Dan Davis - Compatibility genes
Kat - Compatibility is a mysterious thing - what makes some people get on like a house on fired, while others never seem to click? In biological terms, compatibility goes even deeper than that, affecting whether a particular person is a suitable match as an organ donor, influencing our immune response to different diseases, and even affecting our romantic and childbearing partners. To delve deeper into these molecular mysteries, Dan Davis, a Professor of immunology at the University of Manchester, recently published his book The Compatibility Gene. And, as he explained to me, it all started with a curious scientist called Peter Medawar.
Dan - In the summer of 1940, he was one day sitting in his garden and a plane crashed a few doors down the road from where he was sitting. At that time, he was an expert in antibiotics so he was called in to treat the burned airman. At that time, you knew that you could use antibiotics to prevent the wounds being infected. But when Peter Medawar paced around the war wounds hospital in Oxford, he realised that there was some problem. Although you could stop the wounds being infected, you couldn't actually help the wounds really heal. And that was because for some reason, you couldn't take skin from one person and graft it onto the skin of someone else.
Kat - So, you can't just patch someone up with someone else's skin.
Dan - Exactly and that is quite mysterious. If you think about it, surely the molecules and cells that we're made of, our skin is made of? It's pretty much the same.
Kat - Yeah, your hand looks like my hand. What's the difference? Mine is just smaller.
Dan - Right. So, why can't we just take skin from one person and stick it onto someone else? What is it that makes that not work? Actually, at the time that Peter Medawar realised this was a major problem, people generally thought that there was some problem in the way the surgery was done, that we weren't quite able to do the stitching and the sewing, and moving skin around. And if the surgeons could perfect the technique then it would probably work out. But of course, that turned out to be completely wrong.
Kat - What was the next stage in that discovery? What is it about one person's skin that means you can't just glue it onto someone else's?
Dan - So, what Peter Medawar did was immerse himself in that problem. So actually, he moved to Glasgow and there he worked with a surgeon Tom Gibson. Tom Gibson, he was working within Glasgow happened to mention that he thought that when you transplant skin from one person to another person, and then did the same thing again, the skin was rejected much faster the second time around. Peter Medawar seized on that anecdote because he realised that that's the hallmark of an immune reaction. So you know that when you get flu, you'll be able to react with the exact same flu a bit better the second time around. And that's the hallmark of the immune system reaction. So, he sees on that anecdote as perhaps there's something about the immune system that causes skin to be rejected when it's moved from one person to the other. So then he moved back to Oxford and he tested that idea in rabbits. He took 25 different rabbits and moved skin from each rabbit to every other rabbit and then did it again, and then showed that yes, indeed the skin was rejected faster a second time around. It took 625 operations on rabbits to prove that point. So he was going to win a Nobel Prize for that but at that time, it's just hard work.
Kat - I guess it did pay off in the end. So, moving forward from that, we discovered that you can't take skin from one person, put it in someone else, you can't take skin from one rabbit and put it in someone else. Presumably, that's the same reason why you can't just take some organs or some blood and just randomly put it in someone else too.
Dan - Right. So, it comes down to the differences in the genes that each person has. We all have the same 23,000 or so genes - the human genome. And 99% of our genes are identical. But something like 1% of our genes vary from person to person. So the key issue in understanding this is really, what are the differences in genes between people?
Kat - This kind of make sense though because you look at humans and we're all broadly built to the same plan. We've got the head, two arms, two legs, most of the right organs, and all that kind of stuff, but there are unique differences between us. So, this kind of shouldn't have been that surprising.
Dan - Right, it's not that surprising that genes vary to some extent between individual person. What's really surprising is what those genes are. Like you just said, we have the same rough body plan and if you thought about what genes might be different between me, you or everybody else, we might think of genes that perhaps dictate our hair colour, eye colour, skin colour. So it turns out that the genes that vary the most between each individual person have absolutely nothing to do with how we physically look. The genes that vary the most are formally called the major histocompatibility complex genes. In the book I wrote about this whole topic, I called them the compatibility genes to abbreviate that. The crucial thing is that these genes work in our immune system.
