Latest / Art of the Question / The Dark History of Gene Editing - Matthew Cobb - #23

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The Dark History of Gene Editing - Matthew Cobb - #23 · Art of the Question

• speaker-0: First of all, thought it would make sense to kind of get to understand how do you first get interested in CRISPR and gene editing and why. speaker-1: well, yeah, I mean, first part is a kind of disclaimer. ⁓ I am not a genetic engineer of any kind. had never crispered anything apart from bacon when I was younger and at me. And, ⁓ but I am interested in science and technology in particular, the history of genetics and the, mean, I, I, I'm a What's the best way to describe me? I've retired now, so I'm not anything anymore, but I studied the effects of genes on behavior and the evolution of behavior through interactions with genes and so on. So it's an area that I'm very interested in. And I had already been interested in the history of molecular biology, of which this is a kind of subset, partly because I... to pay a tax bill. I translated a very famous history of molecular biology from French into English about 30 years ago. And that got me, I found that absolutely fascinating. And so when CRISPR came along in 2012, 2013, I paid a great deal of attention to it, although I hadn't been paying much attention when the kind of foundational work had been done because I'm not a microbiologist and I'm not interested in... the kinds of things that people were studying. But very clever people immediately realised that if there was this innate immune system, or this immune system in bacteria, which is kind of finely identified in about 15, 20 years ago now, people realised that, okay, maybe we could programme it, maybe we could make it do something that we're interested in rather than the bacteria defending itself against viruses. And these clever people realised that and I didn't. I just literally turned the pages of the scientific journal because that's not what I was interested in. But when CRISPR was actually turned into, that potential was realised, which took about six years, five, six years, I did pay attention because it's obviously very powerful technique. My prime interest was how could this be used for fundamental research is what I've always done. But it became very clear very soon that there would be other implications. in about one of the things that ended up being ⁓ the focus of this was the potential of using ⁓ CRISPR for ⁓ manipulating human DNA, which I think is extremely significant and very, very worrying. And so there was a big, to discuss this, was a big Jamboree held in Washington, a summit, the first of a there's been three or four, I can't remember, global summits on this technology, four, yeah. And so I said to the BBC, ⁓ I emailed them, I happened to know somebody in charge of the radio science unit at the BBC and said, well, look, there's going to be this really important event. The BBC has not covered this topic at all. And why you send me to Washington for this summit? And they said, well, Our budget can't quite stretch to that, but if you want to make a program about it, that'd be fine. So I did. And that was the BBC's first program on radio or TV about CRISPR. And I was trying to show one, how it was exciting, and two, how it was potentially problematic in a series of different ways. So that's kind of the origin of my interest. And it became particularly focused in actually during the pandemic. ⁓ so the pandemic was pretty terrifying. ⁓ but I had, I guess, apart from being ill a couple of times, ⁓ a good pandemic in that I made another BBC, ⁓ radio series, this one about the history of genetic engineering, which is kind of the backdrop to, ⁓ CRISPR, ⁓ three parts radio series in which I interviewed many of the pioneers and so on. And I also wrote a book called the, genetic age, ⁓ in the English version. It's got a rather more dramatic title in the UK, in the US rather. It's called As Gods, a Moral History of the Genetic Age, which I thought was a terrible title, but it seems to have worked in the US. Anyway, that's a long answer to your short question. speaker-0: No, I love long answers. We have all the time in the world. So this is absolutely fantastic. I mean, the American market is quite different from the European one, right? So I mean, whatever, whatever works to get the word out there, I'd argue. ⁓ But I love that you made the segue to your ⁓ other book there about the history of gene editing, because that seems like a logical starting point to me, at least. When we, when did we first start fantasizing about editing our genes of, of, genes of animals or plants? when, when, how far do we have to go? speaker-1: Well, mean, probably there, I mean, long before there were genes. mean, you know, people have been manipulating ⁓ organisms inadvertently because we're predators, right? So whether we're eating animals or plants, we're still choosing which animals to ⁓ eat or we're selecting particular plants. And that has an effect on the gene frequencies in the population. I mean, there's some fantastic images that I show to my students from today of ⁓ these plants that grow on a particular mountainside and the plants were originally had very bright coloured flowers and these were very prized by the local community and now kind of after about 50 years of harvesting all of the flowers are kind of intensely camouflaged against the grey of the stone simply because people have taken all the colored ones because they were easy to find and the ones that survive are the more camouflage ones. So this is inadvertent manipulation of gene frequencies effectively. So we've always been doing this. The issue is when do we start thinking about how we can do it deliberately? And that's partly in terms of the naturalized domestication of animals and plants where people in a very empirical and kind of ill thought out way started to think, well, you know, we can change, we can get a tame a horse or we can get a fatter sheep or whatever, but none of that was systematic really until the 18th century. I think the first kind of science fiction idea about what we can do in this respect is a kind of little piece of imaginary writing, a fictional writing by Sir Francis Bacon, the early English philosopher. of proto-scientist who imagined this island where they had enormous power over in particular hybrids, so between two species and they could make new hybrids and they could change them at will. So he's got no idea how any of this works, but he can imagine that this might be possible one day. So if you really want to go back, you've got to go back to the early 17th century. to, I think in more concrete terms, if you want to talk about genes, then that was by the, even before we knew exactly how genes work, before the genetic code was cracked, once ⁓ everybody became pretty confident that DNA was a genetic material ⁓ in the 1950s, I mean there wasn't a great deal of evidence in fact, but it was a very strong working hypothesis, then people started to imagine, well okay maybe we can change this deliberately, and they knew this would be decades away, but they imagined that this would be possible and it was kind of floated, including to cure genetic diseases and therefore to alter humans. this coincided with, I mean, in general, people talk about the history of science, we imagine that eugenics, that is the deliberate policy of changing the gene frequencies in human populations, which was very strong in Europe and North America in the early years of the 20th century, ⁓ which led to horrendous things being done, particular to ⁓ sterilisation of people with mental illness, in particular women. ⁓ This was both in particular both in North America and in Sweden. And indeed the North American model was the model taken, the legislative model that was in the States at the time, was taken by Hitler as the model for what he wanted to do ⁓ in Nazi Germany and indeed did do. So it's generally taken that the horrors of the Holocaust, which were involved, ⁓ you know, this kind of horrendous eugenic policy, that led to a disappearance of eugenics and people just stopped thinking about it. It's not at all true. It carried on and there were plenty of very clever people who thought that we should, ⁓ for example, Francis Crick, the co-descriptor the Double Helix, I've just written a big biography of him. And one of the things he was convinced of until the early 1970s was that ⁓ rich people in some way had better genes than poor people and that they should therefore be encouraged to have more babies and poor people should be discouraged which is just kind of so stupid as to barely deserve comment but it shows you that there was these ideas about manipulating