Instant Genius - Genetic testing, with Sir Peter Donnelly

Episode Date: December 2, 2022

Professor of Statistical Science at the University of Oxford, and founder and CEO of Genomics PLC, Sir Peter Donnelly tells us about exactly what genetic screening can tell us about our health and what we can do to stay healthy regardless of our genes. Hosted on Acast. See acast.com/privacy for more information. Learn more about your ad choices. Visit podcastchoices.com/adchoices

Hey, how are you? Ready to go for a run? Running connects us to a rush of energy that flows through our world. The cheers of friends that unlock a new gear within us. The intersection of interests that inspires a run crew. The support that gets you over the finish line. Connection is why we move forward and what inspires us to keep going. Let's run there.

Learn more at brooksrunning.com. If data management is slowing down your business, you need the Intuit ERP. If one entity is here and one here, and one here, and one here, you need the Intuit ERP. If scaling your business feels like start starting over, you need the Intuit ERP. Intuit Enterprise Suite is the AI-native ERP solution that consolidates, migrates, and automates, all in one place. Learn more at Intuit.com slash ERP. Whether it's a movie night or just midday, Skinny Pop is a salty snack that keeps on giving.

Made with just three simple ingredients for an irresistibly delicious taste and a large serving size that lasts. Deliciously popped, perfectly salted. Skinny Pop, popular for a reason. Shop Skinny Pop now. This podcast is sponsored by name, audio, and focal. Streaming has made music more accessible than ever, but true listening is about more than ease.

It's about quality. British audio experts name audio, alongside French acoustic specialist focal, combine handcrafted tradition with cutting-edge innovation and high-end materials, delivering digital precision with analogue warmth. So you can experience exceptional sound at home. Music just as the artist intended. Visit name audio.com to learn more. Hello and welcome to Instant Genius, a bite-sized mask club.

us in podcast form. I'm Jason Goodyear, commissioning editor at BBC Science Focus magazine. In a recent documentary, the Australian actor Chris Hemsworth discovered he is at a higher risk of developing Alzheimer's after taking a series of genetic tests that predict the risk of future disease. It turns out he carries two copies of a gene that predisposes carriers to developing the disease. The news came as something as a shock to him and has led to him taking a break from acting to concentrate on his health and future.

but how accurate are genetic tests? Should we all be having them? And what can we do if we're genetically predisposed to certain illness and disease? In this episode, I speak to Sir Peter Donnelly, Professor of Statistical Science at Oxford University and the founder and CEO of Genomics PLC. He tells me exactly what genetic screening can tell us about our health

and what we can do to stay healthy, regardless of our genes. So in the documentary series that's just running now on Disney Plus, the actor Chris Hemsworth took a genetic test that flagged him up as being at a higher risk of developing Alzheimer's disease. And after finding this out, he's taken a break from acting to think about his health and his future. So obviously this throws up a lot of questions. I think the best place to start is let's have a look at the tests themselves. So say I'm going to have one, what happens, you know, and how do I go on about having my genes analyzed in this way? There are different ways of getting that kind of testing done.

Quite often it would happen in a medical context if people were thought to be high risk or if they had disease running in the family where we know there's a strong genetic component, then in the UK, the NHS, but doctors could order the right genetic tests. But it's sometimes possible to get these done in other ways from commercial companies. usually they would involve taking a sample, a biological sample from the individual, typically either a blood sample, which is a bit more common for medical tests, or a saliva sample. And then that would be sent to a laboratory. The laboratory would take the DNA out of either the blood or the saliva and then analyze it for the pieces of genetic information

that the test is trying to find. Yeah, so you mentioned that sometimes these tests are done on the NHS, sometimes they're done by private companies. I mean, is that the same if you take one on the NHS or if you take it from a private company? Is you having the exact same test? There are different technical ways of measuring the bits of DNA you need. So different companies, I mean, some of which may be supplying the test to the NHS and some would be doing it commercially. They may not use exactly the same experimental technique, but they're all trying to measure the same thing. They're trying to measure us either specific things or in some cases many things in our DNA. And they will have been shown to be reliable ways of measuring that.

