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Meet the Solutionists, with Mark Scott
Season 3, Episode 4 transcript and episode notes
There's no one else on the planet just like you. So why do you take the same medicine as everyone else when you get sick? Professor David James sees a better way... And it starts with your genes.
In your DNA - the future of medicine
There’s no one else on the planet just like you. So why do you take the same medicine as everyone else when you get sick?
Professor David James is an expert is obesity and diabetes, and he says the current medical system isn’t good enough. But as researchers and clinicians learn more about how our genetics work, a better path is beginning to clear.
David explains how your genetics and environment interact with one another and influence your health, and what this means for the future of medicine. You’ll also meet Harry and Stewart from David’s lab, who share how this groundbreaking research gets done.
Mark Scott 00:01
This podcast is recorded at the University of Sydney's Camperdown campus on the land of the Gadigal people of the Eora nation. They've been discovering and sharing knowledge here for 10s of 1000s of years. I pay my respects to Elders past and present, and extend that respect to all Aboriginal and Torres Strait Islander people.
Stewart Masson 00:28
So now that we're in the lab, it's really important that we put on our safety equipment, so gowns and safety glasses to just protect us from anything in the lab, but also to protect the things you're working with in the lab from yourself. So what I'm doing here is I've got some tubes that have got some tissue in them, and I'm just adding some stainless steel ball bearings to the tube so that when we put them in the tissue laser, the bead will break down the tissue to free up what's inside the cells, the proteins and the metabolites and the DNA, or whatever it is we're trying to study.
Harry Cutler 01:04
Sort of like a giant mechanical mortar and pestle. So the tissue laser lets us analyse about 20 samples at a time, but it's quite a fast process, and so you can just cycle through tissues in a matter of hours. You can get through several hundred.
Mark Scott 01:22
You're not well, you go to the doctor and you find out what's wrong, you get the medicine. It's been that way for as long as I can remember. But how do we know it's the right medication, the right dose. How do we know it's the best thing that can be done for me? Because aren't we all unique? Shouldn't the medicine be responding to that uniqueness to me? Professor David James is an expert on metabolic diseases at the University of Sydney, and he's seeking to understand how these diseases, like type two diabetes take hold, and how we can prevent them. And part of that is looking at a bold new frontier of medicine tailored precisely for each of us. Hi, David, precision medicine sounds like something out of a sci-fi movie, but lots of people are hotly pursuing it now. Just explain to us what precision medicine is.
David James 02:28
Precision medicine is an attempt to go beyond where medicine is today, which is really, as you said, a one size fits all approach. If you and I go to the doctor with the same disease, we'll get the same drug at the same dose, irrespective of our body dimensions, our gender, etc, etc. So that's just one example of how I think we've reached a point where this is not good enough anymore. So precision medicine is an attempt to deliver medicine with greater efficacy, so that the drug will work better and with reduced side effects.
Mark Scott 03:09
You're particularly interested in precision medicine in the context of metabolic diseases like diabetes and cardiovascular disease. Where do you see the goal? What's the great opportunity in this space? And why do you think a tailored solution will bring far better outcomes?
David James 03:24
So if you or I were to go along, freshly diagnosed with type two diabetes, to see a physician, we would be told, firstly, you should try to manage it with lifestyle. You should try to eat less, do more exercise, and we would be prescribed the first line of medication, a drug called Metformin. It's reliable. It's been around for 50 years, but the problem is, we'll then be sent away, and three months later, we'll come back to see the doctor, and the doctor will determine whether that drug has worked or not. In many cases, it won't work, and in those cases, an additional drug will be added. Another three months will go by, and that process could be repeated four times. By the end of it, that person could be taking four different drugs, whereas what I would like to see is if we could do a test on people right at the get go, and that test would tell us you should be taking drug Y, so that you immediately prescribe drug Y, save all those problems, and you save the potential dangerous adverse effects from taking four medications instead of one.
Mark Scott 04:45
The foundation of the work that you're describing here, the opportunities comes back to the Human Genome Project, which is now 20 years on. What did we learn from that project, and how has that been a breakthrough in the science that could lead to the applications you're discussing?
