Prof: Well today we're
going to talk about evolutionary
medicine.
 
And there are some resources
that you can use,
if you get interested in this.
 
There's a book,
got twenty-three chapters in
it.
 
There is a website called
Evo-Med Symposia,
that you can go to,
and you can have talks on the
evolution of HIV,
antibiotic resistance,
etcetera;
and that's in Streaming Digital
video.
 
So each one of those talks
lasts about an hour.
So if you get interested in any
of that, you can actually
see--and by the way,
it's not just the PowerPoints,
you see the people giving the
talks.
So if you want to actually more
or less meet these people and
see what they're like,
that's a place that you can do
it.
 
Now the range of issues in
evolutionary medicine is really
quite large.
 
And I often get asked--you
know, people haven't heard the
term before, they don't know
what evolutionary medicine is.
So here is a description.
 
Okay?
 
Part of it is that we contain
traces of our evolutionary
history and they bias our
responses in significant medical
issues.
 
So there's the hygiene
hypothesis about autoimmune
disease.
 
There is our genetic variation
for resistance and drug
response.
 
There are traces of the
selection that illnesses,
that diseases,
have written on our genome.
Then there are issues in
reproductive medicine.
And the human life history is
really quite special.
If you contrast us to
chimpanzees or bonobos,
human females are capable of
pumping out children about twice
as fast as a female chimpanzee,
and the only way they can do it
is by having help.
 
So it indicates that we have
been highly social for a long
time, and our life history has
responded to that.
You know something about
genetic conflicts,
imprinting and mental disease,
because I talked about that
earlier.
 
Then there are the issues of
ovacytic atresia and selective
abortions and mate choice,
which are an interesting part
of reproductive medicine.
 
A big part of evolutionary
medicine has to do with the
evolution and ecology of
disease.
And diseases have adaptive
strategies.
They have their own agendas.
 
They have, many of them,
have developed ways of avoiding
our immune responses,
of manipulating hosts.
Some of them manipulate us;
that's what coughing and
sneezing is about.
 
That's also what making us
extremely tired and lying down
is about, in malaria.
 
Their virulence evolves,
they evolve drug resistance
rapidly, and those are very
significant medical issues.
Then there's all the
information that's coming in now
from evolutionary genetics and
genomics about where viruses
originated.
 
So, for example,
the detective work necessary to
determine that the sooty
mangabey was the ancestor of
HIV-2 is done with molecular
phylogenetics,
and that the chimpanzee is the
ancestor of HIV-1;
that the SIV living in the
chimpanzee is the ancestor of
HIV-1 is done that way.
 
Then there are very significant
differences between different
kinds of bacteria,
in terms of their genetics and
their population biology,
particularly in how readily
they can do horizontal gene
transfer.
So that if a bacterium in one
species evolves resistance to a
certain drug,
how likely is it that that
resistance gene will get into
another species?
Okay?
 
That's obviously a critical
question, and it depends on the
particular kind of evolutionary
genetics that that bacterium
has;
and they vary in this respect.
Okay?
 
And then there are all of the
issues about under what
conditions do new diseases
emerge?
And that itself is quite a
growing field.
Then there's all about the
degenerative diseases.
Okay? How did aging evolve?
 
And given that we have an
evolutionary theory of aging,
what can we expect to be the
characteristics of the aging
organism?
 
Are they going to be simple or
complex;
and if we fix one thing,
will another thing break?
That kind of issue.
 
We can view cancer as an
evolutionary process.
Every cancer is its own little
microevolutionary process.
A population of cancer cells is
a genetically heterogeneous ball
of growing cells;
that has important implications.
And then there are links here
in degenerative disease--in
heart disease,
obesity and diabetes--back to
traces of our evolutionary
history.
So that's the scale of the
issues.
If we think about the--oh let
me just run through that
quickly--
if we think about traces of our
history,
we usually think about
hunter-gatherers and the kinds
of groups that they lived in.
If we think about the
evolutionary biology of
diseases, we think about things
like Ebola and HIV and malaria.
And if we think about
degenerative diseases,
we think about this process.
 
So that's what evolutionary
medicine is about;
it's about a lot of different
stuff.
Okay?
 
So I can't talk about all of
that.
I've just described the course
that I gave last fall in
Copenhagen.
 
Okay?
 
