How bacteria share genes: ‘Streptococuus’ and ‘Neisseria’

(video 70)
I think of myself as a bird man or a fruit fly man, I don't know anything about bacteria, I
never did a course in... in bacteriology or microbiology in my life. But it so happened that,
almost 10 years ago now, my wife was working in a lab next door to a group of people who
were working on antibiotic resistance in bacteria. And they, I think, initially thought it was a
problem in protein chemistry, what is it that was changed about the enzymes that made
them resistant to penicillin? But they increasingly, I think, realised that they were working
on a problem which had to do with evolution, and very rapid evolution. And Sheila
suggested to them that they might actually not be wasting their time if they came to talk to
me about it. And it was great for me, because for the last five years I spent most of my
practical working time actually thinking about just this problem. And, you know, I get my first
hands on the data and I'm able to think about it. And it is actually... rather, it's almost eerie,
actually, the way that penicillin resistance has spread round the world in bacteria, in 50
years, since the first serious clinical use of penicillin. And now that we can actually
sequence genes, and, sort of, trace them, we can actually give a history of it in some
cases. Bacteriologists have the nice habit, when there's an epidemic of something, they
isolate the bacteria and they put some of them in the deep freeze, so that it's as if all your
fossils are in the freezer and when you want to know what their genes are you just pull
them out and sequence them. It'd be lovely if you could do it with dinosaurs, but you can't.
But here we've got an evolution... a bit of evolutionary history where we can actually go to
the freezer and take out the ancestors and have a look. And in streptococcus, which was
the first bacteria which they really worked on, it's actually a very sad story, that the first
genes, the first bacteria resistant to penicillin, were found in New Guinea and in the
northern part of Australia, but particularly New Guinea, in the years immediately after the
war. And what happened was that foreign troops, both Australian troops and Japanese
troops had been in New Zealand... in New Guinea and had infected the natives with
respiratory diseases caused by streptococcus, to which they were totally unresistant and
were really suffering seriously from respiratory diseases. And it's almost fair to say that
New Guinea was sprayed with penicillin... I mean, it was used in a sort of mass, uncritical
way. And it, in the short run, was effective - it did indeed cure the diseases, which is good.
But the first resistant streptococci emerged during that period. And they did so in an
interesting way. They did it by sex, and we can do that by sequencing the genes and
looking at the genes responsible. And it turns out that the so-called Penicillin Binding
Protein Gene, which is the main one that changed, has received a great insert from
somewhere, by which I mean, most of the gene in the resistant and the sensitives are
identical, but a piece of some hundreds of nucleotides in the middle of the resistant strains
is quite different from the sensitive ones. And you can say, that bit's come from
somewhere. In streptococcus, we still don't know where it came from. Though, in the
second bug we looked at, which is neisseria, which is a cause of meningitis and
gonorrhoea, we do know where the gene came from and we know where the insert came
from - it's exactly the same story, a piece has come in, and we can identify the source.

[RD] From a different kind of bacteria?

From a different kind of bacteria. In the neisseria case, it came from perfectly harmless
relatives of neisseria, they're also neisseria but they're not causing meningitis or
gonorrhoea or anything like that. And I wouldn't be a bit surprised if two or three of us in the
room right now had it in our throats. They're quite harmless commensals. And they just
happened, by chance, to be resistant to penicillin.
Penicillin
(video 71)
Penicillin kills bacteria by binding to some enzymes called, rather curiously, penicillin-
binding proteins. When I first heard of them I thought their function was to bind penicillin, it's
nothing of the sort. Their function is to make the cell wall, and the penicillin comes in and
binds to them and prevents them making the cell wall and the bacterium dies. Now, we find
that some of these commensal bacteria are naturally resistant to penicillin. That means to
say, if you take an isolate out of the freezer, which was put there before the clinical use of
penicillin, back in the 1940s or something, they're already resistant to a drug they've never
met, and I think never could have met it. I mean, there's plenty of penicillin being produced
in the soil by soil... fungi, and so if I found a soil bacterium which was resistant to penicillin,
it would make sense as having happened by natural selection. But it's very hard to explain
why something in our throats which could never have met penicillin, I think, should have
this resistance. I think it's just a matter of chance as to whether the penicillin could or
couldn't bind in an appropriate way to the enzyme. On the other hand, once a piece of that
gene was transferred into a... the bacteria in our throats, and penicillin was being used, the
selection favouring it would be enormously powerful, of course.

