Good evening everybody. Thank you so much for coming. Thank you to those joining us online, uh, from your sofa. Great to have you as ever. Uh, this is my second lecture in this series about evolution. And for those of you who have seen the first one, you'll know, we talked a bit about, uh, evolutionary ideas, where they came from, why they're important, and maybe why they're more important today than they were even when they were first thought of today. I want to take a slightly different tack and talk about randomness in evolution. Um, and the reason I want to talk about that is because I think people quite often sort of labor under this illusion about what evolution is like. Um, and quite often that's wrong. So very often we think of evolution, and sometimes we picture it like this, um, exactly like this, like a linear process. We started out billions of years ago as a kind of simple blob down here, um, very little structure. And over time, life has got more and more complex. Um, and if you go back particularly to the Victorian era, you can see these rather wonderful posters in which, you know, everything else is irrelevant. And the pinnacle of evolution is humanity, preferably a guy with a big beard, actually in Victorian era. Um, and, and obviously that was the, uh, the, the kind of culmination of evolutionary processes. Um, and nothing actually could be further from the truth. Uh, evolution is certainly not linear. It doesn't have a master plan. We're not all traipsing our way towards some kind of ultimate goal. Um, it is at its heart random. Um, and in particular it is diverse and it is branched. So if you think about that, it makes a lot of sense, right? If we map out every species, uh, on the planet, they're all related to each other in some kind of large tree-like way. And this is a very old diagram, um, from actually not long after Darwin published his book, but showing already at that stage, people thinking about evolution, uh, as a tree of branches. Uh, and the really important thing to think about, of course, is that branches split, they grow, uh, but they also end all the time species are going extinct, things are stopping. Uh, there are entire branches of this evolutionary tree that no longer exist. Um, and that is part of the natural process. Uh, and broadly speaking, extinction is just as important as creation of new species in terms of evolution. Uh, and species go extinct, really, uh, for one of kind of three reasons. The first and the one we think about most often is they can be poorly adapted to the environment they're in. Typically, they were quite well adapted. Something has changed in the environment, and now they are less well adapted. Um, and the unfortunate dodo is a good example of that. Um, being a big fat flightless pigeon on an island, uh, was actually really good idea for a long period of time, millions of years probably, um, until Dutch sailors arrived, uh, and realized that being a large flightless pigeon on an island was an excellent source of protein. Um, and within 50 or 60 years, of course, the dodo was extinct. It was well adapted to its environment. The environment changed by the introduction of another species, IE humans. Um, and it was then maladapted. It couldn't fly away, couldn't run away, uh, and became extinct. And species go extinct like that all the time. When the environment changes, it gets hotter or colder. Food sources change, predators appear, predators disappear. All sorts of things, uh, change. But that's not the only reason why species go extinct. They can also go extinct if they're out competed by a similar lineage. They haven't changed in their, uh, adaptations and the environment hasn't really changed, but a competitor has come in and has displaced them. And this, of course, is something that is sort of happening as we speak in the United Kingdom to the red squirrel. So the red squirrel is our endemic native squirrel. Um, uh, and, uh, as you know, uh, the gray squirrel introduced from the Americas is bigger, faster, um, more aggressive. But in particular, the gray squirrel carries a disease squirrel ps uh, to which it is fairly resistant. And red squirrels definitely are not. Um, and so the red squirrel has been pushed really into a very marginal species in the United Kingdom by competition from a closely related, uh, other species. And this idea of species, species competition happens quite a lot and is quite a common cause of extinction. But the, the cause of extinction that I want to dwell on for a moment tonight, um, is this one the entirely arbitrary and random cause of extinction. And the most famous example of that, of course, is the one, um, that you have the illustrated here. Uh, this is the collision with a meteorite that is now, uh, well understood to have brought to a close the era of the dinosaurs about 66 million years ago. Um, and so this big lump of rock, we estimate about, uh, 10 kilometers, six miles wide collided with the earth, caused an unbelievable ecosystem upheaval, uh, and led to the extinction of we estimate three out of every four species present at the time. This is not an event to which you can be adaptively optimized by evolution, right? There are not species out there that are kind of bulletproof to asteroid impacts. Um, this is random and it is so random because if that asteroid had been, you know, a few miles to the left or a few miles to the right, much earlier in its journey, it would not have collided. And who knows what would've happened, but whatever it was, we wouldn't have had this mass extinction. Um, and, and, uh, eradication of the dinosaurs. So chance plays quite an important role. Um, and the important thing about chance is that it has lots and lots of knock on implications. So clearly, when a species go extinct, there are big losers, not least the species that has gone extinct. It was probably quite depressing, um, to be a dinosaur and go extinct, I imagine. I dunno, maybe it's great to be extinct, but, but the dinosaurs themselves lost out by going extinct. But of course, so did lots of other species about which we know absolutely nothing. There were, however, undoubtedly things like tape worms specific to different dinosaurs, um, parasitic invertebrates, fleas, mites, lice, um, that we know today are typically very, uh, ho specific. And so it's probable, in fact, I would say almost undoubtedly, uh, true that the dinosaurs had their own species living on them. They might have had, for example, invertebrates that fed on their d all of which went extinct when the in dinosaurs went extinct. So there is a knock on consequence of extinction to many, many other species. We tend to get kinda less wedded as, as humans, you know, we get very worried about rhinos going extinct. We don't worry so much about the rhino tapeworm. Maybe we should. Um, but nonetheless, those species do, uh, get a knock on impact at the same time. But as well as losers during extinction, you have of course winners. Um, and say for example, this image here, uh, these two little chaps are what's called Sids Sids. Um, these were organism small animals, um, that were present at the time of the dinosaurs. Um, and they were largely fairly small in, in physique, um, and we believe nocturnal. And the reason they were fairly small and nocturnal, uh, was because if they had evolved to be fairly big and roam around by day, uh, they would've been eaten by things like this. Um, so they were sort of forced into this ecological niche. You can think of things like mice and rats today, um, by hiding from the dominant predator type dinosaurs at the time. So when the asteroid came along and wiped out these chaps, there was a big fat ecological niche into which this lineage could expand, and that is exactly what it did. And Therapsids went on to form the basis of all, uh, modern mammalian species. Um, and it's pretty reasonable to argue that had that mass extinction not happened and the dinosaurs not been wiped out, therapsids would never have evolved into this mammalian lineage. And actually the world as we know it would look radically different, uh, except that we wouldn't know it 'cause we wouldn't be here either since we descend from this lineage. So that chance event has shaped evolution