Kat - What are they doing in the immune system? So, you would expect as humans, we're exposed to all sorts of threats and dangers and unpleasant things. Why do we have these fundamental differences between our immune systems and the genes that are involved in them?
Dan - To understand why these genes are different between different people we got to backtrack a bit and talk about how the immune system actually works. So as you know, genes encode for proteins and then the proteins go and do stuff in the body. These genes make a sort of cup shaped protein. So I'm sort of holding up my hand doing a cup shape.
Kat - I'm holding a coffee cup - a coffee cup-shaped protein.
Dan - So we're on a podcast but anyway, there'll be 100,000 copies of this particular protein at the surface of nearly all your cells and it's in a sort of cup shape and it's holding in the groove, as you're holding the coffee cup, the coffee cup would be a sample of other proteins that that cell is currently making. So, what happens is the genes that vary the most between each individual person make this protein molecule that presents up at the surface of the cell, samples of all the other proteins that are currently being made inside that cell. Then your immune system has cells that look at those samples of protein. If they see something that's never been in your body before then there must be something inside that cell that is alien to your body, perhaps stuff being made by virus or bacteria, or some other kind of germ. And then the immune system will know there's something wrong with that cell and they'll either kill it or they'll summon other immune cells to deal with it.
Kat - So, it's kind of a bit like a molecular quality control. It's going, "Okay, does this look normal? Does this look normal? Does this look normal?" And if something doesn't look normal, the immune system goes, "Oh! Right, let's sort that out."
Dan - Yeah, perfect! That's the great explanation. So, the key issue then is why are they different? Why do we all have slightly different versions of these genes that make these proteins that are presenting samples of what's inside our cells? So, it turns out that if you're infected with one type of virus, say, flu viruses- so you get flu virus and I get the same flu, and you might recover in 4 days and I might get better in 5 days. One of the reasons for that would be that we have different versions of these genes. So, that would mean that for a given type of virus, the version of the gene that you have might be better at presenting a sample of something being made by that virus. It turns out that although my gene might be a little bit worse at dealing with that particular flu, it might well be better at another type of flu. So, the overall message is that we have to have this diversity so that we are as a species, as well as individuals, strong at fighting all the possible different kinds of viruses that could infect humans.
Kat - I was going to say, it doesn't on the surface of it sound like it makes evolutionary sense for say, you and I to be different in our response to the infections that we're both exposed to but as a species then - so we have to think about it in evolutionary terms in a broader way that it's about how diverse our species immune system is rather than just my own.
Dan - Yes, it's quite complicated because actually, it works at the level of the individual as well as the species because you also have more than one copy of this gene in you. So you have a diversity in you as well. So for example, we're talking here about class one versions of these genes and you have three copies from your mom and three copies from your dad. So you actually have six different versions of that gene. So you have a diversity of these proteins and I do, and we have different ones, and the next generation then shares in a mixture of all the differences passed on from one to the other.
Kat - Give me an idea of this kind of diversity in these compatibility genes, say, between people in the UK, people around the world. What sorts of numbers of variations are we talking about?
Dan - An enormous variation. So as I've said, you have three copies of these genes and they're actually called A, B, and C and roughly across humans, there are roughly a thousand different A genes, a thousand different versions of the B gene, a thousand different versions of the C gene you could have. And you'll inherit one of those from your mum, one of those from your dad, and they could be - in principle - anyone of those thousands. So, it's the combinations of six that you would have are enormously diverse. So, out of about 18 million people that are in one of the databases that are held by the charity Anthony Nolan that uses this information for matching people for bone marrow transplants, out of that 18 million that I had, roughly, about a million of them are absolutely and completely unique, and in other numbers within that would share sets of the genes with other people. So, just these three genes almost entirely define your uniqueness.
Kat - This to me makes it sound like, how does any kind of transplant work at all? So how well do you have to match a transplant for someone based on these genes to make sure that transplants don't get rejected?
