In Our Time - Genetic Mutation

Episode Date: December 6, 2007

Melvyn Bragg and guests discuss mutation in genetics and evolution. When lying mortally ill with cancer, the British geneticist J.B.S. Haldane penned the following lines: Cancer's a Funny Thing:I wish I had the voice of HomerTo sing of rectal carcinoma,Which kills a lot more chaps, in fact,Than were bumped off when Troy was sacked...Haldane knew better than most that many cancers, and many other diseases, are caused by genetic mutation. A mutation is an error in reproduction between one generation and the next as the copying mechanism that allows you to inherit your parent’s genes goes awry. Mutations are almost always bad news for the organism that suffers them and yet mutation is also a giver of life. Without it there would be no natural selection, no evolution and, arguably, no life on this planet. It’s not unreasonable to see life itself as a mutation and to understand this may also hold the key to aging and disease. It is, in the Darwinian view of life, the raw material of evolution.With Steve Jones, Professor of Genetics in the Galton Laboratory, University College London; Adrian Woolfson, lectures in Medicine at Cambridge University; Linda Partridge, Weldon Professor of Biometry at University College LondonTags

This BBC podcast is supported by ads outside the UK. Thanks for downloading the In Our Time podcast. For more details about In Our Time and for our terms of use, please go to BBC.co.com.uk forward slash radio 4. I hope you enjoy the program. Hello, when he was mortally ill with cancer, the British geneticist JBS Holden came up with the following gallant lines. Cancer's a funny thing.

I wish I had the voice of Homer to sing a rectal carcidine. which kills a lot more chaps, in fact, than were bumped off when Troy was sacked. Professor Haldane knew better than most that many cancers and many other diseases are caused by genetic mutation. Indeed, to understand mutation fully may explain the ravages of illness and even unlock the secrets of aging. But mutation, so often a destroyer of life, is also its creator. Without it, the variety of living things on earth simply wouldn't exist. It is, in the Darwinian view of life, the raw. material of evolution.

With me to discuss mutation in genetics and evolution, Steve Jones, Professor of Genetics in the Galton Laboratory University of College London, Adrian Wolfson, a molecular biologist who teaches medicine at Cambridge University, and Linda Partridge, Weldon Professor of Biometry at the University of College London. Steve Jones, can you explain what mutation is? Mutation sounds simple, in some ways it is. It's simple errors in copying the genetic material mistakes.

and evolution is a series of successful mistakes. It picks up the mutations that are better at copying themselves in the wild. Historically, it was first of all seen as something rare and exceptional that almost never happened, and many people still think that that's the case. But in fact, it's intrinsic to our daily lives and to our evolutionary history. During the course of this program, everybody around this table, everybody listened to the program will undergo tens or hundreds of thousands of gene mutations, most of which they'll be entirely unaware of

will have no effect at all, many of which will be repaired, but some of which may well kill them. So it's an extremely important process. It's at the basis of genetics. Genetics couldn't work without diversity. Genetics is the science of difference, and without mutation there'd be no difference.

Without difference, there'd be no evolution. So it's thanks to mutation that we are not all still in the primordial soup. Can we talk about these, let's call them copying errors in DNA? Can you just describe them in more detail so that we can all clearly understand this key word for the rest of the conversation.

They're like, in some ways, they're like language errors. They're like the differences that take place over the generations as people, as language is passed on and evolve into different languages. And just like language, they're not simple, there aren't any straightforward rules. The simplest of all just involve one shift in one chemical element of the DNA. And even that is enough to cause a huge amount of damage. the famous African condition known as sickle cell anemia, which if you've got two copies of a particular mutation,

can be extremely damaging. That's the simplest kind of change you could imagine. Just one base change, as we would say, in the DNA. And there are plenty of those. But as we learn more and more about the process, it turns out, first of all, it's more complicated, and it's more dynamic. Many, many mutations are due to excision

or cutting out of great lengths of DNA. Others, perhaps more surprisingly, are due to the insertion of bits of DNA, a doubling up kind of stuttering process, even more surprisingly again, some of those seem to have a life of their own, the mutation actually makes an effort insofar as DNA can make an effort,

to copy itself, even if it, and multiply itself, even at the cost, even at a certain cost of those who bear it. So it's like many things in biology, it's rarely pure and never simple, and the more we learn, the more complicated it gets. You're not a man to throw away hyperbole, and so when you say millions of changes in the next three quarts of nara,

as we do this program. Clearly you mean that. Now, what... Yes. We can't feel them. Are we going to be different people, three quarters of an hour on to any substantial extent?

