Genetics

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Melvyn Bragg: ... characteristics were passed on when the next when the next crop of peas were grown. In this slow and systematic way, Gregor Mendel worked out the basic law of hereditary 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 science 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 and science of the gene is Steve Jones, Professor of Genetics at University College London, and author of many books, including "The Language of Genes" and "Almost Like a Whale" "Origin of the Species Updated". Also here is Richard Dawkins, Charles Simone 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 NARC Research Professor at the Galton Laboratory University, College London\b .

Steve Jones let's start with Mendel, why did he choose peas, how did he go about it, and when did he know he'd made some sort of breakthrough?

Steve Jones: Big questions, unfortunately I don't have my slides with me! He chose peas because they differ from each other in striking characters, discrete 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 to be interested in inheritance, in fact if you look at the records in the monastery before Mendel got to work - they were very interested in sheep breeding and they'd measure the thickness of wool and the weight of sheep, but they didn't count them, these were the continuous characters. Mendel's great strength...

Melvyn Bragg: What is counting... ? Can you just... I'm sorry to be so very specific... counting as distinct from measuring?

Steve Jones: 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 fact the most interesting characters are the ones you measure - intelligence, behaviour, that kind of thing. But the simple characters are the one's you count, and that's really what Mendel did, and that was his... really his soul but amazing breakthrough to discover that you could indeed impose very simple arithmetic laws on the way these distinct characters tall and short peas 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 the next. So that two individuals of the same appearance, could have the same 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.

Melvyn Bragg: So I just want to get this absolutely straight for people as it were coming in on the start of this Mendel... I don't mean the start of this programme, the start of this notion. In his monastery garden, has he worked before as a biologist, I mean he 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?

Steve Jones: Well all Nobel prize winners are lucky in hindsight! And the... my great fear as a scientist without question, is not to choose an interesting question to work on, now 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's because people thought the inheritance of characters in peas as uninteresting, because why should there be any rules of inheritance that applied to both peas and to human and to sheep? But of course now we know 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?

Melvyn Bragg: Richard Dawkins, the classical era 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?

Richard Dawkins: Mendel's work was rediscovered in 1900, independently by three people, who themselves were doing work on various different kinds of creature, and they looked up the literature and found Mendel and at that point they realised 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 Steve? William Bateson thought of himself as anti-Darwinian and he actually said quite disparaging things about Darwin, and the early geneticists in the 20th century- the early 20th century, thought they were doing something quite different and something quite un -Darwinian, 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.

Melvyn Bragg: What's the significance of establishing a link between chromosomes and genes, Richard Dawkins?

Richard Dawkins: 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 their 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, the you're statistically likely to inherit another gene. 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, that was a very... it was a very neat example of of in a sense of converging from two different directions on what is true.

Melvyn Bragg: Linda Partridge you're a molecular geneticist, working practically on the genetics 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?

Linda Partridge: That's a very interesting one. Fruit flies were around in laboratories at that time, mainly because they just flew in there, they're 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 West Africa with humans all around the world on fruit. Because what fruit 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 for behavioural things. What fruit flies like is alcohol, they'll approach anything that's fermenting and producing alcohol...

Melvyn Bragg: I'll resist any jokes on that!

Linda Partridge: (Giggles)... 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 adopted as the ideal genetic organism.

Melvyn Bragg: It's almost like a little fairy tale how - as I've read - how Thomas Hunt Morgan discovered that he could use the fruit fly in this way - isn't it?

Linda Partridge: Yes, he was in a laboratory where a number of extremely talented people were working, there were his own two students Bridges and Sturtevant - who actually did a lot of the heavy lifting with drosophila and also Muller, who was doing a lot of mutogenesis, 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.

Melvyn Bragg: Are fruit flies helpful because they breed so quickly?

Linda Partridge: That certainly turned out to be an advantage, yes, they get through...

Melvyn Bragg: So you can go through very many generations very, very quickly?

Linda Partridge: Ten days.

Melvyn Bragg: Really?

Linda Partridge: Yes.

Melvyn Bragg: Speed up the process?

Linda Partridge: Absolutely.

Melvyn Bragg: Fast forward fruit fly.

Linda Partridge: And you can get very large numbers too, 'cause females can produce 500-1000 eggs in a lifetime.

Melvyn Bragg: So what would you say was the significance of Thomas Hunt Morgan's discoveries?

Linda Partridge: He very firmly established the chromosomal basis of inheritance. He showed that by looking at the transmission rules for these different mutations that you could map genes on chromosomes. So you have - to use Richard's analogy to use 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, and the reason for that is that these strings sometimes break, during the formation of the germ cells and join up again, with the corresponding string 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 breakage is 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. \b

Melvyn Bragg: So how did this reflect back into and restir the Darwin pot, Steve Jones?

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. Morgan's great contribution as you've just heard is to give the gene a physical nature, and to emphasise the fact that genes are discrete units, okay - they are some thing which you can see. Darwin who was a great genius, was really unique among scientists I think, in that he was honest, in that in that when he saw a problem, he agonised about it, he didn't brush it under the carpet as we tend to, if there's an insoluble problem, and if you read the Origin, which is fairly heavy going, but is well worth reading, he as a... 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- at a kind of liquid model of inheritance, where inheritance is 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 who's name was Fleaming 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 then it's 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 agonising 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 it 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. (Laughter)

Melvyn Bragg: So digital replaced analogue Richard Dawkins, mosaic replaced blending, can you just develop that a little more?

Richard Dawkins: Yeah... I mean... I always felt about that, that although it's perfectly true that Darwin was greatly discomforted by Fleaming Jenkin's point, actually Fleaming Jenkin's point was against the known facts already, you didn't need Mendel, because if Fleaming Jenkin 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 twentieth 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, and Fisher made the slightly trite point that if you mix male and female you don't get hermaphrodite, you get either male or female which itself is already a model for particulate inheritance.

