In Our Time - Genetics

Episode Date: December 13, 2001

Melvyn Bragg looks at the development of the science of genetics. In the 1850s and 60s, in a monastery garden in Burno in Moravia, a Franciscan monk was cultivating peas. He began separating the wrinkly peas from the shiny peas and studying which characteristics were passed on when the next crop of peas were grown. In this slow and systematic way Gregor Mendel worked out the basic law of heredity and stumbled upon what was later to be described as the fundamental unit of life itself…the gene.But Mendel’s work was ignored when he published his findings in 1865, and it was not until the 20th century that he was rediscovered and the science of genetics was born. What effect did the discovery of the gene have on Darwin’s ideas? How do our genes work upon us, and how can we manipulate them?With Steve Jones, Professor of Genetics and Head of the Galton Laboratory at University College London, Richard Dawkins, Charles Simonyi Professor of the Public Understanding of Science at Oxford University and the genetic scientist Linda Partridge, NERC Research Professor at the Galton Laboratory, University College London.

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or wherever you get your pods. 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 four. I hope you enjoy the program. Hello, in the 1850s and 60s in a monastery garden in Berno in Moravia, a Franciscan monk was cultivating peas. He began separating the yellow from the green peas,

the wrinkly peas from the shiny peas, and studied which characteristics were passed on when the next crop of peas were grown. In this slow and systematic way, Gregor Mendel worked out the basic law of heredity and stumbled upon what was later to be described as the fundamental unit of life itself, the gene. Mendel's work was ignored when he published his findings in 1865, and it wasn't until the 20th century that he was rediscovered and the signs of genetics was born. What effect did the discovery of the gene have, retrospectively, on Darwin's ideas?

How do our genes work upon us and how can we manipulate them? Much has been said on the morality of genetics, but here to discuss the history and science of the gene is Steve Jones, Professor of Genetics at University College London, an author of many books, including the language of genes and almost like a whale, origin of the species updated. Also here's Richard Dawkins, Charles Simoni Professor of the Public Understanding of Science at Oxford University, who's the author of books such as The Selfish Gene and Unweaving the Rainbow, and the genetic scientist Linda Partridge, NERC Research Professor at the Government. Galton Laboratory University College London. Steve Jones, let's start with Mendel.

Why did he choose peas? How did he go about it? And how did he... When did he know he'd made some sort of breakthrough? Enough to publish what you did. Big questions. Unfortunately, I don't have my slides with me. He chose peas because they differ from each other

in striking characters, discreet and different characters. Mendel's great strength was that he was really the first biologist to count anything. He certainly wasn't the first biologist. just interested in inheritance. In fact, if you look at the records of the monastery, before

Mendel got to work, they were very interested in sheep breeding, and they measured the thickness of wall and the weight of sheep, but they didn't count them. These were the continuous characters. Mendel's great strength was a take... Can you just read, I'm sorry to be so very specific, counting as distinct from measuring? Well, you can count, for example,

round or wrinkled peas. You can measure the amount of carbohydrate in a pea. It's continuous. You can measure human height, but you count human blood groups. Now, in the most interesting characters are the ones you measure, intelligence, behavior, that kind of thing, but the simple characters are the ones you count.

And that's what Mendel did, and that was really his soul, but amazing breakthrough, to discover that you could indeed impose very simple arithmetic laws on the way that these distinct characters, tall and short piece, say, passed down generations. And from that, he inferred that the actual appearance of the individual was actually separate from something which was within it and passed unchanged from one generation.

to a next. So the two individuals of the same appearance could have a different genetic constitution, as we would say. And that really was the foundation of genetics. And genetics is an astonishing science because it's the only science that traces itself only to one person, which is Mendel. All other sciences, chemistry, evolution, physics can trace themselves back through hundreds of years and thousands of people, but not genetics. It was one man only. So I just want to get this absolutely straight for people as who were coming in on the start of this man, I don't mean the start of this program, the start of this notion of, he He's in his monastery garden.

Has he worked before as a biology? I mean, obviously has. He's done all sorts of other things. This monastery is interested in biology anyway and zoology. And so does he choose the peas by accident? I think it was you who said he was very lucky to choose peas, or was he very clever to choose peas? Well, all Nobel Prize winners are lucky in hindsight.

