Artificial Selection: How Humans have Shaped Evolution - Robin May

So I think everyone pretty much at school these days learns about evolution by natural selection, survival of the fittest, all of those kind of concepts. Um, and today I want to turn that a bit on its head and think about what happens when we start to mess with evolution. The Gresham College lecture that you're listening to right now is giving you knowledge and insight from one of the world's leading academic experts, making it takes a lot of time. But because we want to encourage a love of learning, we think it's well worth it. We never make you pay for lectures, although donations are needed. All we ask in return is this. Send a link to this lecture to someone you think would benefit. And if you haven't already, click the follow or subscribe button from wherever you are listening right now. Now let's get back to the lecture. And I want to take us right through things that have happened for thousands of years and maybe nudge us towards the end in the direction of what might be coming around the corner. Um, and it's a bit of a spoiler alert, ready for, uh, my next and my final lecture, uh, which is in a couple of months time where we're gonna think about, uh, wild speculation about the future of evolution, uh, which is essentially a way of me saying, if you find tonight's boring, definitely don't come back in a couple of months time, 'cause that'd be a real waste of your time. Um, so I wanna talk about artificial selection. And what I mean by that is the ability of some organisms to influence the evolution of other organisms. So if you think about evolution, classical evolution, right? It's based on the principle that most organisms over reproduce. We have more offspring than one. And that those offspring are diverse. They're not identical to their parents, they are genetically different either because of sexual recombination. So for humans, the fact that you have to have a partner and so your kids are some blend of genes from both of you, or even if you're an organism like a bacterium and you do clone yourself, you are still introducing variation through things like mutation. So the basic principle is all organisms produce lots and lots of offspring. Those offspring are all a bit different. They compete for resource. And the ones that are best placed to maximize their use of that resource, they are the fittest. They will survive and pass on the genes, uh, and the rest of us die out and don't contribute. And that is the basic principle of evolution for all living organisms forever, as far as we're aware. But what has happened, particularly in, in sort of recent, uh, evolutionary history, although possibly before that too, is that organisms influence each other. So part of that selection is, is obvious. If you are a cheetah and you eat an antelope, you've done quite a good selective process on that antelope. Um, but there are more subtle ways in which you can influence evolution. And of course, the kinda master species are doing that for good or for ill is ourselves. Humans have been messing with the world essentially ever since we came into it. And in particular, messing with the evolution of other species and the species. I want to think about first this evening when we think about how humans influence. Evolution is one that many of you, uh, may interact with very regularly. It's this one. Our best friend, the domestic dog. And domestic dogs, as you all know, come in all sorts of shapes and sizes. Um, they are all though the same species pretty much. So they can all reproduce with each other, practically speaking can be a bit tricky for some of them. But in theory, they're able to reproduce with each other because they're one species. But they are remarkably diverse. They are not remarkably diverse because of natural evolution. It is not that these things have been out there in the Savannah and they've specialized in different ways. They are that way because we have created 'em, we have shaped them in that way through a very, very aggressive process of evolution through an artificial selective process. And there's been a huge amount of work on this, which I think is really reflective of, of our kind of current understanding of evolution, uh, particularly on the back of advances in genetics. So what we now know is that the origin of domestic dog is probably about 30 or 40,000 years ago, uh, from, uh, from the gray wolf. Okay? So up here in the top corner. And that is sort of undisputed. One of the interesting things about that date, I think, is that it predates humans, uh, switch to a sedentary agricultural lifestyle. So this is before the date when we started living in villages. It's before the date when we started, uh, having crops and farming. We were still hunter gatherers. And people can speculate wildly about how we domesticated dogs. Um, but one kind of plausible hypothesis is that wolves are likely to have congregated around early human tribes 'cause we were hunting, uh, and there would've been waste, there would've been bones and carcasses and stuff for them to scavenge. Uh, and wolf puppies are quite cute. Uh, and so maybe early humans, uh, had those puppies kind of close to 'em, might've fed them a bit. And so you get this kind of process of domestication. So 30 or 40,000 years ago, this lineage broke off from gray wolves. Prior to that, wolves themselves obviously had evolved from common ancestors. And what you can see here down the side are lots and lots of things that are sort of related to dogs. And actually what you notice is they're all pretty much look like dogs, right? Jackals, uh, foxes even. They all more or less look like dogs, even though their common ancestor goes back millions of years, perhaps a couple of millions of years. Um, but largely speaking, they haven't changed that much. Whereas the domestic dog domestication in the last 30 or 40,000 years now looks incredibly diverse. And I think if you were an alien suddenly beamed down onto the planet, you wouldn't immediately look at all these and go, oh yeah, they're all the same species. Um, but you probably would look at most of these and think they might be the same species. So domestic dogs have evolved far faster than any of their natural, uh, relatives. And that is because we have selected them. And actually the pace at which this has happened is quite extraordinary. So for the most part of that 30 or 40,000 years of history, we think that domestic dogs looked pretty much like wolves. They were all pretty much the same. It's only actually in terms of, uh, Romans, the Roman Empire, that we start to see documentary evidence of breeds of dog and then only one or two. So in Roman literature, you can see people talking about big dogs and small dogs, um, but certainly not the diverse breeds of dogs we have now. And in fact, if you look at the, uh, several hundred breeds of dogs that are recognized by, uh, breeding associations today, the vast majority only go back about two or 300 years. So that diversity of dogs has largely cropped up just within a, a blink of an evolutionary eye in the last few centuries. And that is, I think, quite remarkable. And it, it gives us a great power, particularly when we combine that with advanced genetics. And there's a lot of interest now in using whole genome sequencing to try and understand this process. Not because we are necessarily interested in dogs, although of course we are, but also because they are a fantastic model. And they're a fantastic model for two reasons. First of all, there's a huge amount of diversity, a great Dane and a little chihuahua. They're really quite different. So there's a lot of variation, which must be genetically programmed, right? You don't have two chihuahuas. Uh, and the puppy of a chihuahua grows up to be a great Dane. It grows up to be a chihuahua because they're genetically programmed. So there are genetic programs that cause that body shape, but within a breed, actually the genetic diversity is very, very restricted because breeders deliberately breed chihuahuas with chihuahuas. And so you get a very, very tight funneling. So what you end up with are groups of dogs that are very d very different between them, but incredibly similar within the group. And that gives you a very powerful genetic tool. And that's what you see here. So this is a, a whole genome tree. So imagine it's kinda branched out as a tree, but coils around of uh, many, many major dog breeds. Uh, and what it turns out to be