Dan - Obviously, you'd try and match as many as you can and it's true that some genes have more importance than others. It depends actually on the exact type of transplant you're doing. So for bone marrow transplant, you would match certain genes, but for other types of transplant, it's less important to match say, the C version of the gene and more important to match the B version gene. And so, there are some nuance to all of that. So by and large, it's important to try and match these genes as best you can.
Kat - We've talked about the role of these genes in transplantation, in compatibility with organs and tissues. Are there any other aspects of our lives and our health that these genes influence?
Dan - There are several areas where these genes will crop up that have nothing to do with the immunology. These areas of science are much more controversial. For example, there is a famous experiment done where women were asked to rank the smell of t-shirts that had been worn by men for a couple of days. So men were asked to wear t-shirts, plain cotton t-shirts, they were told to refrain from sex, not enter a smelly room, and then these t-shirts were put in to cupboard boxes with little triangles cut out. Women would smell these t-shirts and then they would rank how sexy they thought the t-shirt smelt. And then the results were compared to the version of these compatibility genes that the men and women had. It turns out the women preferred the smell of t-shirts worn by men who had different versions of these compatibility genes.
Kat - Now, why would that be? I mean for a start, let's forget how horrible that sounds - sniff these disgusting t-shirts - ladies, enjoy! So why would we want someone that's different? Surely, it should all be about compatibility and finding someone who's the same as us.
Dan - So, the idea behind that would be that you seek a sexual partner that has different versions of these genes to yourself so that it would maximise the diversity we have in these genes in our children that then keeps the human species very diverse in these genes that allows us to be strong at fighting all kinds of infections. But it's an idea more than a proven fact. There are many difficulties with that kind of experiment. So firstly, smell is very, very difficult to study. So, you're recording this interview digitally. Sound can be digitised very easily. TV is obviously using a digital version of a picture but smell cannot be digitised or analysed in any way. How do you describe the smell of vanilla? It's just a very hard thing to study. Secondly, if the women ranked the smell of t-shirts say, 5 out of 10 compared to 4 out of 10, what would that mean? Obviously, any human interaction is incredibly complex. The extent to which a change in smell can impact someone's behaviour is highly controversial and extremely difficult to study.
Kat - If I had to choose between - do you want to sleep with a 5 out of 10 guy or 4 out of 10 guy? My answer is, neither can I have the 10 out of 10 guy please.
Dan - Very good! So, it's very hard to pin that down to an impact on human behaviour. But there is some good evidence in animals. So for example mice would run down a Y-shaped track and they can choose to mate with either one of the other two mice. And they do prefer to mate with another mouse that has different versions of these genes. So, there is some fundamental biology in that because it's true even in animals. But mice do that by smelling each other's urine so that's probably a skill lost in us.
Kat - That's a whole section of Tinder you that you don't want to go down.
Dan - So, it's so hard also to build up a picture from experiments done in mice to relate that to anything that we might. So, there's probably some interesting fundamental biology in that story but it still is quite a controversial subject. So, where the evidence is much stronger on a stronger footing perhaps is in the likely chance of problems that can happen in pregnancy. And so actually researchers in Cambridge University have done some research for example that show that the likelihood that you have problems in pregnancy such as pre-eclampsia or foetal growth restriction does correlate with the mum and the dad having particular versions of combinations of immune system genes. So although a deep understanding of that is to be honest, quite fuzzy, it fits the general theme that these genes can be important - not just in the immune system but also in reproduction as a way of making sure that these genes stay exceptionally diverse amongst human kind.
Kat - What do we know about compatibility between different species? For example, could we take the liver of a pig and put it into a human? There's a desperate shortage of transplant organs for humans. Why does or doesn't that work?
Dan - The difficulty there is that you would have an immune reaction against these molecules that have never been in your body before. But of course, there are ways in which the body becomes tolerant to things that had never been in the body before. You know, in the food that you eat is an obvious example.
Kat - With the advent of these precision genome editing tools that we now have, these things like CRISPR, does that bring us the capacity to kind of switch up people's compatibility genes and even make animal organ suitable for transplant? Is that the kind of future? What would happen if you just took out someone's MHC completely?