David James 05:01
Yeah, well, I think for me, personally as a scientist, I would have to say that Human Genome Project has been the greatest project in science ever undertaken. So the genome in humans is a compendium of 3 billion little chemicals locked together, arm in arm in a long string, okay, 3 billion pieces of information. Now in that is encoded everything that happens in every cell in our body. The important point to realise about the genome, though, is it's a blueprint. It's a static blueprint, and from that comes the working parts that enable all the cells in our body to function, our heart to beat, our brain, to think, and so on. All of those things are encoded by the proteins the working part, which comes from the genome. So it's a little bit like a house. You think you've got a blueprint for the house, but that's just the beginning. It's a static process, and it's the bricks and the windows and the doors that are the working parts of the house. And you change the blueprint, and then you need more bricks or different kinds of Windows, and that'll give you a different kind of a house, and it's exactly the same for the genome. The genome can change. Your genome is different to mine, and that means that your cells produce different amounts of proteins than my cells.
Mark Scott 06:33
Is it radically different to yours? What's in common and what's different?
David James 06:37
So one of the great things that the genome has taught us are the differences, not just between you and I, but between you and monkeys, you and rats, and it's extraordinary. The difference between you and I and a monkey is about 1% at the level of our genome. Fantastic. The difference between you and I is incredibly small.
Mark Scott 07:02
But in that incredibly small difference, there's a world of difference in how exact medical intentions could work for us.
David James 07:10
And that's really where I would say the greatest opportunity that biology provides us today.
Mark Scott 07:17
And is the great difference between us, genetic difference that goes back through the generations, or is it the lives we've lived?
David James 07:26
It's both. And you know, this is actually the biggest challenge. So it's not just the genes, it's not just the environment that we all live in, but it's how the two interact. Okay, can I give you an example? In Greenland, we have indigenous people called the Inuits, and they've been living on Greenland for, you know, many, many, many 1000s of years. And historically, you couldn't grow crops on Greenland. So Greenlandic Inuits ate fish, and their genomes evolved coordinately with this fish-eating behavior, so they probably developed the genome that was well suited to eating at the high fat diet upon the introduction of modernisation in the last 30 to 40 years, unfortunately, the Inuits have become one of the most diabetic races on planet Earth. The genomes have been sequenced of the Inuits, and they have a mutation in a gene which we actually work on in our lab that is responsible for handling carbohydrate. So there we have a mismatch. These folks, they lived for 1000s of years eating fat. They have a genome that's probably perfectly suited to eating fat, and they had a mutation in a gene that handles carbohydrate, and maybe having that mutation for them at that time was beneficial. But now all of a sudden, in the blink of an eye, they're eating sugar, and that is a beautiful case where the genome can't keep up with the changing environment, and what you have is an epidemic of disease.
Mark Scott 09:17
So you're looking for the insights to drive changes in metabolic diseases. There, there are other diseases which seem well down the road on this journey, cancer being one, if someone's diagnosed with cancer, does genetic testing help?
David James 09:35
Absolutely, I would say cancer, at the moment, is having the biggest wins in precision medicine. Australia's leading the way. We've got people over at Prince of Wales, people in Peter MacCallum in Melbourne, really top notch. They are sequencing people's tumors, and then they're trying to see what's specifically mutated in an individual's tumor and matching the right therapy with that mutation.
Mark Scott 10:00
And this is giving rise to things like immunotherapy.
David James 10:02
That's one of the branches of this, and it's incredible.
Mark Scott 10:06
Why is cancer further ahead? Is that a funding question?
David James 10:10
It's partly but it's also because, certainly diabetes a classic case where the genes and the environment interact. I think for cancer, there is also an element of that, but it's not quite as dominant. The other aspect, interestingly, is that most people, our politicians even, I was down at Parliament House recently, and there's a lot of people think that diabetes and obesity are purely lifestyle related diseases. They're self inflicted. About gluttony and slothfulness, absolutely incorrect. These diseases are genetic.
Mark Scott 10:52
If it's genetic, why is there an epidemic?
David James 10:56
Because the environment has changed in the last 30 years in such a way that it is just like the Inuits, we've got an inappropriate interaction between the environment of today and the genes that were bubbling away there over the last 100,000 200,000 years. So the environment has changed too quickly,
Mark Scott 11:19
And then some people will have a genetic predisposition David: Correct Mark: That changed.
David James 11:24
That's right, just like the universe. And look, we know it has to be more than just the environment, because if it were just the environment, all of us would be obese.
Mark Scott 11:33
Yeah. Now you're still learning and doing great research here at the University of Sydney. I understand you've got a famous colony of mice. Tell us about them.