is that actually, if you do all the dog breeds of the world, there are roughly speaking about 23 groups, clades of dogs. Those are the colors you see here. So you can bunch dogs together and those people in the audience who own dogs know that, right? So a Yorkshire Terrier and a West Highland terrier, you know, they're different, but they're kind of similar. Great Dane and a bit different, Illation different again. And so you have these 23 big clusters where you have dogs within them that are kind of similar, okay? Terriers, pointers, spaniels, et cetera, et cetera. And then within those 23 groups, you have of course the great diversity of all the different terrier breeds and all the different spaniel breeds. And, and that turns out to be a really, really powerful tool for understanding how genes do all sorts of things. And one of the things that we have used that for is the ability to combine that genetic information with all the information that dog owners themselves know about how particular breeds perform. So if you think about that, we all know that even if you don't have a dog, right, there are certain dog breeds that, you know, if you're walking past'em in the street, you might take a step to one side 'cause they're a bit, you know, dodgy. Um, there are certain dog breeds that you wouldn't leave at home with your carpets'cause they're gonna chew it up. Um, there are some dog breeds that just sort of sleep in the corner all day long and you're there, it boring really. Um, and these behavioral traits are breed associated, so they must be genetically associated. Um, and so this kind of genetic analysis gives you an ability to ask how genes control behavior. And that is, um, exactly what has been done. And I think just to kind of think about this diversity, uh, in scale, it's quite astronomical how much things can change over time. So here we have, I think he's deceased now, unfortunately, but this was the previous record holder for the biggest dog in the world. Uh, this, I think he's called Zeus. So Zeus, uh, was just over a meter at tall at his shoulder. So he's up here somewhere. He's a great Dane obviously. Um, and here on the other side, uh, you have the smallest record holder, maybe Schwab here, who I think is nine, just over nine centimeters the shoulder, which is quite, you can put all in your pocket if you want. Um, so the, but they're both dogs, right? So the genetic diversity that has, uh, been driven over the last few thousand years has created these, um, these individuals that are so wildly different. And let's just put that in context. So around, uh, the time of the Roman empires is the first time you see evidence of, uh, significant breed differences. Not as significant as this, but deep breed differences. So, so let's imagine, let's go back a little bit before that. Let's go back to the time the ancient Greeks. So two and a half thousand years BC for example. And you think about that. Um, and we take an individual human here. Oops. Uh, so this is Socrates. Um, so, uh, I don't actually know how tall Socrates was, but let's assume that Socrates was roughly, uh, kind of miso size, maybe a little bit smaller. If humans had evolved at the same rate as domestic dogs since Socrates was alive, then I would be looking at this audience out here. And some of you would be about the size of a European hair. So you'd be down here somewhere, um, and others of you would be the size, uh, of an African giraffe. And your head would just about be scraping the ceiling of this rather lovely hall. So in the same period of time, we have evolved nowhere near as fast domestic dogs. And that is because this process of artificial selection accelerates evolution at a remarkable rate. So we can then use that information and we can say, okay, over this period of time, genes have changed and they've changed in ways that have influenced, uh, dog size and shape, but also in ways that have influenced their behavior. And you can map those two things onto each other. And so, um, here we see that, so this is, if you like, a two dimensional representation of how similar genetically particular dogs are. And what you see is exactly what I was just mentioning, that there's a huge variation between particular lineages. So for example, here, Spaniels and ascent homes, very, very different from each other, but within the group, very, very similar. Okay? So now you can use this kind of map and map onto it. Things that we know are behavioral associated with breeds. So for example, excitability and people own dogs know some dog breeds terrier spaniels, they get soup used. You don't have to say the word walkies, and they're up and they're racing around going nuts. Other dog breeds from the African and Middle Eastern ones pretty mellow, you know, you have to say walkies 17 times and they still look at you like really? Um, and so that excitability is somehow genetically predetermined. And, and you can see that mapped out here in terms of an independent quantitative score of excitability. So now we have a trait, a behavioral trait, how excitable you are and genetic data to go with it. So you can start to ask questions about what are the genes that control these behaviors like excitability. Uh, and there's an absolutely fabulous example here, which I wanted to show you. So here, this is work from Elaine Oanda, uh, where they have looked at a trait that is particularly striking, which is working with livestock. So if you think about Coley dogs and herding sheep in this country, for example, but also some of the livestock guardian dogs that are, that are used up in the mountains to sort of sit and guard, um, you know, sheep or goats for a long period of time. They're extremely good at working with livestock. They are very trainable. They have all these kind of traits that are not necessarily shared with with other dogs. Uh, so, you know, we have a small terrier at home. There is no way I could train her to herd sheep ever. Um, so there is something about, uh, the trainability of these dogs. So now if we assume all those dogs have some shared characteristic, which is the trainability around livestock, other dogs don't, you can ask using that genetic information, what genes are shared by all these colored types of dog. Um, and absent from all the other ones, what are the genes that might contribute to this? Um, and when that was done, one of the fascinating things was that it came up with a relatively small number of genes, including this one. EPH five and EPHA five is a very interesting gene 'cause we already know a bit about that and we know that it's function is to control neural plasticity. So this is the ability of neurons in the brain to make and break and remake connections. And this is the process by which you un you, you create memories essentially. So when you create a new memory, your neurons are breaking connections and making new ones to, to cement that learning in your brain. This gene controls how readily they're able to do that. And what we see in these herding dogs is they have a version of this gene, which seems to increase neuroplasticity and that fits right. Coly dogs are highly trainable. They need that plasticity to be able to learn. And so what humans have inadvertently done is we have selected for a variant of the gene that confers a particular ability, which is the ability to learn and then herd livestock. And what turns out to be enormously useful, not just for dog owners, but for all the rest of us, is that this gene is also in humans and has actually been previously associated with attention conditions in humans. So things like a DHD, um, and some of the autism spectrum disorders where people are particularly focused or particularly dis focused, are associated with mutations in this gene. And, uh, although it's not yet proven, it's kind of a nice hypothesis, right? You have things like thinking about coly dog, an ability to learn to be incredibly hyperfocused on sheep. But anyone who's had a coly dog and doesn't trade into the sheep knows if you leave them alone for too long, they start to use that kind of hyperfocus for all sorts of ills and tear up the bedroom carpet and do all sorts of terrible things, um, in a way that is not a hundred million miles away from some of the attention disorders that we see in humans, uh, with the same sort of mutations. And so we can learn from that, uh, deep study of dogs, perhaps things that are relevant, uh, to human conditions too. So that process of selecting dogs has been