Yes, certainly. Without question. You'd have aged by three quarters of an hour. That's at least. On this subject, I might have aged by a lot more than that. And some of that's cut in mutation. Interestingly enough, you and I Melvin, and the three male members of this panel,

will have more mutations than the single distinguished female member, simply on the grounds that men never rest when it comes to mutation. We make sperm all the time, even when we're on Radio 4. And that process involves lots and lots of mutations. As a result, there's a strong tie between the mutation rate in the next generation and the age of the father.

That just shows how powerful mutation is. It's a dynamic process that happens to all of us, to all your listeners, men more than women. And mutation is briefly on this one, because we're going to come back to it, it is the raw material of evolution. Without mutation, we would not. be able to continue to evolve and ergo exist. It's the fuel for the Darwinian factory really.

Adrian Molfson, if mutation is responsible for the great variety of life of NER to take a step forward from what Steve was saying, yet most of us around this table, most of us listening look more or less alike. Giraffes all have

more or less the same length of neck and so on. What's holding back from an infinite know, it's almost freakish variety and diversity. Well, in order to address that question, we first have to really ask a very fundamental question, which is what is life?

Now, obviously, that in itself is a complex question, maybe best left for another day. No, no, we can never go. But one thing we can certainly agree is that unlike non-living things like a pebble on the beach, which will slowly degrade with time and which won't be able to replicate its structure into the future, living things are characterised by the fact

that they are not only able to store information, which generates their form and enables them to execute certain functions. But it also perpetuates that information across time. And interestingly, I mean, DNA happens to be the technology of genes. I think it's quite possible that there are other technologies in which the information of life can be held. But the interesting thing about DNA is that unlike, for example, an old gramophone record which stores information in an analog way,

said if a gramophone record is scratched, it degrades irreversibly. The clever thing about DNA as a technology is that it's digital. So that means that if you damage a little bit of it, it can very easily, it can only really go to one of four things. So the other DNA is double-stranded, so the other strand can immediately be used to repair the mistake. So the question is, how do these mutations occur? And as Steve said, when DNA is replicated,

the enzyme which actually uses one strands to create the other does make mistakes. Fortunately, these enzymes also perform a function which is known as proofreading. So like a clever editor in a good newspaper, it goes back over its work and repairs the mistakes that it's made. And different polymerases have actually a different sort of fidelity, so to speak, so that some make more errors than others. But there are other mechanisms as well which preserve the integrity of the information. For example, enzymes which are known as DNA repair enzymes.

So if one imagines, for example, the railway lines that crisscrossed the world, which are damaged every day by wear and tear, and indeed when they're constructed mistakes to make, the DNA repair enzymes, a bit like the railway repair men, who come along and fix all of the mistakes and then the damage. It still doesn't quite answer the question that an amateur outsider like myself are likeness, why, given the diversity, given the millions of changes that Steve introduced us to a few minutes ago, why we're all more or less the same height, let's stick with us,

me can go to giraffes or davids, and that sort of thing. Why isn't it more diverse? Yeah, well, the two ways of answering that question. The first, of course, is that if the evolution itself has, if you like, very precisely defined the rate at which mutation is allowed to occur, how often a mutation can fix itself. Now obviously if that rate was too high, you'd reach a kind of catastrophic state where the information would melt away. If you were a scribe copying the Bible

or one of Shakespeare's sonnets and you were so bad at copying that you made too many mistakes, eventually it would become gibberish. Alternatively, if you copied it with too much fidelity, it might be true to Shakespeare's original work, but it might be more interesting to make the odd mistake. So that's one reason,

is that the actual rate of evolution itself, the rate of mutation has been very carefully honed by evolution to sort of avoid this error threshold whereby you create catastrophe. However, the other, of course, important fact, is natural selection. And that's the biggest selector of all, which destroys organisms which have deleterious mutations and ensures that a species broadly keeps its principal morphology. Briefly, and there seems to be a paradox, doesn't that? Because mutations are both creators and destroyers of life. Can you correct that paradox?

