The Evolution of Imperfection: The Science of Why We Aren't and Can't Be Perfect - Professor Laurence Hurst

The Director of the Milner Centre for Evolution, Professor Turi King, talks to Professor Laurence Hurst whose new book titled; The Evolution of Imperfection: The Science of Why We Aren't and Can't Be Perfect, has just been published.

Episode Transcript

(00:02):
Hello and welcome. You are listening to a podcast by the Miller Centre for Evolution at
the University of Bath. I'm Professor Turi King, your host, and today I'm talking to Laurence Hurst

about his new book, The Evolution of Imperfection:  The Science of Why We Aren't and Can't Be Perfect. (00:12):
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It is published by Princeton University Press and available in all good bookstores.
So, Laurence, what drew you to the idea of imperfection as a
subject worth writing a whole book about?So, when I was a student at school or very

(00:35):
early in university, I thought evolution was just the dullest of dull subjects,
I thought was so obvious. So, I was shown pictures of black moths on a black background and was told
that they weren't eaten as much as white moths on a sooty background. And because of this,
the black moths increased in frequency, and this is natural selection, and isn't it amazing? And I

(00:55):
was sitting there going, no, this is just obvious.And likewise, if you think about the most
conventional image that we have of evolution, in fact, put the word evolution into Google image
search, you can do now, nearly everything that comes back is the same picture. And it's this
so-called march of progress with, you probably know the image anyway, the chimp on the left,
knuckle walking, emerging to the fully grown human. And in all of this is the concept of

(01:21):
evolution as being a progressive process.Now, what we've discovered in the last 20,
30 years or so is when we look at our genetics, particularly, progress and
perfection do not obviously spring to mind when you're looking at particularly human genetics.
So, the premise of the book really is that, are we missing something about the evolutionary process?

(01:46):
And if we are then looking at instances where in what we see doesn't obviously make sense in
terms of this lovely progressive view. That's where we're going to find the answers to what
we're missing. So that's the real premise of the book. And in many regards, it was also sort
of simply born out of fascination and curiosity.So, I very much grew up and was trained within a

(02:09):
sort of evolutionary tradition where the answer is selection. No matter what the question is,
the answer is selection. So, no matter how weird things may look, we just have to invent a really
cunning selectivist explanation for it. And it's not clear that that is true anymore. There are
many other processes within evolution that aren't natural selection, and that could explain some of

(02:31):
our peculiarities. So, what are those? How does it work? And so on and so forth. And
that very much is what the book is about.So, you talk in your book about previously
imperfection was put down to kind of five main interconnecting factors
and that they still hold, but you've got other ones that you want to add to these.
So, let's have a look at these first five though. So, the first one is that it takes time for

(02:56):
evolution to catch up with a changing environment.Yeah, and this is sort of evolution 101,
because the problem that we're having to think about is that certain things start
out rare and become common. So, you could imagine I mean, let's go back to our moths,
for example. The trees are black, but before the trees weren’t black, the moths were white. So,
it's not simply overnight that all the moths go, you know what the best idea is to be black now.

(03:20):
So, it's not like, you know, Apple released an update to the iPhone system. And in principle,
everybody with an iPhone on the planet can go, update now. That's not how evolution works,
we can't do it in parallel. Rather, what would happen is there'll be lots and lots of mutations,
but some of them may turn a white into a black. In fact, we know that is exactly what happened,
and we know what the mutation was in that particular case. And again, it starts out rare.

(03:44):
So, there may be only one moth when the population is black when the background
is black. Next generation, it's probably going to be a little bit more, why? Because they're less
likely to be eaten. So, this is classical natural selection. But it can't convert a population one
day into the ideal population the very next day.So, it’ll go one maybe two individuals will be
black in the next generation, maybe three will be black in the generation after that. But it's going

(04:08):
to take time. And because evolution takes time, even if natural selection is the only process
going on, we're going to expect to see certain things not being as good as they should be.
So, all the way through that particular process, for example, we will see that there are black
moths against a black background. But until that process is finished, they'll still be white moths.

(04:30):
And you go why? Why are these moths white? The background is black; it makes no sense. Well,
yes, just give it a bit of a while.So, this is known as evolutionary lag.
And we think it actually is part of an explainer for a number of human features, one of which is,
some people suffer particularly bad backs. And it turns out that halfway down your back

(04:50):
on one of the little vertebrates there, called Schmal’s Nodes, and if you have these things,
you are more prone to having a slip disc. Some people have them, some people don't. And it turns
out that the backs that most closely resemble chimpanzee backs from the ape ancestor backs,
those are the people who get bad backs.Because walking upright is very difficult,
it's very painful thing to do if you don't have the right back structure. So, it looks as

(05:15):
though one thing we've been adapting to is walking upright. And we haven't all finished the process,
as it were, because evolution takes time. And so yes, some of us it looks as though have bad
backs because we've still got more chimp like state, which is fine if you're crouched over
and it turns out that one of the relief for this particular back is to crouch over like a chimp.
And it’s interesting, because one of the other kind of factors is thought to be that we are

(05:39):
no longer in the kind of environment that we evolved in. And so, you talk about things like
obesity. We previously didn't have terribly much food around. And so, our genes are kind
of predisposing us towards absorbing as much energy as we can. Now we're in an
obesogenic environment, there's food everywhere.Yeah, so one of the other classical explanations

(06:00):
for why evolution doesn't achieve perfection, you look at organisms and go, that organism
isn't perfect, is either because the organism has changed environment and the lag arguments kick in,
or you actually were adapted to one environment, and that environment has now changed. So,
they’re sort of the same explanation.And as far as a number of human conditions

(06:21):
are concerned, obesity would be one of them. It looks as though much of this is
a very rapid change of environment. And those changes include multiple things. One is change
of diet. And there's one argument which I think is quite attractive. We don't know if it's true,
but it's quite an attractive argument, which is that what would an ancestral human crave?