for the following 66 million years. These kind of chance effects, these massive asteroid strikes are fortunately, uh, very, very rare. Um, they do happen, but they are, they are pretty rare on the scale of things. But that doesn't mean that random chance is not an important feature in evolution. In fact, it's a very important feature in a much less dramatic, but much more common, uh, sort of way. You don't need mass extinctions to show the importance of chance. Um, and, uh, to illustrate that, let me go back to, uh, an illustration I did in my previous lecture, those who've seen it before. Uh, you can doze off for a minute. Those who haven't, um, stick with me. So, uh, let's imagine there's a species, uh, that has arisen. This is a blue blob here. Uh, and the basic principle of evolution is that species reproduce. They over reproduce. They typically produce more offspring than can be supported by the environment they're in. Um, and genetic processes such as mutation, recombination, um, pairing, if you're in a, if you're a sexually reproducing organism, uh, lead to diversity in your offspring. So your offspring don't all look exactly like you do. Um, and they're, they have different phenotypes, they have different abilities to survive in the environment. The ones that are not well suited to their environment then, uh, die very rapidly. Say for example here, the little red star, that was a bad organism. It's gone. Um, but some new diversity is retained. And over time, if that new diversity is optimal for the environment, uh, they will go on to reproduce and you'll end up with new species, for example, over time and so on and so forth. That species might then diversify some more. Um, and, uh, this is what leads to that, that tree of life. So, um, that is the basic process of evolution. But let's, let's run that clock again. So imagine the same process here. We have the original founder organism. It has its offspring. Some offspring are not well suited, they die. Um, but at this point here, you have two offspring, which are essentially equally well suited to the environment and in the previous image go off to form two lineages. But imagine this is happening back in the era of the dinosaurs in the, in a kind of warm puddle somewhere. And at that very moment, a passing, I'd know iguanodon or something, puts its foot wrong and steps on one of these lineages, it's gone extinct before it even existed. And now you have reshaped the entire rest of the tree because now you haven't got a lineage down here. So that chance effect, that squishing of that early microbe has changed the subsequent evolution. That's one sort of chance of effect. But what about a second one? So imagine this other lineage is still going like it did before. It's evolving in a normal way. So it's producing offspring that are slightly different. So here we have, for example, two dark blue ones and a pale blue ones. In the previous example there is continued growing and diversifying the same place. But imagine now in that muddy puddle back in sort of the dinosaur era, um, there is some kind of current, I know that it rains and, and the water washes one direction or the wind blows and the droplet goes somewhere else. Um, and what happens, uh, by chance, completely by chance, is these two slightly different organisms are in different places, different physical places. And now imagine that some kind of barrier comes between them. So maybe they've, you know, it rained a lot and they washed out and then it stopped raining and now it's dry and they can't get back. You now have two slightly different organisms in two slightly different places. They can't reintroduce to each other. Um, but they carry on, they reproduce. And what you end up with essentially are two populations that are different and isolated from each other. And if millions of years later, a biologist like me comes along and has a look at it, they might think to themselves, oh, well clearly this one here is well adapted to this environment and there's something different up there that makes that blue one better adapted to it. But that's not true. That's, this is a random process, right? And this process of randomness, um, is, has been a really big shaping factor, um, in the evolution of many, many species and is a process that we know today as the founder effect. Um, and to illustrate the founder facts, I'm going to, I'm going to borrow a volunteer if I may. Um, does anyone care to come up front? Be brave. Oh, someone dropped something. That's an excellent volunteer. Come on. Who was that? Who dropped something and wants to, wants to admit it? I promise I'd retain you unharmed in a few moments, but maybe I can, maybe I can borrow. Can I borrow this gentleman on the end there with the beard? Are you brave enough to come up? Yeah, come on. Come. You say what happens if no one volunteers? We have to volunteer somebody. This is the moment to run away if your family don't know you are here and they think something really important. Excellent. Thank you so much for having, what's your name, sorry? Feris. Feris. Okay, so welcome on board. Thank you very much. It's got a really difficult task for you. So here, um, I have a population of organisms, other organisms are available. If you're watching this, I'll cover the brand name. So there's a population of diverse organisms like the ones here. Now, what I'd like to do is grab a big handful of those. Well, oh, this is a man who's done this before. Look at that, right? And we're going to distribute those on this. Thank you. So what we've done here, we have samples of population, um, of organisms, and it is very diverse. So if you take this population somewhere new like that might puddle, it will grow. And you'll still have organisms that look a bit like this and organisms that look like a bit like this and so on and so forth. Excellent example. But now do that again. Take a smaller handful, smaller than that.<laugh>, I see you've done this before. That's much better. Well done. Thank you very much. God, don't invite him to your party below me. Um, so now we have a very small population and now we have only two organisms, two types of organisms. So we've got in our island. Now, uh, these two organisms, they're reproducing. But this one, for example, is essentially extinct.'cause it wasn't picked. This is a founder effect. You've picked a small number, other genes have been left somewhere else. And now whatever happens to this population, unless new organisms come in, can only ever involve the genes that are present in these two organisms. And that is a founder effect. And you get the chocolates as a present. Thank you very much. Bra round of applause for our volunteer. You didn't get the whole handful up, you just be greedy. Okay? So that's a founder effect. Founder effects happen when a small chunk of a population by chance, are separated from the other. And all the genes that are not present in those individuals are therefore not present in the subsequent lineage. Um, and they happen quite a lot in evolution. They particularly happen in geographical sites where you have restrictions to the movement of organisms in and out such as islands. So islands very often exhibit founder effects. Um, and there are lots and lots of examples of this, but this is one of my favorites. So this island here, dunno if anyone's been, this is Dennie, this is one of the channel islands. So just off the coast of France, it's very, very small island and Dennie, um, does not have native hedgehogs. Okay? So the rest of the United Kingdom, um, has hedgehogs that they like this, but all the new does not, didn't have native hedgehogs. However, in, uh, the 1950s and sixties, um, some slightly, uh, uh, you know, probably unwise individuals, they decide what they do is they keep some pet hedgehogs. So they're quite cute. Um, and then in a story that is very familiar for human intervention all around the globe, of course the pet hedgehogs escaped, um, and thought, wow, it's a whole island here. This is brilliant. Um, and set up a, a population. So now Als has hedgehogs. However, if you go to Alny and look at their hedgehogs, um, roughly 50% of the hedgehogs that you might pick from Alden knee, uh, look like this. How cute