very, very directional. So early on, maybe not so much, but certainly the last few hundred years, people have been deliberately choosing particular dogs to breed with each other. It's a very deliberate process of selection. But over the time we've existed on the planet, humans have done a lot more selection that is much more inadvertent, but nonetheless equally if not more influential. So I wanna talk a little bit about some of these inadvertent, um, changes that we've done. And I'm gonna start by the innovative ones that have turned out to be incredibly useful. Uh, and the place we see this most, I think is in our adoption of what we now call agriculture. Uh, and so in an early lecture we talked a bit about how humans started to, uh, start a farm essentially about 10,000 years ago, actually in many different locations around the world at the same time. But the area where this has been most intensely studied is what we call the fertile crescent around what is now the Mediterranean and sort of Middle East. And what we believe happened was that um, people who previously had been hunter gatherers, uh, started gathering seeds to eat. Obviously they wouldn't, they might have come back to a camp, they might have s spilled some of that seed. And then if came back in the following year, they find the thing they'd gathered is now growing there. Uh, and cotton onto the fact that actually it's a lot less work to kind of grow stuff here than to go and gather it and bit by bit start to create agriculture and farming. Now of course, when hunter gatherers went out to gather what they gathered was not a random sample, um, of, of what is out there in the right. I dunno if who, who cares to admit to having been bramble picking your blackberry picking or scavenging the wild? If you've done that, yes, definitely me. Do you, do you pick a random selection of blackberries? No. Right? You pick the big juicy ones, not the horrible, seedy little ones. So what you bring back is not a random sample of what's out there in the population, what you bring back, the ones that you are most interested in, the big fat ones, the juicy ones. That is an evolutionary process. We are selecting something that we like better. And so what you see during the early days of, of, uh, agricultural development by humans, um, is that process of accelerated evolution, uh, happening. So for example, if we look at grains and cereals, which are one of the earliest crops for which we have evidence of domestication, we see a very rapid evolution, uh, between about 10,008,000 years ago. So for example, here we have some data on grain size of barley. And what you can just about see here is if you look at an early site, a site, an archeological site, which was a very recent, uh, after the beginning of agriculture about 10,000 years ago, in the white dots, the barley grains we can find in the archeological record are quite small, but very rapidly, a slightly later site up here in the black dots, all the barley grains are much bigger because that accelerated process of evolution, people have picked bigger grains, they've grown them, and they're bigger the next generation, and they do it again and again and again. And we are accelerating this move to a larger grain size, very rapidly, a process of accelerated evolution that's quite straightforward for grain size. Uh, but it turns out to be true also of lots of other interesting traits. Um, so for example, as we've moved towards these larger grain sizes, we've also thought about or not thought about, we have inadvertently selected for things that are beneficial in terms of yield. And, and the time we see this happening most dramatically is with the use of tools in agriculture. And by tools I don't mean tractors, I mean very, very straightforward things, uh, like the sickle. So it wasn't very long after the start of agriculture that we start to see evidence for tool use in agriculture and in particular things like sickle. If you think about it, that makes sense. If you go out and gather grains by picking individual wheat grains, that's gonna take you quite a long time to get a meal. If you go out with a sharp influence and you cut a big sheath, then you might have enough for a meal in, you know, a couple of minutes. Um, so these, these tools provide a benefit except there's a problem. The problem is that plants, including cereals, they produce seeds because they want to reproduce, not because they want to feed people, right? So, uh, plants grow seeds and seeds are there to disperse those plants and to grow new generations. So they are deliberate, designed to spread widely. And most wild relatives of cereals, um, have what's called shattering grain. So if you find a wild wheat and you tap it when it's ripe, the seed goes and shoots everywhere. If you come into a field of wheat with your sickle and you start slicing away, um, on wild wheat, what you will end up with a lot of sticks and very few seeds.'cause as you're doing that, you're spreading seed all over the place. That's not very effective. However, there is a mutation that occurs, um, quite commonly actually in some cereals that changes. This pheno changes this ability and you lose the ability to shatter you from non shattering. And that's because instead of, uh, separating the seed from the seed head, uh, you, the plant retains a kind of a stick that attaches the seed on. So then actually the seed is not, is not dispersed naturally. That's a really bad idea. If you're a natural weak plant, the last thing you wanna do is keep your seeds stuck with you because you're not gonna disperse at all. But if you are out as a human gathering wheat and you're bringing it back again, you will massively select for any mutants in which the seed is still attached to the stalk.'cause they're the ones there when you come back. So what we see in the archeological record very rapidly is a switch from the, so-called shattering type, the wire type to a non shattering variant. And very early on we see that the entire population essentially of serials shifts from this natural process of shattering to being mutants that don't shatter at all. And it turns out that's because it's a very, very easy to do this. So there's a single, uh, letter change, DNA letter change that will change you from this shattering type to non shattering. So the mutation happens commonly, it is very firmly selected. One of the most interesting things about this is that this has happened again and again and again in different crops, in completely different parts of the world. So we see this switch from shattering to non shattering in wheat and barley in the Middle East. And we see it in rice in the far east happening at the same time because people are providing the same selective force and evolutionary force on all these different crops by gathering it in all the time. And this is probably the first example we have ever in the history of the planet of evolution, favoring a mutation that is actively disadvantageous the species. It's in right survival of the fittest. This is a very unfit phenotype in the wild, these plants would die out 'cause they don't disperse their seeds. They're now dependent on humans for dispersal. But we are a very powerful evolutionary force. And so we have selected for this trait that is actively disadvantageous to the host it's in. And we have driven that process of unnatural evolution, if you like. And we have course have done that again and again and again throughout agriculture, initially by accident more recently, very deliberately, uh, by programs of crop breeding and livestock breeding. And we have all sorts of species. So for example, we have dairy cattle which produce far more milk than their carved needs. Um, actually they're also selected for, um, sort of a lack of maternal instincts. Most modern dairy cattle, uh, you can take their calve away and they're actually not that bothered. Um, you know, evolutionarily speaking, it's a very bad idea. Uh, but it's been selected for because farmers don't like fighting with their cows to get their calves away. Um, and so we have selected these traits. We have chickens that lay sterile eggs every day. Not a very good trait out in the wild. Very useful if you're in farming. And so we have again, and again and again, selected species for traits that are for the species itself, disadvantageous for us as humans. Hugely important. Those processes are, if you like, in the beginning, inadvertent. We didn't deliberately go out and select for, uh, non