humans did not go away ⁓ they were not always but generally ⁓ reasonably well-intentioned But there were also very strong racist currents as well that, you know, black people were inferior and therefore they shouldn't have babies or whatever. into this mix of this continuous rumbling of misguided thinking about eugenics eventually emerged the possibility of manipulating DNA very directly, i.e. not simply saying, well, can, you know, rich people should have more children will gradually become a a nation of smarter and richer people. But rather that there are specific changes that we can introduce deliberately, very precisely, either to say cure a genetic disease, or if you really wanted to go down that road to actually ⁓ alter the population some way. And that happens in the 1970s, virtually as soon as genetic engineering in bacteria. becomes a reality, that is a desired change could be introduced and alter the activity of a microbe. the most, mean this happened incredibly quickly in that the first kind of practical realization of this was in 1972 in a very crude way. But within three years, a startup was designing a microbe that would synthesize the two basic elements of insulin. And by 1977, this had actually been achieved. That is, you could now produce insulin in a microbe and all insulin that is used today, everybody who's watching or listening who uses insulin or has a relative that uses insulin, that insulin is made through genetic engineering through by putting a gene with a known sequence into a microbe and then it churns it out and then you do some jiggery pokery and hey Presto, you've got insulin. So this really happened very quickly. The technology was proved to be not only effective, incredibly lucrative. So people got very, very excited about it and all mixed up with the general excitement in the 1980s. The kind of, know, get rich quick, greed is good Wall Street ⁓ kind of ideas, both in, in America. as well on the venture capital which was funding this, but also in to a lesser extent in Europe and around the world. this together with things like ⁓ Apple computers that really changed the world, but it was driven. The initial spark came from genetic engineering, the idea that you could make vassums and some people did make vassums of money by coming up with a very simple ⁓ way of manipulating genes. speaker-0: Right. And this eventually culminates into what we know today as CRISPR, which as it is my understanding is pretty much the gold standard of gene editing, at least in the sense that CRISPR allow, and please correct me if I'm wrong, but CRISPR in theory allows for very specific editing of certain traits. So we can... filter out one element of one's genes, whether it's a plant, an animal, or even a human, and we can say, hey, this is where ⁓ usually ⁓ we see the eye color is being determined. We can tell that these are blue eyes. Let's change him to green. I'm not saying we're doing that currently, but that's in theory what's made possible by CRISPR as I understand it. Please, ⁓ do, ⁓ speaker-1: I think that's a really good example because it's the kind of thing that people think is impossible, but in fact highlights the complexity of this. that, mean, I would start by nuancing, you start, well, we've got a trait that's determined by this gene. And although there are traits that are determined by single genes and by a particular sequence, in particular in case of genetic diseases, where it may be just one base pair. that is defective. For example, the case of sickle cell disease, it's a single base pair, one letter of DNA is altered that changes the shape of the protein that's produced by that gene. That protein carries oxygen in the blood and therefore it produces these substantial disease symptoms, pathological symptoms in people with sickle cell disease. However, that's in fact pretty rare. It's the kind of thing you learn as a an example, a very simple example. But to take the case of your eye colour, ⁓ there are about 25 genes at least involved in eye colour and there's no single gene that will produce blue eyes or green eyes. And even what you're told at school, that blue eyes are recessive, that is if you've got blue eyes, you must have two copies of a blue eye gene. Whereas if you've got brown eyes, you might have one brown and one blue-eyed gene, that's not actually true. And part of the problem is this, at school it can cause intense questioning because technically if that were true, then two blue-eyed parents could not have a brown-eyed child. And so when teachers explain this to 13 year olds, they kind of think, wait a minute, my parents have got blue eyes, I've got brown eyes, what does that mean? Now it might well mean that things are not as they expect. ⁓ but it's equally possible. And basically if you've got two parents with different colored eyes, you can have technically some are very, very unlikely, but you can have any color eye in your child. It's simply because the genetics is in fact very complicated. However, having cleared that up, I think fundamentally you're correct in that what CRISPR, at least on paper, and we'll talk about the differences between paper and reality is that it enables you to. Introduce into a cell a ⁓ set of molecular components which are derived from bacteria. Which will target a particular sequence of DNA. So that's why I differed about the trait. What they're targeting is not a trait. You don't know that. All they know is the sequence of DNA which you've decided. And which will then alter it. with luck in a very, specific way. So you can introduce bits of DNA, you can remove bits of DNA and so on. So this is, as you say, this is a, was a step forward. There've been a whole series of different gene editing techniques. The term gene editing was developed around about 20 years ago, was coined about 20 years ago to relate to a much more arduous way of doing this kind of thing. Then there was another system which was everyone got very, very excited about which lasted about a year because CRISPR just came out of nowhere and was far, far cheaper, far, simpler and immediately changed at least ⁓ in particular changed fundamental research. That is that people using virtually any organism, if you can rear it in the laboratory, you can isolate its cells, you can do a CRISPR experiment on it. And that became very, very powerful and all sorts of things that would have been science fiction at the beginning of this century immediately became possible, organisms that you got from the wild and you were rearing the lab, could now understand much more about their physiology, behaviour and so on. speaker-0: Right. And how do we use CRISPR today? Because we can think of basically anything that carries DNA, that has DNA, contains DNA, which is pretty much all living organisms or not pretty much all living organisms that we know of on earth. So let's start with plants. we, we using CRISPR to, for example, enhance our crops at the moment to make them more resilient for certain I don't know, diseases or whatever? speaker-1: Yeah, absolutely. And this has caused a bit of ⁓ an existential philosophical crisis in the EU in particular, because as you know, you're not allowed to use genetic engineering in human foodstuffs in the EU. You can feed it to cattle, which you then eat, but you're not allowed to directly consume these products of GM and all that goes back to the end of the 20th century. There a lot of scares, not just about genetic engineering, but in general about food security. In particular, there was something called mad cow disease, which was prevalent in UK, which called terrible, killed about 150 people when it was transmitted to humans through eating beef that hadn't been properly rendered. in the slaughtering process. And this led to a kind of mania, in particular in the UK, but also it then spread into Europe. was protests about the... it all got mixed up between fears about food, genuine issues about food security, and then kind of nationalist or continentalist opposition to various international policies about the globalisation of trade and the ⁓ spread of what the French called Malbouf, so McDonald's and crappy food, you fast food and with lots of calories and fats and all the rest of it. So the whole thing got very, very complicated. The result of which the EU in its wisdom said, right, you can't use this technique of the old style genetic engineering, which was pretty crude and would involve big chunks of DNA being removed or in particular added. And so people were worried that it wasn't just the DNA that you're interested in that was alternating, making the plant more productive or whatever. But it was also the rest of the stuff that was floating around that could have effects on either