QUT ExecInsights – Matt Brown on the promise of genomics for treatment of cancer and disease

Distinguished Professor Matt Brown, QUT Director of Genomics, talks to Kate about the collaborative research which is revolutionising our understanding of the causes of rare and common heritable diseases, cancers and even infectious diseases.

Kate and Matt speak about the speed of technological change in genomic research and the inherent challenges of international collaborative research.

Read more about Professor Brown’s research.

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Transcript

Kate Joyner 0:05
Welcome to QUT ExecInsights, brought to you by QUTeX Professional and Executive Education for the real world. I’m your host Kate Joyner. Today we’re continuing our cool QUT series where I speak to some of my QUT colleagues who are at the cutting edge of research with real world implications. With me is Distinguished Professor Matt Brown, whose work with a wide range of collaborators in genomics is revolutionising our understanding of the causes of rare and common heritable diseases, cancers and even infectious diseases. Professor Brown has a university wide role as director of genomics, and works with colleagues at QUT’s Institute of Health and Biomedical Innovation, and the School of Biomedical Sciences. He’s a clinician scientist who trained initially as a rheumatologist, before heading off into a career in immuno genetics research, initially at the University of Oxford, and then at the University of Queensland. His particular interest is the disease ankylosing spondylitis, where he has played a major role, dissecting the genetic causes of the disease and developing new treatments for it. He’s also deeply interested in the translation of genomics into clinical applications. Hi, Matt.

Matt Brown 1:14
Hi Kate, thanks for that introduction, and well done on pronouncing ankylosing spondylitis.

Kate Joyner 1:18
Ankylosing spondylitis. I did practice that! So, did I get it right?

Matt Brown 1:21
Yeah, you did.

Kate Joyner 1:22
And what does it mean? What is it?

Matt Brown 1:24
Okay, so it’s a rheumatic disease. So it’s a disease which predominantly affects the spine and pelvis, and causes inflammation and swelling and stiffness in joints and ultimately results in bone forming across those joints, and fusing them hence, ankylosing, meaning joining and spondylitis, inflammation in the spine and pelvis. But it’s a particular interest, because it’s the risk of developing it is almost entirely inherited.

Kate Joyner 1:53
So it’s just bad luck.

Matt Brown 1:54
It’s bad luck. Yeah. And so for a genetics researcher, it’s a, it’s a really good disease to study because we can work out what the genes are that are involved in causing it, and thereby come up with ideas about how we might treat or prevent it.

Kate Joyner 2:08
So that actually, though I haven’t got this on my list, Matt, and can I call you Matt, incidentally, I should’ve called you Professor Brown to this point. And before I always get permission to, I use the Christian name.

Matt Brown 2:18
When I get called Matthew by my wife, I know I’m in trouble. So, Matt it is.

Kate Joyner 2:22
Matt. Thanks, Matt. So one of my colleagues said to me, could you ask, what is the difference between genetics and genomics? I’m assuming one comes out of the other does it, like…

Matt Brown 2:33
Look, I think it’s a pretty semantic difference. So genomics is, I guess, more broad than just DNA, it’s RNA. And the other structural components of that make up chromosomes. Genetics, I think, is more purely the study of just heritable variants. And so actually, I think, though, that the two are pretty much used synonymously nowadays,

Kate Joyner 3:04
Okay, that’s answered my colleague’s question, I said, I’ll get back to her on that. So Matt, you came to my attention through, as we often see with our colleagues, we get to know their work through the media. So I looked at your work in the weekend, the recent Weekend Australian, and it had to do with, I’m going to translate it as getting quite personalised about treatments for certain kinds of cancer. So being quite specific. So is, is that sort of part of your research interests generally. And those of you know, the colleagues that you work with, here at QUT and elsewhere?

Matt Brown 3:42
Yeah, so the article in The Australian was about using sequencing approaches to profile mutations in cancers that then predict how they’re likely to behave and how they’re likely to respond to different treatments. Obviously, chemotherapy in particular. And so one of the benefits of the Human Genome Project was it was a massive investment in the capability of doing DNA sequencing. And so now we’re at a point where we can reasonably cheaply sequence cancer, and identify all of the mutations that actually drive the cancer and make it behave the way it actually does. And what people worked out was that instead of treating cancers merely on the basis of what the organ of origin of the cancer was, but instead you treat it on the basis of the gene that was mutated, that caused the cancer, that you can do better.

Usually, in fact, you take into account both things, not just the mutation, not just the organ. But what happened was that about seven or eight years ago, we had built up a very large sequencing capacity here in Brisbane that we were using for research, but as a clinician I was always looking for ways that we could translate that into clinical practice. And we realised that we would be able to do this, that this research capability had come about and that it really should be applied in clinical practice. And so that’s what we’ve been doing. So we are the only NATA accredited that’s a certified pathology lab accredited service that provides comprehensive cancer sequencing in this state.

