Gene genies: Meet the researchers mapping our DNA to combat cancer

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis. Let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

We all know someone who has been touched by cancer and sometimes can't help but ask… after all our advances in science, technology and medicine, why does the cure for cancer still elude us, and how can we prevent it in the first place? Why is there still confusion about the myriad of causes? Researchers are now turning to our genes to ask deeper questions about how cancer develops and how to fight it by looking at the patterns in large samples of sequenced DNA and cancer cells.

PETER CAMPBELL
So I’m Peter Campbell. I study cancer, I sequence the genomes of cancer which means I analyse the DNA that cancers have and try and identify what it is that makes that cancer behave the way that it does.

CHRIS HATZIS
That’s Peter Campbell, Head of Cancer, Ageing and Somatic Mutation at the Sanger Institute of genomic discovery.

SEAN GRIMMOND
I’m Sean Grimmond. I’m involved in trying to understand what makes cancers tick and trying to see if we can find Achilles Heels in them to treat them better.

CHRIS HATZIS
And that’s Sean Grimmond, Bertalli Chair in Cancer Medicine at the University of Melbourne Centre for Cancer Research. Sean and Peter share their research experiences, hope, insights and discoveries with our reporter Dr Andi Horvath.

ANDI HORVATH
So gentlemen, how pervasive is cancer? Everyone knows someone that's had cancer and decades ago, I remember it was a real hush-hush thing; people underwent quite severe treatments with lots of side effects and there was always the recurring nightmare. But today there's a better chance of survival, so give us a picture of cancer in society today. Where are we?

PETER CAMPBELL
Cancer remains a very difficult disease and unfortunately a number of people will still die from it, in fact, you know, more than 30, 40 per cent of us will die of cancer and, you know, those people will still suffer with it. As you say, a huge number of people are actually going to be cured of their cancer and we are curing more people than we ever have before, we're picking the cancers up earlier, we're treating them better, we have a wider range of therapies and so we are making progress, but it's slow and it remains a very difficult and pressing challenge.

ANDI HORVATH
Sean, include your story.

SEAN GRIMMOND
So look I think we've seen over the last 30 to 40 years that we have steadily got better with cancer overall. So we're now seeing that about 50 per cent of people, once diagnosed, would live more than five years. The grim reality is, is that for some cancers we do spectacularly well now, but there still are some that have been left behind, if you like, that our standard approaches really hasn't improved the outcomes for some patients, for some cancer types.

ANDI HORVATH
So there are cancers and there are cancers. Which are the tricky cancers?

SEAN GRIMMOND
In terms of the cancers that are trickiest, these are the ones that we would see the five year survival being sort of 10 per cent or less. Probably one of the best or one of the most serious would be pancreatic cancer, also brain cancers, lung cancers, oesophageal cancer are quite poor. But we also have a wide number of very rare cancers where as they've been so uncommon, we don't have a good playbook on how to tackle them best, so they tend to have quite poor outcomes as well.

PETER CAMPBELL
I think to sort of follow up on that one, one of the interesting or the most difficult things that we've struggled with is that we've gotten better at treating the first stages of cancer, so when we pick it up early, we can definitely cure it and make a real impact on it. But if we pick it up too late and the cancer has begun to spread around the body, then pretty much for many of those cancers, we don't have any viable solutions for curing it at that stage. It remains probably the biggest challenge, I think, for cancer medicine at the moment, is how do we manage that process once the cancer has begun to spread or what we call metastasise around the body.

ANDI HORVATH
What's changed over your time in studying cancer? Because both of you have been at it for a while, what have you seen change in diagnosis, in treatment and prevention? Shall we start with diagnosis? What's changed there?

SEAN GRIMMOND
I think that what we've really seen in the last decade is the steady increase in diagnoses which involve the DNA of a patient. We've known for many decades that cancer arises through the accumulation of damage to your DNA and really the technologies by which we can make sense of that have gone from one little part of a gene at a time, to one gene at a time, to the possibility of looking in fact at your entire genetic blueprint and where that technology is just hurtling forward at a fantastic rate.