(06:42):
Well, it craves the thing that's really important for building a body but are rare in their food.
So fat, sugar, salt, and now think about Big Mac and fries. In a sense are junk food is tallied to
the things that we should have wanted to eat, because they were rare in our ancestors. So,

(07:04):
it's a perfectly nice argument, probably true, I don't know, but the consequence of all of this is,
of course, now we have food aplenty.And there are some very interesting
analyses done on Pacific islands, for example, where people were studying the islanders with
a diet which was more like the ancestral diet, and then in comes food aid or in some cases just

(07:24):
people were buying up the land for mining, which made everybody instantaneously rich,
at which point they shift diets and type two diabetes rates just go through the roof.
People become obese and they now die of something else. They die of complications of
type two diabetes, of cardiac diseases, etcetera, etcetera. Whereas on some of these islands, they
were studied for quite a while. No one had heard of diabetes, and no one had heard of obesity,

(07:48):
and what is a cardiac disorder? None of these had ever occurred before. People were dying of
infectious diseases, mostly, and things like that.So now, yes, there's a strong argument that we are
in an environment where our diet isn't matching our body, but the other things that we seem to be
finding where we're not matching our environment is we've made our environment it's thought much
too clean. So, there's a thing called a hygiene hypothesis, which postulates that we are now

(08:14):
living in these sterile chambers known as houses with double glazing, with Dettol wipes. Sorry,
Dettol. We got beautifully clean surfaces.But what's not so well known is many of these
allergies and autoimmune disorders really are sort of very, very recent things. So, over the

(08:34):
last 50 years, there's been a massive explosion in things like eczema and indeed type one diabetes,
that's also our immune system attacking us. But go back and look at the literature, for example,
and things like hay fever and asthma. You get the occasional report in the 19th century,
but the rate has been going up ever since. So, the question is,
what's going on in all of these autoimmune, all these allergies are going up incredibly fast.

(08:57):
And we know, for example, in something like eczema. If a mother wants to make sure her
kids don't have eczema, just go and visit a cow farm. Kids bought up on farms almost never have
autoimmune diseases. This first came to attention because somebody noticed that third born kids are
much less likely to have one of these autoimmune or allergic conditions than first born kids,

(09:18):
because the first-born kids are looked after, the third born kids, I should know this, I am one,
they are basically left to go feral.And so third born kids, it turns out,
have a bit of an advantage as far as allergies are concerned. And there's some quite nice evidence;
it's something to do with exposure to bugs and training the immune system.
Interesting when it comes to things like peanut allergy, for example. For many years the advice

(09:40):
for peanut allergy was just to avoid peanuts. Do not give kids peanuts before a certain age. And
it turned out this was actually encouraging peanut allergy. Now we know you need to train the immune
system. And so now the advice is mum, eat peanuts. Kids eat peanuts from an early age as possible.
And that, it turns out, prevents peanut allergies. So, it's again, it's about exposure to stuff that

(10:00):
we've been taking away and exposure to these good bugs, it turns out, looks really quite important.
And then that produces all sorts of interesting questions. So, there's one
interesting literature developing at the moment about what are the consequences of being born by
caesarean section for example. So, it turns out a lot of the bugs that your average baby
is exposed to come from the birth canal. But the caesarean section takes away the birth canal bit.

(10:26):
So, it is known that babies born by C-section do get more allergies,
do get things like eczema and hay fever and so on and so forth, more commonly. And so,
there's this interesting idea that's been trailed in randomized controlled trials in a couple of
places, namely, to take the bacterial concoction that is lining the birth canal. And if a baby is

(10:48):
born by C-section, to sort of spread it on them. The result so far quite mixed. And it may not be
necessarily birth canal bacteria that are missing. But again, it's all coming down to this idea, that
actually we've put ourselves in a position where we're the right body, but the wrong environment.
And evolution can only tinker with what's there. You use this lovely analogy in your book of an

(11:10):
old house and wiring.Oh yes.
And putting plumbing in. So, talk us through that.Yes. So again, another truism. You go, could I
design the very, very best organism to live in environment X, whatever. And in principle, if
you know the idea of natural selection, you should be able to derive what the very best organism is

(11:31):
for that environment. But we don't see this.There is a nerve, for example, that runs down
from our brain to our vocal cords, but it goes underneath the artery that goes out the heart,
the aorta. And in giraffes, this makes a many meters long detour. In principle,
it only had to go a couple of inches, but it goes all the way down to go all the way back up again.

(11:52):
And there's a similar one where in the tube that runs from the testicles to the prostate. So,
at the base of the bladder is the prostate gland. And in mammals it goes all the way over the
tube that runs from the kidneys through to the bladder. And you go, why is it? In both cases,
these things are making strangely long detours.And the answer we know in both of these cases is

(12:13):
because evolution is and can only be a tinkerer. By which we mean, if you look at the past history
of these things, the tube, for example, from the testicles through to the bladder, you find
in fish, for example, and other vertebrates, but there the gonads are internal. And so, it doesn't
really matter whether you go over or under. But in mammals the testes then drop. But the tube going

(12:36):
still has the same developmental instructions, sort of, turn left at kidney and then move down.
And likewise, the nerve that develops from brain goes all the way down, all the way back up again.
That too has the same sort of instructions. In the fish it makes no difference whatsoever
whether you go under or over, but in us the neck and the head extend and goes under and
has to go all the way back up again. And so, yes, if you want to understand this, then

(12:59):
understand the strange anatomy of my old house.So, I used to live in the lovely 18th century
house where there was plumbing and wiring all over the place. You know who ever thought of
this? You know, the wiring running across ceilings and diagonally across walls and
things like, and you go why?And of course, the answer is,

(13:20):
when these houses were built, there was no plumbing and there was no electric. And so,
they've all been put in after the fact, as it were. And in many regards, that's evolution
for you. You can only tinker with what you got. So, those houses are not the perfect house, they
weren't designed to have electricity and plumbing in them. They got them after the fact, as it were.