It took two months.
 
>
 
So I could give you some
important classical themes.
I could give you some
surprising new insights.
I could give you some
overarching general messages,
such as our bodies are
compromises that impose indirect
costs;
or that evolution takes time;
or pathogens have their own
agendas.
I could present research,
stuff I've worked on myself.
I've done a fair amount on the
evolution of aging,
and I'm currently working on
how natural selection is
operating in contemporary human
populations.
Or I could give you messages
primarily aimed right at
practicing doctors;
so practical applications in
clinic and public health.
 
And this is what I chose:
I chose Mismatches to
Modernity.
 
So I'm going to talk a little
about thrifty phenotypes,
and parasites and autoimmune
disease;
and then I'm going to talk
about how pathogens have their
own agendas and evolve rapidly.
 
Okay?
 
So I hope you've got the
picture.
This is a small portion of the
subject matter of evolutionary
medicine.
 
But these are arguably
important themes.
So the point about thrifty
phenotypes is this:
Early life events are failing
to predict late life
environments.
 
Perhaps they used to be good
predictors,
or perhaps those early life
events were correlated well with
the environment in the
Pleistocene,
for ten or fifteen years,
something like that.
What we do know is this:
if you nutritionally stress a
mother and infant,
the fetuses and infants will
have increased risk of obesity,
diabetes and cardiovascular
disease fifty or sixty years
later.
And the initial data that
demonstrated this came from the
Dutch Hungry Winter.
 
The idea is that stress early
in life is switching the
individual into a physiology
that's very effective at
conserving energy,
but it is inappropriate if
there's an adequate diet.
 
So the muscle cells become
insulin resistant,
fat becomes concentrated in
special depots.
And we now have a lot of data
indicating that this is the case
in humans.
 
So they come from the Dutch
Hungry Winter of '44/'45,
when the Nazis basically cut
off the food supply to
Amsterdam, and actually to much
of Holland.
But you can also see this when
there have been historical
famines in Scandinavia.
 
In the late nineteenth century
there was a famine in Finland;
and more recently,
in the U.K.
and the Philippines.
 
And you can reproduce this in
rats and sheep.
By the way, the fact that you
can reproduce it in a model
system is quite important,
because it means that for
whatever reason that thing
evolved,
that kind of reason must also
have been there for something as
short-lived as a rat.
 
Now if we look around the
world, about 20% of American
adults are obese.
 
Interestingly,
in rural Mexico,
60 to 70% are obese.
 
That's not something you'd
necessarily expect;
go into rural Mexico,
you don't necessarily think
that those people have a lot of
money to eat a lot of food,
but they are obese.
 
The incidence of diabetes is
exploding;
so late-onset diabetes is
exploding.
As you might expect,
most of them are in India and
China, simply because the
populations of India and China
are so large.
 
And this is becoming a really
significant portion of the world
health budget.
 
So these are significant issues.
 
And if you look at percent
obese across many countries,
the least obese nation is
Japan, and a lot of the European
countries kind of have low
levels.
But the ones that have very
high levels of obesity are the
U.S., U.K., and Germany,
Australia.
These are not necessarily the
ones in which this kind of
nutritional stress early in life
would be very frequent.
It is much more likely that as
countries like India and China,
and countries in Africa and
Mexico,
go through the demographic
transition,
and go through the economic
transition into developing
countries,
so that they have a parental
generation that was more food
stressed,
and an offspring generation
which is more well fed,
and more exposed to junk food,
that you will get this kind of
a response.
 
So when we look at this kind of
data, there's a lot of this that
probably really isn't due to the
thrifty phenotype hypothesis.
I would guess that of the total
amount of obesity that you see
in the world,
the part which is really due to
a developmental switch being
thrown early in life,
and then setting that phenotype
up to respond inappropriately to
a rich diet late in life,
thereby developing heart
disease and obesity and so
forth,
at about the age of fifty or
sixty,
is probably somewhere down
around 5%.
So not all of it,
but probably a significant
component.
 
And the argument is that that
was something that was adaptive
in the Pleistocene environment,
because if you could switch the
offspring into a thrifty
phenotype,
it would have a higher
probability of surviving the
dangerous childhood years and
making it perhaps to its first
reproductive event.
 