So they're measuring the same thing. They sometimes do it in slightly different ways. Yeah, so we're talking about DNA. We're talking about genes. So let's sort of start from basics there then. So in Hemsworth's case, we're talking about just a couple of genes. But what's the human genome? How big is the human genome?

What are we talking about there? So our DNA is the chemical material, which contains all of the information that our cells use to do their stuff, to make the proteins that make them function, to build up tissues and organs and eventually people. We get one copy of our DNA from our mother and one from our father, the one from our mum through the egg, and the one from our father through the sperm.

The totality of the DNA is called our genome. So that's just a word for all of the DNA. The DNA itself is a long chemical, and it's made up of different components. You can think of it as a long list. And at each position, there's one of four possibilities. So four different chemicals make up the DNA. They happen to start with letters, A, G, C, and T.

So you can think of DNA as a long set of instructions written in an alphabet that has four letters, A, G, C, and T, our English alphabet has 26 letters. And in total, we get three billion letters of DNA from our mother and three billion letters of DNA from our father. So each of us, in every cell in our body, we've got those six billion letters. So that's obviously a huge number. So we're talking about analyzing the fine detail of this,

if we can call it a genetic sequence. Is that correct? Correct. So how do we go about doing that then? That seems like a hell of a job. Yes, so there are ways now in which you can measure all, read all three billion letters, or in fact, because we've got two copies of it, we've got one from our mum and one from our dad. At any one of those positions, we'll have two different, or maybe two copies of the same DNA letter, the one we got from our mum and the one we got from our dad.

So there are experimental technologies now called a whole genome sequencing, which read all three billion letters. There are other technologies which read the subsets of the letters in genes, and we can talk in a minute about what a gene is, or there are ways of just measuring one position, or just measuring a small number of positions or a small region of the DNA. And we can think of them as just sort of different experimental approaches. Yeah, so you mentioned there, that was going to be my next question. When we're talking about a gene, you know, what exactly are we talking about? So a gene is a piece of our DNA where the letters in the DNA contain explicit instructions that help our cells make a protein.

Proteins are made up with building blocks called amino acids, and there's a code. In the gene, there are three genes are read in segments of three letters, and each set of three letters codes for one of the 20 amino acids. So you can think of the machinery in our cells as going along, reading the first three letters and working out what amino acid that is. And there's other machinery that gets out of amino acid and sort of gets it ready. And then it reads the next three letters. And then the machinery gets an extra amino acid and they join together. So a gene is a set of letters that tell ourselves how to make a specific protein. And they differ in length.

So a gene might be hundreds or a few thousand. DNA letters long, but some genes are much longer than that. Now, our DNA, if we look at the totality of our DNA, only about 1% of it is the genes. The rest of the DNA, which used to be called junk DNA, we now understand a bit, we called the junk DNA before we understood what it was doing. We now understand more about it, but not everything about it. That has other information. For example, there's information in the rest of our DNA, which tells a particular gene when it should be making that protein. You can imagine if there's a gene, all of our cells have all of our genes. So there might be some gene which is making something that's really important in the retina

in our eyes. That protein might be very important in the retina, but you absolutely don't need that protein in your tongue. And so there's instructions in the DNA that will be able to tell that gene, I want you to make this protein if you're sitting in a retina. But the same protein, in your tongue won't be turned on. So is that what you mean when you talk about gene expression? That's exactly, yeah. So gene expression is the technical term for, as a way, when you turn the tap on and the machinery starts making the protein associated with that gene,