you or on the environment or whatever. Must be said, there's no evidence of that. GM crops are quite fine to eat. And if you go to America, you're going to be eating it because it's everywhere. In particular, if you eat maize, what they would call corn, then, you know, tortillas and stuff like that, then it's all got, it's all GM and nobody's harmed from it. However, this is the only, the is the EU in all its wisdom. So now you've got a problem because what CRISPR does is to convince the cell to change DNA in particular way. And the components that I said, all these bits of molecules that are derived from bacteria, They are very rapidly metabolized so the cell gets rid of them. So you've now got a piece of DNA which has been altered. There's nothing else there. It is simply a sequence of bases in a long thread of nucleic acid. So how can you tell the difference between that and something that has been ⁓ changed by the old way we've got of... which is how we got all the plants we've got at the moment by creating variants either by happening... upon them or more traditionally now in 20th century plant breeding you bombard them with radiation, you create mutations because you've broken the DNA in various ways and then you select those plants that survive in whatever particular conditions, know, they can do better with less water or whatever or they're more, they grow bigger, you whatever it is you're interested in. So that's an incredibly arduous process and you can now kind of jump over many, many generations of plant breeding and do this more directly. But how can you tell the difference? You know, if you had two DNA sequences, one's been created using CRISPR, the other's been created through this artificial selection, you can't tell the difference. So the EU is still arguing over this. They initially said, okay, well, CRISPR is terrible, it's GM and we don't want that. But there's been a lot of pushback, both from scientists and agriculturalists who say, look, this is really, really important. We can change things fundamentally. think whatever you, you know, the key issue in all these cases is whatever you've done, you need to be absolutely confident that it is ⁓ both safe for humans and also safe for the environment and there's not going to be untoward consequences. And that is always, I think that should apply not only to, and does apply, not only to, you know, engineered crops, but also traditionally created ones. speaker-0: Yeah, but I can understand why it's such a sensitive topic, right? Because on the one hand, on paper, it looks amazing. Like, hey, you remember that we can only grow these crops three months a year. Like if we edit the gene just the slightest bit, then they grow six months a year. that way we lower the price, which is good for everyone. And the farmers can get a higher income and we don't have to import. all of this from from China anymore and therefore we reduce the CO2 CO2 output, cetera, et cetera. But then maybe because you've now extended the timeline of which this crop can grow, maybe one animal will overfeed on it and therefore ⁓ become, I don't know, ⁓ abundant in an area which will cause like a domino effect of entire things that we could never have foreseen. Like can we ever be certain of the effects? We might be certain of the effects in this particular organism, what it will do to the mice plant, but we won't know for sure what it will do outside of the plant. speaker-1: Yeah, mean, ecology is complicated. ⁓ I guess the only sad truth you could say is that ⁓ most industrial scale agriculture is carried out in pretty bleak conditions where there's not a lot of biodiversity left. I mean, I'm being slightly facetious there, but that is true. is that the, you know, this is the great, you know, 60, 70 years ago, 1970s, people were terrified. that the world was going to be overpopulated. There's all about it, we've got the population bomb by Paul Ehrlich that basically everybody's going to starve to death because there are too many people and the food supply can't match it. And that didn't happen for all sorts of, in fact, even better in a way than that, we've actually massively decreased child mortality. the population, the healthy population is much bigger than it used to be. ⁓ That seems to be, population growth seems to be levering off now and now we've got something else, know, some people are now terribly concerned about the opposite, well, who's going to wipe my ass when I'm 80 if there are no young people, but know, population growth is declining, so how are we going to keep the retirement, pensions going and all the rest of it? Let's leave that to one side. The key thing is that we haven't starved to death because of the power of ⁓ agriculture and of fertilizers and of new crops which were developed using the old technique. The downside of having all us people, which has been great because we've got lots of very talented people around the world, has been the consequence of the ecosystem. And that has got nothing to do with genetic engineering or anything like that. And so what you have is, you know, agriculture, mean, this is kind of the case in Holland, which is very much, it's very small country. But, know, the Netherlands are just basically covered over with fields and, you know, agricultural production or cities. There's very little, ⁓ in particular in the western parts, there's very little wild parts of the Netherlands are left. So you've got these regions that are already extremely ⁓ depleted in biodiversity. I think the general point is and the EU in particular I does do a good job on this is that you need to be very careful when you introduce new crops for all the reasons that you've outlined and in general that's what happens already. Can you be absolutely sure? No. There are only two things you can be sure of and that's death and taxes. ⁓ speaker-0: Yeah, I know that saying because I used to be a tax lawyer before I became a journalist. what about the US or China, for example, are we in the EU more careful when it comes to CRISPR and gene editing? Because that's usually what we see, ⁓ Whether it's artificial intelligence or any other. technology it's usually America innovates China imitates and Europe regulates right so is that what we're seeing with CRISPR as well? speaker-1: Yeah, pretty much. mean, was the, you know, CRISPR was born in the, well, the application of it. I mean, it was created, it was discovered in Europe. I mean, they were discovered in microbes in a salt lake above Alicante in Spain. And there were European researchers who were studying these bizarre bits of DNA that they didn't understand. This is over 20 years ago now. And ⁓ The consequence of all that eventually within kind of six, seven years is that this field went from kind of literally two or three people to scores and then by the 2012 hundreds, thousands of people are now involved in this field. But that was driven by much of the initiative and ⁓ the kind of entrepreneurial framework. In particular, the existence of lots and lots of venture capital companies, which don't really exist outside of the US, that they were driving this exciting, this possibility. or rather, the researchers knew that if they hit on the, you know, if they found a gold mine, somebody would help them dig out the gold, right? So they were, that's what they were looking for. So yeah, that, in that sense, the innovation has come from America and a lot of the application. as well. ⁓ Although, know, crisp, because establishing that crops are safe and doing really what you want. mean, plants are pretty complicated things. It might seem very straightforward, but ⁓ getting them to say resist desiccation or to produce, you know, putting particular vitamins into, there's a tomato. that's been manufactured in Japan that will increase African what particular stuff it is. But I mean, you can imagine all sorts of ways of delivering compounds to the body by introducing them into a plant. That in general proves a lot more difficult than it's thought on paper. So crisper crops on the plate, there are very few at the moment. And the way that's not surprising, because this is technology that was only shown to work in, you know, in both microbes and in human cells in 2012, 2013. And given that long time like there is for developing these things and then proving it growing in the field and then making, know, scaling is always a real issue. That is, it may work in, you can see this, for example, in things like the Impossible Burger, these ⁓ plants that have been manipulated to taste. So when you produce an artificial burger, they actually taste of meat. They've got various compounds in them that you think, gosh, this is a burger, it's meat. Scaling that ⁓ and producing