(13:42):
So yeah, it's quite hard to imagine how you could actually get around of these things. So, some of
these things are probably sort of built in and you can't do much about it, because evolution can only
work on the mutations that come in here and now. And they can't radically restructure anything.
And then we get some sort of interesting, related problems. So, I mean, imagine I give
you this problem. Your challenge is to find the perfect solution. The perfect solution in

(14:04):
this case is to be at the top of the tallest place on Earth. So, the top of Mount Everest.
So why am I using this analogy? Well, natural selection is a bit like a hill walking process.
Survival of the fittest. The better replace the not so good, they in turn get replaced.
And there's a sense in which fitness is going up and up and up. So that understanding from natural

(14:24):
selection that the next one in has to do better than the prior one in, and so on and so forth.
That would suggest you are getting better and better and better and better, going up and up the
mountain. So that's where the analogy comes from.And so, if you were going up and up a mountain,
could you actually get to the top of Everest if I now give you all the rules? So, these other rules,
you’re only allowed to go uphill.Because of selection being positive…

(14:45):
Because a selection. So, if natural selection is the only thing that we got to operate with.
Yeah.Then you only have to
go uphill and you're blindfold. You're not allowed to sort of survey the environment, and this comes
back to the idea that actually evolution can't go, oh that's a brilliant solution, let's go there.
Yes.Selection can only
respond to the mutations that are here and here now. So, mutations come in, does it increase your

(15:06):
fitness? Yes, it does. We move up our mountain.Next constraint is, so you’re blindfold,
you can only move up, and you have to start with where you're starting from. Now of course if you
start from where you're starting from, almost nobody is going to get to the top of Everest.
No.You will go to whatever
the local little peak happens to be. So here we have a quite a sort of undulating landscape,

(15:29):
and we put out a thousand people. They will each come to some peak, some will
be higher than others, even just on a, you know, a fairly narrow scale geographical distribution,
because there will be little undulations, as soon as you've got to the top of the undulation,
the rule is you stop if you can't go any higher, and you're not allowed to go downhill. So,
you get to the top of a small hill, as it were.And that, we think, is one of the problems of

(15:52):
natural selection. We actually call it the peak jumping problem. So,
if you found one good solution, can you now find the even better solution?
And so, for example, when we look in, there's been about 30 or so independent evolution of
eyes. And it's not clear they've all got to the very best eye even for that organism.

(16:12):
So, us and octopuses, for example, we both have a very similar sort of structure of eye. Light comes
in through a lens, there’s a processor at the back very much like a digital camera, actually. But the
real oddity is that while they are very similar and they send nervous instructions back to the
brain, and the brain interprets what's seeing, in the octopus, those nerves run out of the

(16:33):
back of the eye. So, the photo receptor is sort of correctly oriented, you might say. It picks up the
light and shoves the signal out through the back. In vertebrates, it tends to go the other way. The
nerve cell goes back into the eye. And so, we have to take all the bundles and put them out through
the back of the eye, which gives us a blind spot.And you go, okay, here we have two solutions to

(16:55):
the same problem. They look incredibly similar in most regards. We know they're independently
evolved. And one, the octopus I would say, has got to a higher peak than the human eye has gotten to.
We've got this funny little problem that we have a blind spot at the back of the eye,
the octopus doesn't. So, in terms of eye Olympics, the octopus wins.

(17:17):
So, the last one is that the world of possibilities is limited for evolution.
Yeah. So, there are solutions that you might imagine that would just be damn good solutions,
but you just simply can't get there. So, I think, for example, if I was living in Africa,
I would really like to be able to run faster than anything that's going to chase me. But actually,
with the human body plan, you can't do it. But we see this sort of thing actually quite

(17:43):
interestingly in some of our genetics.So, one of the peculiarities about being
a mammal is that almost all mammals, two exceptions the sloths and manatees,
we actually all have the same number of neck vertebrae, and that includes the giraffe.
But you go to your local natural history museum, or just Google it and look at the neck of a

(18:03):
long-necked dinosaur, like a Brontosaurus or something like that, or of a long-necked bird,
birds are really just dinosaurs. And what you find is when they make long necks,
they make more vertebrae, to make a long neck. We increase the size of our vertebrae.
Why have we got these two different solutions? The one that the birds do seems to be a better
solution. It looks as though we can't do that solution for rather interesting reasons. It turns

(18:26):
out you do occasionally get babies born that have actually got an extra number of vertebrae. So,
the mutation is possible, but they nearly always die of cancer very early on,
so they tend to be inviable. So, there's something about the way our genetics works,
which means if you add a vertebra, you die.But in your book, you talk about, yes, you know,
a lot of this works, but it doesn't explain everything. So, talk me through these next things.