And my great failure as a scientist without question is not to choose an interesting question to work on. It's never worried me. But Mendel, very fortunately for him, with the benefit of hindsight, turned to an extraordinarily interesting question, the inheritance of characters in peas. Oddly enough, as you said, his work was largely ignored. But that was because people thought the inheritance of characters in peas was interesting,

because why should there be any rules of inheritance that apply both to peas and to humans and to sheep? But of course, now we know where they are. In the 19th century, nobody had any idea there was a fundamental rule. He was just a pea breeder who cares about peas. Richard Dawkins, clear of genetics is actually the early part of the 20th century, which shows what a very modern and young branch of knowledge. It is in that sense. Can you tell us something that was

going on in the early 1900s? Who was involved and what they were pushing forward with? Mendel's work was rediscovered in 1900 independently by three people who were themselves doing work on various different kinds of creature. And they looked up the literature and found Mendel. And at that point, they realized that there was something important. going on. It was a strange business in the early part of the 20th century because the early Mendelians thought of themselves as being anti-Darwinian in a sense. I mean, William Bateson, for example, who was one of the, he wasn't one of the three who rediscovered it, but he was very quick on the scene after that, and I think he actually invented the word, Gene, didn't he

William Bateson thought of himself as anti-Darwinian, and he actually said quite disparaging things about Darwin, and the early geneticists in the early 20th century thought they were doing something quite different and something quite undarwinian, and they thought that mutation, the random changes in genes, which are, of course, essential for evolution to happen, some of them thought that that was all that happened,

which is a pretty bizarre idea when you come to think of it, because it doesn't explain anything, really. What's the significance of establishing a link between chromosomes and genes, which you know of them? Chromosomes are the long threads, which are a discrete number of threads along which genes are strung, and people had seen chromosomes under the microscope

and seen how they behave. But at the same time, the geneticists such as Morgan and his disciples were working out that, Mendel's original law of independent assortment that all genes segregate independently wasn't actually right and that some genes do segregate together. That means to say that if you inherit such and such a gene from your parent, then you're statistically likely to inherit another gene. And what that means in terms of chromosomes is that those genes are on the same chromosome.

So whereas Mendel thought that every gene segregates independently down the generations and you can treat them as quite independent sort of balls in a bag, the chromosome theory suggested that they're not balls in a bag, they're laid out in strings. And therefore, although in the long run, because chromosomes cross over and exchange material, they sort of behave like balls in a bag, in the short term they don't, they're linked. and the statistical evidence of linkage in pedigrees correlated with the microscopic evidence of chromosomes. It's a very neat example of, in a sense,

converging from two different directions on what is true. Linda Partridge, you're a molecular geneticist working practically on the geneticist of fruit flies, but one of the earliest was, keeping to the history, was Thomas Hunt Morgan. He used fruit flies. Why did he choose fruit flies? That's a very interesting one. Fruit flies were around in laboratories at that time, mainly because they just flew in there. Their commensal, they live with humans and travel around the world with them. So the one that's commonly used in laboratories has dispersed from its origin in probably West Africa with humans

all around the world on fruit, because what fruit flies flies really? like is rotting fruit and also garbage. They hang around dustbins. So they very readily flew into and adapted to lab conditions. They're easy to culture. And they were kept because they were ideal for student projects. So a number of laboratories kept them. And initially, they were used mainly for behavioral things. What fruit flies like is alcohol. They'll approach anything that's fermenting and producing alcohol. I would resist any jokes on this. They also are negatively geotactic, that is they move away from gravity,

and they'll move towards light. So they were used a lot for trying to understand the neural basis of these various behavioural responses. And it was really rather happenstance that they were eventually adopted as the ideal genetic organism. It's almost like a little fairy tale, as I've read,

how Thomas Hunt Morgan discovered that he could use the fruit fly in this way, isn't it? Yes, he was. in a laboratory where a number of extremely talented people were working. There were his own two students, Bridges and Stertivant, who actually did a lot of the heavy lifting with Drosophila, and also Mullah, who was doing a lot of mutagenesis, creating new mutations with x-rays,

including with fruit flies. And as a result, a lot of new mutations of the Mendelian type that Steve was talking about, discrete phenotypes, bodily appearance, eye colour, changes to the bristles, changes to the shape of the wing, started to crop up. And they formed absolutely ideal material for taking forward the Mendelian agenda, looking at how genes travel around together between generations,

the whole issue of linkage, and how that relates to chromosomes. A fruit fly is helpful because they breed so quickly, and there? That certainly turned out to be an advantage. Yes, they get through it. So you can go through many, many generations very, very quickly. Ten days. Really? Yes.