In a clockwork world where there was absolutely no change, we could all stay exactly the same. You could remain Melvin Bragg, Steve Jones could stay a Stephen Jones, a giraffe, could stay a giraffe, a hippopotamus, a hippopotamus. But in a changing world where climates change,

where different species change, where all sorts of social factors and behavioural factors change, you have to see this as a mutation, it's a way in which organisms can track this change. respond to the change and in a sense keep their own place in the hierarchy of living things. So you're absolutely right. There's both this force which is undermining organisms by melting away their information,

but also these other forces, both internal and external, which keep them on track and preserve information. Linda Partridge. Can you tell us how these forces go about creating a gene pool? Yes, so the gene pool refers to the sorts of genetic variations. that are present in a population of animals or plants or people. And mutation is the original source of the variation in that gene pool. So if we think about the human population, there's very obvious variation,

some of which you've referred to, although of course it's constrained, so people have different eye colours, and the genetics of that is fairly well understood. Sometimes the variation is more continuous. So, for instance, height is an obvious continuous. trait, but one that is nonetheless controlled by genetic variation as well as of course environment, particularly nutrition. So we have

this pool of genetic variation that's characteristic of the species. The ultimate origin of that variation is through mutation and then various other evolutionary forces will determine the exact composition over time. So part of the

variation over time comes from simple sampling error. So as the genetic variation from one generation is handed on to the next. That is a sampling process. It's as though you put your hand into a bag of coloured counters, red ones and black ones, and take out a sample. The proportion of red and black won't exactly reflect the proportion of red and back that are present in the bag from which you've taken your handful. The same is true with genes. So there's a random walk in gene frequencies, as they're called, that can happen over generations.

That's called genetic drift. So in addition to mutation, that's an important evolutionary force. The other one, of course, is natural selection. These genetic variations, some of them will actually affect the fitness of their bearers, their capacity to produce offspring in the next generation. And that is natural selection. And that's a more deterministic way

in which the composition of the gene pool can change from one generation to the next. You introduce the word time into what you said a few moments earlier. Can you bring that to bear? Because we tend to think of this, I tend to think of this, as human beings the last few thousand years or so. But we're talking about millions of years, aren't we,

that this evolution has taken place? So for evolution... The gene pool is in building up for a very, very long time and changing all that time. Indeed. And of course that means that gene pools can contain very interesting information about the history of the population. So a lot of the variation that's present has no bearing on the foreman. fitness of the carriers of the genetic variants. And that's very useful variation because it tends

to change in composition in a population in a rather regular way over time, even though genetic drift is a process of sampling error and therefore has a random, well, isn't entirely a random process. It nonetheless ticks over like a sort of random clock as time goes on. And you can use that information, for instance, to determine how long two populations have been separated from each other. So you can use that to work out the history of population movement and separation and also to work out, for instance, when species came into being over a longer evolutionary time scale. So it's very informative the composition of this gene pool

about the history of the population. Can I come back for one moment to the relationship between mutation and the environment in which things live? What effect, is there any maths or any direct effect of the environment on mutation? Well, that's a very rich vein historically over which there's been a considerable battleground, although I think the situation is now very clear. And really, this was one of Darwin's major contributions, even though he knew nothing about the physical basis of heredity.

His idea, and the one that has proved correct, is that genetic variation is in origin random, which is not to say that all kinds of mutations are equally probable. I mean, we don't generally see people with, hair. That's not what's being suggested by the idea that mutation is completely random. The point is that it's random with respect to current needs. So if you take a mouse and put it into a cold environment, it's no more likely to produce mutations that give it a thick fur coat or a thicker layer of subcutaneous fat than if you keep it in a hot environment. So mutations occur at random

with respect to current need. It's not a directed process. It doesn't itself cause evolutionary change in a particular direction. All it can do is to offer a range of genetic variation which natural selection can then act on. But Steve Jones, people would say that surely there are things in the environment that have a really serious effect, and that study in Japan after the dropping of the two atom bombs

of the people affected by them, surely they would discover that this affected the genetic pool in those particular areas and so on. Well, Linda's quite right to say that mutation is it intrinsically around. a series of mistakes. It's like hitting a watch with a hammer. Something is going to break and you can't really predict what is. Certainly things from the outside increased the mutation rate and famously the first one to be discovered was radiation in the 1930s. And it's interesting to look back on those days because it seemed that radiation was an entirely inexorable force