technically we would say that protein, that gene is being expressed. So in this particular circumstance that we're talking about with Hemsworth, so he's been, he's received this test and they've picked out two, specific, well, a single, two copies of a specific gene. You know, how big an influence can just just a single gene have on our bodies and our physiology? We've got about 20,000 genes in total, and you're right, in Chris Hemsworth's case, they looked at, they probably looked at many, but the results he's been talking about, and the significant ones relate to one particular gene called APOE, and we know some things about what that does, but not,

there are many mysteries, as there are with lots of human biology. We all have two copies of that gene. We got one copy from our mother and one from our father. The issue is that there can be slight differences between the copies I have and the copy you have, or even between the copy I got from my mother and the copy I got from my father. Lots of these differences don't make any difference at all to us, but some of them can have consequences. Sometimes those consequences can be really severe. So there are conditions, cystic fibrosis, an example, where if you inherit a mutated copy of a gene, so a version of a gene that doesn't

work the way it's meant to, you can end up getting really sick. Sometimes if you have one copy of a gene which doesn't work, you're fine because if the one from your mum doesn't work, but the one from your dad is fine, often people will notice no consequences. but sometimes that does matter. And then in other cases, if you're unlucky enough to inherit a change version from your mom and a changed version from your dad, there can be serious consequences. So at one extreme, there are a whole range of conditions. Thankfully, they're usually very rare, where if you inherit a mutated copy of the gene,

or in some cases two of them, they're called recessive diseases, you get very sick. Cystic fibrosis is one of them, but there are now many, many others. in other cases, and this is the case in Chris's example, if you have a changed version of the gene, it doesn't definitely mean you'll get sick, but it can make it more likely or in some cases less likely that you'll get sick, again, with a specific disease. That's something I'd like to come back to in a little bit,

but we're talking about mutations of genes. So how does a gene mutate, you know, how does that happen? why does that occur? So we inherit one copy of our DNA, literally one copy. There's one copy in the sperm and there's one copy in the egg of all of these three billion letters. And now every cell in our body has, and there are trillions of them, have a copy of our DNA. So one thing our cells have to do is to make copies, sort of like a photocopy or a copy and paste thing. It has to make copies of our DNA. The machinery for doing that is really, remarkably good, but sometimes mistakes will crop in. And so if one of those mistakes

crops in, you know, I might inherit a particular version of a gene from, say, my father, and maybe I inherit the same version from my mother. But in the copying process, the version that gets passed down will have been copied that I pass onto my kids will have been copied many times from that. And some errors crop in, some areas crop up. And those errors are what introduced these changes. And so if we look, if we sort of compared your DNA with my DNA or even one copy of your DNA with another copy of your DNA, our DNA would agree at about 999 places out of 1,000.

So they're very, very similar. It's worth knowing that if you compared my DNA with a chimpanzee's DNA, and just to be clear, the same is true of yours, if you compared our DNA with a chimpanzee's DNA, they would agree at 99 places out of 100. So there's a lot of similarity, but these places that are differ, they all arise because of these chance errors in copying.

Many of them then get lost from population, so I inherited, but it doesn't get passed on, or maybe a few of my descendants have it, but just by chance, because we only put, although we get two copies, we only pass on one. So there's a sort of randomness that happens that a shuffling in every generation.

Some of them survive in population, some of them get to be more common and some of them don't. And most of these changes, so the one in a thousand where we differ, most of them have little or probably no impact on us as individuals. But some of them can be important. So we're talking about ones that cause illness or disease here. But can these mutations ever be beneficial? Yes.

They can allow the individual to do certain things that needs to do, better or more effectively, and indeed that's what natural selection is. Darwin's idea was that these variants arise by chance, but if they make the organism better adapted to use a technical term, better able to do its thing, then they will tend to be more successful. The individuals carrying those organisms will have more offspring. Sorry, the individuals carrying those mutations will have more offspring, and then the mutation will get more and more common in the population. So mutations can be beneficial. Most of the time, they either, don't have any effect or they're bad for us, but sometimes they're beneficial, and that's,

that's the bedrock of natural selection. It's these chance mutations that arise that then increase in frequency because they confer an advantage on the organisms that carry them. So as we're saying, there's, you know, an incredible amount of genes and incredible out of data in these tests, you know, how accurate are they, you know, how certain can we be if a result comes back, that that is fact. They're very, very reliable. I mean, it's not that there are never errors. I mean, sometimes errors will be because samples are swapped in the lab.