Melvyn Bragg: Briefly Linda can you give us a description of how a gene does replicate itself?

Linda Partridge: Yes, at the level of the DNA, which will bring us on to Watson and Crick quite shortly...

Melvyn Bragg: Next! (Laughter)

Linda Partridge: ... what happens is that the bases along one strand of the DNA pair up with the base that is complementary to them in what is 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 which 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.

Melvyn Bragg: Excellent that does take us to Crick and Watson. Richard Dawkins you've said that they should... they will come to be revered as greatly as Plato and Aristotle, why...

Richard Dawkins: Did I say that?! (Laughs)

Melvyn Bragg: Yes, you either said it or wrote it, but it's in... you can't get away from it... you could be right, who knows? Those of us alive in 2000 years time... or 2500 years time will be able to check up on it...

Richard Dawkins: Okay I'll defend that!

Melvyn Bragg: 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?

Richard Dawkins: 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 that.. 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 the sort of cutting edge journals of molecular genetics and molecular biology, it'sjust 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, into... onto a computer disk, onto paper, you could store it in a book and then thousands of years later you could take that book and then retype it into an organism so to speak, and cause it to be...

Melvyn Bragg: Turn into an elephant?

Richard Dawkins: ... turned into a... 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.

Melvyn Bragg: How d'you think the genes.. or do they, how d'you think that genes affect behaviour?

Linda Partridge: Presumably by an intermediary process, not directly, but by affecting the way that the nervous system is built, by affecting the way it functions once it's built, by affecting \b the endocrine system, the chemical signals that go round the body, sometimes rather indirectly by affecting the external characteristics of an organism so that others behave differently towards it.

Melvyn Bragg: For example?

Linda Partridge: 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 flies smell interesting or attractive or unattractive, and there are genes that modify those. There is one particular one in drosophila where the males come to smell like females, but they still like females...

Steve Jones: Fruitless it's called

Linda Partridge: ... fruit? Exactly, and what you end up with is daisy...

Melvyn Bragg: What's it called?

Linda Partridge: ... it's called Fruitless... and what you end up with is daisy chains of males chasing each other round the fly bottle because they each think they're courting another female.

Melvyn Bragg: Well, you learn something every day, don't you really? Richard Dawkins you talked... you wrote famously in the Selfish Gene, about "they swarm in huge colonies, they're 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.

Richard Dawkins: Yes. The genes are looking after themselves. Organisms are just one way in which genes look after themselves, but their 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 to replicate 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 route of building a fruit fly or building a human or building an elephant, but hat 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 realised 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 can think of it as the robot, the lumbering robot - carries it's 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 it's fate is bound up with the fate of its own blueprint.

Melvyn Bragg: Steve Jones, what's your comment on that?

Steve Jones: Yes I think that's fair, I mean I think it's a bit of a mistake to think of elephants as metaphors, I mean there are elephants out there... (Linda laughs)

Richard Dawkins: No I never said metaphor, I mean it's a way for genes to replicate themselves.

Steve Jones: That doesn't stop elephants having a lot of charm, personality and things you can study...

Richard Dawkins: Indeed not, some of my best friends are elephants!

Steve Jones: .. 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 of 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, development and intelligence and so on. I think there's still a big gap between the two fields.

Melvyn Bragg: Richard Dawkins, the much heralded Human Genome Project, which began in 1990 formally and is supposed to be completed in a couple of years time, it reported back with a working draft last year, and many scientists seemed rather nonplussed by it. What was your reaction to that report, and how important do you think it is?

Richard Dawkins: 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 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.

Melvyn Bragg: Steve Jones?

Steve Jones: Yes I agree, I mean Darwin really knocked us of our pinnacle as creatures that stood apart for the living world. Mendel and the Human Genome Project has rubbed our faces in the mud. I mean everybody knows that we share about 98% of our DNA sequence with chimpanzees. Some people suggest that chimpanzees are therefore 98% human. I'd like to point out under those circumstances that we share about half our DNA sequence with bananas!

So there... we are in the sense of the tree of life, scarcely to be distinguished from common fruits and vegetables, you know, you can go down 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", and 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. They're 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, but in the interesting fashion, we're completely separate from it.

Melvyn Bragg: But it is extraordinary, Linda, that all life on planet Earth, plants, bacteria, animals, humans, share the same genetic code 64/21, now can you - I'm afraid briefly - explain what that means and why it is so extraordinary that all plant... all life should share that?

Linda Partridge: 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 aci, and if an organism has a mutant where there's a mismatch, it's going to insert the wrong amino acid in it's proteins, so it's a very difficult thing to change, it's often called a frozen accident.

Melvyn Bragg: But what we're ... are we saying Richard Dawkins that this means that an extraordinary coincidence.. what... you've said that means all Earthly beings are certainly descended from the same ancestor.

Richard Dawkins: Yes, yes.

Melvyn Bragg: So everything that moves lives breathes, exists around the place comes from the same whatever it was?

Richard Dawkins: 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, it's 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 down the centuries.

Melvyn Bragg: But at the moment we don't think that, at the moment we think there's one...

Richard Dawkins: No... that's right.

Melvyn Bragg: .. overwhelmingly prevailing genetic code, that goes through the lot...

Richard Dawkins: Yes.

Melvyn Bragg: ... which suggests... which actually must logically point to a common...

Richard Dawkins: Absolutely, it's not just overwhelming, it's universal.

Melvyn Bragg: Yes, so what's our common ancestor, something deep below the Pacific Ocean? Steve.

Steve Jones: Well Darwin talked about it, 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 4000

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