it at a suitable price has produced very difficult. The poster boy, girl for all this, as I said earlier on, is insulin being produced in a microbe. That's relatively trivial, it turns out, compared to producing a plant-based burger that tastes nice and that everybody can afford and that you can produce on a large enough scale. there is a lot of understandably, well, you can call it excitement or you can call it hype, right? And clearly for people who involved in startups, then it's a mixture of both. They are committed to the project. They're very excited about it. They're going to devote to it. lot of their life and their energy to producing this thing, but they've also got to get the money and the support and the acquiescence of regulators, which may be easier in the US than it is in Europe, but they still need it. And that's where the hype comes in. So you've always got to be kind of wary of what's going on. China is a fascinating case in point, particularly with regard to plants. So China was the first country to produce a genetic modified plant that was used for consumption. Now, what it was was tobacco, and this was not done legally. It was done by some kind of ⁓ maverick scientists in a part of China where the government didn't realise what was going on. Ironically, the US would not allow the imports of this tobacco, not because of any danger to... people who might die of cancer, because they were concerned about the GM crops. So that happened in the late 1980s. China has since poured an awful lot of ⁓ money into developing new crops, in particular producing cotton that will resist the attack of insects. ⁓ And so an awful lot of cotton, both in China and in ⁓ and in the US is GM because it reduces, I mean it's actually very, oops, it's actually very good. It reduces the amount of insecticide that is being poured into the environment because these are endogenous insecticides produced by the plant which with luck will only affect one specific group of insects, not going to kill bees or whatever. Whereas the insecticide you're going to spray almost certainly will do. So from an ecological point of view, I think these crops are a great step forward. And people don't really care because you're not going to eat cotton. You're wearing it and what do you know? The key, and this is the fascinating point, comes with what you eat. I mean, as I said, insulin is produced in a microbe. Nobody who is injecting that once, twice, three times a day bothers about what they're injecting. They probably don't know. If you tell them, they're going to say, well, that keeps me alive. I'll take whatever. There is no danger, you know, whatever weirdness, I don't want to inject a microbe into my body. But that doesn't happen. People aren't opposed to insulin that is produced that way. Food, however, is where it gets a bit tricky. And you can see this in China because it's not any cotton that gets attacked by insects. It's also rice. And so there's been a huge debate in China, which I was stunned to discover because you have this impression about China being incredibly no opposition, no questioning. And there has been a huge debate in China, in civil society, but also amongst the leading parts of the apparatus, the party and the army, about whether ⁓ GM rice should be allowed or not. Because clearly this is incredibly powerful fundamental part of Chinese culture. And so there There are those, there are generals who say this is all a Western plot. It's going to, it's going to make us all sterile. mean, you know, they make RF Robert F. Kennedy Jr. look sane, right? There's the same kind of stuff that's floating around, but in China. So yeah, they, they've allowed Greenpeace to organize, to protest against production of GM crops in certain GM crops in China. And there've been protests against Chinese. big agricultural companies and pharmaceutical companies buying up the companies in the West that produce these kind of crops. they are very uncertain what to do because of this kind of visceral power of and cultural significance of food and then the idea of it being in some way adulterated in a way you can't tell. That's kind of creepy. I think that's, yeah, so there you go. China is kind of very, like I think most people, think China is very conflicted about the potential, but also recognising that you can't simply impose this, you've got to take people with you. speaker-0: Super interesting. I didn't know that about the rice. But how far are we with CRISPR in general? Like how well do we understand? I mean, of course I understand it also depends per species because in order for CRISPR to work, you have to understand the underlying DNA, which differs from plant, which differs from an animal, which differs from humans, of course. ⁓ But in general, how well equipped are we at the moment to ⁓ actually put CRISPR to use? Is there still a lot to be discovered or have we basically figured it out already and is only the legislation and our ethics that's what's holding ⁓ us back at the moment? speaker-1: I don't think so. Part of the problem is, I I've retired now, but I used to talk to students about this, all of our biology students, six, seven hundred of them would get a lecture from me about the ethics of all this and the problems associated with it. the students would also get lectures from members of staff who were using this technique and would simply describe it in the most positive way possible. And they'd say to me, well, wait, a minute, which is true? Well, they're both true, right? So you can, ⁓ you know, you've got this new tool which enables you to manipulate genes in a very specific way. You're studying mice, ⁓ and you're going to change a particular gene, which does whatever you're interested in. And it doesn't always work. You don't really care because you can produce another mouse that easy. It's not complicated. So in the end, you're going to end up with the mouse, the mutation that you're interested in. You can study that. And I did this through CRISPR. So. That's really not a problem. It will work if you understand the system in sufficient detail. On the other hand, when it comes to, and in particular, it comes to human embryos, we now know that there are, part of the problem is that this, you know, it often describes a pair of molecular scissors, you know, and you can see images of, people actually have scissor images cutting DNA to show what's going on. And this is a very, very kind of simple metaphor. And when you dig into it, whilst it can be the case, in particular in very simple systems that it's, you know, single celled organisms like microbes, can, that's all the, the microbe is, is what it is. So you put the DN, your CRISPR constructs in there and it will do its work. That's what these systems have evolved to work in, microbes, in bacteria. But in multicellular organisms, in particular in embryos, that becomes a bit tricky because an embryo, which is a fertilized egg, so you've got the DNA from both parents, and whether it's a plant or an animal, you've got two copies of each gene, one from each parent, and that single cell is now doing something. It's not simply sitting there like a microbe. Already, as soon as fertilization takes place, the cell starts to do things because it's going to very quickly start dividing to four. And then she turned into a baby or a plant. I mean, it's quite remarkable how that works. So if you then introduce the CRISPR into there, you're not simply doing what you've got ⁓ an environment that is structured in time and space is moving. It's not simply static. And that's one of the reasons why CRISPR turns out to be actually quite difficult to use in certain situations, in particular in embryos of primates, so that includes humans. we're going to talk about this shortly, after the first people, as I said, very soon became interested in using CRISPR in humans to see whether they could cure genetic diseases. And ⁓ one of the consequences turned out very, very quickly to be we now realize that during this process in an embryo, in a primate in particular, then it's not just the sequence you're interested in that gets changed, but whole, in some cases, whole chromosomes. That's all the big structures that have got hundreds and hundreds of genes on. You can lose a whole chromosome, which is not, it's not insignificant. Now, if this happens in a mouse, as I said, you probably won't even notice there'll be an embryo that died. So, you you'll get... maybe you were expecting to get 10 pups out of your female mouse, you're going to get nine. You don't know what happened in that one. You're going to get five, but you don't care because that's not what you're interested in. But if you're dealing with anything to do with humans, then