[RD] But was that gene doing anything in the original ones who just were spontaneously
resistant?

It was certainly making cell walls, but I think the fact that it was spontaneously resistant was
just an accident, that's my guess. It's hard to be sure. And the alternative is that... that it
evolved by natural selection in soil bacteria, and then, by some accidental process, it's got
transferred into the throat.

How bacteria transfer genetic material

(video 72)

Bacterial cells don't fuse, I mean, they don't go into sex as we do, but there are a variety of
ways in which genetic material from one bacterium can be transferred to another. Either
quite small pieces, of a few hundreds or a few thousand nucleotides, up to a whole group of
genes going across. And some of these processes are rather common, some only happen
rather rarely. But the general notion that genes are moving about in bacteria, even across
quite wide taxonomic boundaries, they don't even have to be closely related bacteria for
this to happen always. The bacteria... I picture another analogy, I picture a bacterium like E.
coli, a little like a football team, every now and then they need a new goalkeeper or a new
striker or something, and they can sort of buy one in by these various processes of
horizontal transfer.

[RD] Not even from other E. coli, but from quite different bacteria?

Maybe from other E. coli, but sometimes from quite different bacteria.
The process of transfer in bacteria (73)
I think it's important to distinguish two very different processes. The one that I and my
colleagues have worked on mainly is a process called transformation, which only goes on
in some kinds of bacteria. It does go on in both neisseria and streptococcus, which are the
ones we're working with. This really does look like a highly evolved process for transferring
bits of genes between closely related bacteria. You have really to be a pretty close relative
before you can do it, and it's very common. Gonococcus, the organism that causes
gonorrhoea, was shown by a young colleague of mine, Maria O'Rourke, to be essentially
random mating. I mean, the amount of frequency of exchange of bits of DNA between
gonococci is so frequent that their genes are in what we call linkage equilibrium, it's
complete random assortment from what genes you have at different loci. It says something
about not only their sexual habits but ours. Of course, you'll appreciate that recombination
only matters if you've got gonococcus from two different sources, otherwise it's just having
sex with yourself, and that doesn't have any...

[RD] So they constitute what you might call a gene pool, in a real sense?

That's right, that really do. But that's one kind of recombination. It's one I'm very interested
in, because I'm interested in how did it evolve and so on. The other is a much more
accidental thing. What happens is that there are these what are called bacteriophages,
they're sort of viruses that live inside, say E. coli, as a disease. And they may destroy the E.
coli. And when they destroy the E. coli they make a new protein coat, and they package
their DNA in the protein coat and then they get into another bacterium. Occasionally they
make a mistake, and instead of packaging their own DNA, they package E. coli DNA, and if
that happens, then they carry E. coli DNA into whatever the next cell they attack is. And this
is a much more accidental procedure, it's much less common. It transfers great big hunks
of DNA sometimes. And the... the donor and the recipient don't even have to be particularly
closely related for it to work. And both these processes are going on, and other ones as
well, it's all very complicated.

[RD] So could you almost say that the chunks of DNA that are available to all the bacteria
in the world constitute a kind of giant gene pool that they're constantly swapping in and out
of combinations with each other?