Speed up the process. Absolutely. Fast forward fruit fly. You can get very large numbers too, because females can produce 500,000 eggs in a lifetime. So what would you say was the significance of Thomas Hunt Morgan's discoveries? He very firmly established the chromosomal basis of inheritance. He showed that by looking at the transmission rules for these different mutations, that you can map genes on chromosomes.

So you have, to use Richard's analogy, these beads on a string, and the closer together they are on a string. the more likely they are to be co-inherited by offspring. The reason for that is that these strings sometimes break during the formation of the germ cells and join up again with the corresponding strings sitting next to them. And for that reason, these association rules produced by being on the same chromosome can be broken at a certain rate.

And the further apart the genes are, the more likely that breakages to occur between them. And you can use that to actually determine the order of the genes along the chromosome. And that was really the major contribution of the Morgan group. So how did this reflect back into and re-stir the Darwin pot, Steve Jones? Well, I think Mendel, for example, had no interest at all in what the physical nature of the gene was. Perhaps to him it didn't even have a physical nature. And Morgan's great contribution, I just heard, is to give the gene a physical nature.

And to emphasize the fact that genes are discrete units. They are something which you can see. Now Darwin, who was a great genius, was really almost unique among scientists, I think, in that he was honest, in that when he saw a problem, he agonized about it, he didn't brush it under the carpet as we tend to. It's an insolible problem. And if you read the origin, which is fairly heavy going,

but it's well worth reading. He wrote it several times. There are six editions. And the last edition is much less convincing than the first one because he'd become aware of a completely fatal flaw in his argument because Darwin, insofar as he thought of inheritance at all, had a kind of liquid model of inheritance, where inheritance was a sort of cocktail.

You mixed your gin and your martini, and you had a mixture there which is passed down from each parent. And a Scottish engineer, whose name was Fleming Jenkin, and I have a sort of vivid image of him as a flinty-faced Scot, living in Edinburgh, wrote him a very, very nasty letter, saying, well, this is fine. But what happens if you've got some advantageous attribute that appears in one individual, and he or she mates with another one, and it's then diluted away? How are you going to get it back again?

It's like dropping a drop of ink into a gallon of water. It disappears. And immediately Darwin, in all his honesty, saw this as a tremendous problem for him. And he spent years agonizing over it and didn't solve it. And, of course, the irony is that there was no problem. The gene wasn't a liquid. It was a particle. and he could pass down the generations for a long time

and then reappear unchanged. So really Mendel and Darwin made the perfect couple. The sad thing is, of course, like most perfect couples, they never met. So with digital replaced analogue Richard Dawkins' mosaic, replace blending. Can you just develop that a little bit? I mean, I've always felt about that, that although it's perfectly true that Darwin was greatly discomfited by Fleming Jenkins' point, Actually, Fleming Jenkins' point was against the known facts already.

You didn't need Mendel because if Fleming Jenkins had been right, as every generation passed, the variation should have been halved. And it manifestly wasn't. I mean, we're not four times more alike than our grandparents' generations are. Variation is maintained. Now, it was indeed the marriage of Darwin and Mendel that solved the problem in the 20th century. But as Fisher, who was, I suppose the person mainly responsible for this marriage of Darwin and Mendel, pointed out, anybody in the 19th century should really have been able to see that.

Fisher made the slightly trite point that when you mix male and female, you don't get hermaphrodite. You get either male or female, which itself is already a model for particulate and inheritance. Briefly, Lennie, can you give us an explanation of how, my gene does replicate itself. Yes, at the level of the DNA, which will bring us on, I guess, to Watson and Crick quite shortly. Next. What happens is that the bases along one strand of the DNA

pair up with the base that is complementary to them in what's going to be the new strand. So they essentially code for their reciprocal on the new strand of DNA which they're making. And so you end up with a new strand of DNA that is essentially in chemical terms a mirror image of the one that acted as the template for it. And equally in the original DNA molecule,

the mirror image that was present because there are two strands or two molecules of DNA paired up with each other in each chromosome, the mirror image gives rise to the positive image of the other strand. So you end up with two new replicate DNA molecules, each with two strands. Excellent. That does take us to Cricken Watson. Richard Dawkins, you've said that we will come to be revered as greatly as Plato and Aristotle.

I said that, yes, yes. You either said it or wrote it, but it's in, yes. You can't get away. You could be right. You know, who knows, those of us alive in 2,000 years time, or 2,500 years' time will be able to check up. Oh, okay, I'll defend that. Let's put that to one side. Why do you think it was so cataclysmic the Crick and Watson breakthrough, the discovery of the DNA structure?