shattering grain, but it happened automatically. More recently deliberate or have been beneficial to us, if not to the species, uh, that it happens in. But not all of our evolutionary impact is beneficial. Um, during our history, we have also repeatedly done things by accident that have influenced the evolution of other species in ways that are actually not that beneficial, at least not to us. And there are lots and lots of examples of that. But one of the ones that I think is the most, um, uh, kind of striking, uh, dates only from the last sort of 70 years or so, and it's this one, this is warfarin. So warfarin, uh, is a drug, um, and it's a drug that stops clotting. So it's an inhibitor of blood clotting. And in fact, it might be used, but some of you in the audience might use it. Um, it's prescribed for people in very low dose. If you have, um, a, a propensity to clot. So for example, if you've had a stroke, um, or you're at risk of heart attack, you might be prescribed a low dose of warfarin.'cause it inhibits an enzyme that converts actually vitamin K, which you require for clotting. So if you're given a very low dose of warfarin, you slightly reduce the chance of your blood clotting and therefore getting clots that might lead to a stroke. If you give a high dose of warfarin, it's a very bad idea. It totally inhibits the process and you start to bleed spontaneously. Um, and high dose of warfarin is lethal. It's lethal to humans, uh, but it's also lethal to lots of other mammals. And after warfarin was, uh, discovered in the 1950s, people clocked the fact that this was a very useful drug if you wanted to control mammals that you don't like in particular rodents. Uh, and so warfarin became used very rapidly in the 1950s as a rodent poison. Um, and it would be put in baits. Um, and indeed these unfortunate rats and m would eat the bait, uh, and they would die, uh, swiftly, but pretty horribly from, um, hemorrhage seemed like a wonderful thing, very useful, uh, used in particular in big cities in the us very rapid in the 1950s. Um, but warfarin works by targeting a single enzyme. So there's an enzyme, which is the blobbing here that converts, uh, vitamin K into the functional form to trigger clotting. Warfarin, which is a little molecule here, sits inside that protein and stops it working. That means that any tiny mutation that slightly changes the shape of the protein means the protein doesn't stick to warfarin anymore, and it goes on doing its normal function without being inhibited. It's a way of escaping from this, uh, this poisonous selective warfarin. And, uh, people might call me put two together and realize that actually those kind of changes in evolution happen all the time because of spontaneous mutation. Um, normally there would not be selected for, but if you apply a strong selective agent, like a poison that kills you, any rat that has a spontaneous mutation which renders it insensitive to warfarin, has a massive advantage. And sure enough, we introduced warfarin in the 1950s by 1960, uh, in New York in particular, pest controllers are reporting large populations of rats that seem to be totally insensitive to Warfarin. Uh, and a couple of years later, actually, uh, even in Europe, people started to report mouse populations that were also warfarin resistant. A process by which we have shaped the evolution of multiple species, actually within a very brief period of time, uh, because of this intense period of, of evolutionary selection we've placed on them. Now, warfarin is a pretty unique example, obviously. Um, it's very, very tightly focused around particular species, but this same process is something which is driving a problem that is, should be at least close to all of our hearts. And something we really worry about, uh, which is antimicrobial resistance. Um, so if you're not familiar with it, um, first of all, I'm horrified. Uh, but, but if you're not familiar with antimicrobial resistance is the, is the dramatic rise in bacteria, but also increasingly fungi and viruses, uh, that are resistant to many of our medications designed to target them. And the process that is driving this is the same sort of evolutionary selection that has driven warfarin resistance in rats. Namely, if you apply a drug that is designed to kill something, any mutation in the thing you're trying to kill that renders it insensitive will be very, very strongly selected for very rapidly. And so you are, if you like, um, neutralizing your own weaponry very, very fast. And that is exactly what we see in the history of antibodies. So we've had antibiotics, broadly speaking, for, for under a hundred years. It's a brief snapshot of of civilization. Uh, we had sulfonamides quite early. But actually in terms of mainstream antibiotics, the biggest one obviously is penicillin introduced around Second World War. Um, and actually every major class of antibiotic that we've introduced, which are on the top line here, has been followed generally within 10 or 20 years by bacterial strains that are resistant to that antibiotic. Early on in the sixties and seventies, what we started to see were bacteria that were resistant to single drugs. So for example, you might introduce something like methicillin 1960 here, um, and then actually only a couple years later, in this case, you start to find bacteria that are resistant to methicillin and so on and so forth. By 1980s, this was apparent to most clinicians. And so clinicians being very smart and wanting to do well for their patients, realized that treating the single drug is not such a great idea and started to use combinations of drugs either together, uh, or sequentially in order to get over this problem. Worked for a while. But then what we start to see is the evolution of strains that are resistant to multiple drugs, and in particular, uh, by the two thousands, these extensively drug resistant strains that we're resistant to many, if not all of our frontline antibiotics. And this actually is one of the biggest risks, I think, to the future of humanity. We talk a lot in these series about things that might bring humanity to an end. Um, and there are, unfortunately, there are quite a lot of them, asteroid strikes, climate change. Uh, this is one more to add to the list. I think, uh, we have to remember that essentially many, many of us in this room are only alive because of these drugs. I think it's probably, I want a show of hands, but it's probably rare that any of you in this room will have gone through your entire life, never taking a course of antibiotics. And you assume completely that if you have a chest infection or a kind of slightly dodgy wound, um, that you'll get better with antibiotics. But it was only a hundred years ago that that chest infection or that slightly dodgy wound might have killed you. Uh, and if we're not careful, we'll go back to that, uh, process again, because we have accelerated evolution in a way, uh, that has essentially rendered our own arsenal of drugs are useless. And one of the reasons we've had that process is not just about medical intervention. So these are all medical antibiotics, um, but we have also used antibiotics for all sorts of things that have driven this. So if you have antibiotics as a patient, you need those, you're selecting for bacteria. But actually the amount of antibiotics used in individual patients pales into insignificance historically versus the amount that have been used in things like agriculture. Uh, and this is a process now that is largely, um, being phased out and banned in many countries, including the uk. But until recently, people have applied large doses of antibiotics, particularly to livestock like intensively reared chickens as a growth promoter, as a way to accelerate the growth, uh, of these chickens. Um, because if you remove all the bacteria from a chicken, it actually grows a bit faster, probably because it's scavenging more energy from its food. Um, but you are strongly, strongly selecting for antibiotic resistance. And a lot of this agricultural use has driven, um, the evolution of these strains. More recently, we're starting to see worrying trends that this is not just restricted to, to antibiotics that are used clinically. So for example, if you look at fungicides that are used in agriculture, um, these are not fungicides that are used in patients, but they are often chemically very similar. So here, for example, someone is spraying a field with a fungicide and many are commercially available