Almost you can. And this was sort of the football team analogy, the idea of E. coli is that it
just takes in DNA somewhere when it needs it. And it can buy it from a team in Germany if
it wants to, you know, it doesn't have to stick to another English team. Indeed, this led
some people... there's a... I think he's a Belgian microbiologist called Sonea to say that we
really ought to think of the bacterial world as a sort of super-organism, and what was
evolving is not the individual bacterial species but the organism as a whole. I have to say, I
think this is complete nonsense, because it's, you know, evolution by natural selection
requires that you have a population of things competing with one another, and you can't
talk about natural selection operating on a single whole. But nevertheless, he was on to a
point that there is this whole field of creatures which are exchanging genetic material.
Operons: JG Roth and JR Lawrence. Jacob and Monod (74)

What we ought to be thinking about is not the individual bacterium as the unit of evolution,
but these bits of DNA as the units of evolution. It's an idea that will be familiar to you, of
course. And, let me give you one example of it, it's not my idea at all, it's suggested by two Comentario [RPM1]: Refering to
Canadian microbiologists, [JG] Lawrence and [JR] Roth. I think it's a fascinating notion. R.Dawkins (the interviewer)
There are, in bacteria, groups of genes called operons. The classic one is the so-called lac
operon in E. coli, it's the first one to be discovered. It's a group of genes, which if you've got
them, they're all end-to-end on the chromosome, and if you switch them on, they enable the
cell to digest and cope with lactose. And lactose is a sugar which E. coli doesn't often meet,
but if it does, it can say “Gosh, I must do something” and it can switch on these genes and
start digesting lactose. And it was the discovery of this group of genes, and in particular the
discovery of how the presence of the lactose switched the gene on, which was done by the
group at the Pasteur, particularly Jacques Monod and François Jacob, which really was the Comentario [RPM2]: France?
beginning of our understanding of how genes are regulated. I mean, for me, after the
Watson and Crick paper, the Jacob - Monod work was the most important thing that's
happened in biology in my lifetime. But nevertheless, there's a puzzle. You've got this
group of genes, and there are many operons in E. coli and every bacterium has these
operons, groups of link genes with a switch or switches at the beginning for switching them
on, when you need them. Why are they linked? You see, the thing would work perfectly
well if the 10 genes, or whatever it is, of an operon, were spotted all around the
chromosome, each with its little switch, and when you want them, you switch them all on,
and they can all have the same switch and switch on. They don't have to be together.
Monod would have replied, 'Well, it's easier to regulate them as a single switch,' and that's
a perfectly plausible explanation. Maybe it's just they are together because it's convenient
to switch them all on at once. What Roth and Lawrence point out is that actually being
together has another advantage, it means you can be transferred from one cell to another
together, and they want to suggest that these operons are little selfish... not genes, but
selfish genetic elements. They've evolved under selection acting on them, because as a
group, they can transfer. Now, this is interesting, because if it's true, there are certain
implications. You wouldn't expect to find genes that you need all the time to be in operons,
because you'd have them, you wouldn't need to acquire them from somewhere, they
wouldn't need to move around. The genes you'd expect to find in operons would be the
genes which are only occasionally needed, only in special environments. And then, if you
can work it out, there is selection in favour of tight linkage. And what Roth and Lawrence
show is that, by and large, that prediction is born out, that genes like the lac operon, for
lactose, which are... for an environment which is only occasionally needed, are in operons
linked together, genes for DNA replication are not. You need to replicate your DNA all the
time, and they're spotted all around the chromosome, switched on together, but they're not
linked. And there are other reasons for thinking that maybe this sort of gene-centred view of
bacterial evolution may be the right way of looking at it. The one I'm particularly interested
in, and I want to work on it with a young friend in Paris, is the possibility that the genes
responsible for transformation, this process of sex that I was describing earlier on, may be
the same, that sexual transfer in the bacteria may be being carried out by groups of genes
which are really doing it for their own good, because they want to jump, you know. They're
bored with sitting in the same cell, they'd like to replicate, like getting into new cells. I don't
know whether this'll turn out to be right.
Adaptation at the organism level (75)
I want to... really to think about adaptation at the organism level, as I'm sure you do,
reading your books. I mean you want to understand why an albatross flies the way it does.
Let's face it, you talk about the albatross, you don't talk about the genes of the albatross.
And the reason you can get away with this, is... I think it's your analogy, the men in the
boat; I mean, if you really can't jump from boat to boat too easily, there's nothing for it but to
keep time with the other seven guys and row as fast as you can. And I think that most of
the time in eukaryotes, genes have to rub shoulders, they have to be good mixers and so
on. And I guess the same is true, to some extent, in prokaryotes, but I am increasingly
struck by the frequency with which genes jump across big distances in prokaryotes and find
themselves in quite unfamiliar backgrounds. And I think if we come back and look at
bacterial population genetics, in 10 years time, it's going to be a very gene-centred science.

