Doctors who personalise treatment for precision

When we talk about personalised medicine, I can see a future maybe in 10 or 20 years' time where we all have the sequence of our genome.

The a's, the t's, the g's and the c's that make up all three billion letters of our DNA. And we carry that around on a bank card or a chip, and we use that information to make decisions about how we're going to be treated for particular problems that arise day to day, week to week, month to month.

GAY ALCORN - Hello my name is Gay Alcorn and welcome to a University of Melbourne podcast on the brave new world of work - a series about the future and the skills and the outlook needed to make the most of it.

Today, doctors who personalise treatment for precision. How long will it be before we carry our genomes like driver's licences? And what does that mean for the next generation of doctors?

To explore this, I'm joined by Professor Doug Hilton from the Walter and Eliza Hall Institute of Medical Research. And Professor Ingrid Winship from the University of Melbourne and the Royal Melbourne Hospital.

Now, we know that our bodies are made up of millions of cells, but a lot of people may not know that these cells have inbuilt instructions known as genomes. Is this what the medical world refers to when they talk about personalised medicine?

DOUG HILTON - So my sense is that we're at a tipping point. So, the technology that we have at our disposal for deciphering and reading an individual's genome or the genome of your cancer - which is different from your genome, and that's a really important distinction - is way ahead of what we're doing clinically and what we're doing from it from a treatment viewpoint.

So, we can sequence the DNA of any individual now - almost overnight - and then, with the use of computers and mathematicians, we can begin to understand what that information means. But the capacity to apply that to everyday health care is the point where we're not quite at yet.

The challenge for us is how we translate the technology that we have at our disposal into something that can be used in everyday healthcare, when you might be talking to your general practitioner, who may not be up to speed with all of the new technologies and implications of the technologies.

GAY ALCORN -Do you agree Ingrid? Are we at a tipping point?

INGRID WINSHIP - Oh absolutely. I think the technical possibilities are there. The application is at best patchy. So, I think it would be fair to say we are using genomic technology for testing, but in most branches of healthcare that is yielding an answer which actually is a single gene disorder. And then we're acting in the same classical way as we have before.

There are some areas though that genomics is leading the way and so you can do genomic testing on my constitutional DNA. In other words, the genes that I inherited from Mum and Dad and look at the genome that way. But you can also take a tumour and interrogate that tumour by genomic technologies and look for the changes in the genes in the tumour.

These are not changes that you inherit in the main. They are not changes that you're born with or predispositions. That's a different group of genetic information. But the actual changes the signature within the tumour gives you much more information about the tumour than we've ever had before.

GAY ALCORN: So what does genomics and precision treatment mean for the average patient then? How can we expect to be treated?

DOUG HILTON: I see the genomic analysis and the use of genomic technology as being about more precise diagnosis.

So, what it allows us to do - and this has been a pathway that we've been on for 50 years. And that is, if a woman presents with breast cancer, we don't think of breast cancer as a single disease and for any of the listeners that have had relatives - women or men - who've had breast cancer, we start talking about what the cancer is positive for. That is, what markers are expressed by an individual's cancer that might be different from other women's cancers and we can have things like triple negative and single positive and double positive breast cancers and knowing which markers an individual's cancer is positive for, then leads to more tailored therapy.

So, one of the things that occurs is if we, for example, work with leukemia. We've known for a while that there are characteristic changes in different types of leukemia. Some genes are turned on and some genes are turned off and what another branch of precision medicine aims to do is to find new pharmaceuticals, new medicines that will target a particular change that leads to cancer, but not be effective for other types of changes.

So, it's about going from treating leukemia with a very blunt chemotherapy that has a lot of side effects, to trying to identify a change that has occurred in an individual's blood cells to drive an individual's cancer. And then finding a very specific treatment that targets just those blood cells with those changes, leaving other cells relatively free.

And that's great because it means you can have an effective treatment without having the horrific side effects of chemotherapy. So, hand in hand with precision diagnosis, we also need precision treatments and they often take a lot longer to develop.

So where we'd like to be in 30 or 40 years' time is to have an understanding of all of the different genetic changes that cause cancer. But then to have an arsenal of medicines that we can use and deploy depending on an individual's changes to target just those changes that will lead to great outcomes for the patient.