David James 11:41
Yes, very famous. We're the only academic institution in the world that has these mice. So what's special about them is, unlike most mice that people work within labs, which are what's called inbred it'd be like working with identical twins. So the DNA is absolutely identical in every single animal. And what I've realised, or did several years ago, what's limited about that is that that'd be like me doing tests in you over and over and over again, thinking that I could understand biology and the human population. It's just it's naive. So you've got to study the whole population. So these mice have as much genetic diversity within them as exists in the human population. And that's perfect, because we can now start to study the genetics and the environment very accurately. So one of the discoveries that we've made, is that we got interested in the idea that, you know, most people, when they look at genetics, they try to find genes that are associated with disease. We know there are people who live well into their 90s, who never get any disease. There are these blue zones in the world. Okinawa is one of them that have a very unrepresentative number of what's called centenarians, people who live beyond 100 years of age. These people, they have no cancer, no cardiovascular disease. So the idea there is that those people are probably got genetics that protects them against getting diseases. So anyway, coming back to our mice, so we went looking for genes like that, and we think we discovered one.
Stewart Masson 13:38
Yeah, my name's Stewart Masson. I'm a postdoc in the lab of David James. I'm originally from New Zealand, and I've been working with David for just over three years.
Harry Cutler 13:46
My name is Harry Cutler. I'm a PhD student with David James. Been in the lab for about three years.
Stewart Masson 13:50
I work with Harry. I'm part of the team that supervises Harry. We started working together in 2021 we spent most of the covid lockdown together.
Harry Cutler 13:59
Stewart was actually one of the only people that I saw for about three months. Yeah, it was because we couldn't leave our LGAs and things like that. The only reason I was allowed to leave home was to come in for work Stewart: Yeah, likewise. Harry: And Stewart was the only person in the building.
Stewart Masson 14:09
I just moved to Australia, so that was my Australian experience. Was trying to develop a method to quantify how insulin sensitive mice are as a proxy for humans, because if you want to study insulin resistance, particularly the genetics and insulin resistance, you need to be able to measure it, and we weren't satisfied with the methods that were out there, so that's what we did, and we've been since then we've been sort of trying to piece together the story based on the data we generated that in 2021.
Harry Cutler 14:41
So we've done drug studies where we've looked at the ability of mice to lose weight when they're given an anti-obesity medication, and we find, just like in human populations, that there are non-responders to that medication, we've gone and looked what's the fundamental biology that leads to that?
Stewart Masson 14:54
I mean, there's been decades of work, right, to produce these diabetes drugs. Odmic is the most recent example, but there's been many, many, many, and they don't always work for everybody. And the question is, why don't they work for everybody? And I think if we can understand that, we can use our drugs in a smarter way that saves everyone time, it saves everyone money, it improves patient outcomes.
Mark Scott 15:18
So these are like, genes that make you healthy, rather than genes that make you sick. Extrapolate that thought forward for me, so as I understand say, some cancer treatments will be attempting to target genes and turn off genes that make you sick. Could you see a scenario where attempting to turn on genes or inject genes that make you well?
David James 15:44
Absolutely, you know, I think that would be my ultimate dream. And you know, the problem is, again, if you think about the medical care system of today, we're so hamstrung with just dealing with disease. You know, in the hospitals, in as far as diabetes treatment is concerned, all of our physicians are so busy just treating complications, you know, blindness and trying to prevent amputations, it's just not enough time to for people to think about prevention. And this is where I think we need a big, big investment of resources so that more people can focus on that end of the spectrum.
Mark Scott 16:26
We talk about obesity. The big issue that everyone is engaged in now, or getting so much media attention, is the diabetic stroke Ozimpec, which has been touted as a kind of a profound intervention for people who have metabolic disease. Why is this such a big deal now? And what do you make of the Ozempic revolution?
David James 16:46
I think it's a revolution. I mean, as far as I can ascertain, it's one of the greatest breakthroughs in 100 years. I mean, I used to say the biggest breakthrough was the discovery of insulin, you know that transformed the lives of millions of people literally overnight. If you talk to physicians who treat obesity, as I often do, in the past, all they had was lifestyle. Mark: Yeah David: that's all, you know, a patient would come in, they'd say, look, you need to eat less and you need to exercise more. And frankly, we know that it can work. If I lock you in a room and make sure that you don't eat, I can reduce your weight. But if you're set free in the world, it just doesn't work. That's the reality. This drug. The latest clinical trial shows that you can get the newest version, you can get about 25% weight loss after six to 12 months. That's incredible.