agricultural fungicides are based on a structure called an azel. These are not the same molecules that are used in individual humans, but they are the same group of chemicals and they're structurally very similar. And we have started to see just in the last few years, patients with invasive fungal infections that appear to be resistant to clinical azoles. And when you look at the mutations that those strains have, they're conferring resistance to these agriculturally used azoles too. And if you think about it, that makes a lot of sense because many of the pathogens we encounter that kill us are out there in the environment. We don't always get them from other people. And that's particularly true for fungi. So this is one, this is aspergillus, a fungus that's out there in the environment we breathe in all the time. For most people, it's not a particular problem. But if your immune system is impaired, particularly following organ transplantation, this fungus can grow within your lungs and ultimately kill you. It's treated with azoles. Um, but the problem is this fungus lives out in the environment, particularly in agricultural places. It likes compost heaps, for example. So if you are spraying your fields with a fungus and then gathering in the waste and making compost, you are essentially exposing your fungus to a low dose of the thing that is supposed to kill it, perfect conditions for it to evolve resistance. And what we start to see, uh, and this is a structure of one of the proteins here, what we start to see is that these fungi out in the environment carry mutations that render them resistant to the fungus, uh, to the fungicide out in the environment. The same mutations confer resistance to the fungicide that will be used in a clinic. And so you are essentially producing a population of fungi that are already already immune to the drugs you might need to treat them with. And that I think is a really, really big concern and something that that needs kind of rapid addressing. Okay, so that's a little bit of a depressing note. Let's, let's go a bit more upbeat. Let's think a little bit, um, uh, for the last, uh, quarter, an hour or so about ourselves, we've talked a lot about our impact on selecting other species, cows and we, thoughts and stuff. What about ourselves? Do we select ourselves? Um, and the short answer to that is we do select ourselves like all species. Uh, we are evolving all the time and we're evolving in all sorts of interesting ways. So for example, um, this is a graph I've showed in earlier lecture too. This is a, a very interesting study where people have looked at the human genome, the modern human genome, they've sequenced people like you in the room or you listening online, and they have looked at the rate of diversity in all the 20,000 ish human genes. If you imagine this is the whole human genome here. So chromosome 1, 2, 3, all the, the way to the end, every human gene is mapped and what they say is, so let's look at a sample of, of people in this room so that you know, all of you in this room here, how different are those genes? And what you see is that for most genes, there's not very much diversity, okay? Most of us have genes that're very similar. There are some though that are evolving incredibly fast, that are really, really diverse because they're under very strong evolutionary selection. Um, and actually the single gene in the human genome name that is evolving the fastest is this one up here, LCT. Um, and this is the gene that confers the ability to digest milk as an adult. So most mammals, all mammals, digest milk as, as infants. All of us. We know we don't digest milk as adults. Many humans, that's also still true, uh, but uniquely amongst mammals, most, um, at least in Europe, most humans have the ability to continue to digest milk as an adult. And it's because this gene has stayed on. Most humans don't drink human milk as adults. Let's not even go there actually. Um, uh, but so, so why have we evolved this? We've evolved this because we do drink the milk of other species as adults only since though we've started agriculture, since domesticating livestock. So this gene has evolved incredibly fast in the last 10,000 years, less in fact, um, because of our newly imposed selective pressure, which is that if you can drink cow's milk in the middle of winter when no one else got anything to eat, you are gonna survive. And if your neighbor can't digest that milk, they're going to die. And so we have selected ourselves because of agriculture to have a very rapidly mutating gene that confers that benefit. That's very overt. Example. Drinking milk and surviving is quite an important advantage. Um, but there are much more subtle effects. And one of the things that has, uh, puzzled people for a long time is whether we see evidence in humans of this process known as sexual selection. So most animals compete for mates. If you think about it, most animals have a courtship ritual, and it's not random, right? It's not, your chance of reproducing is not random. You have very successful individuals who reproduce a lot and unsuccessful ones sat in the corner of the disco who don't reproduce at all. Um, and, and this has driven this process of sexual selection. So most animals, um, engage in these kind of courtship rituals and they choose their partners. And perhaps this prime example here of the peacock where the peacock is displaying, uh, to the p hen, um, essentially advertising his pross, right? This tail is of no benefit at all. In fact, it's a handicap, it's a very disadvantageous to have a tail like this. Um, but it has evolved because it's a way for the peacock to signal to the p hen despite the fact I'm carrying around this ridiculous tale. I'm still incredibly fit because I'm really tough and I eat really well and I can fight other people off. I am the kind of mate you want to mate with. It's a sexual signal, okay? These happen in all sorts of animals. Think about plumage and birds, think about courtship, rituals, red deer erupts, all these kind of things. Now, the question is, and the question actually originally posed by Darwin, do humans do this too? Um, and actually we still don't really know the answer, but there are some interesting, um, and maybe slightly controversial anecdotes that, that I wanna share with you that, that suggest we might do. And, uh, with apologies for lowering the tone straight away. Um, the one I'm gonna choose to pick on tonight, um, is, uh, human breasts. Um, and the reason for picking on this is not just gratuitous, is because humans are unique amongst primates. We are the only primate that has prominent breasts in females, okay? If you go to the zoo and you look at gorillas or chimps or bonobos, they, they, their breasts not visible. They're, they're kind of flat, but humans have prominent breasts. You might think that has a fitness advantage. Maybe they produce more milk, um, they're better at producing kids. All those things have been looked at and none of them are true. So there is no correlation between breast size, um, and the ability to produce kids or to lactate or any of these kind of things. And in fact, the best evidence we have is that the driver of breast is nothing to do with their function in producing milk, but they are a symbol of, if you like, fitness, just like the peacock's tail. Um, and that is because one of the things that is a very good signal of, of fitness is symmetry. So if you think about getting infections, largely infections are not symmetrical. If you get spots or wounds or whatever, they're on one side of the body, not the other. And so humans, like most animals prefer symmetry. Symmetry is a sign that you are a fit individual, but you haven't had some horrible infection. Two large prominent breasts, uh, with apologies are a very prominent way of advertising. You are symmetrical and you are therefore fit. And so one of the, uh, suggestions for the evolution of these is that they're a way of advertising your fitness, nothing to do with their primary function. Um, and, and so the suggestion is that the rapid evolution of breast lives in humans has been driven in the same way as the peacock's tail. That's a very visible signal of sexual selection. But one of the ones that I think is most interesting, and actually for which there is now really quite robust evidence, is a completely invisible type of human evolution, um, that relies on this, uh, protein here. This is a protein called MHC. Its function is in your immune