PETER CAMPBELL
Yeah, what those analyses have shown us is that cancer's not just one disease. In fact even within one tumour type, like breast cancer or pancreatic cancer, it's not one entity. Everybody has a different genetic makeup, each cancer's genetically different. So we're able now to describe each person's cancer as opposed to each type of cancer and then the idea, the hope, is that by understanding what is causing one person's cancer, we will be able to choose a therapy that is optimal for that person.

ANDI HORVATH
So by understanding some of the changes in diagnosis and what's happening at the DNA level, how has this changed treatment of cancer over the years?

SEAN GRIMMOND
We've seen, if you think about sort of 30, 40 years ago, there were a limited number of ways that we would look to tackle cancer. There were non-directed chemotherapies and there was radiation that may have been used and what we've seen in recent years is the development of what we call targeted therapies, so these are going to be drugs that are specifically designed to target an altered protein which occurs to a mutation within your cancer. Indeed that particular mutant protein is not present in your normal cells, so it allows us to make a drug that should preferentially target the cancer.

PETER CAMPBELL
I think the other major advance in therapeutics at the moment that's generating huge excitement is in ways that we can harness the body's immune system to attack the cancer. Those drugs are having spectacular effects in a number of cancer types. We don't understand which patients are going to benefit, we don't know really, we know at a kind of superficial level how they're working, but we'd love to know more at a deeper level about how the immune system is interacting with the cancer and why the cancer survives the immune system in the first instance, but then we can tickle it up with some drugs and make a major impact on it.

ANDI HORVATH
On the topic of treatment, what about the re-occurrence of cancer? That also is a bit of a nightmare that hangs in the back of the minds of the cancer patient. Do we have a direction for trying to mitigate that reoccurrence?

SEAN GRIMMOND
I have to say that at the moment, the way that we are treating cancers is relatively processive and you will find that for many cancers that are prone to coming back, we tend to be vigilant and we look for that cancer and we might use imaging techniques or some other new technologies these days to try to catch them early. Then there needs to be a decision made on which drugs you might use. In some instances that's following up on prior experience, so we use the same drug, or in others, once it's come back and they think it's resistant, then they may think about changing to something else. I guess this is another example of where a molecular profiling of your tumour, not when it's first diagnosed, but once it comes back, can give you clues into whether you're going to be sensitive or resistant to the drugs that are available.

ANDI HORVATH
Tell me about prevention. Surely the whole aspect of cancer needs to be clipped in the bud. So what are the efforts in research moving towards the prevention of cancers?

PETER CAMPBELL
Well, prevention of cancer - no discussion about prevention of cancer can avoid smoking as the single biggest preventable risk factor for cancer. We need to think about ways to prevent people starting smoking and to get them off nicotine addiction once they have it.

The second biggest cause that's potentially preventable is obesity and we are sitting on a kind of rising wave of cancers that are going to emerge because of the rising obesity problems in the Western world. We have no idea, frankly, why obesity causes cancer, but the data that it does is pretty much insurmountable. So we need to understand that at a biological level, we also need to know whether weight loss in that setting does reduce the risk of cancer, that's not known.

ANDI HORVATH
Gee, that's hard to test, isn't it?

PETER CAMPBELL
Yes, it is.

ANDI HORVATH
I don’t envy your research assistant. Sean, what about prevention? Tell us about prevention.

SEAN GRIMMOND
Yeah, look I think we've certainly been seeing in recent years that cancers can be preventable and I guess there's a couple of other examples there that we should flag. The first would be here in Australia certain exposure to the sun and the Slip Slop Slap campaigns here in Australia which really have been world leading, we're actually seeing the incidence of those cancers dropping. As we continue to see more people going through and following that from our schools, we hope to see that that will improve or prevent people from contacting those skin cancers, which are all too common in Australia.

The other two areas I'd really highlight would be the likes of vaccination. So we've seen some - Australia has pioneered the cervical cancer vaccine, indeed vaccines against the papilloma virus protect against a variety of cancers, not just cervical cancer, but also head and neck cancer and indeed we see here in Victoria forward-thinking views of where both boys and girls are being vaccinated going forward and that stands to be a health benefit that we're already seeing internationally, we'll only continue to benefit from.