is that? That is a blonde hedgehog, um, blonde hedgehog. So this is a mutation, uh, not an albino mutation. It's called a istic, uh, mutation. It cause them to be paler colored. It's a mutation that occurs in, uh, the native hedgehog population at an incredibly low frequency. It's very, very rare. However, by complete chance, we believe the Albany population started from about four or five individuals. And by complete chance, one of those individuals presumably carried this mutation. It's a recessive mutation, so you don't see it. A hedgehog like this could actually still have one copy of that gene. Um, but it was present in that hedgehog. And because the entire population descends only from those four or five individuals, now this is a very common mutation on Albany, even though it's still rare everywhere else. So this is a founder effect, and it's happened because the original population was small and there has not been incoming gene flow. It's not that hedgehogs, you know, swim across the alderney from the mainland, uh, to, to, you know, go and find a new partner. Um, they are stuck, they're trapped in this sort of genetic island. And those kind of, uh, founder effects happen a lot. Uh, not only in islands, things like mountain tops. Also, if you're a, an isolated mountain peak and there are no other mountains around, that's another example. Um, and in the sea you have it as well where you have areas, for example, of particularly shallow water or particularly deep water surrounded by other types of water. So founder effects is quite important and they are chance, it's completely random, right? The fact that there was a blond gene present in that hedgehog, um, was not predictive. It was not adaptive. It's not a benefit in Albany, it's just chance. Um, they're kinda interesting to ecologists, but much more interesting to, uh, to me as someone who's particularly interested in human uh, and human disease in particular, the fact that these effects also happen in humans. They can happen in humans for the same reason. So populations that were geographically very isolated can also show founder effects. But of course, today the vast majority of the world, the human world is not geographically isolated. You can get on an airplane and go almost anywhere. Um, and yet we still see founder effects and we see them not for geographical isolation, but for cultural isolation. So in particular, the place we see them most often are in human societies, uh, which practice what we call endo omy, IE, the idea that you would only marry or mate with somebody from the same cultural, societal, religious group as yourself. Uh, so for example, uh, these are often orthodox religious groups like the Amish Orthodox Judaism, um, but also they can be cultural constraints. So if you're from a culture with a very strict social hierarchy and you're only expected to marry within your social strata, um, that's another form of genetic isolation. Um, and sometimes there are all sorts of other reasons. There can be even just, uh, sort of cultural reasons in the sense that you have a particular belief system, not necessarily religious belief system. I know you are a, um, a extremely passionate vegan and you will only associate with other vegans. That's a, that's a type of genetic isolationism as well. So these are small populations, and particularly in the case of many religious groups, um, who essentially fled persecution typically in Europe, um, to, uh, the Americas is the most common destination. Many of those originating populations were very small, right? So the Amish, for example, is a great example. Very small groups of people from Europe fled to America, um, and essentially have remained isolated because they rarely, uh, marry and have children outside of that group for a long period afterwards. And so that is the condition in which you find founder effects. Um, and we do find them quite commonly because the way they present most often or the most visible if you like, are when they cause problems. Most of the human founder effects we know about are genetic diseases. Um, so for instance, there is a particularly awful disease called Tacs. Tacs disease is a neurodegenerative disease. It's caused by the lack of an enzyme hexa a if you don't have enough of that enzyme, when you are born, uh, your nerves fail to develop properly and you end up with a, a, a really awful neurodegenerative condition. Uh, and typically babies born with sacs, uh, degenerate over two or three years and typically die before they go to school. This disease is extremely rare in the globe as a whole. It's about one in 300,000, uh, live births across the globe. But in particular populations, including the Armes Orthodox today that Ashkenazi Jewish populations, um, this is about a hundred times more common than it is in other populations. And it's because when those populations were founded, the, the frequency of that gene was higher by chance than it is in the rest of the population and has been retained. And it's really important, um, to think about these things, I think because of the implications they have. And actually, one of the interesting examples of this founder effect, so this mutation that causes sax is also found in another founder effect, um, in Jacob's sheep. So, uh, these many livestock breeds, especially pedigree livestock breeds also suffer from founder effects because they typically originate from a very small number of, um, original Ghana grandparents, if you like. And those of us who have, for example, dogs, quite often there are particular dog breeds that are associated with genetic problems because of the same founder effects. It's got an interesting example where the same mutations crops up in two completely unrelated, uh, organisms. So why is it important to know about founder effects? Well, the first and almost obvious reason for thinking about founder effects is because it can help with medical treatment and medical diagnosis. And in fact, um, in terms of Tay Sachs disease, uh, uh, the Jewish population in, in the US in particular has taken this very strongly on board. And now a very, very large number of people, uh, undergo genetic testing before marrying and before having children in order. And that has really helped a lot in reducing, um, the number of babies born with this disease. So it can help in terms of preventing, um, we can't treat taste acts in that condition in other conditions. It can of course help, uh, with treatment too. But it's also really important when we think about things like, uh, human intervention in ecosystems and in particular when we think about conserving endangered species, because by definition endangered species have very few individuals. Um, and so if we are doing things like a captive breeding program, it's really important to think about founder effects. And that's one of the reasons why, for instance, um, international zoo organizations often trade individual animals to make sure that they're not getting these founder effects where they're all locked into the same genetic background. So I think there's a lot of useful learning from understanding this and knowing about the scale of the impact of those mutations. Also, of course, applies when we think about much more direct human interventions, in particular livestock or crop breeding where, you know, you can inadvertently, you select for a particular trait. I know red tomatoes or you know, beautiful petunias, but you are bringing with it a number of other genetic changes in the background. And if you're not careful, you can get these subtle genetic, uh, uh, founder effects in those situations too. Okay, so that's enough about founder effects. Let's think a bit more about kind of what's going on in the chance level in terms of evolution. So I said a few slides ago, the basic principle of evolution is stuff is changing. You can't prevent that even if you are a clonal organism like a bacteria. Even so your offspring are not genetically identical because of the rate of mutation. So there is this permanent changing of genes in a population, something that we refer to as genetic drift. This idea that even if you do nothing at all, the types of genes in the population change over time. Um, and uh, this