Watson and Crick transformed biology (76)

Watson and Crick just transformed the way we see biology. They made sense of why
Weismann was right and not Lamarck. I think before Watson and Crick, the world just was
very puzzling. How could genes be doing what we claimed they were doing? The whole
thing was mysterious. But certainly, the universality of the genetic material is something
that came as a shock to us, I think.
[RD] Once again, Medawar said, it is simply not worth bothering to argue with someone so
stupid as not to see that Watson and Crick was the greatest discovery. Do you think he
goes too far there?

No, no. I can imagine Medawar arguing with somebody about it though.
Viviparity may be a big evolutionary mistake! (77)
[RD] You were pointing out the sporadic distribution of asexual reproduction in the
taxonomic tree, and you said, 'Wouldn't it be nice if we could find something else that had
the same kind of sporadic distribution,' but you never actually said whether you'd found any
such examples.

Well, I've not done the serious statistics. I mean, nowadays, you know one has to do proper
statistics before you would justify a statement of that kind. But I have a candidate which I
would like somebody to do the statistics on, and it's rather an unexpected one. It's the habit
of producing your young alive, viviparity. Now, you think, come on, that can't be right, all
mammals are viviparous, you know, one big taxonomic group. I think the fact that mammals
are all viviparous is a little like the Bdelloid rotifers all being parthenogens. It's... it's a
curious quirk. By and large, viviparity crops up, particularly in the vertebrates, in a very
irregular way.
[RD] It's very sporadic in teleost fish.
That's right. I would like to see somebody do a serious statistical survey of the distribution
of viviparity in the vertebrates. And I think they might find that mammals are really weird, in
being... clearly mammals, it's an invention that's succeeded.

[RD] It's just one datum.

It's one datum in the statistics. I think someone, you know, your colleague, Paul Harvey, or
one of his students, should have a serious go at it. Maybe there are others, I've not got a
good example.
[RD] But in order for the analogy with asexuality to be correct, it would have to be the case
that... I mean you would have to be predicting that viviparity, when it arises, quickly drives
the species extinct, wouldn't you?

That's right, yes.

[RD] Is that what you want to say?
If that's what the data says, that's what I want to say, yes, I think it's a terrible mistake.
[RD] There are other things, like haplo-diploidy, which have the opposite kind of
distribution, which are not sporadic, which really do characterise major taxa.
Yes, again, when I originally put forward the argument that the taxonomic distribution of
parthenogenesis was... was patchy, I did use the haplo-diploids as a counter example to
show that other breeding systems could, if they arose, spread to whole groups, and it... you
didn't very often get this occasional example. But I'm afraid I didn't do the statistics
properly, I mean, somebody should. In those days, you see, you could make these kind of
statements without doing the statistics. Nowadays, the whole thing has... the rules of the
game have changed and you have to do it properly, I'm afraid.
Are mammals stuck with sex? (78)
[RD] George Williams ends his 1975 book about sex in pessimistic vein, suggesting that he
can understand sex for those animals which he calls high fecundity, but for low fecundity
animals like us, he more or less throws up his hands in despair and says, 'Well, it's just a
frozen accident. Once it's... once you're stuck with sex, you can't get rid of it.' Do you think
that's what happened with, say, mammals, I mean are we stuck with sex because we just
can't get rid of it?