(18:52):
So, there's a couple of observations and the book particularly focuses on these because I think
what's particularly remarkable is over the last 20 years or so, while we had those explanations,
we've had a whole series of observations, and in parallel evolutionary theory, to say, actually,
we don't think those are quite enough to be able to explain what we're seeing.
So, none of them seem to be able to explain, for example, why most of our

(19:15):
DNA seems to be rather pointless. But there are other strange observations,
for example, we now with modern genetics can actually go in and look at very early embryos.
And then what we discover is that about half of eggs, fertilized embryos, numbers slightly
vary 40 to 60%, there's one estimate of at 70%, sometimes it's quoted as 20 to 40, it all depends

(19:41):
on the mother's age, it turns out. But for the average age mother, it's probably of the order
of, oh, around 40 to 50%, embryos fertilized have got the wrong number of chromosomes.
We know mechanistically what the problem is. Something goes wrong when mothers make eggs.
The rate of that problem goes up as mothers get older. But evolutionarily, do any of these answers

(20:03):
tell us? Well, there's one big clue, because we can go down and look in fish, for example.
Look at 2000 fish embryos, just fertilized, how many of those have got the wrong number
of chromosomes from the mother? And the answer is out of 2000, none.
You can do the same experiment in yeast, our lovely laboratory yeast. They had the
same process. You need about 100,000 yeast cells doing this process before you find

(20:26):
one that gets it wrong. So, in cows the rate is about 30%, in pigs the rates 18%,
in mice it's about 20%, and in us it’s rather higher. An unwanted world record.
I define imperfection as one of those features that sort of slaps you around the face and says,
okay, now explain me, because it's not obvious that that's the result of natural selection. Why

(20:48):
would natural selection favour the death of half the embryos? And as it is, we know, for example,
that even if you are a fit, healthy couple, young potential mum and dad, you want to get pregnant,
30% of the time in any given month when you're trying to get pregnant, you will get pregnant.
The remainder of the time, 70%, no matter how hard you try, you cannot get pregnant.

(21:09):
We also know when we look in early human embryos, it's been done in even more detail now,
even in these fit, healthy 20-year-olds, if you go and look in every cell in an early embryo,
90% of them have the wrong number of chromosomes in at least one cell.
So, we got this sort of problem that we have large amounts of DNA that probably doesn't seem to be
doing anything, at least we can't find any trace that it's doing anything. We also, it turns out,

(21:33):
have a very high mutation rate, the highest of any organism. So, we sit in the Guinness Book of World
Records for all the records you don't want.Yeah.
We have very high rates of genetic disease. So, 5 to 10% of us have a, quotes,
rare genetic disease. They are not very rare at all. And that's because we have a stupendously
high mutation rate. We got this stupendously high rate of making embryos with the wrong
number of chromosomes. All of this screams, what are we missing about the evolutionary process?

(21:57):
Yeah, yeah.So, this is where the book really kicks in. So,
we think we've got two classes of explanation for these things. So, the first is related to
a body theory that was developed by Tomoko Ohta who's a Japanese population geneticist. And what
she did was ask a most interesting question. Her question was this, imagine you have a mutation,

(22:20):
and the mutation is a little bit harmful, but not a lot harmful. So, it's not a mutation that's
going to kill you. This is not a mutation that induces childhood cancer. It's not one of those.
It's just a little bit harmful to you.So, jumping gene has jumped, it's sat
in your DNA, it's not really harmed anything, it's not broken a gene. But it's now a little
bit more costly to make a copy of your DNA, just because you're copying some load of rubbish now.

(22:42):
What's going to be the fate of that, she asked. Is it actually possible that
it's going to go from rare to common? Not because of selection, but because
selection isn't good enough to get rid of it.And so, she says, well, you can think of this,
and it's a lovely analogy, a bit like a particle of gas. And particles of gas, if you ever have,
you know, when the light comes into a room and you have dust particles and you can see

(23:04):
the dust particles just sort of bubbling up and down in the room, sometimes going up, sometimes
going down. She said, well, that's really the same as a mutation coming into a population,
and just by chance it can go up in frequency, and just by chance it can go down in frequency.
And she says, okay, what's going to be the fate of those that are little bit harmful.
Now, if you were to take the strict selectionist line, well it's harmful, it should simply be

(23:28):
eliminated from the population. And she says, no, no, no, that's not true. It can be some of
the time, but there's no guarantee it will. It's like a particle of gas. It can bubble up, it can
bubble down, and sometimes they will bubble up, and just by chance they'll keep bubbling and get
stuck to the ceiling. So that's like a mutation coming into a population, it starts out close to
the floor, bubbles about and gets to the ceiling.And she then says, okay, what's the rate at which

(23:51):
that process is going to happen? And is there a predictor of that rate? And can they then evade
selection just by chance? So, she says, yes, they can. And particularly when the populations
are small, that's like having a room where the ceiling is very close to the floor. It's not
that many lucky bubbles that you need to get from floor to ceiling. In a really large population,

(24:13):
that's like having a room with a huge distance between the floor and the ceiling. You need to
be really, have a lot of lucky bubbles to go from rare to hit the ceiling.
Because there's only really two places you can end up. These are sticky particles of gas. You
either end up on the ceiling or you end up on the floor, so you either get lost from the population,
ending up on the floor, or you become an evolutionary difference between two species,

(24:37):
you've got to the ceiling. A process we call fixation in population genetical terms.
And her big predictor then is the population size. So, what this theory says, it's called the nearly
neutral theory. So, they're not quite neutral, as in absolutely no effect. So, their chance
of going up is slightly lower than their chance of going down. So, on the average they're going down.

(25:00):
But the population size then matters. So, her general prediction would be, is if there aren't
many individuals in your species, you're much more prone to these things going from rare to common.
So that transposable element when it lands in our DNA doesn't do us a lot of harm,
it's just a little bit bad for you. And because we've got a small population size,

(25:20):
these things can at some rate get through to fixation, not because it's marvellous for the
species to have 90% of its DNA doing nothing particularly useful. Not at all. It's because
we can't do anything about it. It's because selection is inefficient when populations are
small. And it turns out that this single theory then explains swathes of what we actually see.