system. Actually, it displays foreign proteins and tells your immune system, I've seen this foreign protein from this bacteria. You should get, get busy and kill it, okay? We all have MHC proteins on our cells, and they are highly diverse. So unless you're an identical twin, your particular type of MHC will not be the same as anybody else. And that is because it's advantageous. If you're thinking about using this to detect and display foreign pathogens, you want a range of different options available to you because sometimes one version is better at displaying i adeno bacteria and another version is better at displaying viruses. And so you want that, that diverse options like having a toolkit of different tools. So diversity amongst MHC proteins is a, is a benefit. Um, and so if you are choosing a mate, what you really want is the ability to say, I want to find someone with a different set of MHC, says that my kids will have the maximum diversity available to them. The problem is you can't see mhc. Um, and uh, so how do you, how do you know that? And it turns out that we do know that in a way that we have no understanding of at all, and we know it apparently, uh, by smell. Um, so there's a rather fabulous experiment in which you take, uh, uh, yucky sweaty t-shirts worn by men, um, and you give them to women. Um, and you say, which of these sweaty t-shirts is the, is either the most attractive or the least repellent, depending on how sweaty they are. Um, and therefore use that as a measure of attractiveness. And what it turns out is if you take a random sample of women, they never choose the same t-shirt, but what they choose is the T-shirt from the person who is most genetically dissimilar to them. They are sniffing out literally the person who has a different set of MHC to maximize that diversity. We dunno how they do that. It's no idea how how that happens, but it does seem to happen. Um, and so I think this is a fantastic example where actually evolution is happening without us knowing it. We also don't know, not only how, how it happens, but what it's long term effect is because this is a, a process, if you think about it, where it is not directional. We're not all choosing the same person. So we're not all choosing a strong person or someone who's good at gathering food, we're choosing someone who's different. We're maximizing diversity. And so in some senses, it's jumbling up the evolution all the time, and we don't know how, um, impactful that is long term. But I think a fascinating example and maybe want to think about if you haven't yet chosen your partner, give 'em a good sniff beforehand and, and see what they smell like. So let me finish off in the last few minutes by thinking about this is everything I've talked about has been either inadvertent, we haven't deliberate on it, or it's been sort of deliberate, but we haven't known what we've been doing. We've been choosing, you know, wheat, that's great, or cows that produce more milk. But we haven't known how that has happened. But in the last hundred years, pretty much we've suddenly gained the ability to really understand what happens in evolution and to start to shape it deliberately. We've gained the ability to control our own evolution and the evolution of other, uh, species in a very directed way. And we do this all the time now. So for example, if you're a farmer, it's absolutely routine to do genetic testing on your cows or your chickens or whatever else. Um, and then to mate them according to their genotype and to get the maximum possibility you want. But where it's about to change life, I think, forever, is in ourselves, in humans because we now have the ability to control our own evolution in an incredibly directed way. And actually we've been doing this already a little bit, uh, for the last sort of a hundred years or so. Um, so for example, this is baby, obviously if you don't know it's a baby, you're in the wrong lecture. Um, this so, so, and this is a healthy baby. But there are, as we know, some tragic and, and, and very disturbing, um, diseases that are inherited of, of babies. Um, and I think all parents kind of want to try and avoid those. Very early on, uh, when genetics was kind of in its infancy at the beginning of the 19 hundreds, people realized that these disorders were often inherited and therefore that you had to kind of control over them if you could work out, um, their impact. And this was adopted, uh, by many populations quite extensively, particularly populations in which particular diseases were, um, were more prominent. And the best example of this is disease called Sachs disease. It's a neurodegenerative condition that children are born with, um, and, uh, it's lethal. They have a pretty appalling neurodegeneration and, and die in infancy. This disease is relatively rare overall in the world, but there are particular populations in which it's much more common. And that is due to this process that we talked about in an early electrical, the founder effect, where a small population has grown from a handful of individuals, it often over represents particular genetic mutations that are rare overall, but if they happen to be common in that starter population, they stay common, uh, when the population expands. So this is often seen, for example, in groups where they may have migrated so particularly to the new world, um, and where they tend to reproduce within that continue to reproduce within that group. So for example, religious communities that were persecuted in Europe that then fled to America, but retained within their community structure often have a higher frequency of particular disorders. And so SAC is particularly common in some of those communities, especially the Orthodox Jewish community, where the rate of taste acts is about a hundred fold higher than in, in the random population of the world. Uh, and this community realized that very early on, and actually there's been a program running now for, um, many decades in which you can have yourself tested to see whether you carry the gene for this disease. And if you do, um, you can then phone a helpline. You can work out if you're about to marry somebody, whether or not they carry that, uh, ine in, in as well. And if you do, you might choose either to not to marry them in the first place, um, or to marry, but not have kids, um, or of course, uh, more recently to have genetic testing of your, of your children. And this process has very, very rapidly reduce the frequency of this mutation in that population because of directed evolution. If you like, directed reproduction, that's a relatively blunt tool to test yourself and decide shall we have babies or not. But of course, what has happened in the last less than 50 years is our ability to do this in a very, very precise way. And in particular with the advent of in in vitro fertilization, IVF, so IVF now almost 50 years old, of course, is the ability to create embryos and then implant them, uh, in vitro. Initially it was done purely as a process of producing babies for people who couldn't have them naturally. More recently, of course, what we've started to do is use this to couple this with genetics to test for diseases. So if you go for IVF now, you will be offered a very extensive range of genetic tests if you want them. Several hundred diseases can be identified in embryos. And so classically what happens is you might have multiple embryos created. They might test multiple embryos and say, uh, here is one that doesn't carry any of the 300 main mutations we're looking for. Let's implant this one and not the other ones. And so what we're doing with IVF in some senses is selecting away some of these bigly big disadvantageous uh, diseases, but we're also changing the frequency of genes. So the diseases you can test for in IVF include lethal, uh, many, many lethal diseases, but they also include things that are actually relatively late onset. So things like early onset Parkinson's disease, uh, for example, is one of the tests that you can have. Now, early onset Parkinson's disease is a grim disease, and as a parent, you probably wouldn't want your child to have it, but that child would grow up to be an adult and potentially have reproduced despite carrying that mutation. So you've intervened and changed the frequency of a gene in a way that has never previously happened by by diagnosing it. That tool is still, I guess it's still relatively blunt, much more sharp than the the previous one of testing yourself and