that a very low dose of radiation over a long time would have the same as a high dose over a short time. And given that radiation is certainly going up in terms of the use of x-rays and so on and luminous watchings. even in those days. There was a lot of concern that the human race was on the way to some kind of mutational meltdown. And I often think of the explosion of August 5th, 1945, which is the Hiroshima bomb,

as the most cynical experiment ever carried out in biology, because there was a clear expectation that the offspring of those lucky enough or perhaps unlucky enough to survive that disastrous event would be damaged by mutation, by radiation. And the juveniles

looked at it for 50 years, and the end, they didn't find anything, which isn't to say that radiation is not a powerful agent of mutation. It is, but in fact we can fix a lot of mutations, and that's what seems to have happened at Hiroshima. There are many other things outside. Both Linda and I knew and I, in fact, was taught by a woman called Charlotte Auerbach, who fled from Germany and came to Edinburgh,

and during the war noticed the fact that the war gases, things like mustard gas, caused very, very painful and burns, that would not heal. And these looked, she realized, having been burned herself by x-rays, these looked like x-ray burns, radiation burns. And she thought, hang on,

if it causes these burns, maybe the chemicals cause mutation as well. And she discovered chemical mutagenesis, as it's called. To me, that's a bit like being taught physics by Newton, you know, it reminds you how young biology is, genetics is. And now we know there's a whole gamut of chemicals out there

which are far more powerful, probably far more dangerous agents of mutation than radiation ever was. Can I just say, I know you all want to get in on this one, but I'm just going to back for a moment or two, so that, anyway, Steve, again, staying with you for a moment. Can you take us through how DNA is passed from parents, offspring in reproduction,

and how it builds up to another living being? Just if you can spell that out. I know, it's, but never mind. If you can do that briefly, that would be great. Well, no birds or bees were damaged during this explanation. Well, it's all about sex, isn't it? I mean, I say in my very first lecture every year about genetics, I'm a geneticist and my job is to make sex boring

and at the end of term which it almost is my God they agree with me and mutations are a bit like that I mean DNA is famously a double helix it's a mirror image of itself it's the Janus molecule and when sperm and egg are made what we do is to halve the amount of genetic material in every body cell sperm and egg then meet and the amount of genetic material is then doubled up again

now during the formation it's rather interesting there's a close tie between sex age and death. The three things are three sides of the same kind if that were possible. In that age is in some ways the cost of sex because sperm and egg are in many ways insulated from the effects of mutation. They're put on one side as the germ line, as it's sometimes called, which mutation does happen, but any mutations that do happen are put right far more efficiently than in body cells. So the two things are related to each other. Without mutation, we might all be immortal, but without mutation

we'd all be primeval sludge, so you take a choice, really. Did we take the right one, Steve? You look at it. You're not quite sure. Adrian Wolffson, the simplest form of mutation, as I read, is called a point mutation. Can you explain what that is?

I'd just like to put on record that I'm quite happy being a human rather than a piece of primordial sludge, but a point mutation is a single change in a piece of DNA, and the mutation can either be in what's called a coding region which actually affects a gene and therefore an amino acid in the protein that the gene encodes and there are a number of diseases which can result from point mutations like this although the majority of diseases appear to be the result of multiple mutations.

But point mutations can also occur in the so-called non-coding regions of the genome. And an actual fact, an interesting point here is that we share roughly the same number of genes with mice and even with more humble creatures like the nematode worm. And that came as a bit of a surprise, actually, when the genome projects got underway. We always thought that complexity must be reflected in more genes. But actually, that's not strictly the case, although obviously some very simple organisms like bacteria have far fewer genes. But actually the real cleverness, if you like, if the genome comes from the tricks that they utilize to actually control the way that genes are switched on and off.

So a point mutation, which can only, you know, it's just one little change, can actually change a regulatory element, which can completely change the pattern in which an individual gene is switched on and off, even though the protein itself is unchanged. What causes this? A point mutation. Well, again, a number of different causes. It can either be a simple replication error, as Steve was saying, when the DNA polymerase is trundling along one sequence of DNA, it makes a mistake and then either it forgets to go back and repair it

or the DNA repair enzymes are not working very well that day or it can be damaged and damage again occurs in many different ways free radical chemicals in the cells which have unpaired electrons which are very destructive can damage DNA or radiation or a number of different mechanisms by which DNA can be damaged and Linda Potter did you want to pick up as I saw you holding your finger up when Steve was talking earlier you want to pick up that stitch and then I'll ask you the question I want to ask you.