And, in that environment,
what was going on at age fifty
or sixty was probably irrelevant
because most of the population
was dead by then anyway.
 
So that's the kind of
evolutionary argument that gets
at it.
 
I don't think we actually know
what's selected for this.
I think that we have a
plausible evolutionary story to
tell about it,
but the fact on the ground is
that it really happens.
 
So it's important to know
about, and it might be for the
evolutionary reasons that I just
mentioned, but we don't know.
Okay, now here's one where we
are a little bit more certain.
And again, this is a hypothesis
that is in the category of
things where humans are
mismatched to modernity.
So they are experiencing a
disease which is caused,
in part, by our historical
shift into a civilized state.
It runs like this:
our immune system coevolved
with worms and bacteria.
 
So it more or less evolved on
the assumption that we would
always have worms and bacteria
in our bodies.
And when modern hygiene--so
basically good clean water
systems--
and antibiotics take out the
worms and bacteria,
our immune systems respond
inappropriately.
 
We can see that autoimmune
diseases are actually exploding.
So asthma, allergy,
Type-1 diabetes,
multiple sclerosis,
other auto--Crohn's
disease--other autoimmune
diseases are increasing very
rapidly.
 
And as the infectious diseases
have gone down,
the autoimmune diseases have
gone up.
So there are some spatial
correlations that are
suggestive.
 
I'll show you some data that
are tighter than this.
But if you look across the
planet, you can see that where
diabetes, Type-1 diabetes is
common.
Type-1 is an autoimmune
disease, okay?
You see Type-1 diabetes being
common basically in Europe and
in Australia,
and it's also fairly common in
Saudi Arabia.
 
And if you look at where worms
and leprosy are common,
where countries that have a
fairly high incidence of these
different worm infections,
those are pretty much across
the Tropics.
 
The countries where there's no
data basically,
are in white.
 
So this is a partial plot.
 
And if you look at Type-1
diabetes against tuberculosis,
you see where there's a lot of
Type-1 diabetes there's not very
much tuberculosis,
and where there's a lot of
tuberculosis there's not very
much Type-1 diabetes.
Okay?
 
So that's a negative spatial
correlation.
There's more data than that.
 
In Germany, and in other
European countries,
farm children have fewer
allergies than city children.
If you go to Gabon and you go
around testing by just nicking
people on their arms--which is a
very easy test;
you just apply a little bit of
dust mite egg to somebody's arm
and see whether they have a
reaction--
the kids with schistosomiasis
don't have so many allergies,
and they don't have a reaction
to dust mites.
And if you look in these
countries, adults with less
asthma are more likely to be
infected with nematodes.
And just let me comment before
I take that one off,
that if you are a doctor
working in the Tropics,
you almost never see autoimmune
disease.
So if you go into
Médecins Sans
Frontières,
and you go to Gabon,
or you go to the Congo,
you'll see a lot of infectious
disease,
and you will see a lot of
worms, but you will not see very
much autoimmune disease.
That's the take-home message
from this summary.
Now how might this work?
 
Well worms are big,
multicellular parasites,
and they have to live in our
bodies a long time to reproduce
successfully.
 
When they send their eggs out,
to get into another host,
those eggs are going into an
extremely risky environment,
and it's not very likely that
any single individual egg is
going to make it.
 
So the worms have evolved ways
of living in our bodies,
for a long time,
without being knocked out by
our immune systems.
 
This has been going on for
hundreds of millions of years.
They're very good at it.
 
They are interfering with
signaling pathways that also
happen to be the pathways that
elicit allergies and asthma.
Now think about it from our
point of view.
We got these worms in our
system, and they got to be
really good at living in our
bodies for a long time,
but we have an immune system
that wants to react to them with
a big inflammatory response,
but it's not going to be able
to get rid of them,
because the worms have
out-foxed us.
 
So we have to make the best of
a bad deal.
What we have to do is we have
to down-regulate our
inflammatory response,
in the presence of worms,
so that we don't damage
ourselves;
because inflammatory responses
turn out to be one of the most
damaging parts of degenerative
disease.
That's what's going on in
arteriosclerosis.
That's what's going on in
rheumatoid arthritis;
you know, there's just a lot of
inflammatory response,
damage can happen to your body.
 
So our immune system basically
down-regulated,
in the presence of worms.
 