that's clearly a much greater issue. I think in terms of, this is partly related to the complexity of it that I think when you introduce in this system into multicellular organisms where it has not evolved in particular into an embryo, then strange things are going to happen. We're beginning to understand, I mean, from the very beginning, this was known, and they said, yeah, so we can target this particular DNA sequence. Oh, there are off-target effects, which is this kind of very neutral, safe, off-target effect. What they actually mean is the different bit of DNA than the one you're interested in has been changed in some way. They don't know. unless you sequence the whole organism, you do not know what has happened. You just know that something is, rather than being a pair of scissors, it starts to look like a chainsaw kind of, know, going around all sorts of bits of the genome. Now, we're beginning to understand that just yesterday in Nature, last night in Nature, a paper came out, people looking at the molecular structure of the various CRISPR components, trying to understand how and why these off-target effects are produced. I mean, people are very, very clever. There's a lot of money involved in this and a lot of prestige. So my expectation would be that many of these issues will eventually be resolved, but it's going to be a lot more complicated than pictures of scissors cutting bits of DNA. speaker-0: Yeah. And what about the case of, I'm probably going to butcher the pronunciation of his name. He, Giancu. ⁓ speaker-1: I don't speak Mandarin either, so Her John Quay is how I pronounce it. So is his family name and John Quay is his first name. So he was a... Well, he wasn't a physician. He was an entrepreneur and I think he was a biochemist in training who in the second big jamboree about human genome editing, which took place in Hong Kong in 2017, he announced that he had ⁓ edited ⁓ two ⁓ embryos and brought them to term. So there were now two baby girls in existence and that he had he claimed introduced an alteration in their DNA which would make it less likely that they got HIV. So I think the key point about this is firstly these two embryos were normal. There was nothing wrong with them. He wasn't curing a genetic disease. And as for avoiding HIV, I everybody knows how to avoid HIV. There are very simple things you can do to avoid it. And indeed these days it's not even It's not like it was in the 80s and 90s, a death sentence. There are treatments of it. That having been said, avoid it folks. Very, very simple. Don't share needles, use condoms. That's basically it. And so as one researcher asked, John Quay when he made this announcement, ⁓ what was the unmet medical need? Because if you're going to do something to somebody, you need to be meeting a medical need. There was none. There was none. These baby girls were absolutely normal until he got his hands on them. And what it turns out, as far as we know, because the data haven't been fully released, because there was a huge scandal about this, is that the whole thing was completely botched. And this reveals part of the problem of using the difference between CRISPR reality and the fantasy of a pair of sisters changing a single word of DNA. So the girls are mosaic. That is not every cell in their bodies has the change because he did it in an embryo. You've got to do this in an embryo and the embryo is moving. You know, it's changing bits of it are turning into something. some of the ancestors of the cells of the girls making up their bodies were not affected by this CRISPR. So does that matter? I don't know. mean, people do have. different coloured eyes and stuff. David Bowie had different coloured eyes and stuff like that, so although he wasn't, not for genetic reasons. But people do have, can be mosaic, but this is quite extreme in these girls' cases. With a bit of luck it won't make any difference, right? Because this is one particular mutation, although, you know, the mutation that he wanted to introduce he did not introduce, and one of the girls has a mutation that has never been seen in another human being. So this was absolute disaster. mean, ⁓ we don't know what, you know, the girls are whatever now, seven, eight. In fact, there's another, he's since admitted there's another child involved. And the thing was a complete disaster. All we can hope is they're okay. The Chinese state has completely kind of shut down any discussion or mention of them, which in a way is good because they shouldn't be turned into a circus. And all you can hope is that they're being, ⁓ they've got all the support. from the Chinese state medical. With luck, they won't require anything. I nobody has any idea what's going to happen to these children. So all this is pretty grim and caused a huge outrage. Initially, the Chinese state was very excited and very proud and the news outlets, the state news outlets proclaimed this was a great triumph of Chinese science. But within less than 24 hours, those statements have been taken down because everybody around the world, including leading Chinese researchers said this is complete and it's a disaster. This is a dreadful, horrible experiment which has gone wrong and you know, wasn't licensed, etc. You know, all the support that He Zhangquan had within his region in China just kind of evaporated overnight. He was eventually sentenced to three or four years in jail for practicing medicine without a permit. But he's now out of jail and he says he's going to do it again. I mean, he's convinced he's going to the Nobel Prize for this, which is really quite terrifying. And it must be said that nothing similar has been done. to be very, very clear, CRISPR has been used to develop new cures for genetic diseases. But these are done on adults, that is on, in particular, on diseases associated with the blood because you're going to easily get access to stem cells, that is cells that are going to turn into red blood cells. You can get them from the bone marrow, you can remove them, you can manipulate them in the test tube, you can be absolutely sure that you have only introduced the change you want to introduce and then you can reintroduce these altered cells into the body where they will proliferate and as they have done, cure sickle cell disease. It's absolutely remarkable. And there are various other very, very specific diseases with often just a single base pair that's been altered that have been cured by these techniques. this is incredibly expensive. And with the exception of sickle cell disease, they generally affect relatively few people. So this isn't something that's immediately going to transform the world. even A sickle cell disease which does affect hundreds of thousands, millions of people around the world, in particular in Sub-Saharan Africa, ⁓ this technique is not going to become available to them tomorrow. We know where it's going to be based. It's going to be based in the West with people who can afford to pay for it. it isn't something you can just snap your fingers and change the health of millions of people. ⁓ Other drugs can do that. You know, things like statins, which lower your cholesterol level. They've saved millions and millions of lives for people around the world who not having heart attacks and strokes and so on. Genetic diseases are a bit trickier to deal with. So where it's been successful is in these, what are called somatic interventions. So you're intervening in the body of ⁓ a child often, but also an adult and the DNA that they pass on to the next generation is not being altered. So in animals, there's this separation between what's called the germ line. So that's the DNA that is in your eggs or in your sperm and the DNA in the rest of your body. And you can do whatever you want to the DNA in the rest of your body. It will not alter the DNA of your children. And that I think is, you know, we've got to be very clear on that. The somatic interventions. As long as they're safe, I don't think there's any kind of ethical reason to worry about them because it's not eugenics in the sense of changes. It's medicine, right? You are saving people's lives. You're changing their lives completely. Whereas altering the DNA of the next generation, well, that's a eugenic program. That's doing something to change future genes. And that's where the ethics gets much more complicated. And although you may say, you know, if I've got an environment carrier of a genetic disease, I want to have a healthy child, you know, surely I want to save that child, but the child doesn't exist, right? That's your desire. In fact, what you are treating in this idea is treating the desires of people carrying genetic diseases to have a biological child of their own that is not