It changes the way we think about developing medicines. We no longer do large trials with a very heterogeneous patient group. What we're trying to do is to get precision clinical trials where we can stratify the patients based on those who are most likely to succeed with a particular medicine, and test them in that group rather than testing them on a broad patient group.

INGRID WINSHIP - I run the clinical trials unit at the Royal Melbourne hospital as part of my role and there's been a major change in the way that we do clinical trials. So, the sort of more boutique N of 1 trials where we're moving into a much more precision approach. But part of clinical trials readiness is understanding the genomic basis of disease.

Doug mentioned breast cancer and there are two very good examples. One that's been around for quite a long time which is mentioning receptors. Herceptin is a receptor positive status that some breast cancers have. So that is, testing the tumour and finding a particular signature and there is a drug which is very effective for those breast cancers. As Doug said, breast cancer is not an anatomical diagnosis anymore. It's a - there are multiple different diseases which manifests as a tumour in the breast.

But, at the other end of the spectrum, some women are born - or some people, men and women - inherit an alteration technically called a mutation in the BRCA 1 gene. Now, if you have a mutation in that gene, you're highly predisposed to breast cancer. So, you have an inherited vulnerability. If you develop breast or ovarian cancer on the basis of that, there certainly is good evidence now from clinical trials that there are targeted therapies which work better on women with BRCA constitutional mutations than others. So, we've got one example of precision from interrogating the tumour and one from looking at the genome.

But if you look. Probably the two areas that are best developing, or one of the areas that's better developed in genomics and healthcare, is in the area pharmaco genomics. So, this is understanding the impact of drugs on people with different genomes. And we've known for a long time now that some people react badly to drugs and not really known why. If you take drug response, some people do very well. Some people get no response at all. And some people get adverse events. Now obviously preventing adverse events is a very important thing to do, but also preventing use of drugs that do nothing is really important - particularly in the elderly.

Many elderly people have to take a lot of medications on a daily basis. And if they're not doing anything, they may actually be interacting with each other negatively. It's not good healthcare. And that's one of the learnings that we need to bring and this is where teaching pharmaco genomics to medical students is really important. And in the model at Melbourne, because it's postgraduate course, they're very clinically orientated right from the beginning.

GAY ALCORN: We hear the term big data use a lot in the field of medicine now. Doug, what does this mean for healthcare?

DOUG HILTON - So, my sense is that we have a lot of information that we collect as individuals and we can think through you know the devices that we wear that track where we go. Our phones track where we go, Fitbits track our exercise, the number of steps, often our heart rate. There's a lot of information that we have about activities minute to minute, hour to hour, day to day.

And, yet for most conversations that we have with our general practitioners and our specialists, we're not taking advantage of any of that data. So, really the big data challenge is how do we take, how do we get access to and usefully use all of the data that we have at our disposal? And that might be things like as I said, exercise, it may be our genetics, it may be pollen counts in the atmosphere, it may be the temperature. There's a whole lot of things that that that are measured all the time but which we don't integrate and which are not used to make decisions about healthcare.

And I think one of the challenges in the future will be how we access all of that data. How we integrate it and use it in a way that's useful. And then how we present that to both the patient and the treating practitioner to make decisions about prevention and treatment.

GAY ALCORN - I think from the general public there is an awareness of data being used for prevention these days. People know that where there is a predisposition to, say, breast cancer in the family that you can get tested for that. But it does raise questions at a personal level about whether to get these tests and what to do with your life once you get those results. So how do you handle that from a clinical perspective?

INGRID WINSHIP: One of the big ethical issues at the moment that we're grappling with is at the moment healthcare is very focused on - you get sick, you go to the doctor, you have a test, you have a treatment. And it's not focused on prevention and it's certainly not focused on precision population health, which is what we're trying to do.

But if we actually had better knowledge about what we were predisposed to, we could modify the factors that we can't modify. So, I can't modify my genes, but I might be able to say - well I'm genetically predisposed to A, B and C, therefore I will do the following things. Now that presupposes that human behaviour changes as well. And we all know that that's not quite straightforward!

But one of the big ethical issues around knowing about all your genes is - do you want to know? And how much do you want to know? How much can you know? How much should you know? How much do you want to know? And when you have a single gene test, you find out an answer about that gene.