(25:42):
So, we've got three different measures of how much bloating there is in any given genome.
And it turns out they all agree that you have more bloating, so more of this junkie stuff
when populations are small. And so that we think is why are bacterial genomes and yeast
genomes lovely and live, gene stops, gene starts, gene stops, gene starts, and ours are gene stops

(26:05):
space space space space rubbish rubbish rubbish rubbish new gene. Yes, because yeast and bacteria,
tiny wee things, it's not because they're tiny, it's because they've got massive populations. And
it turns out nearly all of that bloating is then predicted by a theory like that.
It also predicts actually the way our cells function should also be pretty noisy
and pretty error prone. And that's exactly what we find. So, when we make proteins,

(26:29):
we go through an intermediate called RNA, we have to cut that up. And it turns out we're
not very good at doing it. And the rate at which species get that process wrong and make lots of
rubbishy things in the process, not rubbish DNA but rubbish RNA, that is also predicted by how
big your population is. So, if you’ve got a big population, you make the transcripts, you make

(26:49):
the RNA you need and more or less only that one.If you like us, we have to have several attempts.
Our cells just fill up with crappy RNA. And of course, what we then have to do is build
in structures to go, we've got lots of crappy stuff here, we have to do something about it.
So, it's a bit like… yeast you could think of as a rather beautifully well-organized cell in which no
one breaks the law and there's never fire. And as a consequence, you don't need fire engines,

(27:13):
and you don't need the police. Whereas we've got so many fires and so many traffic accidents that
we need reams and reams of ambulances, police, fire brigades. So that's a lot of what's going
on in our cells. Our proteins are going to the wrong places and so on and so forth. So that's
one grand body of theories.Yeah.
Which says our problem is that when we evolved, so people go, yeah, yeah,

(27:33):
but there's billions of us now. Yeah, but there weren't when we evolved. When we evolved, our
best estimate was about 8000, 8 - 10,000 humans, evolutionarily speaking, that's tiny. So, if you
ask how many bacteria do you have in your gut at the moment, the answer is it's in the trillions.
Even with 7 billion current humans, the total number of humans that have ever existed is a

(27:55):
minute fraction of the total number of bacteria that you currently have in your gut. Some things,
simply by being small, have massive population sizes, and that's where we see things that look
genetically perfect. If they're doing something odd, then we're either up against a sort of,
constraint and there's nothing they can do better, or we're missing some explanation. With us, we
know that we're producing funny little bits of RNA all over the place, not because they're necessary,

(28:20):
just because we can't stop it happening. So, these are rubbishness’s that happen when you get small
population sizes. That can't really explain why half of our embryos die almost instantaneously.
Yeah.That's not the domain of weak
selection. So, what we think is going on is that mammals and humans in particular, have another
particular problem that comes from placentation.So, placentation in many regards is lovely. So,

(28:46):
the placenta is the tissue, it's made by the foetus. And it sits between the foetus and the
mother. And in the textbooks, it always says, and the mother provides resources to the foetus
across the placenta. So, you can think of it as a great sort of hoover for mother’s
resources. But it's not simply that it can talk the other way as well. So, it can actually give
instructions to the mother as well.Now what having a placenta actually

(29:11):
means for our biology is a number of things. And one I think is particularly important.
You may be able to see when you consider our reproduction compared to that of, say, a kiwi.
So, a kiwi bird, 25% of a mass of a female kiwi will be the egg while she's generating the egg,
huge investment of resources. She will then sit on that egg for an awfully long time. So

(29:33):
now imagine what would happen if that initial egg was inviable. She's already given up all the yolk,
25% of her body mass. She spent all the time sitting on the egg, she doesn't get off the egg,
she doesn't know that the embryo is not viable. And so, she wastes time
and energy sitting on a dead egg.Now, in mammals, this isn't true.

(29:56):
So, if the embryo dies straight away, the mother does not undergo nine months trying to raise it,
does not give all the resources away. A lot of the time, the mother doesn't even know she was
pregnant. The consequence of this is then that early mortality, unlike what we see in the kiwi,
that early mortality saves energy that can now be given to other kids.

(30:18):
And this is known as reproductive compensation. We can actually get an estimate of the extent to
which it works, there's another mode by which it can work. So, if you are like a mouse,
for example, you have multiple embryos within a brood. What if some of them die? Well, the mother
can reallocate the resources from the ones that died through to the ones that survive, and you
can actually do the calculations in humans.So, we know what the relationship between

(30:40):
human birthweight is and your chance of surviving through to 5. And we know what
the average birthweight of singletons is compared to twins. So, you can imagine what
if you were originally a pair of twins but one of the two died? How much better does the one
surviving now get to be because the other one died? And the answer is about a 40% increase

(31:02):
in body mass at birth. Pretty big effect. And that then translates to about a 10% increase
in the chance of surviving through to the age of five. So, in fitness terms, that's massive,
we're not in the domain of weak selection here.So that's reproductive compensation,
we think it's got all sorts of interesting properties in mammals. And one of which is
it completely changes the game when mothers are making eggs. So, the argument runs like this.

(31:30):
Imagine you're a chromosome and the mother is about to do a really key division. So,
there's chromosomes you got from mum, chromosomes you got from dad. So,
let's think about any one. Mum's chromosome, dad's chromosome, now the whole point of this
process is to produce one cell that's got one of these two copies. That's what an egg is, it's just
going from two copies of everything to one copy. And so, they line up and they are given ropes

(31:56):
effectively. And one rope will pull you one way, and the other rope will pull you the other way.
So, these are the chromosomes they are getting pulled?
So, the chromosomes are getting pulled, the ropes are so-called microtubules, and they get
pulled one way. So, half will get pulled into the egg, half will get pulled into this other thing
called the polar body. Polar body is a tiny little thing, and it's effectively a genetical dead end.