I was just going to follow up on something that Steve was saying about elevation of the mutation rate under some environmental conditions. There was some very interesting work a few years ago with bacteria showing that if you put them in a tight corner so they don't have nutrients that they can use and really the only option

they're looking at otherwise is death, then they can elevate their own mutation rate so they start to produce more genetic variants in a last despairing gasp, trying to produce one that's going to get them past the problem. Well, can I as you about the form mutation called recombination. What's that and why is that important?

What's being recombined in the recombination? Well, that takes us back to the gene pool and all this genetic variants that are present in it. And we each have our own characteristic array of particular genetic variants that we've inherited from previous ancestors. And they're carried around on strings called chromosomes. So they tend to be inherited in groups.

But when the germ cells formed, first of all, there's more than one string present. in the nucleus of the cell. So those strings go randomly with respect to each other to the offspring. So that's one form of recombination. And then within each chromosome, they pair as the offspring are being formed, and they can actually swap bids with each other.

And they're doing that as you speak. Indeed. Sorry, I may have you more to say. I can't get over these millions of things going on while we're just doing a chopping way. It's a very busy place, the genome. Yes, there is a lot going on. I mean, there's an interesting time between recombination and DNA repair, because in recombination, which is it's cutting and spicing of DNA,

actually exactly what is going on, what happens with DNA repair. You're cutting it and you're fixing it. And the remarkable thing is you find a difference in the rate of recombination, cutting and splicing, between women and men. Women recombine much more than men do, so they repair DNA better than men do, so that men do the damage and women repair it. Yes, the way I think about recombination is as a really,

if you think of a row as eight, you know, you've got eight people in a boat, they're all doing a pretty good job, but then you take someone else to cox the boat or take a different position. And they've got the same functions there, but they're slightly different. One of them has got a mutation, and the whole equilibrium of the boat changes. So it's actually reshuffling the components to create a kind of new repertoire. Steve, why do genes mutate? We haven't quite, I haven't quite asked that, so that's an empress-clothes question. It's an interesting question. The interesting thing about DNA, DNA used to be, be called the stupid molecule because it's so simple. Just four bases

what is it? It keeps your earlobes in shape or something until we discover what it did. And it's a very interesting question. First of all, why does it mutate? And why does it mutate at that rate? I mean, the remarkable thing about DNA, there's millions and millions of base pairs, and they copy themselves almost perfectly. Now, to a chemist, that's quite startling.

The chemistry of it doesn't make any sense. To a chemist, you should be dead. As I respond to that, if you're a chemist, you may as well be dead anyway. But the chemistry of it is that it needs to be repaired and gussied up and looked after carefully and tenderly all the time, as we've heard at some length. But why in that case aren't all mutations repaired? And if all, on the other hand, why aren't there many more mutations? And I don't really think we know the answer.

Another way of answering that question is simply to say that the genes mutate because evolution wants them, once in inverted commas, of course, no teleology implied, but evolution has allowed them to because it's a bit like the Red Queen in Alice in Wonderland, all species in a sense are competing with each other to some extent and they have to run in order to keep still. And if you can't change, it's like an arms race, but your competitor is changing, then you're going to be deleted from the gene pool. There's a real trade-off with mutation as well because you couldn't vary the fidelity with which the DNA is copied by how much proofreading is done,

how slowly the things that actually make the new strand, move along and so on. but if you really replicate your DNA very faithfully, it's going to take a long time. And so cells are going to divide more slowly. And so probably the mutation rate is a compromise between how much repair and replication the organism could do and how much it pays it to do in practice, given that it has to get on with the activities of daily living.

Steve, do mutations always occur in reproduction, or can they happen at other times? Well, they happen. I mean, there seemed to be a nice... division between body cell mutations, somatic mutations it's called, and reproductive or germline mutation. But that division is very, very blurred now.