It's totally revolutionised the way we see genetics, indeed molecular biology generally, it's become digital. In a way, it was Mendel who made it sort of digital, because all the stuff we were talking about earlier about particulate inheritance as opposed to liquid inheritance is a kind of digitalness. What Watson and Crick showed is that it's digital to the core. And now if you look at a sort of cutting-edge journals of molecular genetics and molecular biology,

it's just like a journal of computer science. And you can copy and paste, you splice, you invert, you do anything that you could do to a computer tape. You can do to a DNA molecule. And people can do that. It means that just as digital data can be translated from one computer medium to another, You can move it from your hard disk to a magnetic tape. You can print it out on paper. You can recite it verbally.

And any of these forms is literally mutually interchangeable, and that's true of genes as well. You could type out the genome of an organism, literally type it with your fingers, onto a computer disk, onto paper. You could store it in a book, and then thousands of years later, you could take it. take that book and then re-type it into an organism, so to speak, and cause it to be turned into an elephant? Well, that, I mean, my guess is that future technology will make that possible, if not an elephant, at least to reconstitute the genome of the organism. That would have been inconceivable to anybody before Watson and Crick.

They would have thought of genes as having some vague chemical nature, probably pretty mysterious, probably complicated interactions, between chemicals, the way we still think of embryology today. The idea that you could actually store the genome of an organism in a book and then use it again is totally revolutionary. How do you think the genes, or do there, how do you think the genes affect behaviour? Presumably, by an intermediary process, not directly, but by affecting the way that the nervous system is built,

by affecting the way that it functions once it's built, by affecting the endocrine system, the chemical signals that go around the body, sometimes rather indirectly by affecting the external characteristics of an organism so that others behave differently towards it. For example. Well, there's a nice one in fruit flies where there are a number of genes that affect the composition of the chemicals that sit on the cuticle of the fly. And these are very important for communication with other flies.

They make the fly smell interesting or attractive or unattractive. and there are genes that modify those. There's one particular one in Drosophila where the males come to smell like females, but they still like females. So what you end up with, fruit, exactly. And what you end up with is daisy, it's called fruitless. And what you end up with is daisy chains of males

chasing each other around the fly bottle because they each think they're courting another female. Well, you learn something every day, don't you're in? Richard Dawkins, you talked in, you wrote famously in the selfish, gene about they swarm in huge colonies there in you and me. Their preservation is the ultimate rationale of our existence. They go by the name of genes and we are their survival machines. That seems to imply that genes have their own purpose and motivation.

Yes, the genes are looking after themselves. Organisms are just one way in which genes look after themselves, but there are more direct ways. And so if a piece of coded information, which is all that genes are, self-replicating information, can find a nice easy way of replicating itself by just simply doing that, it will do it. A few of them have found it necessary to replicate themselves by the rather roundabout root

of building a fruit fly or building a human or building an elephant. But that is just a way of genes replicating themselves. So you can see an elephant or a fruit fly as a machine, a very complicated machine, built by a cooperative of genes to replicate themselves. plus all the other genes in them which are just replicating themselves parasitically. Given that individual organisms are working for something

and Darwin realized it wasn't just survival, it's reproduction and sexual attractiveness and things. But why is that important? It's not for preserving the species, which is the euphemism often made. What it is is preserving the digital information, the genes, which the individual organisms carry around with themselves. In a way you could think of it as the robot, the lumbering robot, carries its own blueprint around with it, and therefore the fate of the blueprint is tied up with the fate of the organism itself. And once you've got that, then you've got a recipe for gradual improvement of the robot, of the machine, of the body,

because its fate is bound up with the fate of its own blueprint. Steve Jones, what's your comment on that? Yes, I think that's fair. I mean, I think it's a bit of a mistake to think of elephants as men. I mean, there are elephants out there. No, I never said metaphor. I mean, it's a way for genes to replicate themselves. That doesn't stop elephants having a lot of charm, personality, and things you can study.

So, I mean, I think it's a mistake to think... Some of my best friends are elephants. Many biologists suffer from... Well, we all have physics envy, needless to say, because we're not physicists. But those of us who aren't, like Linda, molecular biologists, we have molecule envy, because we don't study DNA. But there's an awful lot out there, which, of course, isn't straight in the molecules. and what's interesting and ironic is that many people who are molecular biologists actually think they ought to be studying complicated things like behaviour and development

and intelligence and so on. I think there's still a big gap between the two fields. Richard Dawkins, the much-herly human genome project, which began in 1990 formally, and supposed to be completed in a couple of years' time, it reported back with a working draft last year, and many scientists seemed rather non-plussed by it. What was your reaction to that report, and how important do you think it is? The number of genes reported was less than had been estimated before. And this was heralded as though it was a major surprise, as though it had some kind of immediate significance for how we look at ourselves.