Kate Joyner 5:15
Hmm, that’s amazing. And what was, I think, what you stopped and paused over the story, the story of the woman who, who undertook this treatment, so the story was sort of run through one particular woman. So there was there’s a certain amount of I mean, obviously, bad luck, but good luck in that she was part, she lived in a certain part of Brisbane. And she had a certain type of heritable disease that had it not been, that’s my understanding.

Matt Brown 5:39
So her disease isn’t heritable. Yeah. All right. I’ll come back to that. Yeah, you’re right. So at the moment, there is unfortunately, a postcode lottery about the availability of this service. So if you live within Metro South, then that health service actually funds this proper cancer genomic testing, if you live outside of that there is testing available. But it’s much more limited testing. And, as a consequence, many patients don’t end up with treatments that they could have if they had more comprehensive testing. So one of the things we’re working to do is to try to convince the government to actually fund this sort of testing of more widely through not just Queensland, but through Australia, because a high proportion of patients do end up getting treatments for their cancers that they would otherwise miss out on, if you’ve got that.

Kate Joyner 6:30
So the the Metro South is a trial or a pilot, is that right? Or just where it’s available at the moment?

Matt Brown 6:36
It’s, actually what’s happened is that the Metro South Health Service, have, I guess, stuck their neck out and said, “We think this is worth doing.” And so they have funded it. Unfortunately, that hasn’t happened across the rest of the state. But this patient that was mentioned in the Weekend Australian lives within the Metro South area, and so therefore, she was able to have testing. So just to come back to the heritable bit. The cancers are caused by mutations in tissues, that are what we call somatic mutations that are not throughout all cells in the body, so they’re not passed on to the next generation, so they’re not heritable. Having said that, about 10% of cancers, people have a heritable predisposition to getting the cancer. And most people know, of course, about the BRCA 1 and 2 genes and the Angelina Jolie story about hereditary breast cancer. So that’s one example of hereditary cancer. But even in that circumstance, people then have a mutation in a cell that ultimately causes their cancers to develop, and that mutation is not inherited.

Kate Joyner 7:38
Okay, yes, I think we’ve all, you know, other experiences in our family or certainly with a friend or colleague. So these kinds of advances are, you know, fascinating and, you know, have such wonderful implications. That’s kind of one aspect of the work of that your personal research and those of your colleagues, what else is happening in your research centre, what questions are you interested in?

Matt Brown 8:01
Okay, so we work a lot on rheumatic diseases. So particularly ankylosing spondylitis that you mentioned, but also some other rheumatic diseases, particularly another one called scleroderma, which I’ll come back to in a little bit. But ankylosing spondylitis. So far, we’ve mapped 115 different genetic variants that are responsible for just short of a third of the total genetic risk of the disease. And we’ve got a big study with about 25,000 cases from around the world that’s currently in the process of completing its analysis. And so we’re the global center for genomics for that disease. And we think that that will roughly double the number of genes that we’ve actually identified. So from those we’ve already made some pretty big discoveries about how the disease is actually caused. And I think now we’ve got a pretty good handle about what actually drives the disease. And we’ve already led to new treatments coming about in the disease.

So back in 2006-7, we identified a genetic variant in a receptor for a protein the receptors called Interleukin-23 receptor IL23R. And if you stimulate IL23R, it leads to the production of other proteins called Interleukin-17 and Interleukin-22. And we predicted that if you blocked particularly Interleukin-17, that it would be effective for the disease. And we went to companies, particularly Novartis, and said we think you should take this drug that you already have in trial for these other diseases where we predict it’s not going to work. And we think it will work in ankylosing spondylitis and psoriasis and it’s now the drug of choice for psoriasis around the world, and it’s a widely used medication for ankylosing spondylitis, and in 2016, past a billion dollars in sales. So that is in one year sales more than, to that point, all of the money that had been spent on genomics and common disease genetics.

Kate Joyner 10:01
So at the point of discovery, so you mentioned a commercial outcome, how does that translate from pure research in the lab? To that to that commercial outcome? What’s the mechanism there?

Matt Brown 10:12
Right? So look, I mean, what happened in that circumstance was that we, we knew that this company had an agent that would work in the disease or should work in the disease. So the commercial outcome was basically we got nothing. On the other hand, you know, it was obviously of substantial benefit to patients. In other diseases that we’re working on, for example, in scleroderma, through our genetics, we’ve identified a potential therapeutic target. And we have a compound which we know that in mouse models of the disease is highly effective. So if you’re a mouse that has scleroderma, don’t worry, we’ve got you covered. So then now we’ve got to look for ways that we can actually take that forward into clinical practice. So that means a lot of a big long process that starts with seeing that the medication is safe in patients, and then doing trials in healthy individuals to see that, that it is safe, and then doing a graded clinical trial program, until you’ve actually done a definitive study to show that it works and is safe. And that’s a several years process.