Now that means both sides of
this co-evolutionary interaction
have evolved.
 
So the causes really are rather
complex.
The parasites have been
removed, that actively
down-regulate the immune
response.
That leaves inappropriate
responses of our anti-worm
machinery,
and that anti-worm machinery
lacks proper targets and is
fooled by inappropriate targets.
There is ongoing research right
now to see whether or not this
is in part the basis for nut
allergies,
which--things like peanut
allergies--
which have really exploded.
 
It appears to be possibly part
of it, but probably not the
whole story.
 
And then, of course,
we have changed our
inflammatory response.
 
And another interesting part of
this--and again this is open
research--imagine your body
having come to evolutional
equilibrium with worm
infections.
So the worms are
down-regulating your immune
system,
and your immune system is
just--it has a lot of other
things to deal with besides
worms,
so it's cranking along,
it's producing a range of cells
that can react to different
kinds of invaders.
 
And it has a screening
apparatus, which is in your
spleen and in your thymus
glands,
to screen out any molecule or
any population of cells that is
recruited by your immune system
to attack your own tissue.
And it's screening along at
that level.
Then you pull the worms out.
 
The immune system is no longer
down-regulating because of the
presence of worms;
the immune system cranks up,
and it throws a lot of stuff at
that screening apparatus.
But the screening apparatus
didn't evolve to deal with that
much stuff.
 
So it's kind of leaky.
 
So it is letting through more
cells that might react with your
own tissue.
 
Okay?
 
That's a hypothesis;
that's not a demonstrated fact.
But what I'm trying to do is
I'm trying to indicate to you
that this issue of autoimmune
diseases arises logically,
either at the points where the
worms had been manipulating
signaling in the immune system,
and then that has been
withdrawn, or it is operating on
the screening mechanisms that
are built in for the immune
system;
both could be going on.
 
Now, what kind of data have we
got?
Well here--this is kind of
small, but basically what you've
got here is a knockout mouse
that simulates Type-1 diabetes.
Okay? So it's a model mouse;
people have genetically
constructed a model mouse,
to make it like Type-1 diabetes
in humans.
 
And then they have infected it
with various kinds of worms to
see whether or not it is
changing the T-cell bias in a
way that would be plausible to
basically down-regulate
autoimmune disease.
 
And these are things that
prevent Type-1 diabetes in
knockout mice.
 
So Schistosoma will do it,
Heligmosomoides will do it,
Trichinella will do it.
 
Mycobacterium--that's TB and
TB's relatives--will do.
Salmonella will do it.
 
Basically infectious agents are
antagonists of Type-1 diabetes
in model mice.
 
And if you ask a little bit
more widely, if you have an
animal model for another kind of
a disease, what can we treat it
with?
 
Well we've got Schistosoma,
we've got Trichinella,
Trichuris and so forth.
 
These things will prevent
colitis, inflammatory bowel
disease, collagen-inducted
arthritis, Graves' thyroiditis,
and so forth,
in model systems.
So there's some evidence in
animal model systems that this
works.
 
So if you decided that you
wanted to do therapy on humans,
using these nasty worms,
which have a big yuck factor,
which one would you choose?
 
Well you would want to have a
worm that doesn't really cause
much pathogenic problem itself
in a human.
You wouldn't want it to
multiply in the human.
You'd want to be able to
regulate the dose.
You wouldn't want the infection
to get away from you,
in treating a human.
 
You wouldn't want it to be
spread.
You wouldn't want it to alter
the behavior in patients that
have depressed immunity.
 
You wouldn't want to be
affected by common medications
like aspirin and stuff like
that.
Okay?
 
Well, which one will do that?
 
It turns out this pig whipworm
has these characteristics.
And what you can do is you can
breed these things in the
lab--I've seen them in Rick
Maizels' lab in Edinburgh,
growing in a little vial;
they're whipping around in the
little vial;
they look like little pieces of
thread--and basically you use
their eggs.
Now here's some data.
 
Patients with Crohn's disease
and ulcerative colitis improved
after ingesting 2500 pig
whipworm eggs.
I mean, you guys all have
issues with what they're serving
you in the dining hall.
 
>
 
How about a little pig whipworm
egg?
People with Crohn's disease who
got a fairly prolonged treatment
with this stuff responded well.
 