It's not because of the measuring process. But these tests are, we're now very good at being able to measure DNA. So in the documentary, Hemsworth is told that he's, I think it's 8 to 10 times more likely to develop Alzheimer's due to this genetic, factor. I mean, initially, that sounds like a huge difference. You know, it's a bit shocking 10 times, but we're working from a base level of risk, aren't we? So what I'm saying is he's not necessarily definitely going to develop Alzheimer's. Now, that's exactly right. As I said, there's a spectrum. There are some diseases where if you inherit the genetic change, you will get sick. There are other

examples, and this is one of those where if you inherit a particular genetic change, you can be more likely, sometimes quite a bit more likely to develop the disease. And then actually for most of the common conditions, most diseases like heart disease and diabetes and many of the common cancers, genetics is a big part of the risk, but it's not one change or two changes. It's millions of positions which each contribute a tiny bit to that risk. So his example is sort of in the middle where, as you say, he is probably about a very important about 10 times more likely to develop disease. And although we're all very aware of a disease like Alzheimer's, it's quite rare.

So there's a big difference between relative risk, which is how much more likely you are than someone else to get the disease, an absolute risk, which is about whether you'll actually get it. So if a disease is incredibly rare in the population, you can be much more likely than somebody else, and still, it's extremely unlikely that you'll get the disease. So the first important point is it doesn't determine that he will or won't get the disease. it just increases the risk for him. So you mentioned there are other diseases such as heart disease and cancer, etc.

So are these types of genetic tests better at picking up risks for certain diseases than others? I think the way I'd put it is there are different types of genetic tests. There are some examples like Alzheimer's disease where we know there's one specific gene we should check. Indeed, there are only a few places in that gene which we need to check. and that can be very informative. For a disease like heart disease, there are some rare examples where specific positions have an impact,

but in general, what we've learned over the last five or ten years is that genetics is that we've known for 50 years that genetics is a major risk for heart disease. What we've learned recently is it is not one place or two places or ten places. There are a million places in your DNA, and every one of those contributes a tiny bit

your heart disease risk. So at one place in your DNA, if you have an A in the code rather than a C, it might bump your risk up by half a percent. You don't really care about that position by itself. And another position, if you have a G rather than a T in the DNA code, it might decrease your risk by a percent. And again, that's not a big impact. What's changed and what I think is really exciting for the field over the last few years is for the common diseases, we now know which positions to look at, and we can measure them all individually, actually quite cheaply, and then combine their effects. So instead of knowing about one change, the combination of these million positions is what we call apologetic, poly because there are many of them, but apologetic risk score.

And those scores, you can think of those scores as a sort of overall summary of your susceptibility to a particular disease, and they can have big impacts. There are, you know, there are 20-fold differences in disease risk for heart disease because people have a high polygenic risk score rather than a low one. For diabetes, it's more, it's larger than that. For some of the cancers, you know, it can be that order as well. So we're now knowing for all of the common diseases, there's a new type of genetic test, there's polygenic risk score, which allows us to understand the risk which previously we knew was there, but we couldn't really measure. Right. So if I were to take one these, I could get, you know, a sheet back detailing my risks of these specific diseases.