has been something that has concerned or has people have thought about for well over a hundred years. Now, how does that kind of random process equate to, uh, adaptation to a particular environment? So let's think about, um, this process of genetic drift. And the person who thought most about this was the pioneering geneticist back in about 1930 Sewell Wright. And he introduced this idea of a fitness landscape that looks something like this. In other words, if you think about, uh, any organism, an organism is, uh, existing in a, in a environment, that environment varies over time and over space. Um, and typically most organisms are quite well adapted to the environment they're in at the minute. Uh, but, uh, there are potentially better combinations. So here is a fitness landscape, and if you imagine what we're looking at here, there are places, uh, where you are very well adapted, like down here in the valleys and places where actually your particular complement of genes is not good for that environment. Up here on the peaks. So here we have a little organism and it's sitting in a valley, it's well adapted, it could be even better adapted over here, right? This is even better. But to get there, it has got to change its genes over this maladaptive, over this disadvantageous peak. So actually, when you think about random chance, so this organism's gonna reproduce, it's gonna change its gene slightly on average, what's gonna happen is it's gonna become less fit, okay? It's going halfway up the mountain. Because essentially, if you think about, I dunno, think about a piano for example. There are about a hundred thousand ways you can break a piano. There are very few ways you can make a piano even better. And that is the same for genes. There are lots and lots of mutations that will wreck a gene. There are very few mutations that will improve the function of that gene. So most of the time when an organism mutates, it gets worse. Um, and therefore what happens over time is that natural selection eliminates those changes and pushes it back to where it was in the beginning. This is called stabilizing selection. So how then might you as an organism evolve from this position to an even better position? There are sort of two routes really. Um, you can do something really dramatic and we'll talk about that in a minute or, um, what you can do is you can gain a mutation, for example, that is actually on its own not particularly good, but if it's not selected against very fast, you might be able to retain that mutation in the background for a period of time. And then perhaps another mutation will come on board, which is beneficial and pushes you therefore right over the edge into this new better location. So there is a, there is a chance process of just hanging on long enough and it's a bit like, I dunno, if you had sort of revising for an exam, there's that moment if you remember that when you're revising, you think, God, I feel like I know less now than I did when I started revising. But if you keep going, keep going, eventually you realize that you've kind of pushed forwards and you now know more than you did before. And this process we see in the fossil record. So for example, someone at the last lecture asked me a bit about the evolution of flight. And this is quite a good example. So this is a fossil early bird. Uh, and you can see up here just about I think these little stubby wings. Um, this bird probably couldn't fly very well. Um, uh, it may not even have been as good as the flightless equivalent that went before, but if those little stubby wings were not hugely disadvantageous and were retained long enough, then additional mutations might have pushed those wings even further. And now you have a fully flighted bird. So you can go through this less fit intermediate to become a more optimal, uh, organism. There's a second important point about this random process. So this is a reconstruct reconstruction, uh, of op tricks, one of the very early birds that we know about. And you can see here it's got it little stubby wings. It remains a bit unclear where the arch tricks could really, really fly or whether it could just glide or kind of flap around a bit. Um, but either way it was probably not, I mean, it's not flying like an albatross, it was not a spectacular flyer. Um, uh, and yet it was sort of on its way to become a fully flighted, uh, bird, uh, like for example the Arctic 10. But there's a really important point here, which is that it is almost impossible for evolution to go backwards, directly backwards at least. So if you remember on that previous fitness landscape you had, you know, it was, it was relatively fit here somewhere, it went up the mountain came a long way down the other side, going back up a very high mountain is incredibly difficult. And so it is with real evolution in real life. If you think of arches, if conditions changed and having these little stubby wings was not a good thing, natural selection could fairly easily have selected for mutants that got smaller and smaller wings and went back the other way. If you're an Arctic 10, you are optimally evolved for life in the air. You're an incredible precision flying machine. Any mutation that messes with your wings is gonna be so strongly selected against it will be extremely difficult for you to evolve back to an unf flighted version. And we see that again and again. So what tends to happen instead is organisms become specialized more and more specialized and then ultimately go extinct rather than des specializing back into some more generic organism over time. So that process of sort of, of gentle genetic drift and selection across the landscape is something that happens a lot in many species, but it's not the only way that you can have new, um, innovation if you like. In evolution, you can also have these processes called genetic shifts, really big leaps in evolution and they're much harder to understand. So here we are in our fitness landscape, again, here's our little organism and there is a place on this landscape where the organism can be even fitter. It's right over here, right? But it's got a long journey to get there. It would have to have all these disadvantageous mutations and climb this mountain in order to get there. It would have to essentially not be selected against, even though it's a bit rubbish for a very long period of time. And that is highly unlikely, much more likely, but still very, very unlikely is or much more successful, if you like, would be to do all of this journey in one go, right? To jump right over here, some huge genetic change, nevermind all these incremental mutations, do something really radical and leap over that, that boundary problem. What you need is a big genetic innovation. But this is very difficult to think about. And and there's an example I think we can take from, um, human behaviors here. So this is the inside of an internal combustion engine, okay? So for most of us, those of us who drive for most of our driving lives, we've driven something that runs on this, right? You put petrol or diesel in one end and essentially you burn it and it drives your car along. This is the internal combustion engine. However, for some of us, more recently we've started driving something that looks a bit like this, uh, an electric car, okay? You cannot get from this thing at the back to this thing here by a series of incremental evolutionary steps. I can't go into an internal combustion engine and say, oh, you know what? I'll take out the oil, you know, no oil, get rid of that. Um, and we'll replace in the air. I'll take out, I'd know the car Beretta and put something else in. Um, you can't move partially from a petrol engine to an electric engine. You either do it in one go or you don't. And so it is also with evolution. There are some big evolutionary innovations that essentially could only happen in one big go, these radical innovative ideas. Now these things are incredibly unlikely to occur, right? But we've had life on this planet for the best part of 4 billion years and it's a really big planet. Um, so if you roll enough dice enough times, you know, sometimes you can get 25 sixes in a row, right? Um, and these are the kind of radical innovations that