Patients with ulcerative
colitis, in a double-blind,
placebo controlled trial--which
is another step up in rigor--
did better on worm eggs than
they did on placebos.
But this is the one that really
gets me, and it's about multiple
sclerosis.
 
Okay?
 
This is a very,
very nasty disease,
and multiple sclerosis is an
autoimmune disease that attacks
the sheaths on the axons in your
brains,
and it does so in a slightly
different way in each
individual.
 
So the symptoms start
developing in different ways,
but basically what's happening
is that you're losing your
brain.
 
And these are some of the
symptoms: numbness,
tingling, pins and needles,
weakness,
spasm, spasticity,
cramps, pain,
blindness,
blurred vision,
incontinence,
urinary urgency,
constipation,
slurred speech,
loss of sex function,
loss of balance,
nausea, disabling fatigue,
depression, short-term memory
problems.
 
People with multiple sclerosis
often go to Switzerland to
commit suicide;
I think about 60 of them have,
because they're faced with
something which is a very
painful way for life to end.
 
Well there was a case control
study done recently in Argentina
that showed that the progress of
multiple sclerosis is a lot
slower in the patients that are
infected with parasitic worms.
And that was convincing
enough--this was a case control
study;
so for clinical medicine that's
sort of the gold standard.
 
You take a bunch of people and
you match them with cases and
controls, and then you see what
happens differently in the two
populations.
 
So the data there was
convincing enough to persuade
the NIH to begin a clinical
trial in Iowa in which MS
patients are being treated with
the eggs of pig whipworms.
Now this is the data from
Argentina,
and the X--by the way,
the four panels are four
different ways of measuring the
progress of multiple sclerosis,
and all four panels have a
five-year time axis on the
X-axis,
and then they have some measure
of multiple sclerosis on the
Y-axis.
And in all four panels the
uninfected patients--
they were matched at the start,
infected and uninfected by
worms,
and at the same stage of
multiple sclerosis--
the uninfected patients got
worse, and the infected patients
did not get worse.
Very clear.
 
When I first got in contact
with evolutionary medicine,
this hypothesis wasn't really
out there yet,
or wasn't very prominent.
 
It came to my attention ten
years ago.
I didn't believe it at the
time, and I'm actually rather
astonished that this is the part
of evolutionary medicine that is
actually resulting in an
important clinical result that
could change treatment and save
a lot of agony.
I hadn't expected that.
 
So humans evolve more slowly
than their cultures,
and therefore we are mismatched
to modern life.
This is important in both our
diet and in our cleanliness and
our hygiene.
 
And it appears,
certainly for the hygiene,
and quite possibly for
certainly people who are born
very food stressed and then
encounter junk food,
that that causes serious
medical problems.
So one of the visions of
evolutionary medicine is that we
evolved to a diet and an ecology
and a social life and a degree
of cleanliness that was
characteristic of a Pleistocene
hunter-gatherer group,
and that that's now changed
radically and we haven't caught
up yet;
our bodies have not yet
adjusted.
The other thing that I want to
tell you about basically is
about how pathogens evolve.
 
And they evolve very rapidly in
response to things that we do to
them, both to antibiotics and to
vaccines.
So the antibiotic resistance
story is in large part a story
about hospitals,
because that's where most
intense use of antibiotics is.
 
Virulence also evolves,
and there are lots of
interesting stories about how
virulence evolved.
For example,
plague in Europe,
from 1348 to 1350,
getting less virulent as it
goes northward;
or a new strain of syphilis
coming into Europe from the New
World and getting into Naples in
about 1500 and preventing the
French army from taking over
Italy at that time,
and then decreasing rapidly in
virulence as it spread.
 
There are lots of stories like
that in history,
and they're interesting.
 
But the issue that confronts us
today actually I think is most
tightly focused on what vaccines
will do,
because we are now
contemplating vaccines for a new
kind of disease,
not a childhood disease.
We're not looking at vaccines
that basically sterilize a
population.
 
We're looking at imperfect
vaccines, and the issue is will
they cause virulence to
increase?
So let's look at these.
 
So a little bit about
antibiotics first.
Okay?
 