Or at least telling you the genetic component of your risk. So heart disease is a good example. There are other factors that affect your risk of heart disease. Your age, whether you're male or female, your weight, your cholesterol level, your blood pressure and so on. And actually, at the moment, doctors already use those factors when you're too young, but when you get to a certain age, doctors already use those factors to estimate your risk of heart disease. And if it's high enough, they will then have a conversation with you about things they can do about prevention programs or, in this case, statins, which reduce your cholesterol. What we'll be able to do in the future, we can just do that much better because we can now capture the genetic component as well,

and it's substantial. So for men between 45 and 55, that genetic component, which we can now measure, captures about the same amount of risk as all of those clinical risk factors put together. So it's just about, it's about for the first time being able to use and measure the genetic component of risk to just do a much better job of working out who's at high risk and who's not at high risk. Because for most of the common disease, we come back to Alzheimer's, but for most of the common diseases, there are things health systems can do. If you're at higher risk for a particular cancer, there are screening programs and maybe you should start them a bit earlier in life or have them more often. For other diseases, there are prevention programs or there are sometimes drugs you can take to reduce your risk. So I think it will be a very profound change in healthcare. We're just going to be much better able to get the right people

into the right screening programs and prevention programs. At the moment, there are lots of people who are at high risk for disease who are completely invisible to the NHS. And this gives us a chance to bring them to light. And as I said, they're natural pathways and things you can do for most of the diseases. That's really interesting because a lot of, when I've been talking about this to other people, lay people, my friends and family, etc. They've all said to me, oh, you know, I don't know if I'd want to have that test done because it would trigger in me anxiety and I'd get really wound up and

worried about it and is there anything I can do about it? But what it seems that you're saying there is actually it's a great thing to know that you're predisposed to a disease. It depends a bit on the disease and it depends a bit of on how big the impact is. So in the case of Alzheimer's disease, the gene that's called APOE that was checked for Chris Hemsworth, that has quite a big impact on his risk of viewing the disease. And at the moment, there's not very much you can do about it. So I think, as you were describing in talking to people you know, different people take different views. Some would rather know and some would rather not know. And that's absolutely up to the individual. I think in Alzheimer's actually research

is progressing really quickly. There was good news yesterday about the latest drug trials for Alzheimer's. So it might well be the case before too long that indeed there are things that you could do and there might be drugs to help reduce the risk or catch it early enough to slow down its progression. But for many, many other, so a disease like Alzheimer's where currently there's nothing you can do, I think that's a slightly different question from diseases, you know, like some of the cancers, where there are screening tests you can have. Take breast cancer, in an example. Women in the UK are offered mammograms every three years

when they get to age 50. There are some women who are at high risk of breast cancer much earlier in life. They could be having, I mean, it doesn't happen currently because we don't know who they are, but we could find out who they are and offer them mammograms earlier. So I think where there's something you can do,

and in many cases we do these anyway, on the basis of risk. It's just about doing it more effectively. This might be a daft question, but something I've just thought of. So Chris has got these two genes. Can they change over a person's lifetime so that it will change from, you know, has it mutated in the first place? Can it mutate to a more benign variation? No, it's a really good question. Everything in biology is complicated, but the sort of short version of that is no. the things you inherit stay the same throughout your life. There will be occasional changes, but what matters for this gene is what it does in the brain.

He will have many, many, many, many, many brain cells, we all do. He'll have many brain cells, and they will all, almost all of them will have this change in them. Maybe there'll be one or two that have had these chance changes in the DNA through the copying errors, but virtually all his brain cells.

cells will have the same copies that he inherited. So we can't, it doesn't change by chance through our life. And although there is new technology that could potentially change genetic material, you have to change it in all the relevant cells. And that's a really, I mean, there are massive ethical issues anyway, which I don't want to minimize. But it's technically very difficult because you've got to change lots and lots of cells. That was what I was going to ask next.