I guess the next thing for us is trying to see where else prevention may be possible. There is a lot of interest in looking at the possibility of improving or minimising or preventing the likes of colorectal cancer or some of those things. There's been some very large studies going on here nationally now looking at the prospect of low dose aspirin in respect to prevention of colorectal cancer, we're looking forward to seeing how that develops.

ANDI HORVATH
Some of my friends have to do the poo test.

SEAN GRIMMOND
Indeed, indeed. Do it - yes, everyone should. When that comes around, I'd recommend it.

ANDI HORVATH
Yes, it comes in a little envelope to your house.

SEAN GRIMMOND
It does, it does.

ANDI HORVATH
With a little scoop and a bottle.

SEAN GRIMMOND
That's it.

ANDI HORVATH
I've seen it.

SEAN GRIMMOND
Yes, I've done it; most proud. So from that you can pick my demographic. I guess the final thing I'd say is that when we think about prevention and cancer, cancer is still largely a disease of the elderly and the good news is, we're living longer. The other good news is that we are not getting heart disease and we're not dying of some of those things that we died of in previous decades. So as they've been steadily removed, we're seeing the prospect of cancers becoming more prevalent.

ANDI HORVATH
Sean, tell me about your cancer atlas. You're working on cancer genomes and you're doing thousands of them.

SEAN GRIMMOND
Yeah, indeed. So I guess the idea is that if we go through and we look, we understand first of all that someone's cancer arises through the accumulation of damage to their DNA, so you can imagine that as being like the hard drive in your computer and we're going to look at the damage that has occurred to that hard drive to make the computer not work anymore. Effectively what happens is that when we do that for a patient, we might find five, 10, 15, 25,000 spots that have been damaged within their DNA and as Peter and I know all too well, maybe one to four of those may be driving the disease.

So understanding an individual by itself is very challenging, but if we actually take hundreds of people with the same sort of cancer and put that together, we have a variety of approaches whereby we can start to sort out the signal from the noise and in doing so, start to work out what are the steps towards driving a particular cancer type. Indeed the more you put together, the more insights we get and there has been a very large international effort that both Peter and I have been involved in, where we've been actively contributing this to ultimately the 50 most common cancers and most important cancers globally.

ANDI HORVATH
So that's fantastic, you're getting all these genomes and you're doing essentially big data analysis and crunching the numbers and looking at the patterns and the rules, the exceptions and as you say, the signal from the noise.

SEAN GRIMMOND
That's exactly right, so we're looking at those recurrent patterns within cancers and indeed looking at the commonalities and differences between them.

ANDI HORVATH
So does that mean there'll be a day where if I am suspected of cancer, you'll actually be doing a genome test?

PETER CAMPBELL
Absolutely. I think that that's the hope over the next five years, that we will get to a stage where we will be sequencing everybody's cancer to identify those genetic changes. In many ways, the challenge for us in the next five to 10 years is to work out how we can maximise the information that we learn from patients who are having treatment and within the health system. There's always been a spirit within national health systems, both in Australia and the UK, of - as part of that contract of the state providing your health care, that they can learn from that experience.

I think that as we think about how we can use genomic information, what we're going to need to do is because everybody's cancer is subtly different, we need to build up big knowledge banks of information about people and the particular genomes that their cancer have and then relate that to what happened to those patients, you know, how did they respond to treatment, were they cured, did their disease come back again. If we can build up those knowledge banks, then for the next person coming in through the door into the hospital, we can compare their genome against this big knowledge bank and then what we might be able to do is to say, well based on this experience that we've built up, we think that this sort of treatment would be best for you and these are your chances of doing well with it.

ANDI HORVATH
What's been the most surprising element on your research adventures and your journey? What sort of caught you by surprise and made you go, wow, that is just amazing?