Basically, you know, as is often said, a chicken is only an egg's way of making another egg, and the same is true of us. And the reason why the mutation rate in the germline sperm and egg goes up with age is because of body cell mutation of sperm and egg are being made. There are many cancers

for example, which are due to mutations in body cells. I mean, cancer in some ways is a genetic disease of body cells. But some of them involve inheriting one copy of a particular mutation and then a second copy taking place in your body cells. So really they're very much the same thing. And just to pick up on Steve's point about somatic mutation, which is of course the mutations which aren't inherited, it's an interesting fact that the human immune system actually utilizes actively a mechanism of hypermutation to actually allow the immune response to evolve in time.

So the immune system actually increases the frequency of mutation in the antibody genes and fires loads of mutations into specific hotspot regions in a relatively non-random way, but it's still stochastic or random, but slightly biased to certain positions. And this enables antibodies to bind better to the foreign entities, viruses and bacteria, which are invading the body. And as well as that kind of adaptive variation, during development, you sometimes just see the results of developmental accidents, just mistakes during copying of the DNA.

Perhaps one of the most striking is that occasionally one meets people who have eyes of different colour from each other. And that's as a result of a mutation in the pigment genes during development. You mentioned earlier the use for unraveling evolutionary history, the use of this information through genes. Can you develop that just a little bit more? Yes, that's as a result of these random programs. processes that we've mentioned. So most new mutations are deleterious. That's very well established now. Most of them are copying mistakes that lead to some sort of problem during development or in physiological functioning or in the brain or something. They're deleterious. They actually damage fitness. But there's also a large class of mutations that aren't like that. They're neutral. And part of the reason for that is that a large part of our genetic material is actually junk. It's not doing anything useful at all. It's just there being carried passively along. I'm going to find out that that junk is useful sometime.

Is it like dark matter in the universe, that it's dark because we don't know anything about it? I think Sidney Brenner, a very distinguished Cambridge scientist, actually said there's always something useful in the attic in amongst that junk. Yeah, and in fact, the very recent stuff, as we know, they're turning up stuff in the junk, which turns out to be very important. So junk is a fall into word. It's like gene. We prefer not to use it. But I think some of it, as Linda says, does look like rubbish.

Before I interrupted you and then the other joined in any interruptions, were you about to say something more? Yes, and everything that they've just said is absolutely true. So there's a real health warning on assuming that all of these genetic variants are in fact selectively neutral. They may be controlling the action of genes at a distance, affecting the way the genome's packed in the nucleus, all kinds of things. But leaving those complexities aside, the basic principle here is that if you're dealing with a part of the genome where the variants are selectively neutral, they don't affect the capacity of the bearer to reproduce, then they do have this clock-like property. And you can pick regions of the genome

that are changing in this way at different paces. And the reason that that happens is that we can then move into areas that are subject to some selective constraint. So for instance, the point mutations that Adrian explained to us, they can affect the composition of the protein that that gene is producing or they may not do so, depending where,

exactly along the length of the gene the mutation occurs, but they are subject to some selective constraint, just not anything goes as it does in some parts of the genome. So those kinds of areas evolve more slowly than the strictly neutral ones. So we can use this clock-like property and pick a clock that's ticking at the pace that's useful for the event that we're trying to date. So if we want to go to very deep events, you know, the origin of mammals, for instance, then we're going to need a very slow evolving bit.

If on the other hand we want to know about recent human population history, then we need a bit that's really whistling along, one that really is neutral. So you can pick the gene that's going to solve your problem, essentially. Unusually in these sort of discussions, we're going from front to back. So who first worked out that genes were subject to a mutation, Steve Jones? The guy who invented the word in the biological context, and it's been used in study of language for a long time, simply meaning change, was a Dutch de, then it's called DeVries, Hugo de Vries,

in the early 20th century, and let's remind ourselves that genetics, in effect, only began just over 100 years ago. And one of the first things, when Mendel's laws, the laws of inheritance were rediscovered, everybody rushed out to see if they could prove him wrong, this being the nature of science. And generally, they proved him right.