We hear a lot about gene editing techniques such as Chris. And is that, you know, how close are we to being able to correct if that's the right word, or at least modify a person's genes if they have this genetic predisposition to Alzheimer's, let's say. I mean, is that something in the near future or is that way off? I think it might be kind of medium term. It's not near future. And I think for something like Alzheimer's where we're talking about brain cells, we'd want to be particularly careful. but that ability to change bits of DNA you can sometimes so for example there are some conditions that arise because your body is not making a particular protein because the copy of the protein

you inherited is sort of the copy of the gene you inherited is broken so you just don't make the right version of the protein so there are therapies now for some diseases which try and encourage other cells to make the right protein or to add the cells in which make the right protein, just sort of make up for it. So that's a slightly easier case where there's something that your body doesn't have and you could encourage or give someone some cells which do make it. Even, I mean, that's sort of cutting edge and we're just working out how to do that. But changing all of the cells in someone's brain is, I think, realistically a long way off. So sort of by way of summing up, do you think we'll ever see a day where we have

entire populations routinely having tests like these? And if so, what would be the value in that? I think that will happen. And it's for the reasons we're talking about a minute ago for all the common diseases. I mean, first of all, it should be up to individuals. No one should be forcing individuals for this. But for most common diseases, genetics is a risk factor. And if we knew about it, we would know for each individual, for each of us,

instead of just saying, you know, here are the sort of 10 or 20 diseases you should be most worried about and here's some generic advice. We could be saying, in your case, Jason, you're at particularly high risk of heart disease. We can actually tell you this when you're in your 20s, so you should work even harder on diet and lifestyle. Maybe it's appropriate to go on drugs to reduce your cholesterol a bit earlier in life. We could do that because we have that special information about you.

If there were a woman and we knew she were at higher risk for breast cancer, we could suggest that she had, she started having mammograms earlier in life. and that will catch any cancers much earlier, they're much easier to deal with, the outcomes are much better. I think these approaches can change the way we do prevention and healthcare. You can think of them one way as, well, it's just about, we do screening and we do prevention,

we can just do it much more effectively. If we're better at knowing who's high risk and who's low risk, we try and do that now, we can just do it better. But I think from a health system point of view, you know, health systems like the NHS, which are creaking currently in, It's not just our health system. That's true of most health systems where costs go up and up and up.

Many people have argued that if we can, they're not really health systems at the moment. They're sick care systems. They wait till people are really sick and then look after them. If we could move the dial a bit and get much better at stopping disease before it happens, that's obviously good for us as people. But it's great for the health system because you're avoiding disease or you're dealing with it earlier when the costs are lower and everything's easier. So I think it's potentially hugely important.

And I suspect, as I said, no one should or will ever be forced for this. But I think the ability just to have, for most diseases, these are risk factors. They like cholesterol measurements. And they won't determine whether you get a disease, but they'll change the odds a bit. And if we can do that and we get a better estimate of disease, that's quite helpful. We've just finished a trial in the northeast of England with GPs, where they added in, that they currently estimate risk for cardiovascular disease with this tool, which combines, age and sex and blood pressure and cholesterol and so on.

And in the trial, we added in the genetic component of risk. And actually it was hugely positive. The GPs involved were very positive. 95% of them said it fitted in well with their, they and their nurses said it fitted in well with their standard workflows because GPs are currently extremely busy, so we don't want to make that worse. The individuals, both the GPs and the patients,

were very positive about the idea that they actually have a better handle on the risk of that individual patient. They can give better advice to the patient. Patients were very positive about having the genetics used. 99% of them said it was helpful. 94 or 5% of them said they had no trouble understanding it. They were really positive. So we've actually done the trial. We've sort of done the test in routine GP practices in England for one disease, for cardiovascular disease, and people were very positive about it. Thank you for listening to this episode of Instant Genius. That was Sir Peter Donnelly.

The current issue of BBC Science Focus magazine is out now. Pick up a copy wherever you buy your favourite magazines or visit ScienceFocus.com. This podcast is sponsored by Name, Audio and Focal. The texture and emotional depth of music can be lost through digital sources or poor signal. Name Audio believes you can have digital precision with analogue warmth.

Alongside French acoustic sound, specialist vocal, Name creates high-end audio systems combining innovation with craftsmanship, so you can listen to music, just as the artist intended. Discover more at name audio.com.