SEAN GRIMMOND
I think probably if I had to think, there'd probably be two oh-wow moments. The first would be while looking for a gene that predisposes some families, thankfully it's very rare, but predisposes families to a variety of cancers, the pancreas, parathyroid and pituitary, I chased that gene for about seven years trying to find that. While looking for that, I accidentally found a gene that encodes a growth factor that makes blood vessels grow, so completely by accident came across something there where I realised that would have a lot of potential, so ended up working on both of that in parallel. Showed me the power of serendipity in science and in fact that's a molecule that's going towards efforts in that many decades later are now going toward clinical trials here in an unrelated area right now.

I have to say, the other time that I really was, I guess, a bit swept away, was when we completed our first Australian cancer patient where we sequenced their genetic blueprint and their cancer genome and were able to then start to say, well within this, we now understand that that should be the root causes and what other insights can we get from it.

ANDI HORVATH
Peter, what surprises have you encountered along the way?

PETER CAMPBELL
I think probably my most exciting time was when I was a relatively junior scientist and I had just taken up a position at the Sanger Institute and we had these machines that no-one quite knew what they did and no-one really knew whether they worked and they said that they would sequence DNA. We said, well why don’t we sequence a cancer's DNA? The data came out and the data's enormous, it's this kind of massive file of basically random letters and you have to kind of work with the computer to analyse it. There were no tools for analysing it, this was - we just got the - all we got back from the machine was a series of letters and from that we had to kind of work out what to do with it and how to analyse it.

So there was a kind of lot of, as you might imagine, false starts and agonising over it and then we would write a little computer program and it would take forever to do it because there was so much data. But eventually we kind of worked out how to do it and the sense of excitement as out of this morass of confusing data pictures and understanding emerged was truly extraordinary, a really exciting time. That, for me, is the kind of magic of science.

ANDI HORVATH
Do you find that some people have misconceptions about cancer or misconceptions about what you do? What are some of these misconceptions that you'd like to correct?

SEAN GRIMMOND
I think the one that I get probably most commonly asked by taxi drivers and things like that, they're a great way around the world, one of the most common questions I get is why is cancer so hard and why haven't you cracked it yet, almost like we're not working particularly hard and just taking our time, we're in no hurry. I guess then trying to explain to people that I think in some respects the scales have only really started to fall from our eyes in terms of understanding just how complicated cancer is and how any two patients can have far more differences between them than
commonalities. Until we can understand that at an individual level, you're not going to conquer the disease for that person. That's a tough ask, but I wish that was one that was more readily understood by people.

PETER CAMPBELL
I would agree with Sean. I think that the biggest misconception is that cancer is one disease. I think really what makes it so challenging to treat is the fact that it's actually only subtly different from normality, actually. The cancer cells, they retain many of the features of the cells that they started out as and they've just subtly altered it, but that subtle alteration is enough for it to behave in a completely destructive way. Unlike a bug, which is completely and utterly different to a human cell, a cancer is fundamentally a human cell, so any treatment that we need to develop to hit the cancer has got a very narrow target window of abnormalities to go at, because you've got this huge pool of normal cells that are basically very similar to the cancer cells. So finding a treatment that picks out that specific abnormality in a cancer cell is very, very challenging.

ANDI HORVATH
Now, gentlemen, let us into your inner circle of the laboratory. What were some of the antics that you're known for? Come on, let us into the inner circle. We want to know who you are.

PETER CAMPBELL
Probably my worst moment as a scientist was when I was giving a talk and you give a talk at a conference and there are questions afterwards and for some reason I'd given this talk and this guy got up and he was completely and utterly incensed by my talk and was really rude and just kept taking me to task on various things that I'd said. At the end of this questioning session, he said, well good luck or good luck with that in the most sarcastic tone imaginable. I muttered something under my breath that was not very polite and then I was like beating myself up for having muttered this thing and then my postdoc came up to me afterwards and said, oh look you really shouldn't have mouthed what you did. Then all the people around me said, oh is that what you said? We thought you said, thank you. Oh that's definitely what I said, thank you.

ANDI HORVATH
Awkward moment. Sean, did you have a nickname in the lab?