affected by the disease. which whilst that's quite understandable, there are other ways of dealing with this which we have which do not involve genetic manipulation. So basically you have to go through IVF, which you have to do with these genetic manipulations anyway. You go through IVF, which as I always like to point out is not easy. It's generally, this is very much fantasized by men, okay, we can do IVF, we can do this and all the rest of it. But anybody who's got a friend, sister, mother, aunt who's been through IVF knows that it is... No joke, it's really hard going in particular for the woman. The man's job is done in a few squirts in a cupboard. The woman has got to have lots of hormones and all the rest of it and have her eggs harvested and so on. But what you can do is if you're a carrier of a genetic disease or if you both are, is you create lots of embryos through IVF and then you select the ones that don't have the disease. And there've been various calculations made to say, okay, well, if everybody did that, how many people couldn't be helped by that. The only way that they could have unaffected children would be by carrying out some kind of genetic manipulation on an embryo. And the numbers are literally in the few hundreds around the world as far as we know. So it is a very, very small number of people could only be have their desires to have a child satisfied. I'm emphasizing that because as I say, no child exists until you put it in. test tube with egg and sperm together and create it. Then you've got an issue. But before that, there isn't one. So you're really treating individuals' desires. we know, so there's a lot of excitement about this, but we know whose desires we're talking about. We're talking about very rich people in the West. We're not talking about a global health. There's not a global health problem in this respect, as I say, with a few hundred people around the world. speaker-0: Yeah, I think it's a very interesting distinction you make there between editing your own DNA, but not in a way that it would cause your sperm to be different or your eggs to be different, which would be harder anyway because I believe they're produced at birth or at least very soon. ⁓ speaker-1: The eggs are the sperm that sperm eggs are produced most bizarrely eggs are produced or decided Determined before the baby is born so girls right when they're in their mother's womb their potential You that their monthly eggs their potential offspring have all been determined gents. We produce it all the time. It's just continual turnover speaker-0: Yeah, no, but exactly. so I think that's an important distinction, ⁓ that we currently at least think if we allow the DNA to be edited in a way that it doesn't, let's just use sperm for an example, doesn't affect the sperm. because I recently had Anders Sandberg on the pod and he's a trans humanist and he believes in total morphological freedom. which basically means that there shouldn't be any limit as to how we can edit our own bodies. And that means biologically, but also mechanically, right? So maybe in the future, if we can implement some sort of brain chip that allows us to have a chat GPT in our brains or whatever, but also in a biological sense. I didn't know that there was this distinction between editing your own DNA and editing the DNA in a way that it will affect your sperm because I thought it would be an interesting question to him. What he thinks as a transhumanist that believes in total morphological freedom. ⁓ If he would go so far to say that you can also edit your own DNA in a way that it would affect your sperm because then you're also making decisions for future life, if you will, even though, yeah, that life hasn't speaker-1: I suspected he'd say it was okay. And of course, that's what parents do. They make all sorts of decisions for their children once they're born. Their children have got no say in. So, you know, we do terrible things to children. mean, again, I'm being slightly facetious, but it's true. You know, we decide what school we're going to go to. We decide what country they're going to live in. So what language they're going to speak. So there's all sorts of things we do and just, you know, children are just treated as our, not as our property. They're our responsibility as a parent. So, you know, and if you're doing it careful, you try not to do any harm. I mean, yeah, I don't have a lot of time for transhumanists, I'm afraid. It seems to me there are much more interesting problems around the world and much more pressing ones than... But I mean, I'd just say, at the moment, there are people who have mental health issues which mean that they are... they feel they need, say, to have a limb amputated. There's nothing wrong with their limbs, legs or arms or whatever. but they, this is an impulsion. And if you go to a doctor and say, look, I've got this impulsion, I want to have my leg cut off, they won't do it. Right? You can have all the total freedom that you want. You would, they are not going to chop your healthy leg off. That is not something that they will do. I mean, you might be able to get, find somebody to do it in a, you know, in a, in a backstreet surgery or, know, somewhere with less regulation, but in general, they will not do it for very good reasons. So, you know, I don't, I don't think we have total bodily autonomy. That's why, you you should wear a seatbelt and you should wear a crash helmet. know, it's just kind of very sensible rules about protecting you from yourself in a way. But anyway, that's, mean, let's not talk about transhumanism. I'm not interested in it. speaker-0: No, I wasn't trying to, but I was thinking about the distinction between editing your gene in a way so that it affects your sperm and in a way so that it won't affect your own sperm. Is that where we currently legally draw the distinction? Is that where the research is going? speaker-1: Well, but I mean, there are very strict. So what is happening despite all the excitement about, about CRISPR and the potential for producing smarter, taller, blonder, I wonder where we're going here, kind of, know, Aryan types in particular amongst certain tech bros. There's a whole layer of tech bros in the US that have obsessed with this and obviously Musk is, I mean, he's not He's maybe quite tall, but he's not blonde. He's not very slim either. But he is, as far as he's concerned, incredibly smart and he thinks it's his duty to populate the planet with as many copies of his genes as possible. So there is this kind of new eugenics coming along, but it's not at the moment being focused on ⁓ doing it using CRISPR. I think because it is just such, it's so unreliable, you know, it's crap basically. You would not want to... ⁓ produce an embryo and bring it to term using CRISPR in a human, even if you had no ethical worries. The yields, as they would call it, of a healthy embryo is so unreliable and uncertain that you wouldn't want to do that. So what they're now getting very keen on is exactly what I said earlier on about genetic diseases. That is, you can... have lots of embryos going through IVF of course, but you know, the woman is simply a vessel for your sperm, so that's okay. She's going to have, produce lots of embryos with you and you can then select, because one of the magics about, magical things about ⁓ human, many vertebrate embryos in general, is that you can remove a cell at a very early stage when there's kind of say eight cells. If you remove one of those cells, the embryo just gets on. It doesn't bother about it. It's not like you haven't got an arm or something. This is going to be where the arm is going to be and we take it out and there you've got a baby with only one arm. It doesn't work that way. So basically there's a lot of what's called homeostasis. The whole thing balances and works itself out. Interestingly enough, if you try this with an insect or an octopus, it doesn't work. You can't do that. But with a vertebrate, you can make those changes. So you know what the DNA of the embryo is. This is how you do it with genetic diseases. So now in the USA there are lot of companies which say, right, okay, there are lot of, we can know from studies of human DNA and particular links between the phenotype, what the parents are like, what the carrier of that DNA is like, their intelligence, if you can measure that, their height, their weight, their skin colour, their hair colour. We can correlate those phenotypes as they're called with the underlying DNA sequence. So you've got enough data then various factors are going to kind of pop up. And therefore we could say to you, right, you've got hundred embryos, which is an awful lot, but let's say you could get a hundred embryos. We can