Kate Joyner 11:18
And takes a lot of patience. I don’t mean patients. Being patient, rather than patients to to experiment, let me be clear. So I was quite interested, you know, you’re speaking about technology and what it’s enabling. And I was interested to read about the DNA sequencer, and how much quicker and cheaper it is to do that kind of research maybe even 10 years ago. So are we advancing technologically in our ability to, to understand the genome? And how are you, are we predicting more advances in technology, technological enablement?

Matt Brown 11:54
Yeah, look totally. The rate, the ability to sequence DNA has massively changed during my career, so that when I started in genomics in the early 1990s, you could in a day, maybe sequence a couple of hundred bases of DNA, remembering that there are 3.3 billion bases in the average in a human cell. So now, we took delivery of a new sequencer towards the end of last year, and it will sequence three or four whole genomes every other day, at a cost of about 1500 Australian dollars. So that’s a massive increase. But there are already other technologies that are around in development, which will be cheaper and faster than that.

So there’s a Moore’s Law of computing about the, basically the change in processing speed of computing chips. And that also applies to the cost of DNA sequencing, where they predict that every year the sequencing costs will halve, and pretty much that is the case. So that’s what’s been happening. And there’s a lot of competitive tension in the marketplace at the moment with new companies coming on board. And I think that we’ll see that, you know, sequencing costs for whole genomes will come down to in the region of the cost of an MRI scan in the next two or three years. In which case, it’ll be something that people have done fairly routinely.

Kate Joyner 13:18
Have it done routinely. And you can’t really anticipate the consequences of what that might be, if we’re all just, you know, tested for our genome early. But yes, lots of lots of…

Matt Brown 13:30
Potential risks, but on the other hand, there’s also lots of potential benefits. So for example, in clinical practice, we normally end up treating patients who have established disease. And for a long, long time, people have said we should be looking earlier in disease and moving towards preventative medicine. So preventative medicine generally works best if you can target it to people who are at high risk. If you try to introduce preventative medicine across a whole population, we’re only a small fraction of the population is actually at risk, you will never succeed because nobody will actually do the the interventions. So identifying people who are at high risk is something that we can now do for many common heritable diseases. And so I think that’s going to be a really big change over the next five to 10 years that we’ll see in clinical practice, is that people will be using genomics to assist in early diagnosis of disease, or in pre symptomatic disease, or even in groups who are just at high risk of disease, so that you can target screening of those people.

So for example, if you are at high risk of prostate cancer, that you have appropriate PSA testing, blood testing for prostate cancer, whereas those who are at low risk don’t need to do it, or mammography, for breast cancers is another situation that you could think of that. Or that you could have preventative interventions like people who are at high risk of cardiovascular disease being more likely to be treated with statins to reduce their cholesterol. And I think that that’s going to mean that genomics will enable a really big change where we’re treating pre symptomatic or early disease rather than, or preventing rather than waiting until people have disease. They’re diagnosed with it and then trying to deal with it. And so that would be a really big shift.

Kate Joyner 15:13
So it’ll have public health policy implications, and hopefully some efficiencies and benefits.

Matt Brown 15:21
Yeah, absolutely.

Kate Joyner 15:22
Yeah. So although you’ve mentioned that the cost of sequencing is going down, there’s many aspects of research that are labour intensive and cost intensive. So I’m assuming that’s why most of your research seems to be done in, in collaboration with, you know, other centres nationally and internationally. Is that the way we generally do research, I don’t think there’s much can be achieved just by QUT with its own means is that right?

Matt Brown 15:48
I think the situation is in genomics, in particular in common disease research, that you need to have absolutely massive sample sizes. So for example, the studies that are looking at genomics of height as a model trait. Looking at now, more than half a million individuals that have been, that are being included in the genetic studies. For the ankylosing spondylitis study of 25,000 cases that we did, that required participation of China, Europe, North America, as well as Australia. We just don’t have enough patients.

Kate Joyner 16:25
Oh, I see. So that’s the problem, it’s not the money so much, it’s mostly to do with access to sampling sizes.

Matt Brown 16:31
Yeah, it is. But having said that, the, particularly the genomics isn’t cheap. And if we do try to do large scale whole genome sequencing at the moment, you know, think about 25,000 people times 1500 dollars per whole genome, that’s a seriously expensive project. And the individual project, the next step of trying to work out what you, so you’ve identified the genetic variant, you then need to work out how it functions to cause disease. And that process is also a very expensive, time consuming process. And therefore, people tend to work together in big international collaborative consortiua for that as well.