Well, I think it's very possible. I do remember attending a meeting on parthenogenesis in

Scandinavia, this must have been 20 years ago or so now. And I wrote in 'News and Views'
for Nature, when I came back, just describing the meeting, as one sometimes does. I
commented that we had recognised at this meeting that there were two major taxa which,
as far as we knew, were never parthenogenetic. One are mammals, and I'm ignoring the
one observed, or one claimed observed case, because I'm not entirely convinced.

[RD] You mean Jesus Christ or Dolly the sheep?

Oh, Dolly the sheep is fine, no, I was meaning Jesus Christ. I think the evidence in the case
of Dolly the sheep is fairly good. But... the other actually, one are the mammals, the other
actually is the conifers. There are no parthenogenetic conifers, so far as I know. Almost the
next week, there appeared in Nature a letter saying, 'How can Maynard Smith be so
ignorant as to not to know why mammals were never parthenogens.' And quoting this
curious phenomenon of so-called imprinting of genes, the evidence is that in mammals, a
few genes, it's not most of them but just a small number of genes, are labelled, in a sense,
as to whether they came from father or mother, in the foetus, and it's called imprinting, you
know, a little stamp saying, 'I came from mother.' And in some tissues, only mother's gene
is active and the gene from father is not, and in other tissues, only father's gene is active
and mother's is not. And I think, actually, David Haig has now given us a very nice
evolutionary explanation as to why this imprinting works the way it does, but that certainly
wasn't known in those days. But given that that's true, for the fetus to develop properly it
must have one father and one mother, at least. If it hasn't got a father then the father's
gene tissues fail and vice versa. I felt a little cross about this complaint because the data
hadn't at that time, about imprinting, had not even been published, so the fact that I didn't
know it seemed to be excusable. It was some years later, actually, that I discovered why
conifers are not parthenogens, it's much more obvious. I was reading a review about the
inheritance of chloroplasts and mitochondria in plants, and it turns out that in the coniferous
plants, the chloroplast is inherited through the pollen grain. And, clearly, if you don't have a
pollen grain you're not going to have a chloroplast, you're not going to grow. Now, I've
called these things sexual hang-ups, but... you call them frozen accidents, I think it's
basically the same idea; that if a group has been sexual for a long period of time, then
other, quite secondary, and in some ways quite trivial, secondary adaptations may be
attached on to the male-female differentiation, and once that's happened, the reverse
mutation may be exceedingly difficult. And... I'm inclined to think that mammals... we don't
get parthenogenetic mammals because of sexual imprinting, we don't get parthenogenetic
conifers because of the enhancement of chloroplasts.
Dolly the sheep & Would you clone yourself? (79)
I'm genuinely puzzled by Dolly the sheep. I think it's a fascinating problem... I mean I think
it's a fascinating result. But I read the paper in Nature and it didn't seem to answer the... I
mean, it convinced me that the phenomenon is a genuine one, and that's exciting, but it
didn't offer any explanation of why it worked, because I would not have expected it to work,
and most people in the trade would not. So, I think there's a very real puzzle about Dolly.
[RD] If somebody came along and said we want to clone Maynard Smith, what would you
say?
Not on your life, I think. My feeling is that the only person whose interest should be
considered in the matter of cloning human beings is the future clone. I really would not wish
to be a child, being brought up, knowing that I was genetically identical to this old twerp. I
mean, you know it goes back to... I remember when it wasn't cloning but it was artificial
insemination by famous donors, was a popular scheme. And I had this image of this
wretched child who had been conceived by sperm derived from Francis Crick, and I had
this picture of two parents looking down at the child and saying, 'When are you going to
discover something?' It'd be awful. And I think it would be terrible to be brought up as a
child, knowing that in some way or other you were expected to be... the genetic replica...
sort of follow in the footsteps of some already existing adult. I mean, if somebody cloned
me and took the clone away and could be absolutely certain that the child would never
know who he was or who he was meant to be like, I don't think it would matter, but then I
don't suppose they'd want to do that. No, I think the child is the person you have to mind
about in these contexts, not the person who thinks how nice it would be to have lots of
copies of me.