(32:16):
So, you're sitting there on this plate, now stop thinking about chromosomes at
this moment and start thinking in your most Machiavellian of Machiavellian terms.
So, there's me and there's Turi, and I don't want Turi to win and survive,
I want me to win and survive. Not because I don't like Turi, it's because I want to win and survive,
that the sort of evolutionary game. And we are lined up on a cliff edge and two ropes are thrown

(32:40):
out and we both grab one. One rope will drag us to safety; one will drag us over the cliff edge.
And this is like these chromosomes. One will drag us into the egg, save us. One will drag
us over the cliff edge, go to the polar body. So, the ideal way the system is set up is that half
the time you will get the rope that saves you. Half the time I'll get the rope that saves me.

(33:04):
But then equally, half the time I die, half the time you die. If we were to repeat the experiment,
many times over. And that's how the system is sort of set up to make sure that when we go
from having two copies of every chromosome, we now get one copy of every chromosome,
because we don't want to have any missing, and we don't want to have two of any of them.
But now be Machiavellian. So, I've blindfolded you, so you don't know which rope you've got,

(33:26):
because obviously if you know which you've got…Cheeky thing.
Or if you can see them there will be a mad dash for the rope that's going to save you. Yes. So,
imagine you can do this. Imagine our peak undo and go, oh, I've got the rope that's going
to take me over the cliff of death, what's your best thing to do now? Well, there's a
thing known as centromere drive, where parts of chromosomes actually flip over and they go, oh,

(33:48):
I don't have the right rope. I'm going to now nick the right rope and I'm going to force you take the
wrong one. You still get 50/50 segregation. But I made sure I'm the one that gets into the egg.
Turns out that's very common in many organisms, in fact, flowering plants do it as well.
But what was noticed is a real quirk of this, which is if I just simply drop the rope and go,
I'm killing the egg. I'm killing the egg, and I'm killing the embryo, I win because of

(34:12):
reproductive compensation. Not seen in the kiwi, not seen in the fish, and not seen in amphibians.
Why? Because I just killed the egg, but that means the mother now can reinvest. She's going
to make another kid. Well, that next kid, I might be the lucky one who gets into the egg. Or rather,
my clonal relative would be. Because the next time we do this, the next bunch of chromosomes,

(34:33):
the Turi chromosomes and the Lawrence chromosome, it’s our identical twins doing the game. And so,
I can save my identical twin by killing the embryo if I don't get in, and you go,
okay that's nonsense, chromosomes can't behave like that. But there's a beautiful set of
experiments done in mice which show they do.So, it turns out that across the egg,
there's a gradient of a chemical called tyrosine, and some chromosomes,

(34:56):
if they have a low amount of Tyr oscillation, end up dropping the rope. But they don't,
if they’re on the other side of the egg. And so, they only drop the rope when they're going towards
the cliff of death, as it were, when they're going over the cliff, they drop the rope and go,
no, I'm not taking this, and they stay in the egg.And so, this, we think, is the explanation for why

(35:19):
mammals have such high rates of the chromosomal anomalies. It's because it actually pays
chromosomes to kill embryos, because the mother just simply reproduces again. And then she's got
a good chance that the next one will contain the Machiavellian chromosome that started this
process. So, these are things that more generally known as selfish genetic elements. And I always
tell my undergraduates, if you understand selfish elements, you understand evolution because they do

(35:42):
the weirdest things, things you could not imagine. Your first inclination about what evolution can
do, selfish elements say, no you're wrong.Yeah. Because they're directing evolution.
Yes, yes. So, for example, in fruit flies there are mutations, for example, that kill half the
sperm. And you go, okay, how is it advantageous for mum, dad to have half the sperm die? Well,

(36:03):
it isn't. The male actually has lower fertility, the female has lower fertility,
but it's the mutation that kills the sperm, only kills the sperm without the mutation, so
it wins everybody else loses. Which is why these things are known as selfish genetic elements.
And it throws a complete spanner in the works in terms of how we understand evolution.
Yes, absolutely. And then placentation as a whole just makes us so prone to these sorts

(36:28):
of manipulations. So, for example, as I said, we always think that, oh the placenta takes in
resources from the mother to help the foetus grow, but the gestational diabetes occurs, for example,
when mothers often get diabetic part of the way through. And we think what's actually going on is
the placenta is actually putting in chemicals into the mother to stop her turning glucose into the

(36:50):
storage chemical to keep it in the circulation, so they get more of it. And the mother responds
by producing more beta cells in the pancreas to make more insulin, this looks like a tug of war.
Yes.And then we
get really funny things like, pre-eclampsia in humans, which affects 5% of human pregnancies.
Most fascinating of all human disorders, I think, because it's potentially lethal for mum and baby,

(37:12):
humans specific, 5% of all pregnancies.So, it turns out that prior to advances in
modern healthcare, there were three great killers of mothers and human mothers dying more than just
about any other mother we know. Any childbirth before about 1800, there was a 1% chance the
mother would die, stupidly high. So human birth is very dangerous. Pre-eclampsia, your maternal

(37:33):
blood pressure just goes escalatingly stupidly high. What on earth is going on? Kills mother,
kills baby. Why hasn't evolution solved that one? And far from solving it,
it's human specific. So why do we have this rather obvious imperfection? It's to nobody's
benefit. You’d have thought it'd be gotten rid of. And we think we understand that to some extent.

(37:53):
So, it turns out the human placenta is particularly invasive. So, lots of placentas
just sort of sit nicely one against the other and things diffuse across it. Ours burrows into
mum and burrows quite heavily into the maternal interface, the so-called decidua, and we think
that's probably the case because we've got particularly big brains and the point at which
the placenta particularly invades is actually the point at which the brain really needs to develop.