One of the big changes that occurred in genomics in the mid 2000s, was because the genomics became so expensive, the Wellcome Trust to funded the first what we call genome wide association studies, insisted that you actually had to make all of the data publicly available within six months of it coming off the sequencer.

Kate Joyner 17:33
Okay, big ask.

Matt Brown 17:34
Well, it really focused people’s minds on actually getting the data analysed, because it was going to go public at that point. And the result is there now these massive banks of data that’s meant that that Wellcome Trust data has been used hundreds of times over. And greatly increased its utility.

Kate Joyner 17:53
Yeah. And what can we expect from from that open data availability? So it’s kind of applications that we never would have thought of, people coming from all kinds of angles, and perhaps integrating with other available data sets?

Matt Brown 18:07
Yeah, totally. Yeah. So just a simple one. For example, when in a in a disease gene mapping study, you take a group of individuals for who’ve got the disease, and you compare them with a group of individuals who are healthy, healthy controls. So the fact that they actually had a group of healthy controls that were genotyped meant that you didn’t need them to recollect and re-genotype any healthy controls, because they’re already there. So that halved the cost, at least of doing any study.

But now there are lots of rare data sets. So for example, when we’re doing the sort of functional genomics, trying to work out how the genetic variants actually cause disease, you need to know how each genetic variant operates in lots of different cell types, and of course, in the body there are hundreds to thousands of different cell types.

And so groups are going around and purifying those cell types, and then characterising them completely, and putting that data into public databases so that then another group coming along can say, “Oh, well, I’m interested in Gamma Delta cells” or something, goblet cells or something like that. And you’ll be able to just go to a database and say, “Right, well, here’s my genetic variant, that’s the cell type, and how does it influence it?” and things like that without having to go and repeat that experiment for yourself. And that massively speeds things up.

Kate Joyner 19:25
Massively speed things up. And we can’t know how that, yeah, what might be possible because of that, it sort of goes into the complex space, doesn’t it when that kind of thing happens. Is there any, these large research collaborations are there tensions that build up in terms of who gets who gets credit and who gets which slice of the pie and those sort of things? Are they hard to manage?

Matt Brown 19:51
Look, look, there are often tensions. But generally what happens is that people rotate authorship around and go to considerable lengths to actually acknowledge the fact that this, that these studies can’t be done by one individual. So actually, the tensions have turned out to be less than they should be. Having said that, there are some countries where there’s less sharing than would be recommended, too. So for example, China does not allow either biological samples like DNA to come out of its, out of the country, or genetic sequence to come out of the country. So they do not deposit any of their research genomic data into public databases. And yet, they’re one of the biggest world users of public data. And that really winds people up.

Kate Joyner 20:41
I can imagine. You probably answered my final question, we’ve covered a bit about what might happen in the next five to ten years, it’s probably all we can really see. 20 years is probably too long to kind of envisage. But what questions do you think that we’ll have answers for maybe in five or ten years that that we don’t have now?

Matt Brown 21:01
Look, genomics is actually making huge discoveries about the basic function of people, and also about all different diseases virtually, that you can consider. And so, you know, clearly there are some really massive unanswered questions in biological sciences. And genomics is contributing a lot towards those, how the brain works, what causes neuropsychiatric problems. And all through to, you know, what causes cancer and things like that. Those are, those are things that genomics is contributing to, I don’t think any field of research is going to answer those on its own.

So I’ve mentioned about what I think is going to happen to the practice of medicine. Also about what’s happening in cancer. We haven’t touched on microbiome research, which is another thing that genomics has enabled.

Kate Joyner 21:53
That’s the gut, right?

Matt Brown 21:53
Well, it’s the gut, and also any other surface where you have bacteria, virus, fungi, and things like that. But DNA sequences have meant that we can now profile all of the bacteria that somebody might carry on a particular surface. Whereas in the past, you’d have to actually take a sample and you know, get out agarose plates and culture every bacteria separately, which means that the vast majority of bacteria you would never identify. Now, you can do that with a simple sequencer and get a result, which will tell you precisely the number and what type of bacteria and even what sort of bacterial resistance genes they carry. And so that’s completely revolutionising microbiology. And that’s a, that’s something that has come about through the investment in the Human Genome Project, because it meant that sequencing capability got cheap enough to do it.

Kate Joyner 22:44
It did. I think we’ll have to follow up, Matt. I think we have we just have way too much material for one short podcast, but we have touched on some of the management aspects, which I think covers you know, being an ExecInsights podcast. But look, I thank you for your time and we’ll have to catch up again in a couple of years, I think to see what’s what’s materialised. So thank you so much for your time today.

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