we're talking about. Very, very rare, but nonetheless, very important for the process of evolution. And the example of this that I most like is one that I can show you here. So what you see on the screen in front of you, um, is an immune response, okay? This is some work that we did in my, in my other job at Birmingham. So this is looking at the response of your T cells. You remember those T cells, they're part of your, um, uh, immune response that fights viruses in particular. And what you see, in fact, lemme go back and uh, play that one again if it, there we go. What you see here is these T cells are the green cells. They start off green and if they, if they replicate, they lose their color. So what you see over the course, this video is those T cells less and less green because they're busy replicating and they're replicating because they are responding to, uh, an immune response, an immune, um, antigen. And that is being presented here by this rather blobby cell you see in the middle. This is a dendritic cell. Now, hopefully pretty much all of us in this room have fairly recently had AC ovid 19 vaccination. Um, and when you've had that or indeed any other vaccination, what you've had is a bit of foreign protein produced in, in various different ways depending on which vaccine you had injected into your body. That foreign protein has been picked up by these cells and has been waved around to stimulate T cells and mount an immune response to protect you. The way it does that is that your body has something in the order of, you know, 400 billion, uh, T cells floating around inside it. Almost every one of those has a different receptor on its surface. And this is my rather rubbish cartoon of that, a different receptor on its surface that is looking for foreign proteins, each one specific for a different protein. So what happens when you have c ovid 19 vaccination or indeed a covid Ovid 19 infection, is that those foreign proteins are being displayed by these cells and T cells are zipping past going, don't recognize it, don't recognize it, don't recognize it, don't recognize it. And eventually one goes, oh yeah, that's the one that fits with me. Brilliant ta-da. And as soon as it does this t-cell then starts reproducing. It will mount an immune response against the infection if it's the full virus. Um, and regardless of whether it's a virus or a vaccine, it will also produce memory cells, which is what protects you the next time around. And that's the principle of vaccination. But there's a problem here, right? The human genome has about 20,000 genes in it, and yet you have got billions of T cells with billions of different combinations of t-cell receptor on, on the surface. How can 20,000 genes give you a receptor? That varies in such an enormous way and it has to vary in such an enormous way because it is no good being able to recognize any 20,000 proteins, uh, because there are far more proteins on far more pathogens than that. You need a much bigger repertoire of things to recognize. So we have a problem, you've only got 20,000 genes, but you need to come up with millions of different combinations. And that is a problem that has been solved invertebrates. So organisms like ourselves, um, by this remarkable process of modular genes. So if you look at the gene that encodes that T-cell receptor, it's not a single straightforward gene, it's a gene that is arranged in modules like Lego blocks basically. So it has a bunch of blocks over here, another bunch here, another bunch there. To make the functional protein, you only need one of these, one of these and one of these. And so what happens during the development of each T-cell is that a certain point, an enzyme comes along. This one up here, it's called rag and rag cuts up the DNA only at this particular location and sticks it together again in a random way to rearrange those Lego blocks into a receptor. And so you can imagine now if you have, I dunno, a bag of red lego and a bag of blue and a bag of yellow, there are lots and lots of different combinations you can make of that. And so with a very small number of modules, you can come up with a very large number of T-cell receptors. Now the really surprising thing about this, so this is a weird process, right? This is an enzyme that is cutting your own DNA and sticking it together sounds like a bad idea. Um, and it doesn't exist anywhere else. If you look in evolutionary trees, invertebrates don't have this, plants don't have this. Only vertebrates have this, okay? So it arose around the time that fish arose and it arose all of a sudden there's nothing like it in animals that were there before. And then tatara is suddenly there. And that is really weird. How does an entire system evolve in the middle of nowhere? And it feels almost like it's kind of being jettisoned in from outer space or something. It's massive innovation. It's like that car suddenly going from a combustion engine to a, a battery-based electric engine overnight without figuring out where it's coming from, but it's not coming from outer space. In fact, what we now know where it's come from is really quite unique. And we know that by looking at the underlying protein that does it. So that protein that cuts and sticks your DNA together rag it's called, um, you can make a three dimensional structure of, um, and you don't need to worry about the details. The protein is the blue and the yellow EBIT here, okay? So it's like a, it's like a barrel. And what you can see here if you're in aficionado is the DNA, which is that double helix here, two strands of DNA going through the middle of the protein. So what's happening in your T-cell is this protein is cutting and sticking this DNA together. But now if you look in all the other proteins we know about, there's another protein here. And I don't think you have to be a biochemist to say, Hey, these two proteins actually look pretty similar. So this protein here, the yellow bit looks really like the yellow bit here. The biggest difference is what it's doing with the DNA. It's folding the DNA in a different way. But nonetheless, these two proteins are very similar. And this protein has nothing to do with the immune system. This is present in, in a, uh, a piece of DNA called a transposon. And transposons are selfish pieces of DNA that are found in pretty much all organisms. They're a little bit like viruses. They sit in your genome, they copy themselves, and they move themselves around. They have typically no benefit. Uh, in fact they're often detrimental. They're kind of parasitic, but they have existed for, well, hundreds of millions of years. We we can't go back far enough to find out when they, when they were created. Um, and so why, why do these two things look the same? Well, they look the same.'cause if you're a transposon, if you're a piece of DNA that needs to replicate and move yourself around, you need an enzyme that cuts yourself and sticks yourself somewhere else, which is what this does here. And so what looks like it has happened, in fact we're now pretty convinced it's happened, is during evolution at the time, just prior to the, the origin of vertebrates is presumably a transposon jumped into the DNA of an early, uh, animal that was going to lead to the, to the vertebrates. And when it jumped out again, it left behind this gene for this enzyme. And over the millions of years since that enzyme has turned out to be rather useful because it can be co-opted into cutting and pasting together these modular gene elements that go to make your t-cell receptors and indeed also your antibodies. And so we have borrowed this idea, just like electric cars have borrowed the idea of batteries from mobile phones and everything else, and lifted it lock, stock and barrel into our own physiology in order to drive our immune systems. And this is radical innovation evolution style in one game. So innovation does happen, randomness happens. Um, but I kind of want to end on a, on the, the idea about just how important random luck has been. And and before I do that, lemme just take a straw poll here. So generally people think of themselves as either being typically lucky or typically unlucky, right? So are are you the kind of person who always hits