(38:17):
And as humans, we're born with particularly big brains, and are born particularly heavy
given our gestational age compared to other primates. But it's thought because of this,
you also have another problem, which is that dad's proteins sitting there in the foetus
are getting shown to mum. Now, if you think about something like vaccination, what vaccination does
is it gives you foreign proteins and says, okay, now attack, but you don't want to do that if the

(38:41):
thing that you're about to attack is either your own gut flora, semen if you're a mother,
and babies. You do not want to be a mounting an immune response against the babies.
But it looks as though pre-eclampsia comes about because we need so many resources, we
are putting the foetal tissues and the placental proteins into very close contact with the mother,
and if the placenta gets a bit distressed, it turns out the mother can then sort of mount an

(39:04):
immune system response against it and go, I don't like those proteins. I don't recognize
those proteins. Usually, they're kept at sort of arm's distance, as it were, and at which point
the placenta then gets stressed and it starts saying, give me more resources. And it does that
by changing the blood pressure. So that forces more resources into the placenta, as it were, but
also that's what pre-eclamptic placentas also do. And then they sort of take it too far as it were.

(39:28):
And why we know this is almost certainly an immune related problem is, it turns out that
you can prevent pre-eclampsia by having abundant unprotected sex. And it's one
of the peculiarities of humans is we tend to reproduce all the way through the cycle. Lots
of mammals just reproduce sort of at the point where the egg is ready as it were.
And in fact, in other mammals, the egg only becomes ready when mating happens.

(39:48):
That’s very handy…In humans we have sex all the
time and the egg only appears a certain amount of time. But we think humans are doing this because
we're training the mother's immune system to say, you're about to meet some proteins that
you don't know anything about, please don't respond negatively to them. So, it’s a sort
of anti-vaccine. And that's what we sort of do with our gut flora as well, we have instructions
saying please tolerate. And if you don't that's obviously Colitis and Crohn's disease.

(40:12):
Yeah. So, there's obviously implications for the fact that we have very big brains and that's,
you know, development in the womb. But there's other implications to this as well, isn't there?
So, our big brains in a sense I think are fight back against the tyranny of natural selection.
We are in an appalling position in many regards genetically, the highest mutation rate, stupidly

(40:34):
high rates of chromosomes getting it wrong, and eggs that are getting fertilized but dying before
mother even knew she was pregnant. Stupidly high rates of miscarriage, just horrible, you know,
awful processes. But with these big brains we can do medicine. And so, we can actually do something
about this. And I guess one of my favourite statistics is if you go and look at, as I said,

(40:55):
the historical record, the chance of a mother dying in childbirth is about 1% per child birth.
The lifetime mortality risk is about 10% or so.But with advances in health care since about
1950 or so, these rates have been going down and down and down. So, you ask,
what are the major killers? Why do you die after giving birth? And it's bleeding after

(41:15):
birth, it's infection after birth, and it's pre-eclampsia. Those are the three big killers.
Pre-eclampsia, what we can do about that is now that we can recognize it you can at least
do an emergency delivery, and that turns out it cures pre-eclampsia. If the placenta isn't there,
pre-eclampsia goes away. And that rate, 1% has now gone down. So, in the UK in the last survey,

(41:38):
the rate of maternal mortality is now 0.01%. It is now most unusual.
There's nothing much to fear about childbirth anymore.In fact, there was a very interesting survey
done a few years ago by the British Medical Journal. So, it was established in 1847,
and so they asked the question, since 1847 what do you think have been the greatest developments for

(42:01):
medicine? Not necessarily in medicine, but for medicine. And the list is really interesting.
Number one was to me an utter surprise, because it was the development of the toilet and clean water.
And it turns out this is more or less taken away, typhoid, all those diseases that were incredibly

(42:22):
common even in mid-19th century London. And every big city had a cholera problem,
but they're gone. So that was number one.Then after it was the usual suspects vaccine,
antibiotics, anaesthetic, and at number five was DNA.
So, I think what that's telling you is that we actually have such a big brain that we can do

(42:44):
something about a lot of diseases but noticed that a lot of that disease is about infectious disease,
and that's absolutely right. If we look prior to the modern age and ask what kills you,
well, it wasn't old age for the most part. It wasn't cardiac diseases. It wasn't senility and
dementia. And for the most part, it wasn't cancer. These are first world disorders of

(43:05):
a population that is being kept alive far beyond what they usually would have been able to manage.
And what kills people? And actually, we see the traces in our DNA as well. So, if we ask where
is our DNA particularly different from that of chimps, for example, every species shows the same
pattern it turns out, anything to do with host parasite co-evolution. So, things that allow us

(43:27):
to resist malaria, that's a hotspot for selection.And we ask, what kills people? What kills people
is mostly some sort of infectious disease. And of course, vaccines and antibiotics to a first
approximation have solved that one. But as I said, we still have problems because we have
a high mutation rate, 5 to 10% of us have rare genetic diseases. Diseases like sickle cell anamia

(43:50):
aren't rare. If you go to sub-Saharan Africa, 1 to 3% of individuals suffer from sickle cell anamia.
And so, to some extent we are replacing infectious diseases with genetic diseases
or problems of aging, with a hefty dose of really bad diet and not enough exercise...
No…Diseases.
This is us changing evolution because no longer are people dying before they

(44:13):
reproduce, they are actually living past the reproductive age, and we die from other things.
Yeah.Essentially.
In many regards, as far as genetics goes, the most remarkable technologies are the ones that
really are coming on stream now, and that's gene therapy. And actually, asking about gene therapy
in evolution terms is quite interesting. So let me explain a little bit about what gene therapy is.
Yes.So, if you are unlucky