Dan - If you say, made an organ a blank so it had no compatibility genes to cause a reaction, on the face of it, then the immune system wouldn't have anything to look at. It wouldn't have this protein reporting samples of what's being made inside cells. Actually, some viruses do that. Actually, one of the things I have discovered early on in my career was that HIV removed the compatibility gene protein from the surface of cells. But actually, you have another arm of your immune system. You have white blood cells called natural killer cells that actually check that that process of immune surveillance is working properly. If they notice cells that lack those compatibility gene proteins then they also know something is wrong about that cell and then they proceed to kill the cell or deal with it in some way. So, you have another arm of your immune system that is looking for a loss of these proteins. It's a concept called 'missing self' that came from Klas Karre. He first thought of the idea when he was a PhD student in the mid-1980s in Stockholm. It's a wonderful idea and it turns out to be entirely true that you have this other role of the immune system looking for a loss of healthy proteins as a sign of disease, just like you have a large part of the immune system looking for things that are alien to the body as a sign of disease.
Kat - What do you see coming in the next 5 to 10 years of the future, if that's not too hard to look that far ahead?
Dan - So, I think that in terms of specifically around these genes, I think there are already emerging correlations between the versions of these genes that you have and the types of drugs that are going to work best in you. I think there is some potential for that to become more of a mainstream endeavour. My own research is actually in using what are called 'super resolution microscopes' which are microscopes that won the Nobel Prize last year. We visualise exactly where all these proteins go to make an immune reaction happen. So, the frontier in a way, or at least this frontier that I'm involved with, is that although we understand that these genes make a protein and they signal to the immune system whether or not there's a problem, we don't understand very easily how all the different proteins interact together for this complex decision to be made. So another way of thinking about that is, okay, we understand that this protein might signal to an immune cell that there's a problem. Because when the immune cell touches another cell, it actually takes about 2 to 5 minutes to make the decision as to whether that other cell is healthy or diseased and why is that...
Kat - Having a think...
Dan - Right. So what is it doing when it's having that 'think'? and so, the way that we tackle that is by really imaging how all the different proteins move around with each other and then the cell makes a final decision about whether the other cell is diseased or healthy and it should be killed or spared.
Kat - It sounds like there's lots of exciting research to come out of that in the future. But what generally would be the take home message you want people to understand about these compatibility genes?
Dan - These are important stories for the medical outcome, the number of lives saved through transplantation. But actually, the reason why I wanted to write this story and wrote a book about it is not solely about the medical output. It's also about the fact that this story is the ultimate celebration of human diversity. So, the greatest tragedies throughout history from the holocaust to the slave trade have all been about misunderstanding the differences between people. And it turns out that the greatest genetic differences between people have nothing to do with how we look like, but it's to do with how our immune system works. And it turns out that those differences between people that determine how our immune system works are essential for how we survive disease. Here's the most important take home message of this story that there's no hierarchy in this system. So, it's not that any one person has better or worse genes. It's the diversity in our genes that are essential for how we survive disease. And there are very clear explicit examples of that. So for example, for HIV which gives people AIDS, obviously, the best way to avoid AIDS is not catch HIV. But if you did catch HIV then a certain version of these genes would make it a longer period of time on average before you are likely to develop full blown AIDS. So, that version of the genes would be somewhat beneficial or could be beneficial if you were infected with HIV. But that very same version of this gene that helps you with HIV is also a risk factor for giving you certain kinds of autoimmune disease. So, no one has a better or worse set of genes, but across the whole human population, it's the diversity that allows us to survive disease best of all.
Kat - Everyone's a little bit mutant?
Dan - Everyone is a little bit mutant!
Kat - Dan Davis from the University of Manchester, and his book The Compatibility Gene is out now. What's more, he and I will be talking about my new genetics book, Herding Hemingway's Cats, at an event on the 30th May at 1pm on the Good Energy stage at the Hay literary festival. I've got loads of speaking events coming up around the UK talking about the book, so if you want to keep up to date find me on Facebook at facebook.com/KatArneyWrites or follow me on Twitter - I'm @harpistkat