in life. Now the statistician's life is not sexy, but at the end of the day you have a lot of power not only to do things with data, but also to choose where you do it. So I got interested in doing something in medicine and I was very lucky to have a wonderful mentor in John Mathews; that sent me off on this career.

Interviewer: So if you had to choose, it's always a loaded question, what your contribution to the health of Australians has been through the work you've done, what would that be?

Prof. Hopper: I think the contribution will be – because I don't think it's by any way over – getting a proper handle, a population–based perspective on the role of genetics and the environment on our health. I'm not a geneticist, I'm not a card–carrying environmentalist; I just want to have a rational view. It's trying to get over the idea that we have to have an open mind, we collect the data, we see what it tells us, and then we make informed decisions. I think we live in a society now which is making knee–jerk decisions – it has for a number of years – and we really are not benefiting I think from the lack of foresight and deep thinking. And the climate change argument, I think, is very interesting. Whether or not you believe the data on climate change is real or not, I think what it's come back to realising is there are bigger issues, that we have to be thinking more than five or 10 years. We have to be thinking 30, 40, 50 years and hopefully it's just really the contribution will be to put in place evidence–based, not making up your mind before you see the data, not coming in and seeing things for political reasons, just being open minded. And I would love to be proved wrong on some of the things I said 10 years ago.

Interviewer: It's about being the honest arbiter?

Prof. Hopper: Hopefully, yes.

Interviewer: It sounds to me as though you've had to preach that method repeatedly, it's about changing people's way of thinking?

Prof. Hopper: Well, I went to a meeting of epidemiologists and someone had a lot of money they wanted to spend on making a difference and the moderator went round the room and asked everyone what they did in their life to protect themselves from getting cancer. And the exercise researcher told us about how much jogging she did in the morning, and the people that studied different dietary factors told us about the pills they took, and I realised that these people were believers; they'd already made up their mind. They weren't necessarily coming with an open mind. I'm sure that criticism isn't just for epidemiologists. I think a lot of us have that problem – we are human beings, after all.

Interviewer: That's right, exactly. Now, John, you've recently become an Australia Fellow of the NHMRC. Congratulations on that. It's a very prestigious honour. Clearly the NHMRC has been a big part of your life and maybe an important contribution to your career?

Prof. Hopper: Well, from the moment I was appointed by John Mathews way back in 1980, I've been supported by NHMRC. So I owe everything. Again, thinking back to my father, it's quite a privilege to be actually paid to do your hobby, to do what you love doing. But I think there's also a sense of responsibility, which is certainly not lost on NHMRC research fellows, that we owe a lot, we have an obligation to make sure that this money does have an impact and come back to us. So the Australia Fellowship was a fabulous award, but I think it really brings with it an enormous responsibility, especially to those of us lucky enough to be awarded it in the first rounds, to make sure this is a success.

Interviewer: We need many more people to follow in your footsteps and other Australia Fellows' footsteps. How are we going to keep inspiring these young people to join the ranks?

Prof. Hopper: Well, there's been a lot of talk about this. I mean, Australia puts sports stars up the top there. I mean, it's been fabulous, what we've achieved in sport in the last 10 or 20 years at an international level, for example the Olympic Games as a measurement, has been an extraordinary thing. But I talk about Australian medical research has actually done the same as Australia did at the last Olympic Games. In terms of per head per population, we are kicking arse, as they say. And it's harder to identify individuals because it's actually very much a broad group. We can identify one or two individuals, but it's not really fair, because it's actually a group effort. It's a very strong network of researchers and it is hard to inspire people to stay on in the career, because it's incredibly competitive, you often don't know whether you've got a job next year until November of the year before, it's not enormously well paid – it's not badly paid; but having said that it's improving and has improved dramatically over the last 10 or so years. And I think the way things are pointing I'm hopeful that will improve again and again.

We've still got a long way to go to establish the sort of research career structure and the level of funding that, for example, the United States have had over the last few decades. And I think that's where we should be aiming. We have so many advantages in Australia in the way we relate to each other, the way we collaborate with each other. The population from our point of view as scientists is enormously cooperative. They hold medical research in a high regard. We get terrific participation rates in our studies and we're not hung up yet too much about privacy and other issues. We are a fairly rational practical society.

Interviewer: But coming back to the young people in high schools who are thinking about where they want to go, you've said it was really your father who probably opened your eyes for you in terms of science, but what about people who are thinking whether they should do science or they're not sure, or as you say the lure of bigger dollars eventually is going to come from doing a commerce degree or a law degree. So we've got to switch them somehow. What's your muse?

Prof. Hopper: Well, I think you only live life once, and depending on your personality, some people want to have money and live a happy rich life, and it's understandable, none of us want to be poor and miserable. But I would say to young people who recognise that they have talents, that they are good at things, that they are good, clever, that they have actually a wonderful opportunity to contribute to society. And it may take time, but at the end of the day the contributions you can make if you follow through in an academic career into science is quite extraordinary. You don't really see it for the first 10 or 20 years. It's only a bit later on that you start to realise that especially within a country the size of Australia you can actually make a difference, you can actually go and knock on the door of the Health Minister, you can meet the Prime Minister, you can talk to people who matter, you can meet the leaders of business and so on who are the really influential people in making things happen. And that's what I've learnt, especially in the last 10 years, that I don't think I could have had any sort of impact if I'd lived in a very big country, but within a country like Australia, there is a chance for us all to do something.

Interviewer: Of course, but at the same time you're potentially having a global impact because the results of the work that you do will be taken up by others and extrapolated.

Prof. Hopper: Well, that's right. We're just human beings like the rest of the world. So we put in a grant to NIH on colorectal cancer and one of the reviewers said they couldn't see how studying Australians in terms of colorectal would benefit American patients, and I felt, 'Well, that was a very broadminded view!'

Interviewer: Indeed. John, thank you very much for your time today and good luck with your future endeavours.

Prof. Hopper: Thank you very much.

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