Being married to Sheila Maynard Smith (80)

{I skip this one}
2 theories on sexual inequality (81)
There are two theories on that, as it happens, two quite convincing theories; either one of
which would be fine if only the other one didn't exist. The first one is actually due to Geoff
Parker and myself, who did a game theory analysis of... we started with an isogamous
population, a population of organisms producing equal sized gametes, and asked, 'Is this
evolutionarily, and could it be invaded by individuals, either producing much bigger
gametes or much smaller ones?' And we showed that there were circumstances in which it
could so be invaded. But interestingly, the invasion would be, you'd have small motile
gametes, and then the invader would be the one producing great big gamete, which shows
that in spite of what it says, you know, that males are actually the first sex, which is nice,
we were there first and women only came along afterwards. That's one view, and I think
it's... there's even some supporting evidence. Looking at... well particularly there's a group
of algae called volvox, in which the theory predicts exactly which one should be sexual and
which one shouldn't and it works out very nicely. Not sexual but dimorphic.

[RD] How could the first one have been the male, because it doesn't make the economic
contribution?
Well, perhaps I'm stretching a point by claiming they were males, but they were motile, they
had little, you know, they had flagella to drive the cells along.
[RD] But also tiny.
And tiny, but not so tiny that they didn't have enough cytoplasm there to make themselves
work. The essence of being a female is to produce a large non-motile gamete, and all
gametes were small and motile initially, I think. But there is an alternative view, which I
quite like, which is due to Lawrence Hurst and Bill Hamilton, I think, and others, which is
that it really has to do with the inheritance of these organelles - chloroplasts and
mitochondria. And it turns out that almost universally, organisms transmit their organelles,
their... their mitochondria, let's say, only from one of the two parents. Of course, even if
you're isogamous - it sounds crazy this - but an organism which is isogamous nevertheless
has what's called plus and minus mating types. You can't tell them apart except chemically,
by looking at them you can't tell, but plusses will only fuse with minuses. And this is,
obviously, you'd say, well, that's because otherwise, no sooner has an organism produced
gametes than they'd fuse with one another and you'd be back where you started. And I
think that's right, it prevents selfing. But it then turns out that even in organisms with
isogametes, the organelles are inherited from only one side. In chlamydomones, for
example, which is a little alga, the mitochondria [are] inherited from one mating type and
the chloroplasts from the other. And the argument is that the reason that's important is that
it doesn't offer the opportunity for selfish behaviour on the part of mitochondria, the
mitochondria don't fight one another, so to speak, and the chloroplasts don't fight one
another. And I think that's essentially correct as an explanation. And some people have
wanted to suggest that this is the origin of unequal gametes. I mean, the gametes are
already unequal in a sense, they either contain chloroplasts or they don't. And the
argument has been that you evolve large and small gametes as a way of preventing other
kinds of selfish elements, parasites and so on, spreading. I'm not convinced that the
argument works, but better men than I am think it does, so we'll see. I like the one that I
invented myself, one always does.