Mark Scott 17:49
And that will have a remarkable effect on health, long health, long term health.
David James 17:53
And a whole range of diseases. You know, obesity, it's not only linked to type two diabetes, it's linked to cardiovascular disease, a whole series of cancers are linked to obesity, neurodegenerative disease. So you know this is going to be an absolute game changer at one level.
Mark Scott 18:12
Are you worried there's not an off ramp for it? I think some of the coverage would suggest once you start taking this, you're going to need to take it for the rest of your life.
David James 18:20
That’s correct. As data just out, it says that people that go off it regain two thirds of the weight within a year.
Mark Scott 18:29
I suppose there are a lot of medications, though, we know we'll be taken for the rest of our lives David: Sure. Mark: So should we be worried about that?
David James 18:36
I think so, because there are side effects. Again, it's such a new drug, we don't yet know what all those side effects are going to look like.
Mark Scott 18:43
But does it work for everyone?
David James 18:47
No, and that's one of the problems. So again, latest data shows that it's a large trial down many 1000 people over a year or two, and only 44% of people achieve weight loss of greater than 10%, many people showed absolutely no weight loss at all.
Mark Scott 19:07
And is that due to their genetic predisposition?
David James 19:11
We don't know for sure. I can only speculate, but I would say almost certainly, it's a combination, again, of the genetics and the kind of food they eat in the environment that they live in.
Mark Scott 19:21
So it's a breakthrough drug, but it's not a precision drug.
David James 19:24
Not yet. And again, I think this should be and will be a major focus of research to find a test to predict those that will respond.
Mark Scott 19:36
What you see in the global phenomenon is that it's wealthy people who have the money to access it, many of whom will not be in greatest need for that kind of drug. Are you worried at the price tag?
David James 19:50
It's our biggest concern. Yeah. I think the last thing we want to be doing is creating medicine for the rich. I think that is absolutely inexcusable. It is an expensive drug to make. It's, it's not like your typical drug. It's actually it's a protein. It's a large molecule, and you have to synthesise it in a lab and make it in huge vats. It's really a big, big drama, if you consider this, probably about a billion people on the planet right now, who probably could do with as epic, the math just doesn't stack up. So we need to somehow either make it more cheaply, or what I would prefer to see is to take alternate approaches, more focus on public health. One idea is that we get people to take Ozempic to lose weight, and once that has happened, we implement public health strategies, subsidised food, more organised exercise programs for the public to keep the weight off. And I think that's the kind of thing we have to be thinking about.
Mark Scott 21:03
So if I have family members who've had type two diabetes, if I have family members who have Alzheimer’s say, and I show no signs of these things yet, should I have tests done to tell me that this is a possibility in my life? Am I better off knowing? What would I do with that knowledge, and is this going to be a common part of my life, my children's life, grandchildren's life?
David James 21:30
I always say there's no point giving somebody bad news unless I can give them some good news as a follow up. So in other words, there's no point me telling you that you're going to get disease X, unless I can tell you what you can do to avoid getting disease X Mark: Now, you can do something about diabetes. David: You can do something and cardiovascular disease. Mark: Alzheimer's? David: Their, exercise, for example, has incredibly potent effects on cognitive ability. So I would argue that's certainly something that if you knew that you had the genes for that Mark: Have you had a peak yourself? David: Of my own? Mark: Yeah David: I have not, I have not what you're going to ask me, why now?
Mark Scott 22:12
Yeah, why?
David James 22:14
Why? I'll tell you why. Because I don't think we're ready for prime time yet. What I believe is that you know we're getting there, but there's no point peaking unless you can enjoy the spoils of everything that's there to be had. So I want to wait until I can be assured that I'm going to get the right information and it's going to be accurate and I can do something with it.
Mark Scott 22:46
Are you worried that health insurers are going to want you to take that test?