We're already grappling in the clinical scenario with the fact that we do have panels of genes. So, they are roughly appropriate to the clinical reason that somebody has come to have that sort of testing. But we are able and we do, now in practice, sometimes do whole exome sequencing and whole genome sequencing (which is looking at a whole lot of genes, or all of the genes). And so, you may come in to have a test about cancer and find out about a heart disease. And the question is how willing are people to know that? How ready are people to know that? And this is why the community engagement so important.

DOUG HILTON - So, my sense is that whole genome sequencing will be commonplace. Most diverse will be carrying around our genome sequence on a bank card or a chip or in some form and that we will use that sequence in ways that Ingrid just outlined.

That is to inform the care or prevention that we have for today for the diseases we are most worried about. And that might be, you know, I want to go in for a general anesthetic for a particular procedure. And the anesthetist will want to know which will be the best anesthetic for my particular genome. And they will be able to dial up a half a dozen genes, or the 50 genes, that predict good outcome under anaesthetic and choose the right one. So, I sort of see it as a passport that you carry around for your life and you use for the particular challenges that you're facing at that point.

GAY ALCORN - Are we're close to that do you think? How far away is that?

DOUG HILTON - Look I think we're probably 10 years away from that. One of the big challenges is around healthcare infrastructure. So, having a good electronic health care record. So, not only can you carry around your genetic and genomic information, you can carry around a history of what you've been prescribed. Perhaps through visits to lots of different GPs, as you move interstate or go on holidays, or visit hospitals, or perhaps travel overseas. Being able to carry that around in a way that is accessible to whomever you're going to for care at a particular time is also really a really important step. And one we've not invested in entire healthcare systems.

So, in Melbourne there are a couple of hospitals that have a wonderful experience putting in new electronic medical records. The Children is one. The Austin is another. But, if we look around the Melbourne University precinct there are lots of hospitals that still have paper records. And that's really inefficient. And what it runs the risk of is that that we're not using all of the information at our disposal to be able to make the best choices about our own lifestyle and our own management of disease.

GAY ALCORN - Well, a couple of reflective questions to end. One is I guess relevant to generational change. I mean if you were starting out in research or medicine now, give advice to your younger self. What would you tell yourself with the knowledge you know now about what you will need in your profession? Ingrid?

INGRID WINSHIP - Well I made my career choice to be a geneticist when I was about 14 which is longer ago than I'm willing to admit. But I could see that the unlocking of genes was the future of medicine. And as it turns out, that was not a bad career choice, because there certainly has been a revolution in what one can understand about genes.

GAY ALCORN - And Doug? A young scientist?

DOUG HILTON - A young scientist, or a young doctor. I think the things that I would suggest would be - sample research. Research is different from conventional learning whether, you know, at a high school or at a university. So, medical students at Melbourne Uni get six months to do research as part of their graduate medical course. Find something about which you're passionate and then do research for six months so begin to understand what evidence based medicine looks like. Evidence based decision making.

For a young scientist, I would say stick with it. Get as much computer science programming and mathematics under your belt as you can. Even if you then specialise in biology, it's going to be a tool box that you want at your disposal.

INGRID WINSHIP - And I think one of the most important things that a young doctor needs is to be able to work in a team. The solo practitioner is probably not enough. You may see one doctor as the consultation, but that doctor is informed by their readings and their interactions with others.

But as we embrace more complex medical problems, multidisciplinary teams - teams of allied health professionals, nurses, other people involved in healthcare, as well as community advocates - are very important. So if a young doctor wishes to be successful, learning to be part of a team is really a very important skill set.

DOUG HILTON - I think it's a great idea to have scientists that are not medically trained spending, ideally, you know, a week or a couple of weeks, with a doctor, a medical doctor doing everything that they do. Equally I think it's great if we can get our clinicians, as I said, during their training to spend some time doing research to open their eyes to that side.

And I was recently in Oxford where one of their programs is to have their clinicians spend time in industry. So, that would be pharmaceutical industry for a lot of them. Again understanding the pressures of taking new medicines from discovery through to the point where they can be prescribed. So, I'm a great advocate for people getting out of their comfort zone and seeing the world from a different viewpoint. And I think if we do that then we'll end up with a much better medical research and general community.

GAY ALCORN - You have been listening to a University of Melbourne discussion between Professors Doug Hilton, Ingrid Winship and me, Gay Alcorn.

In the changing world of work, the Melbourne Model is preparing students for the future beyond their degree. To find out more, visit unimelb.edu.au and look for Melbourne talent.