It was even suggested that because the number of genes was about half what had previously been thought, therefore genes can't be important after all, and environment must be important instead, which is a complete misunderstanding of the way things were. work. I think the human genome project is an immensely important piece of human enterprise. I link it with the space race, which is another hugely expensive. Some would say boondoggle. I admire the human race for undertaking these great projects. I'm very glad it's been done. Yes, I agree. And I think, I mean, Darwin really knocked us off our pinnacle as creatures that sort of part from the living world. Mendel and the Human Genome Project has rubbed our faces in the must. I mean, everybody knows that we share about 98% of our DNA sequence with chimpanzees.

Some people suggest that chimpanzees, therefore, are 98% human. I like to point out under those circumstances that we share about half our DNA sequence with bananas. So we are, in the sense of the tree of life, really scarcely to be distinguished from common fruits and vegetables. You know, you can go out to bacteria, which are vastly different from us. But there is another way of looking at that, which I think geneticists ought to do more often, is to say, okay, well, we're 98% similar to chimpanzees in DNA, but we're not 98% chimpanzee.

We're uniquely human. In some ways, that takes us back to a pre-Darwinian time because all the stuff that we're interested in, general things like consciousness and happiness and so on, really may not be particularly coded into DNA. There are things which only we can do as far as we're aware. I don't think a banana's got half as much consciousness as me because it's got half my genes.

So perhaps in some ways there's a certain hope for humanism in this discovery that we are in the boring fashion, part of the living world, and in the interesting fashion we're completely separate from it. But it is extraordinary, Linda, that all life on planet Earth, plants, bacteria, animals, human, show the same genetic code 6421. Now, can you, I'm afraid, briefly, explain what that means and why it is so extraordinary that all life should show that? The way that the thing works is that a particular sequence of bases in the nucleic acid, the DNA, the hereditary material, a triplet codes for each amino acid that is inserted into the protein that's made by that gene.

And there's a set of rules for which triplet determines which amino acid. And if an organism has a mutant where there's a mismatch, it's going to insert the wrong amino acid in its proteins. So it's a very difficult thing to change. It's often called a frozen accident. Are we saying, Richard Dawkins, that this means that extraordinary coincidence. You've said that means all earthly beings are certainly descended from the same ancestors. So everything that moves, lives, breath, exists around the place, comes from the same whatever it was.

Yeah, everything that's been looked at has essentially the same genetic code. The differences Linda talked about are very minor. The frozen accident point is it's the same. not just that it's a mutation. We all have mutations all the time, but a change in the rule book means that a mutation would simply flood the whole genome with nonsense instantly. And so that's why it couldn't change once it had happened. It's theoretically possible that there could be two quite different genetic codes. I mean, life could be divided into completely two camps, life A and life B, which have completely different genetic codes. And that would indicate two

separate origins of life which have gone on evolving ever since. But at the moment we don't think that. At the moment we think there's one overwhelming prevailing genetic code that goes to the lot which suggests which actually must logically point to a commoner... Absolutely. It's not just overwhelming. It's universal. Yes. So what's that common ancestor? Something deep below the Pacific Ocean?

Well, Darwin talked about... Darwin got more or less everything right and he talked about life starting in a small, warm pond somewhere. And one's best guess is that's what happened. Now we're talking more than 4,000 million years ago here, around 4,000 million years ago. So it's guesswork. There have been various attempts to reconstitute of life. What you're going to say it's still going on? There are still small, warm ones.

Probably not. They're eaten by bacteria if there were any. Yes, probably not, because the problem, life is of its nature very unpleasant. Once it gets going, it doesn't like any competition. Especially rubbish ancestors. It eats its ancestors rather than worships them. That's right. So I think it only, it may have started several times, quite possibly, but the system natural selection worked with great viciousness from day one, and only one version succeeded.

And it's very hard to see where you would squeeze in a new life now. Where would it go? How could it get started? How could it compete with all the amazing life that's here already? So I think we stick to the warm pond. We don't know where it is. It is conceivable, as many people suggest, that it's down in the deep ocean somewhere where you do have a big chemical reactor. But that's just another way of saying we don't know much about the deep ocean. Well, thank you very much indeed. I really enjoyed that. Steve Jones, Richard Dawkins, and departures, thank you very much indeed. And next week we're going to be talking about ancient Rome.

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