the red light, especially if you're late or are you the kind of person who you know, gets in just as the train is pulling out and manages to jump into the door and the light? So those of you who think you are lucky, please raise your hand. Very interesting. And those who think you're unlucky, raise your hand. Ooh, it's, well clearly you are here. The lucky ones are winning. What can I say? You we'll come to the lecture. Um, so, so, so what I want to convince you, all of those of you who raised your hand second, who think you're unlucky, you are so wrong. You are incredibly lucky. All of us are incredibly lucky. Let me demonstrate one reason why we're so lucky. If you think about human evolution, this is diagram, uh, by Chris Stringer over the Natural History Museum, uh, now slightly outta date, but that shows, uh, the last couple of million years of human evolution, right? So as you maybe know, uh, for most of the time in which human-like organisms have existed, there have been multiple species present on the planet at the same time. In fact, this is the moment we are living in is one of the very rare moments when as far as we know, we are the only human-like species on the planet. But for most of human history, actually we've shared the planet with other human-like organisms. So here, um, going back to one and a half, 2 million years, homoerectus is over here. This is for people who are kind of keen on this is what's called the Hobbit, the ensis small, um, uh, small human from, uh, Indonesia. But these organisms lived, they they separated. We had different species like antecessor, so on and so forth. And the only one lineage went on to produce modern homosapiens, uh, which is this heidelberg against this lineage here. Uh, that led to Neanderthals, Deni Havens and ourselves and what we now know from work published just a few weeks ago actually, uh, which is quite remarkable. What you can do is you can look at all the diversity of modern human genomes and you can work out from that how big the population of humans was at its narrowest. Because if you think about that, so if you think more ge genetic diversity must have come from a bigger population. So the more narrow you are like that founder effect, the less diverse you have. And you can do some very fancy mathematical modeling and you can work out based on, uh, modern human genomes, how many or how few humans there have been at different points. And the most remarkable thing about this new work is that it indicates fairly confidently that back about 900,000 years ago, the human population or the population of breeding individuals that led to modern humans was no more than about 1,300 individuals. And most remarkably, it was at that level for probably a hundred thousand years. So just to put that in perspective, 1,300 individuals is about the same number as we currently have of giant pandas in the wild. Uh, and it's 10 times more, uh, than the number of snow leopards we have in the wild. Um, it's also slightly smaller than the average secondary school. Um, and is roughly the number of people that you are estimated to have met by the time you're about 13 or 14. And the hu entire human population was at that level for about a hundred thousand years, a whisker away from extinction for a really long period of time. And so I think on that particular note, all of you, especially those of you who think you're unlucky, should actually sit back and think, wow, it's pretty amazing lucky that I'm just here. And maybe on your way home after this particular lecture, you could slip into the casino or buy yourself a lottery ticket. Just to round off, thank you very much, Robin. Thank you. That was an absolutely fascinating lecture and I'm sure we're all feeling pretty lucky right now, but let's see if you get quite so lucky on the questions. I feel like there should be a drum roll for that <laugh>. Yep, indeed. Okay, so, um, actually I'm gonna combine a couple of questions which are asking sort of, sort of similar things. So we have a question from, uh, Bernard, can two species merge eg by interbreeding rather than one replacing the other by out competing? It, isn't this what happened with Neanderthals and us? So that sort of goes back to what you, you were just talking about a moment ago, but I'm gonna combine that with Lawrence's question, which sort of talks roughly similar sort of area. If a small population is separated and develops unique traits like the hedgehogs on , what are the possible effects if they are ever reintroduced and then they sort of breed with the original population. So a lot of interbreeding there for you, Robin. Yeah, that's one of the things that, one of the delights to work on evolutionary biology is you get to talk about all sorts of inappropriate things like, you know, uh, interbreeding, um, even just to to, you know, to young school children. Um, okay, so the first question, can two species recombine? Yes they can. Um, so the place that most often happens actually is when you've had, uh, that process that we talked about earlier called allat speciation. When something has split geographically to two areas and has then gone off its own particular direction, it can be quite distinct. Uh, but then if they're reintroduced, if they're still sexually compatible and able to mate with each other, they they can and do, uh, into breed. And there are some quite good examples of that. In fact, there are examples if you think about things like, uh, Scottish wildcat in this country. So there's quite a big concern that Scottish wildcats, which is an endangered species, um, are capable of interbreeding with domestic cats and indeed do. Um, and so, uh, as those, as those two species come together, you see them as assimilating. There is quite a concern that the wildcat will no longer exist because essentially everything will be a hybrid, uh, before long. So that that certainly happens. The second question from Lawrence about, um, what might happen if you have a a, a founder effect population that's reintroduced, there're essentially sort of, uh, two or three kind of options there. So the first one is that they might just blend in quite smoothly, um, because if they're still sexually compatible and they're not selected against, you might end up reintroducing'em. So for example, blonde hedgehogs do occur albeit very, very infrequently on mainland uk. So if you introduce the population of blonde hedgehogs, it's possible that you just end up with, you know, a very diverse population. I suspect I don't have evidence this, I suspect being a blonde hedgehog is not a great move. Generally like white things in the night that get eaten kind of risky, but you never know. Um, so they might, they might survive. Second one is that they might be, um, selected against for some particular reason. And actually lots of animals, particularly humans unfortunately, um, are very good, good in innovative at selecting against things that look quite like them but not quite. Um, and so you might end up that the population is either eliminated or retained, but genetically distinct, uh, within it. Um, and the third option of course is that maybe whilst they've been isolated, they've accrued some kind of additional changes that are actually turned out to be really beneficial. Um, less likely that, but it's possible that a founder effect, um, population might then move to dominance. And that's what sometimes happens on, uh, some islands for example, where a founder population moves from one island to another and actually is really good and takes over. Uh, so all options are on the table there. Okay, great. Um, haha, do we have any questions from the floor? Okay. Um, So a microphone coming whistling down the corridor corridor here, one Of the front he'll start here. Don't worry. Say you'll get, You'll get a chance. Um, one, one thing which I heard was that you can't go backwards. Uh, how does that explain the laws of ity by Mendel where he has predicted that, you know, from the ninth generation things can happen right up to the ninth generation? And also, uh, if you can explain amongst the, uh, the, the, our ancestors humans, all other species, uh, like uh, the minan man have all disappeared and only homo sapiens are there