David James 22:51
Of course, and, you know, I think again, this is where we're going to have to have legislation around this, very accurate legislation. But you know, having said all this, I've been around for a while, and I remember back in the early 80s when we were all sort of cloning genes. You may remember that time, and in the streets of Boston, the public were marching and protesting. And this was, this was going to be terrible, you know, we're going to create mutants all over the place and, Mark, here we are. You know, 45 years later, and actually, it's nothing but good has come from that. Once upon a time, people with type one diabetes that inject themselves with insulin. That insulin came from pigs and cows. Today, that insulin is made by recombinant DNA technology.
Mark Scott 23:44
You sound very excited about where the future could take all this.
David James 23:48
Absolutely I'm excited, because the way medicine is delivered right now is not good enough, and you can see an opportunity to make it better. But more importantly, this whole big data revolution, you know, I can see so much opportunity if I think back to the kinds of experiments we used to do 30 years ago and how long it took us compared to what you can do today. I'm talking 1000 fold improvement in speed and accuracy with which you can do things, I think, as a young person growing up today, a career in science offers so much excitement.
Harry Cutler 24:37
We're now standing in front of the mass spectrometer. So what this looks like is two boxes, and the first box is where all the samples go. So you put the samples in the bottom, and then it's a series of pumps that pump liquid around into essentially a fishing line, which then goes into the mass spec. And so the second figure of these boxes looks like something from Star Trek, really. It's got lights and it's got shiny metal bits, and inside that is a bit of equipment that lets us quantify the amount of proteins in those tissue samples that we've just been working with. This is the biggest collection of mass spectrometers in the southern hemisphere as well. And so there's about five proteomics instruments. And there's also things that measure metabolites and lipids and basically any biological molecule that you might want to measure.
Stewart Masson 25:22
So we've just been through the we've just taken you through the Charles Perkins Centre, and we've been in our laboratory, where we do a lot of tissue processing, and we've been down to the mass spec facility, where, thanks to the efforts of everyone in Sydney Mass Spec, we can analyse 1000s of proteins and metabolites and lipids at a time, and by combining that with genetically diverse mice that we work with, we can start to unlock how do your genetics influence your biology and your metabolism in a really intimate way. And then hopefully, with that information, we can start to predict why do drugs work for some people and not others, and can we develop new therapies that will work for more people and really make some breakthroughs.
Harry Cutler 25:59
I think one of the things that excites me about working in the Charles Perkins Centre in David's lab, more generally, is that a lot of the things that we do weren't possible 10 years ago, and so even doing mass spectrometry on this sort of scale was just unheard of a decade ago. We've come so far so quickly that I really don't know what the next 10 years will look like. We sit around at lunch and laugh about the things that people used to do 30 years ago in science, and it's really exciting to think, what will they be laughing about that we did today? And I'm sure that some of this tissue processing that we've shown you will be some of that, you know, they'll just, there'll be these methods for analysing biology that we just can't think of yet. And it's really exciting to be a part of that.
Mark Scott 26:40
I'm Mark Scott, the Vice Chancellor of the University of Sydney, and I've been speaking with diabetes expert David James. You've also heard from Harry Cutler and Stewart Masson, both researchers from David's lab. If you enjoyed hearing about the future of health, you might also like my discussion with Dr Carmel Harrington about getting better sleep.
Carmel Harrington 27:01
One of the things, or many things, our brain does when we sleep is bed down memories. So memory is a very complicated process, and the hippocampus is very much involved in it. And if we don't sleep enough, what we find is that we lose the ability to encode memory.
Mark Scott 27:18
Check out that episode now and follow the solutionists in your favorite podcast app so you never miss an episode. The Solutionists is a podcast from the University of Sydney produced by Deadset Studios. This episode was recorded at the Faculty of Arts and Social Sciences media room, and our thanks to the technical staff here you.
The Solutionists is podcast from the University of Sydney, produced by Deadset Studios. Keep up to date with The Solutionists by following @sydney_uni on Twitter, Facebook, and Instagram.
This episode was produced by Liam Riordan with sound design by Jeremy Wilmot and field sound recording by Gia Moylan. Executive producer is Madeleine Hawcroft. Executive editors are Kellie Riordan, Jen Peterson-Ward, and Mark Scott. Strategist is Ann Chesterman. Thanks to the technical staff at the Faculty of Arts and Social Sciences Media Room.
This podcast was recorded on the land of the Gadigal people of the Eora nation. For thousands of years, across innumerable generations, knowledge has been taught, shared and exchanged here. We pay respect to Elders past and present and extend that respect to all Aboriginal and Torres Strait Islander people.