choosing to reproduce, but relatively blunt. But what has happened just in the last decade or so, is our ability to do really remarkable things. Um, and this perhaps is one of the most, uh, remarkable ones to be reported just in the last few years. Here's John Zang, who's a clinician in the United States, and he is holding, um, what is now sort of slightly ancy known as the three parent baby. Um, and the reason this, they, it doesn't really have three parents, but let me explain why it's called that this is a baby born to a couple who have an inherited, they know they have a risk of an inherited disease called Lee syndrome. And Lee Syndrome is, uh, one of a group of diseases that are called mitochondrial diseases. And let me explain what that means. So if you, uh, reproduce normally, uh, what you have, I hope this is not a spoiler alert for anybody. What you have is a sperm and an egg, right? Sperm fuses with egg. Um, and what you end up with, uh, is an embryo in which you have a mixed set of genes from both your parents. But there's a slight caveat here, the the red dot and the big blue.here on the nuclei where your genetic material is, um, uh, contained. Um, and all of us are roughly speaking a 50 50 mix of those nuclear genes from our mum and our dad. But there's a tiny little bit of genetic material that you don't inherit from both your parents, and it's carried in the little blue, um, ovals here called mitochondria. These are parts of your cell that produce energy you need, you have in all your cells pretty much, um, and they are working your way to produce energy, but they have a tiny, tiny bit of DNA from themselves, just 37 genes. So the nucleus has about 20,000 genes, but the mitochondria has 37 genes, but they are very important ones. And actually, interestingly, that's because mitochondria's origin million, billions of years ago is as a free living bacteria that has now been kind of co-opted into us. But you see your mitochondria have their own genome. When you fuse a sperm and an ache, you fuse those 20,000 genes for your nucleus, but you only inherit mitochondria from your mum. Okay? So all of us, you know, who are dads, um, we are actually slightly less inherited in our kids, uh, than your, your partner, your female partner. If you have a mutation on your mitochondria that causes disease, um, this can be very disa disadvantageous. Um, and because the, the MIT might not function, and there are actually a large number of syndromes that are driven by mutations in one of those 37 genes. Um, and so for most of human history, this has been unavoidable. There's been a problem, and there are lots of these conditions out there, but what has happened just in the last few years is the ability to overcome this. Um, and so what John Zang did, uh, with this couple who knew that they carried a mutation in the mitochondria in the, in the, uh, wife's mitochondria, they'd had two babies previously with Lee Syndrome who had died. Um, and they were desperate to have another one that would be healthy. Um, so what they did was they created what is now known as the three parent baby. So sperm from the dad as per normal mum's egg and a donor egg, okay? What you do is you take a donor egg in here in blue from a healthy individual who doesn't carry the mutation, you remove from that egg, the nucleus. So all the genetic material except for the mitochondria, you transfer in the nucleus from the mum who wants to have the baby. And then you fuse this egg with this sperm. And what you end up with is a baby in which the same 20,000 genes are a mixture of mum and dad, but critically, the mitochondria come from the donor, pseudo mother, if you like the other one. And this is exactly what has happened in this baby here. So this baby, for the first time ever in human history, has genetic material from three immediate parents. It's only a tiny amount, 37 genes from the other mum. But nonetheless, it's something that would never have happened naturally. And so we have created, if you like, a totally novel genetic combination, uh, in this baby. Uh, and I think, you know, for very good reasons. But of course this opens a whole new door of Eli. More critically, we have now got tools to start to do this also on those genes that are within the nucleus, those other 20,000 genes. And in particular, um, this process of CRISPR editing, which won the Nobel Prize a couple of years ago, allows us to very precisely edit genes. There is a global moratorium preventing this being done in humans because a change that you make in a gene of a baby in this way will be inherited forever. And so there is an agreement globally not to do this in, in children, but like most agreements, people break the rules. And indeed it has happened. Uh, so there were twins born in China a few years ago who had been edited. They had been edited for all the right reasons to render them resistant to HIV'cause they've been born to an HIV positive mother. Um, but, uh, they are, they are different. They are different, fundamentally different from any baby born before because they have been precisely edited. That mutation could have arisen randomly anyway, but it has been directed, uh, and produced. And the person who did this ended up in prison. But nonetheless, the twins are alive and out there and are a new type, if you like, of human evolution. I think this, this kind of totally transforms our understanding of evolutionary direction because now we have a process which has reshaped, if you like, a gene pool, uh, forever. Um, we'll have to see what happens, who knows what will happen going forward. But I think these tools open a new box and potentially a whole new era in human evolution. And I guess one which would be very interesting to watch, and my personal feeling is I suspect ultimately it will start to shape human populations in ways that we have never predicted before. And who knows, this interesting mixing pot of human species might start to have all sorts of genetic mutations that have been created rather than spontaneously selected. Uh, which is something we'll talk about in the final lecture of the series in a couple of months time. Uh, but that's it for tonight. Thank you very much. Thank you. Um, the sweaty t-shirt test <laugh>, does it only work with women doing the sniffing? So is it a bit like peacocks, it's the women, the females doing the selection, or does it work the other way around as well? Yeah, um, it is just like peacocks. So for the guys in the room, disappointing, but we are rubbish at it. Uh, so, so yes, so women can detect, uh, diversity in, in male t-shirts. There's no evidence that men can even more interesting. There's actually a bit of data suggesting that how good women are depends on the menstrual cycle. So you're better at some periods of the month than others in a way which seems to reflect fertility, um, which, which actually brings a whole new perspective. You go clubbing on a Friday night, so what's going on? But<laugh> it was about, um, the way that genes naturally select. I read something recently about a garfish and about how similar the genes are to how they were millions of years ago. Is that, is that, is that something that's, is that new or is this something that's been found in other populations as well? Yeah, so the, so the rate, there are basically two big drivers of the rate of genetic change. Um, so the first one is I guess how much you might need to, so what we see quite often are species that apparently have existed more or less unchanged for a long period of time. So the sealer camp people are familiar with is this kind of ancient fish, for example, in the Indian ocean that appears not to have changed for, uh, hundreds of millions of years. We of course don't have genetic data going back that far, um, but it looks really like fossil seed cans. Um, and that is most likely because essentially if you are optimally, um, evolved your environment, there'll be subtle changes. But if the environment doesn't change, you don't need to evolve to these. There'll be random mutation, but actually you are kind of not under the same pressure to go. And actually that graph I showed of human genes, most human genes are not evolving very fast because the, the kind of gene you need to, I dunno, metabolize carbohydrate or, you know, produce sperm or eggs, they haven't changed that much. What you see is only the ones that have a direct impact have evolved fast. So that, so one reason is if the environment's not changing, um, the other