enable you to choose the handful that have got the best, that have got the sequences of DNA that are most likely to be associated, say, with being tall or being super intelligent or being Aryan in whatever way. And so they sell their service basically. And this is illegal in the USA. It is completely illegal in the UK and in Europe. is you cannot, you can't select an embryo on the basis of sex, right? We don't allow that. I mean, that'd be relatively trivial to do. We don't allow people, unless there's very, in the UK you have to have a, there have to be a sex-linked genetic disease for you to be able to do that. There's a very, very limited numbers of cases, but in general, you're not allowed to, you've got to take pop luck like the rest of us do, you know. like we do when you babies in the ordinary way, you've no idea what's going to come out. Who knows? So this idea of selling services is this genetic screening service is becoming very popular. However, that having been said, many of the companies so very rapidly gone bust. was a big company in New York, which festooned the subway last year with adverts saying, you know, produce a better baby or something like that. I mean, it's very, very clearly eugenic in its in its tone talking nonsense about the proportion of the intelligence of an individual is based on their DNA. I mean, it's just rubbish or height even. mean, right, who is the world's tallest nation? You should know the answer to this. Yeah, it's the Dutch. So why is that? Is it because something has happened to your genes? Because it wasn't always that way, right? speaker-0: Yeah, the Netherlands. speaker-1: No, Edam or whatever it is, There's something in simply the Dutch food that's left you to go really tall. If you go to a museum and you look at a medieval set of armour, suit of armour, you know, they're all kind of, I don't know, one metre fifty or something, one metre sixty. And nothing's changed except the food. The DNA is the same overall, but these people didn't eat very well, so they were quite short. So, you if you want to have a tall baby, feed them. If you want to have a smart baby, do your best with books and, you know, culture and all the rest of it. So these companies are advertised, I mean, basically it's a scam. It's a waste of money. but people in the particular in the USA are very keen on it, but it is illegal in certainly in Europe and in the UK. speaker-0: It's also pretty difficult to know whether you've been scammed, right? Because you just get the one baby. it's like, is... Maybe it come out very well, this is like... Imagine if we didn't get... This is the best we can do, apparently. Yeah, figured... speaker-1: I mean, you know, there's all sorts of terrible things about parent offspring relation. We're talking about, you know, ⁓ parents deciding things for their parents for their offspring. I mean, this is even worse, you know. mean, you know, you know, the advantage of doing things in the random way is that there's no responsibility. didn't choose, you might have chosen to have a child or decided to keep it, but you haven't chosen this particular child. Whereas now there's going to be all this pressure. Well, you know, I expect you to get to Harvard or whatever, or be a champion sports person or whatever it is, whatever fantasy the generally male parent has about realizing their frustrated desires in their offspring, which happens in lots of families, that is now going to be present in spades. But you know, that's their problem. We'll see this 30 years down the line. I think your point is much more astute, in fact, that, you know, hey, you you're the, yeah, you're great. You're marvelous. What they don't know is that there was an Einstein or a Mozart that they flushed down the sink. know, because it didn't fit in with their particular preconceptions of this company about what make to good. mean, Einstein and Mozart were not simply to do with their genes, I'm sure of that. But, you know, remarkable individuals for whatever reason, combination of genes and environment, who knows, you know. It is, I mean, that's part of the great thing about being human is it's all very unpredictable. speaker-0: Yeah, no, I agree. And what's next for CRISPR? Because it sounds like we are doing active research still, even though we have pretty strict legislation in place in order to prevent us from from eating modified crops, for example, or speaker-1: That's going to change, that will change, I think in the EU as well. It's still going through the various courts, but I don't see how they can argue. If you can't distinguish between two cells that have been propagated in different ways, what difference does it make? But there may be that the population doesn't like it, right? In which case, it may be legal, but people say, well, actually, no thanks. I don't fancy that. speaker-0: Yeah, but I mean also the sickle cell disease you mentioned, like it does sound like we are actively working with CRISPR to bring the science forward. yesterday there was a paper released, so we are still actively. It's not like, oh, this is unethical, we've shelved it. So I'm just curious, where are we going? Like, will we figure it out? And what does the future look like? What do you think? speaker-1: Well, I expect there to be more ⁓ somatic genetic diseases treated ⁓ in using these various techniques. I mean, there's all sorts of different ways of doing things. ⁓ But there will be, this is going to become increasingly frequent. And with luck, then diseases that affect ⁓ larger numbers of people, but are more complicated, like muscular dysgraphy. will eventually become amenable to being treated in the individuals, in a, by altering an embryo. But part of the problem often of this is getting the, that's why I said people are focusing on blood because it's easy relatively. Muscular dystrophy affects every muscle in the body. So you've got to find a way of treating it, which is, I mean, it's very, very hard to imagine. I mean, there are attempts being made and that I am confident in people's ingenuity and the pressure from and support from the disease community. So a lot of this work has been done in particular by consortiums of patients and their families who suffer from rare genetic diseases who may not be able to get enough money to, know, there's no commercial companies are interested in this because the market's too small. a few dozen people around the world. But enough of these groups get together. of small patient groups, this has been the reality, they've been able to encourage with donations from the public ⁓ the development of this kind of research. So that is going to increase and more more rare diseases will be being treated by these CRISPR and associated forms of genetic manipulation. I guess to be the thing that I'm most concerned about and which is most alarming is the... kind of nightmarish fusion of this approach with ⁓ AI, these large language models that can do all sorts of apparently do all sorts of clever things, although often not. so there is a, mean, from the very beginning of genetic engineering, people became alarmed that it would be possible to create bioweapons. And indeed, the Soviet Union did exactly this ⁓ in the 1970s and 1980s. They used these new techniques not to create insulin but to create new microbes that would be absolutely horrendous if they were ever to be released. So there is the possibility that ⁓ AI will supercharge the development of such weapons and that is a very very alarming possibility and this is I mean the fantasy of the security agencies which they put on to us is ⁓ this is all going to be terrorists in a basement carrying out dreadful things. Well, yes, that may be the case, but what I'm really worried about is you. Security agencies in the West and in the East who will be then get an appetite for creating bioweapons that at least technically might be very, very specific. mean, in an apartheid South Africa, they were trying to create ⁓ microbes that would specifically kill black people. Now, I think that's going to be very hard to really target your enemy, which obviously In case of South Africa, the black people were the enemy of the apartheid state. But that is the kind of nonsense that will... well, it's nonsense, I... it's, you know, worrying and dangerous fantasies that may well end up gripping parts of the security apparatus around the world. And at the moment, part of the problem is we have an international convention on biological weapons. which was signed in came to force in 1975 at the same time as genetic engineering was being developed which has been completely unable to prevent the creation and development but thankfully not deployment of these weapons by at least by the USSR probably