and we don't seem to be combining to produce anything of a new type, Right? Right. Okay, so, so the, so the first question, so it's not that you can't ever go backwards, but it's generally very strongly selected against. And if you think about it, that's because you tend to get, organisms tend to get more specialized. So for instance, giraffes have evolved longer and longer, longer necks to deal with higher canopies. There are other things that have shorter necks and browse the canopy below. So if the giraffe was to now move backwards to that shorter neck variant, it's competing with other things that have occupied that niche. So it's quite hard to go backwards, um, easier to go forward. It does occasionally happen, um, but it's difficult to do in terms of, but what you are referring to with Mendel, and I think that's that's a really good point is that if you have very genetically distinct organisms that can steal into breed, what you often get is this, uh, the, the hybrids from those look sort of ancestral. And this is a, this is a process. So Francis Galton back, um, shortly after Darwin published his book actually talked about this as, uh, regression to the mean. This idea that you go back to some kind of, uh, standard thing. And it's a little bit like if you breed different breeds of dog together, you tend to get something that looks sort of like a wolf really. Um, because the combination of different genes they have tend to blend together to come back to that sort of, um, thing. So it's not really going backwards, but it is sort of a blend to an ancestral characteristic. The question of humans is a great one. Why is that only us? Um, and uh, I mean I can't answer that 'cause we don't really know. Uh, but uh, what I would say is that they're not really completely dead. So if you are, um, so for most of us in this room in fact are harboring some Neal DNA, so we know, know that homo sapiens and Neals into bred and most, um, Europeans for example carry about 2% Neal, DNA. Um, and if you are from, uh, Polynesia that part of the world, you also have typically about 3%, uh, um, genetic information from the Denis, another now extinct lineage. So we did breed and we did incorporate things. Actually there's some really great examples in the immune system of genes that are today beneficial that we have inherited essentially from the Anals and Denis. So this idea of re taking the best and moving on, uh, why they went extinct is an interesting question. I mean, lots of people speculate maybe we made them extinct 'cause we, you know, bashed them over the head and stole their food. Um, uh, or maybe the climate changed and somehow, somehow we were adapted to it and, and they were not. But you can't run the clock backwards to find out, sadly. There we go. We're all going to be sort of looking around the room wondering who's got the most Neanderthal. It's gonna pop back to the uh, pad for the next question. And, uh, uh, this is, this is a really good question. I think, what are the ethical implications of intervening or not in relation to evolutionary processes? Especially as, as someone like me coming from a historical background, very aware that there's a sort of lot of historical and quite politicized framing and loading around what we decide is desirable trait that we want to preserve and what we decide is a undesirable trait that we need to, to deal with. So love It. Yeah, that's a nice tool and I mean the history of evolution unfortunately has got lots of very, very dark periods when, uh, when exactly that has been sort of, um, misused in my view for all sorts of nefarious aims. So what are the ethics? I think the biggest challenge we have, so there's two parts that I think is the human part and the other animal part. So, um, the, the other animal part, I think generally we can use this as a beneficial information. So for example, when you're doing captive breeding programs, you should be thinking about this to make sure you don't get these found effects. A a good question and a tricky one that I obviously can't answer is to what extent should you try and bring back something that's not there? So there's a big active discussion about should we try and get dodos or mammoths or these things back up because they, they've gone, especially species that we have made extinct like dodos. Um, and that is very tricky I think, because on the one hand you say, well, we, we made them extinct, we should probably fix that. On the other hand, you know, we are part of evolution too. Human predation is an evolutionary force. Um, and to what extent do you say, okay, so maybe we should reverse all the ones that we made extinct, but what about the ones that have been driven extinct by our pet cats or our dogs or by rats or, you know, uh, so very, very thorny. So I think no, no great answer there for humans, as it stands at the moment, um, essentially every country in the world prohibits what's called somatic gene therapy. So you can't change genes in an individual in a way that would be inherited by your offspring. So if you've got a genetic disorder, um, you can absolutely, you can screen embryos, you can do all this kind of stuff, but you can't change your genes even though we now have the power to do that in a way that permanently alters that in your, in your DNA to inherit. And that is very difficult. And the reason we say that is because clearly if you start doing that, you are into whole process of eugenics and you know, the, who gets to decide what is and is not a legitimate change and so on and so forth. On the other hand, I do take, you know, I see that the, the challenge that people, particularly people who know they're carrying mutations that might be particularly dangerous to their children and would wish to permanently change that as opposed to, you know, onic screening. Very tricky ethical issue. And I think one that's not gonna go away anytime soon. In fact, it's gonna get bigger and bigger as we get more and more powerful genetic tools to change it. We're just carrying on on this line for a couple of moments, couple more questions in and around this sort of area. So, I mean, for example, you mentioned the sax disease, obviously very terrible, um, and anyone with it dies early, but are there ever advantages to having certain, or being, you know, having these sort of isolated groups that carry certain genes, you know, can, can there ever be good news stories? And then related to that, and again, coming back to this sort of slightly more historical consciousness of, of, you know, the process of, you know, the space in which science operates. How do researchers differentiate between what they're confident to call random chance, naturally, quite strongly deterministic factors like the cultural, um, influences that you were describing. Great. So I'm gonna start with the second one. So how do you know it's random versus, um, sort of somehow selective? So there are ways to do that. And one, one way you can do it mathematically is, uh, DNA is made of these different letters, um, and it encodes proteins, right? So essentially there are 20 amino acids. So a change in your DNA that changes in amino acid will have a functional consequence, like your eyes go from blue to brown or whatever. Um, a change in your DNA that doesn't change. The protein generally is invisible. And so what you can do in an organism is you can measure the number of invisible genetic changes and the visible ones and then you can, and basically if the, if the visible ones are more present than you'd expect by chance you say, okay, this gene is under selection. Um, so a very good example of that, uh, for example is the gene for lactose tolerance. And we see in the human population, uh, that that gene, particularly in Europe, um, is, has changed massively more than you would expect by chance. And that is because historically there was a big advantage in being able to metabolize lactose when you didn't have any other food around, for example. So you can see that process of randomness, um, uh, which is, yeah, so that's, that, that is definitely present. Um, in terms, and the other question was on oh, beneficial mutations. That's right. So, so I think this is a, there's a really good point here