reason there might be constraints on those particular genes. So one of the things we often see is that a gene that relies on another gene and another, another gene, is much harder to evolve. Because if you, so if you imagine for example, a protein and it's receptor, if this one changes and it doesn't stick anymore, then this one has to change at the same time, otherwise it's not gonna work. And it's much harder to evolve those multiple things. So anything where you are dependent on a much more complicated network evolves more slowly. And that is one of the potential saving graces for antimicrobial resistance is if you can combine lots of treatments in ways that it's very hard to evolve individual resistance to, you'll reduce the rate of evolution in the bacteria because they can't do 19 things at once. Uh, not an easy fix, but yeah, that's, that's, that's one of the reasons. Um, I'm gonna take a, a, a couple online. The, the now you, you, you, like a disturbing number of bre college professors have, have, have, have forecast ways in which the human, uh, species might come to extent. We've, we've, we've had asteroids when, and we've, uh, the sun exploding and, uh, the, uh, climate change dragons more recently. Um, uh, and talking about dragons, <laugh> and uh, and adding, uh, an uh, and antibiotic resistant, uh, bacteria. Um, can you sort of give us a bit more insight into, um, the, uh, how, how often we're able to create new antibiotics versus the speed at which the, uh, the, the, the bacteria are trying to beat us? Yeah. Uh, it's another bad news story, I'm afraid. So one does not equal the other and it's not in our favor at the moment, <laugh>. Um, so, so how often, how rapidly we can develop antibiotics, it's actually a bit different how often we have. So we have not developed new antibiotics at all much in the last sort of 40 or 50 years. Um, and that is largely for two reasons. One of all, people thought it was fixed. We thought 1960s, great, give people antibiotics, job done, no need for research. Secondly, they're not very economically rewarding. If you're an investor, a drug that you only use for a very brief period of time in a few people who get sick and actually needs to be quite cheap as otherwise they're not gonna take it, is not a great investment. Versus something like a monoclonal antibody for cancer where you might be taking it for years and it costs huge amount of money. So there has not been much investment in the market. How, if we can get over that economic hurdle, how easy is it about new antibiotics? There's a lot of activity now in looking in the natural environment. So many antibiotics come from other species that create them as a kind of way of microbial warfare that's quite promising. Most recently, one of the most exciting things is directed antibiotic production. So you can look at a protein, for example, a bacteria really needs and design a molecule that might fit and make it stop working. Um, that is sort of in its infancy, but kind of starting to come. So I'm, I guess I'm cautiously optimistic. I think we have the ability to solve this problem. Uh, like, but it's a bit like climate change. We have the ability to reverse climate change. Will we do it in time? Hmm, good question.<laugh>. Excellent. Um, uh, gentleman back, Uh, coming back to the SM test, is there any evidence of a difference between populations where women can choose husbands and where the husband had chosen for them so that the SM test wouldn't apply? Yeah, so, so that's, so the, the choice of partner is a very interesting thing. So, so there will be differences because obviously what you might choose for your children, for example, or in the case of think about royal family, where sort of your, your citizens kind of nudge you in a direction of a political reasons, um, are not necessarily evolutionary functions, but they are nonetheless, they have an evolutionary impact. So for instance, if you think about, um, uh, the British royal family, uh, you know, going back a couple hundred years where there's this very strong incentive for European stability, um, and you know, it's no sort of big surprise that, uh, genetic disorders like hemophilia were more common in the British royal family into fairly recently. Uh, because essentially you are, you are breeding within a, a less diverse gene pool than the rest of us commoners. Um, so, so those kind of processes do still influence evolution. Um, I think one of the, one of the most interesting things is that very often the reason you're choosing partners is based on sort of cultural behavioral things. Um, and, and many of those are, there probably is a genetic component, but it's much weaker. You know, you are, there's no evidence, for example, there's genetic inheritance of the kind of religion you might have. There is actually some evidence that how, uh, religious or not you are is partially genetically determined. Um, but your choice of whether you're Christian or Muslim or anything else is not driven. But that has been historically a very big driver of who you were, um, you know, married off to either from yourself or from from your parents. So those kind of genetic effects are probably much weaker in human society, but, you know, look hard enough, you might find some of those influences. Um, I, I'll take another one on online there. A couple of people asked, um, quite similar questions about the, uh, the extent to which, um, you, you, you, when you look at your dog example, we've transformed dogs in size and shape, um, quite dramatically. Um, but we haven't done the same with other domesticated animals in quite the same scale. Is is there a reason that we haven't done that level of change in other animals? Yeah, so, so largely I think that's about what your sort of objective is. So we have done that. I mean, cattle, pigs, chickens, you know, chicken derives from a jungle fowl. There's not a lot of similarity between this anymore. So, so we have massively done it in some species. Others. So cats are a good example where actually cats are much less sort of, you know, uh, precise. They're obviously breeds of cats, but they're not quite as, as diverse. Some people would say that's 'cause cats have domesticated us rather than the other way around <laugh>. Um, uh, but, but that's true. Uh, there are no real genetic barriers to that with the slight exception that inbreeding is generally quite a bad thing. So you, you start to accrue these, uh, mutations, um, and depending on the amount of these mutations that are present in the original stock, that may be a bigger problem for some breeds than others. Um, so, so, but there's no real barriers. It's largely just about which species we have sort of chosen, if you like to select for True. Um, any more questions in the room? Uh, okay, so I'll, I'll I'll take, uh, 1, 1, 1 last one, uh, online. Um, and that's, uh, would we, where we've developed resistance to antibiotics, uh, what about, uh, other forms of drugs such as, uh, where for painkillers will they follow the same path? So for drugs that work on humans, they won't, unless obviously unless they kill the human, in which case it's quite a strong selective pressure, but there's also quite a strong pressure on drug companies not to design drugs that kill people. Um, so, so that we, where, but a, a drug that works on another organism, um, would, would potentially select it in the same way. Um, and so for example, one of the very interesting areas is not really a drug is, is the gut microbiomes a lot of interest in the gut microbiome. People starting to change their diet or their behavior and stuff in a way that will influence their gut microbiome. Evolutionary speaking, the gut microbiome or the organisms in it will then also evolve in response to that. So if we all start eating more, I dunno, yogurt, um, what you will find is that the organisms in your gut adapt to that and start to evolve in a way that uses it. And, uh, you know, let's find out a couple of thousand years from now, maybe we'll all have, you know, McDonald's optimized, uh, microbiomes, who knows <laugh>, Uh, ladies and gentlemen. Uh, so an air of sadness, I have to actually draw proceedings for a close this evening. Um, we have had only so many Gresham college lectures, which have managed to combine into one talk for the inevitable extinction of the human species and sweaty t-shirt <laugh>. Um, uh, please join me in thanking this evening speaker, our Gresham College professor of physics, professor Robin, me.