by China may well be by Israel we don't know the West USA France, Britain and so on, their interest in this they claim is purely defensive. I'm not sure what a defensive interest is. Obviously we don't know what's going on. I think all we can say is that although these weapons have been around for a long time, they have not been deployed and one of the reasons they haven't been deployed is it's not like a nuclear weapon where you can put it on a warhead and that's it and does terrible things and it will kill people in the environment and you know, they're okay, there'll be fallout and all the rest of it, but it's relatively localized and a biological weapon, which will replicate. I that's the whole point, right? So it copies. you know, it will then spread around the world. And we saw with COVID, which was not designed and was not developed in the lab, which was almost certainly all the evidence points to a classic spillover from animals, just like we're seeing with hantavirus at the moment. is, You know, animals like us are full of viruses. Most of the time there's no problem. Every now and again, they enter into the human population and then a small change enables us to transmit it to each other. And it's no longer a problem for bats or pangolins or whatever it was with COVID, it now becomes a problem for humans. And that's also obviously what we're worried about with the bird flu, which is global pandemic killing lots and lots of wild birds around the world at the moment. Although humans can get it, we can't transmit it to each other or it's very, difficult. Were that to become as easily transmissible as ⁓ COVID, then we would be in a very bad situation. Same with antivirus, but for the moment that hasn't happened. COVID looked terrible, but it was pretty piddling. was just basically an extremely bad flu. These other things are on a different scale, an order of magnitude worse. ⁓ The fantasy of the security agencies is that, okay, well, you could do this, you know, with an AI, people in a basement or whatever. Well, yeah, but how, you know, it's not really a, it's going to, these are weapons that are of global, potentially global scale. So what's the point? You know, in general, you want to kill a specific group or country or damage a particular set of crops, right? You the Russians were not only developing agents to kill people, they had a whole program developed to destroying agriculture. So you could develop new viruses that would wipe out plant, know, crop production, which would clearly be devastating. And maybe countries are doing this now. So how do we control that? mean, you the regulation is the real issue and that is very hard to get. At a moment when, you know, the US in particular is withdrawing, I they're no longer part of the World Health Organization, you know. crazy, we've just had a global pandemic and now they've withdrawn from the WHO. They're not going to start signing international agreements that will restrict their activity. And even, you know, if they had signed, like Russia signed up to the Convention on Bioweapons and just carried on regardless doing what it wanted to. So that's what I'm really worried about. That's the future that is very concerning and you end up just kind of hoping that people are sensible and don't do this. do it because it's going to be devastating if it all goes wrong or if it goes right from their point of view and they release one of these things in a war. ⁓ speaker-0: Yeah, that seems an unprod... it seems like a very unpredictable weapon though, like you mentioned. And you've mentioned AI there, which I think is interesting because we've seen AI being used in medicine because it's able to try out ⁓ endless amount of new variations of something and therefore it seems to be speeding up medicine, for example, pretty well. I can also imagine like... Again, I'm not a scientist, so I don't know, but I can imagine a future where we'll use AI in order to map out the human body even better. So we'll be able to ⁓ use CRISPR in a more precise way and maybe do get to a future where we can use it as the molecular scissors. Like you mentioned before, think once we get to a scenario where we understand it like a hundred percent, You'll probably also see some black market gene editing where, where people like, Hey, you want to have a two meter tall, ⁓ blonde muscular son that will probably be a professional football player. Like hit us up. Like if you pay us a million dollars, we'll do it for you. Like that's, that's, mean, if it's possible, then I see a future where, where black market will arise for sure. speaker-1: Well, that's very bleak. ⁓ mean, you might be right. ⁓ But at the moment, say, you know, there's all sorts of things we can do and there's all sorts of markets for them. But that doesn't necessarily mean that it becomes at all widespread or effective, I guess is the point. ⁓ I mean, part of the problem would be the investment. OK, let's say you've got your footballer. Take the example you've just taken. I mean, you know, you can, can, let's say you invest that you really want to do that and your, your child is 18 and they're, you know, they're beginning, they're going to, they're going, they start training with Paris, San Jermain or Real Madrid or Manchester city. And then they break their cruciate anterior cruciate ligament and that's it. They're out. That's it. All gone. I mean, if I was going to do it, I wouldn't do it with a sports person because it's so random. ⁓ I wouldn't want to invest all that time and money and hope and pressure in something that is so extremely risky that you can, know, there are so many boys and girls who are great sports people, but all artists, you know, this works in ballet as well. You know, my daughters did ballet and they very quickly realized that although they were good and they enjoyed it, they didn't have whatever it took in the head or in the body or wherever to make that difference and you know that when you watch sprinters in the Olympic Games you know between the guy who comes first and the guy who comes last and he's like who remembers him you know it's gonna be half a second or something I you know yeah I'd be I'd be barely out the starting blocks by the time they finish so these are these are I think these are fantasies partly because there's such a the genetic involvement you know we shouldn't be ⁓ beguiled by the possibility of curing genetic diseases based upon a single base pair or a very small genetic variation and any of the other things which are incredibly complicated and have got a very strong environmental component. Most of the things we're interested in in human culture are not our diseases because that's pretty miserable. We're interested in what people can do, their creativity, their performance in whatever, artistic or sporting or whatever field and those are going to be multiple origins and whilst people might be paying money for it, they're wasting it. know, I've got a very nice, I can sell you the Eiffel Tower if you want, you There's lots of people who will go along, gullible people who invest money in the, know, there are all sorts of old people these days are getting conned out their money by people, by falling in love with people on the internet who don't exist but turn out to be some scammer somewhere and they extract all their money. So people are going to do crazy things with their money. I don't think that necessarily means it's going to have a consequence. Save your money, be nice to your children, feed them well, educate them well, cross your fingers. speaker-0: Matthew, this was absolutely incredible. I had such a great time. Is there anything we haven't touched on that you would select? speaker-1: I'll have to come back and talk about them again. speaker-0: Yeah, I mean, I would be I would be very open, open to that idea. ⁓ Where can people go if they want to keep up with I mean, you mentioned you were retired, but you're still like you have written a bunch of books. Are you still active on on any other platforms if people are interested to follow? speaker-1: I mean, they're really interested. I'm on Blue Sky. Like many scientists or vast majority of scientists, I abandoned Twitter once Musk took over, not simply because I loathe Elon Musk, but because it became unusable. So Blue Sky, which lot of people complain about saying, ⁓ it's just small. So what? I mean, that's where I am. If you want to follow me, I'm on Blue Sky and you can just put in my name and you'll find me. speaker-0: Incredible. Okay, Matthew. Thank you so much. ⁓ Yeah, like I said, this was amazing. ⁓ yeah, hopefully maybe we can run it back someday in the future. speaker-1: Well, if people are interested in this, I'm happy to come back. That's great.