There were simple particles that were passed unchanged from one generation to the next in all kinds of creatures. This is this Augustinian, the August Monk who worked with pea plants. That's right. But DeVries... In the second half the 19th century

and published in such an obscure journal that nobody read it for a great number of years. Yes, that's right. Hugo DeVries, the Dutch fellow, was doing this with a particular plant called Enothorah, which is a evening primrose, and he thought he found that Mendel was wrong because he'd cross plants together in particular combinations

and find quite unexpected flower colours, particularly, in their offspring. and he said, hang on, there's something different going on here. The gene isn't something a stable particle, it can change. It can change dramatically and really quite quickly. And that really led to a great rethink about particularly the process of evolution, where people began to saying, oh, Darwin was wrong. It's all due to these enormous jumps in mutation from dinosaur to bird in one leap,

that kind of stuff. But actually, the plant he worked on in Othra Lamarckiana, we now know has a very strange system of very, very high mutation rate. So as usual, he became a very... famous by being lucky, he worked on the same thing, on the right thing. And then we enter Thomas Hunt Morgan in departure, the 20th century American

geneticist who brought us the word gene or brought into language and worked on the fruit fly. Yes, who also introduced my favourite organism into genetics. Yes, he's my hero, T.H. Morgan. Still. Yes. Actually, it

was amazing really that they persisted with the flies in that laboratory. He was trying to understand the material basis of heredity and how genes were transmitted between generations. And he had access to Mendel's work under debrises. He knew all about that. So we're talking about the 1920s, 30s in America. But he became very impatient with the kind of formalisms that came from Mendel,

which tended to revolve around identifying variants and counting outputs of crosses and then inventing hypothetical underlying physical structures that might explain them. He wanted to really go to the matter of heredity and identify it and understand how it works. and to do that, he needed an experimental organism and one in which he could artificially produce genetic variants. So initially they tried to induce mutations in the fly with chemicals, with radiation, with temperature and so on. They hammered away for two years and got absolutely nothing.

So it was really quite remarkable that they possessed it. But eventually, they actually got a spontaneous mutation, not one that was a result of their efforts at all. It was a random spontaneous mutation. It was a fly that had a white eye. Sorry, I interrupted you. That's an interesting sort of example of environment Not having any effect at all

And the random thing At the point was he spotted the white-eyed fruit fly It was the case of the prepared mind He knew what he was looking for And normally the flies are red And suddenly this white one appeared And from then I'm just a second We can't stop the story that way

Hanging on to the ending of this He saw the white-eyed fruit fly and then Well the first thing they did was to let it escape So there was a complete pantomime While they were chasing this thing around the lab And eventually they found it on one of the windows And managed to recapture it But then he started doing cross-es

with it. And that produced some very interesting results because he could show that the thing was being inherited in an orderly fashion, but one that depended on the sex of the fly. Actually, the very first mutation they got turned out to be what's called sex-linked. It's on one of the sex-determining

chromosomes. So it was inherited in the classic sex-linked way like colour blindness. It essentially skipped generation and also tended to turn up more often in males than in females. And as a result of that, they were able to start to the inheritance of this mutation

to the inheritance of one of of these physical structures, the chromosome, that they could actually see down the microscope. And that was the beginning of the chromosome theory of heredity. Can I turn to disease now? Steve, do you want to quick... I mean, there's a spin on the famous white eyes, which every geneticist does as a student, is that quite recently it was discovered, actually,

that it's a very strange kind of mutation that's due to the insertion of a bit of foreign DNA into that particular gene, which would be completely alien to Morgan's thinking, but just shows again that what seemed like a rare, unique event intrinsic to the organism itself may actually have a much more complicated molecular cause. Adrian Wilson, as I said at the beginning of the programme, it's been very influential the study of genetics in our understanding of disease.

Do you think we should change the very classified disease because of what's developed in the study of genetics? That's an interesting question, actually. I mean, if you go back to somebody like Parkinson, who, you know, a physician working in Hoxton in the 19th century, who actually demonstrated how the old skill of the physician, which was observation, and by observing patients for protracted periods of time, he was able to realise that this complex set of symptoms

that you see in patients with Parkinson's actually formed a disease entity, and this is based upon, if you like, morphological characteristics, things that he could observe. And of course it's the same in biological classification system. The Linnaean system is based upon morphology. This is, of course, there in the modern world, you could argue quite inappropriate and very, very out of date. Because our modern knowledge of Parkinson's, for example,

says that in fact Parkinson's, in some cases, has a genetic cause, which is very clearly identified. In fact, there are about 12 different mutations, which can create that phenotype. But in many cases, there isn't a simple genetic change, there are complex changes. So what this suggests is that when we treat Parkinson's disease as a disease, we're using one type of therapy,

and we're going to assume that it's going to work for all these different people. But in actual fact, what's clear is that this disease entity, which we call Parkinson's, can genetically be broken down, if you like, into several different disease entities, each of which would probably behave in a quite different way to one medicine. So in actual fact, one can envisage a completely new classification of all human illnesses based upon genetics. Can you develop that, Stephen? Can you tell us how many diseases? I call it by how many that they know of already,

because there's always more to come, isn't there, at science? There's another important word for that a word in genetics, which is O-M-M-M-I-M, which has the rather politically incorrect full name of online Mendelian inheritance in man. And that's a very, very boring database. Anybody out there can access, just type it into a search engine. And that has just a list of all the genetic diseases, some of which are extraordinarily rare.