[RD] Yes, I confused that with Parker, Baker and Smith, which is similar.
It's the same idea. No, I'm perhaps making unfair claims for myself here. Parker, Baker and
Smith, came up with the idea, and it's essentially the same idea. They showed it to work in
a particular case, by computer simulation. I, in my sex book, showed that the principle is
quite general, and applied game theory to it to show that the conditions under which it
would work, so I... in a sense, I did the analytical proof that it works, but they had... the
basic idea was theirs.
The essential difference between male and female gametes (82)
The essential difference is that if a female gamete is very expensive, male gametes are
really rather cheap. Consequently, a female will not benefit by mating lots of times,
because her fecundity is limited by how many eggs she can produce. A male will benefit by
mating with lots of females, because his fecundity is not limited by his ability to produce
gametes. And in the beast that I worked with, Drosophila subobscura, it was very striking,
that the female mated once in her life, a male could mate five times a day. And their
attitudes, if I can put it that way, towards mating, were very different. The male... female is
extremely choosy and selective, not only would she only mate with members of her own
species, but they had to be the right age, they had to be fit and healthy, and she had
methods of discovering whether they were fit and healthy though the courtship dance. The
males were... you could get a male to attempt to mate with a blob of wax on the end of a
bristle that you moved in the right way, he'd dance with it, and when you held it still, he'd try
and mount it. I mean, he just wasn't a very discriminating organism. I'm afraid, it's what's to
be expected. But once you get the formation of a pair bond, and... which lasts through a
breeding season, or through life, and you get both parents investing in the offspring, then,
of course, it is as important to the male as the female to select an appropriate mate. And
you get these very elaborate mutual courtships in many birds, for example, where both
parents are feeding the young and making equivalent contributions; except, always, of
course, the female has to lay the eggs, but otherwise the male may be doing as much, to
make the nest, to look after the kids. Going back to the very early ethology that Julian
Huxley did on grebes, for example, where you can't tell the male and female apart by
looking at them, and they have this extremely elaborate courtship in which they're both
having to perform to convince the other. So it really does depend how much investment you
put into your kids.

Experiencing feminism in science (83)

{skip this one}
[RD] Newton's Principia is a rape manual.
Kimura and King: Neutral theory of molecular evolution (84)
I had a slightly curious position on that when the serious debates were going on. I mean,
when Kimura's paper was published... Kimura and King, it's - one's so bad at dates, 1961,
could it be? - anyway, whenever, when it was first published, this led, particularly in Britain,
to deep hostility to the notion that anything could be selectively neutral. The whole tradition
of British population biology had been if you find a genetic variability, it must have some
kind of selective explanation, and if at first you don't find it, you must try, try and try again,
until you do. And the suggestion that there were genetic changes out there which were
selectively neutral, was really deeply distasteful to these people. And there was really quite
an extraordinary level of debate on the issue. Which... and what seemed to me so strange
at the time, that people felt they had to take sides. I remember, it was at its height at a
period when Dick Lewontin spent a year in my lab here. And I remember we talked about it
and we both agreed that at the moment we couldn't see anything really decisive, one way
or the other. And we kept on trying to think of decisive statistical measures or experiments
one could carry out, to decide whether the neutral theory was true. And we kept on coming
up with ideas and then deciding that they wouldn't really settle the issue, because, you
know. And so we both agreed the only sensible thing was to do was to say we don't know,
it didn't seem to be necessary in science to say you know when you don't. But almost
everybody else seemed to take rigorous sides. I think that the... this degree of polarity has
disappeared, and I think today most people who've thought about the matter seriously,
really see the value of the neutral theory as a kind of null hypothesis. The great beauty of
the neutral theory is it says, there is no selection. It is then possible to work out, in great
detail, what you expect to happen, and what you expect to happen to distribution of gene
frequencies, their rates of change in time, and all sorts of things of that kind. Once you start
saying there's selection, anything goes, because you don't know what the selection is, you
can't predict anything. And so the neutral theory provides one with a really admirable sort of
null hypothesis against a background to which you can... you can pick out the cases where
clearly it's not neutral, and you can say, 'That's selective because it doesn't agree with the neutral
hypothesis.' So, I've no doubt at all that Kimura's contribution was profound and really has changed population genetics.