about, um, uh, probably the strongest argument about intervening against intervening is that you can't predict what's gonna be useful, right? So we're sitting here in the middle of London, those of us in the room today, for example, being able to, I know, see stuff and respond very rapidly is quite an advantageous trait if you're in London because if you cross the road and you don't look first, that that is a very strong selective pressure against you. Um, four or 500 years ago, uh, a much better selective trait would've been, you know, being able to wield a sword and, I don't know, whittle sticks to make fire all sorts of different things. Um, and so what has been beneficial has changed over time. Um, and you know, you couldn't have predicted 400 years ago that a mutation that helps you spot cars coming would be beneficial, right? Um, so I think you can't kind of look forwards in that way. Uh, but there are definitely examples of mutations that have become beneficial, um, particularly around things like sight. So some, so in fact, that's quite an interesting example that, um, it, the different individuals in this room will have different ability to, to perceive different colors. Um, and generally that's probably not advantageous. Uh, but if you are out in the wild, if you like, the ability to see different pigments might be advantageous in terms of looking at fruit, um, that is ripe, for example. So there are mutations that might be useful. And I think the best argument against us trying to think ahead for that is that, you know, if you make a genetic change that seems like a really good idea today, it might turn out to be a really bad idea in a couple of hundred years time. So, um, there is definitely something, at least for me about retaining the randomness, um, as a, a sort of insurance policy for the future evolution. Great. We have a question from the floor. We're quite often asked to worry about extinctions and endangered species, but as a specialist, are you worried<laugh>, am I worried about extinctions? Oh, I am actually quite worried. And the reason for that, so extinction is a natural part of evolution, but the pace of extinction is what is radical different now. So if you look at, uh, you know, the sort of history of life on this planet, there have been probably five or six mass extinctions, um, very, very fast ones. They're caused by things like meteorites hitting the piece in the planet. We are essentially creating our own mass extinction at the moment, um, as a pet. And we think it's slow, but it's not really slow in evolutionary terms. Um, and uh, so, so I am worried in the sense that I'm worried kind of firstly as a human. I think it's, it's kind of a bit miserable to think that we're sort of denuding the world's ecosystem. But secondly, with a very pragmatic hat on, every time a species go extinct, you lose all of its genetic innovation to the future, right? Um, and the place that we, that I think that's most important, if you think very selfishly about medicines, most of our antibiotics come from organisms out the environment. Typically bacteria or fungi. Every time a an uncharacterized bacteria or fungal species goes extinct, you don't know whether that one was actually producing the compound that was gonna cure your cancer or your heart disease or something else. And now you never will 'cause it's gone extinct. So I do think it's really important to try and reign in that. Um, that's not to say you can ever stop extinction, it's part of the normal process. Um, but the pace at which humans are doing it sort of willy nilly I think is is a big concern, unfortunately a bit depressing. Okay, So just time for a couple more. I think, um, humans would not exist if they did not reproduce, right? Got that. Do you believe that today's society fails to acknowledge the instinct we have to procreate? Oh, that's a nice thorny one, isn't it? Are we sure gonna take that one? Shall I just leave now? Now? Okay. Right. Um, uh, so, uh, so humans would all exist if we didn't reproduce. That's definitely true. Um, do I, do I think that we are reigning in? No, I don't think I, well, so let's play that. If, if we didn't reign in our desire to reproduce, um, then what we would be doing is subjecting ourselves to the full weight of natural selection, right? So we might all have 25 babies and the vast majority of those babies would die. Um, and so you'd be acting like a normal wild species. I think most of us as conscious human beings would say that's a bad idea. Um, you shouldn't be bringing organisms into the world just to die. Um, so, so I, so I'm not concerned. I think it is a good thing. And actually I think, you know, reigning in human reproduction, um, uh, more is probably not a bad thing for the planet as a whole. Um, I think there's a sort of secondary questionnaire, I guess, about to what extent, um, that process might shape future evolution. And that is very interesting. I mean, typically in most western societies, uh, many western countries are not at self replacement, right? Many of us on average don't have two children, um, who then go on to have other children. And so, uh, the population is shrinking, other parts of the world are growing. And so you get an evolutionary change with that because genes are different in different places. Um, is that a problem? I don't particularly think so. Um, the interesting question becomes when you start to think about things like the impact it might have. So clearly we are living at a time when many of us have met partners from very far-flung parts of the world, um, who you wouldn't have met even a few hundred years ago. You're bringing together interesting genetic combinations, and I personally think that's fabulous. Um, but it is really interesting to think thousands of years from now whether, you know, a future geneticist will look and go, wow, look at this massive bloom of diversity in the human population. I wonder what happened back then and not realize it was 'cause we had, you know, transatlantic airplanes all of a sudden. And finally, um, we've done a lots of talking when sometimes it's sometimes sort of seen for this, uh, hapless population that things kind of just happen to us and the best we can do is kind of try and respond intelligently to the random chance. But Ellen wants to know, are there models of evolution that acknowledge or incorporate a bit more of a sense of how, um, a population kind of impacts back on the niche they're in and that actually changes alters that that environment. Yes. Um, there are, and well, humans I guess are the prime example of that. And this is something that's elaborated on quite a lot by, uh, people like Richard Dawkins in his extended phenotype. So this idea, so the phenotype is your sort of the physical manifestation of your genetic changes. And the point he makes in that book is that, you know, an immediate physical manifestation is brown eyes, blue eyes that are, but if you think about something like the beaver building a dam that is also manifest of they're genetically programmed to build a dam, and so they are shaping their environment, um, by genes and therefore they are selected by evolution to do particular things. Um, and I guess you could argue that humans are very much doing that at the moment because what are beneficial genes today are very often completely unrelated to our ability to just survive and procreate right now, if you think about the things like your ability to get a steady job and to, you know, meet a nice partner and all that kind of stuff, which are related to traits that are not about being able to, you know, get, most of us can't forage while mushroom is successfully, for example, and we don't die because we can't do that. Um, but a complete inability to function in society that as computers and reading and literacy and all those kind of things is quite a disadvantage. Um, so there you've got essentially an extended phenotype that we have created ourselves, and now we are selecting each other based on this ecosystem that we have produced. And I think that's a very interesting kind of extended phenotype that we're living in, right the minute And on that extended phenotype. Ladies and gentlemen, please join me in thanking Professor Robin.