And about a year ago it passed 10,000. So many of those may be repeats, many of them may not be genetic diseases. But in some senses, all diseases are genetic, all are due to mutations. I tell my undergraduate class to look at the person to the left and they're right, and I say that two out of three of them will die for reasons clearly connected to the genes they carry, to the mutations they carry. But then I'd say, cheer up, if I've been talking to you in Shakespeare's time, two out of three would be dead already because they'd have starved or been died of cholera.

So the genes, the mutations, become much, much more important as we die older and older because they build up with age. Actually, Melvin, it's worth just saying at this point. You know, our discussion is largely focused on mutations in DNA, and that's fair enough because most of them are in DNA, but we should be aware of another type of mutation, which is known as an epimutation. And an epimutation is a mutation in, if you like, the way that genes are chemically modified by the addition of groups called methyl groups. And there are diseases, for example, prior to Willie Syndrome,

just as one example that comes to mind in which patients become morbidly obese and various other problems. But there's no actual change in the DNA with these patients. It's actually a mutation, if you like, an epimutation in the way in which the gene is imprinted, the way in which the DNA is chemically modified, which causes a change in the way the gene is switched on and off. Linda Bartridge, can you ask you to what extent we can see aging as a result of mutation? That's a very interesting issue

and actually it follows on very naturally from the idea of genetic diseases because one of the very interesting albeit tragic classes of human disease are ones that have a delayed age of onset so that's to say an individual can inherit from their parents a mutation which is there present in all their cells

from birth but the effects of that mutation don't become apparent until they're older so very obvious case is Huntington's disease, which is a severe mental brain disorder, average age of onset of symptoms is 35 years old. So it was actually Haldane, who you referred to at the beginning, who pointed out that perhaps mutations like Haldane's, not individually so severe, but cumulatively with the same effect, ones that became apparent only when the individual was older, that they

might explain the aging process. Because as Steve's pointed out, during most of the same. most of human evolutionary history, most people would have been dead by that time, and they'd certainly have completed their family size. So a mutation that has this devastating effect now, probably for much of human history, would have had very little effect on fitness. Briefly, Adrian, last we're going to the end of this programme, do you think that we're going to be in a position to control these mutations much more than we can do now?

Well, you've got to realise that until now, really life and the history of life her life has been characterized by natural processes, natural selection. It's no chance that that word was used. It's clear, though, that we may well be reaching a time where natural changes become consigned, if you like, to history themselves, and that we reach a moment where we actually are able to artificially mutate genes and even to design living things from first principles.

I really think that that's very, very, very possible. And in fact, the whole question of whether or not you can compute an organism from its DNA sequence is an interesting one. And if we were able to, on a computer screen, for example, look at all the possible combinations of DNA sequences, we could probably predict the existence of creatures which have never previously existed. And if we chose to, we may even want to build them.

Do you see that as the future, Steve Jones, finally? Possibly as the distant future, I mean, we can certainly alter the mutation rate. Now, people can give up smoking. That'll drop their somatic mutation rate. They can have children young. That'll drop their germline mutation rate. So, like most things in healthcare, the answer is entirely predictable.

Right. I don't think... It's any more to that? I've got about 20 seconds left. I don't feel like a... What's it called? An auctioneer here. You were too brief there.

All right. Well, thank you very much, to Linda Partridge. Thank you very much, Steve Jones. And to Adrian Wilson. Next week we'll be talking about the Sasanian Empire, which is founded in AD 224. It was a rival to Rome. It traded with China. It was based in Persia.

Thank you very much for listening. Good morning. We hope you've enjoyed this Radio 4 podcast. You can find hundreds of other programmes about history, science and philosophy at BBC.com. com.uk forward slash radio 4.