SEAN GRIMMOND
I don't think so, we're all far too busy being serious in the lab. I'm trying to think. The lab where I first started in, was actually in Armidale in New South Wales.

ANDI HORVATH
New South Wales, yeah.

SEAN GRIMMOND
Sort of halfway between Brisbane and Sydney and it was the animal science laboratory, so that was a place that - fantastic set of teachers there and researchers who really worked in complex genetics, which I think has stood me in good stead moving on and trying to understand how they do animal breeding and some of those things. As we now work in very big populations in humans, I found out - I realised years later how valuable that was.

I think that we had some pretty cheeky times there in that set of labs. I do have very vivid memories of, I have to say that OH&S probably wasn't as strict as it is these days and I used to, as I was very studious, I would cook up lots of spaghetti bolognaise and freeze it in the minus 80 freezer so no-one would nick it in the laboratory. Unfortunately one of the researchers had been to Indonesia and collected water buffalo samples which were promptly confiscated by AQIS and they took my weeks' worth of dinner at the same time. I was marched down to the head of department to explain why I was keeping my dinner with a series of water buffalo samples I knew nothing about. I can assure you now that things are a lot stricter, a lot more sensible these days.

ANDI HORVATH
Now you've got the opportunity to take the mic, take the soapbox, I want you to profess. Make a meme. Tell us what you'd like the public to think about next time they look at, I don't know, their lunch. This is your opportunity fellows, make us a meme.

PETER CAMPBELL
Science isn't linear. It happens by accident. It kind of bumps along, bumps backwards, it really - it isn't as kind of clear cut and full of breakthroughs as we think. It's a lot of argument and discussion and controversy and failed theories.

ANDI HORVATH
That's the reality of science.

SEAN GRIMMOND
Yeah, it's a tricky one. I've got a couple of things going through my head right now. I mean I think in terms of where we are with science right now, we have an unprecedented period where technology and science is coming together and for some people, that's very, very scary. For some people, they're very keen to ignore it or deny it. I would really encourage scientists and community to embrace that, because what we're seeing right now, certainly the types of advances that Peter and I have been involved in, even what we were talking about when we first started on this journey with the cancer atlas seven years ago, we would have thought what we're doing right now is almost science fiction, that we can now look at single cells and make sense of their genomes.

I fully believe that within five years that a genome could be the cost of an x-ray, between and x-ray and an MRI. It's going to really change the way we do everything, not just cancer, but also a whole pile of other things within our healthcare. Change is good, we just have to work out how to embrace it and we need to start to be proactive.

In hindsight when we're talking about this sort of - the idea of genomics in healthcare, it isn't just about taking the guesswork out of chemo and giving you what we think is going to be the best drug. It's going to start to give us insights into maybe you're going to react very poorly to a particular drug that's available, rather than get a very good response. We need to weigh both of those up in making a clinical decision. There may be a predisposition in your family and that's the reason why you have cancer. That actually will pop up from these studies too and we have to work out how we make the most of that.

So then when you think about it, this sort of approach won't just help with treating the cancer, it could treat - it could relate to the types of pain relief that you have and whether your genetics will make you prone to one or another. There's all sorts of aspects of clinical care that could be improved upon using this; we're just at the beginning of that road.

ANDI HORVATH
Do I blame my ancestors for my cancer?

SEAN GRIMMOND
I think I'd blow bad habits before I'd be blaming your ancestors for 95 per cent of the population.

ANDI HORVATH
Gentlemen, thank you.

PETER CAMPBELL
Pleasure.

CHRIS HATZIS
Thanks to our guests Peter Campbell from the Sanger Institute and Sean Grimmond from the University of Melbourne Centre for Cancer Research. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on September 18, 2017. You’ll find a full transcript on the Pursuit website. Audio engineering by Gavin Nebauer. Co-production by Dr Andi Horvath and Claudia Hooper.

Visit our sister podcast Up Close which features in-depth and long-form conversations with seasoned researchers across many fields. Check out the rest of the amazing content on the Pursuit website. And if you're listening to this on iTunes, drop us a little review.

I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.