(44:35):
enough to have say haemophilia or something like that. There are a number of things that we could
do to help. So, you routinely would have to have blood transfusions. So, you've got a misinformed
protein, it's not allowing your blood to clot when it should do. You bang your head or something.
Most of us would just have a small bleed on the head and we'd be fine. If your haemophiliac,

(44:55):
you're dead. So, cure number one is not a cure, but it is a therapy. And that is we’ll just give
you regular blood transfusions. So, you're not making the proteins that enable your blood clot,
so we will give you blood that can clot.There's recently been developments whereby
you can also have an injection of something that looks a bit like one of these clotting factors,
and does the same job, but again, it's like a plaster over a wound,

(45:19):
it is not getting to the problem at its core.So, the idea of gene therapy is then different.
Now what you are going to do is going to go, I'm not going to give you blood transfusions. I'm
not going to give you a synthetic or an actual version of the protein. I'm going to give you
the wherewithal to make the right version of the protein, the one that will stop this disorder.
And so, we can make the gene in the lab, we can put it into a virus, and we can give it to you.

(45:43):
And depending on how it's done, sometimes we just take out bone marrow, engineer the bone marrow in
the lab and give you back your bone marrow. That can be done for sickle cell anemia, and peter cell
anemia, for example. Or we give you an injection with your gene of interest loaded into a virus,
which hopefully goes to the tissue of interest and gets inserted into your DNA, or at least
into the cell. And so, there you've got something different. You've got the ability to stay alive by

(46:09):
making your own version of the protein. So that's gene therapy, and potentially it's very exciting.
But evolutionarily speaking, it's not a populational cure because you are not
going to transmit the corrected version of the gene. The corrected version of the gene
sits in your bone marrow or your liver. It does not sit in your testis or your ovaries. And so,

(46:29):
your kids can still get the disease. So, in effect, we are asking an interesting
question. We're keeping people alive who now can't have kids, but they can also now transmit the
very mutation that they have to be cured of.And so, there's an alternative which is very
highly contentious, which is called germline or embryonic therapy, whereby basically you take a

(46:50):
very early embryo, like just fertilized egg, you correct it at that stage. But this is so
very contentious because I'm not simply curing the person, I'm also effectively curing their
offspring. And so, we're really messing with the human gene pool in doing this. But whichever one
you do; in a sense you are messing with the human gene pool. You’re either keeping people alive,

(47:11):
but we were doing that before, but they're still transmitting the disease, or you're
actually changing the genetic constituents.At the moment, there's a moratorium on human
embryonic gene therapy. We don't know if it's safe enough yet. There are all sorts of problems with
gene therapy and every trial, it’s always fingers crossed, let's hope nobody dies. The first gene
therapy trials had to be stopped because they ended up killing the kids who should be being

(47:35):
cured. The gene turns out, inserted next to genes that cause cancer and cause them to upregulate
to make more of the cancer-causing protein.And so, it's been a long and difficult path
to get to the position where we think a number of these safety issues can be gotten around. But
there are still cases that are very worrisome. And in the development of gene therapies,
individuals have died because of vast immune overreaction to, again the therapy.

(48:00):
So, this is us trying to cure that imperfection.That’s real cure, that’s real cure.
And the ethics…Are difficult…
Yeah…Are very very difficult. And
I come back to the notion that I think we've got a pretty good understanding of the human
genome. They're just mostly bloated, most of it is unnecessary. But if you were to give me a sequence

(48:20):
of a DNA where we've inserted a gene therapy gene and ask me, from what we currently know,
is that going to be safe? I don't think I can tell you the answer. If you insert into the
rubbishy bits of our sequence, it tends not to work. It tends just to get shut down. Because
we've got a system to go, actually that DNA we don't want, shut it down. So that's one problem.

(48:41):
So, lots of them also insert close to genes, but then the question is if they insert close
genes they won't get shut down. But are they going to affect the neighbour genes,
and that was always our problem. So, people have come up with the notion of a, quote,
safe harbour. A safe harbour is a location in your genome if something inserts into it, it'll be
alright. We still don't really quite understand where it would be safe to put these things.

(49:04):
So, for the somatic therapies, those where you're curing the patient but not affecting
the offspring, I still think you really need to know what the risks are. Germline therapy
is still being considered, there's a moratorium on it, but only for really the most severe conditions
for which there is no other possible cure. So, something like early onset parkinson's disease,

(49:26):
huntington's disease, for example, these neurological conditions and dementias, gene
therapy semantically isn't going to do anything because it can't get into the brain and operate
in every brain cell, that's not going to happen.But if you go to the very earliest embryo and go,
oh you're likely to have huntington’s disease, can we edit that out or can we give you the
right version of the gene, so you don't have a problem? People are seriously thinking, okay,

(49:48):
what would be the ethical guidelines for doing that. And in principle that is then a cure, and
those individuals will have offspring who would not have huntington’s disease because they would
have the right one. But I think people are still going, we do not know the negative consequences
here. So, if you don't know those, that is way too risky, I think. I think most people are very much
erring on the side of caution on this one.So, if listeners are going to take away one thing

(50:11):
from your book, what would you like it to be?I think it's very straightforward, that actually
evolution is much more interesting and sophisticated than my naive, arrogant
young self-thought it was. There are all sorts of interesting processes whereby you can end up with
completely weird solutions, but they make sense.Laurence, thank you so much for talking with me.

(50:39):
If you would like to read Laurence's book, The Evolution of Imperfection:
The Science of Why We Aren't and Can't Be Perfect, it is published by Princeton University Press
and available in all good bookstores.This was a podcast by the Milner Centre
for Evolution at the University of Bath. I'm Turi King and thank you for listening.

(50:59):
If you have any thoughts or comments on this or any other episodes, please contact us via social
media or for more information about the Milner Centre for Evolution, you can visit our website.