Almost all of the bacterial
genes that allow them to process
the drugs that we use,
and deal with those drugs,
that provide them with
resistance,
evolved before the human drug
industry existed.
And that's because bacteria
have been engaged in warfare,
chemical warfare,
with each other and with fungi,
for hundreds of millions of
years.
And they are biochemical
maestros.
They have developed a large
spectrum of synthetic capacity,
and it's out there naturally in
nature.
There's about a ton of bacteria
per acre in a cropland;
that's about 10^(17th )bacteria.
 
That's an enormous number.
 
There's a lot of info that can
be stored in 10^(17th) bacteria.
Here's a little bit of data.
 
Drug resistance evolves in the
soil and in wild animals.
So if you go out and just take
out samples of spore-forming
bacteria from soil,
that's not near a hospital,
that's out there,
every single one of 480 strains
of bacteria was multiply
resistant,
and there was no existing class
of drug that was effective
against all strains.
 
That's just natural variation
that's out there.
Okay?
 
That is the downside of
biodiversity.
There's a lot of evolutionary
potential in natural bacteria.
If you go around the outback,
in Australia,
and you sample enteric
bacteria, that is gut bacteria,
from various Australian
mammals--you do this essentially
by collecting feces--
what you find is that they have
multiply resistant strains of
bacteria;
and they have never been close
to a city, or to human beings
that are taking antibiotics.
 
So that's on the one hand;
that's what's out there
naturally.
 
Now what are we doing to it?
 
Well the agricultural use of
antibiotics is quite important.
I'm going to talk a bit about
hospitals in a minute.
But the reason that farmers use
antibiotics is that by reducing
the amount of energy that their
pigs,
cattle and chickens have to put
into resisting disease,
their pigs, cattle and chickens
grow more rapidly.
So it pays them.
 
If they use antibiotics,
they increase their production.
So one antibiotic that's
actually quite critical is
vancomycin.
 
Vancomycin has been the last
line of defense against multiply
resistant staphylococcus aureus
for about twenty years.
You don't want resistance to
evolve to vancomycin.
If it does evolve to
vancomycin, it becomes very hard
to do surgery in hospitals.
 
Well Danish farmers were using
vancomycin, and the Danish
government noticed that and
banned it.
So we have a before/after
comparison of how frequently do
you pick up vancomycin resistant
enterococci bacteria in
Copenhagen, in the city?
 
Well it dropped from 12% to 3%.
 
There was a 9% rate drop in the
rate at which doctors picked up
vancomycin resistant bacteria in
the city,
when they stopped using it out
there on the farms.
That is a measure of how dirty
the meat processing plants are,
on the one hand.
 
Okay?
 
There's crap getting into the
meat.
There's a movie about that,
by the way, about McDonald's;
it will really turn your
stomach.
But it also indicates just how
important the widespread
agricultural use is.
 
Now the other place where
there's really a lot of
antibiotic use is in the
hospital.
Okay?
 
So the Center for Disease
Control estimated--
I think this is in 2003--that
there were 90,000 residents of
the United States that went into
the hospital for some other
reason,
picked up a resistant
bacterium, and died of a
bacterial infection that they
didn't have when they went into
the hospital.
And when the cynical
researchers checked the claims
to the health insurance
companies,
they discovered that the actual
number was probably ten times
higher than that.
 
So this is just for comparison.
 
AIDS was killing 17,000 a year
in the U.S.
at the time;
flu about 37,000;
breast cancer about 40,000.
 
So there are actually more
people who were dying of
bacterial infections that they
acquired in hospitals than of
all of these leading killers
combined.
Now the bacteria that live in
hospitals are almost all either
resistant or multiply resistant,
because that's where so many
antibiotics are used.
 
And it's a good thing to use
antibiotics in hospitals.
Okay?
 
When you bring somebody into
the Emergency Room,
or if they're in Intensive
Care, and they are possibly just
a few hours away from having to
have an operation,
you don't want them to be in a
susceptible state.
You want them to be clean,
when they go into that
operating theater.
 
So you're going to use
antibiotics on them to increase
their probability of survival,
if they have to have a major
operation.
 
But the consequence of that,
which is of benefit for the
individual, is a cost for the
population.
And resistant strains are much
more expensive to cure.
The cost of curing one case of
TB, if it's not resistant,
is about 15 to $20,000.00,
and the cost of curing one case
of multiply resistant
tuberculosis is about a quarter
of a million dollars.
 
So it's about ten times higher.
 
So the economic burden for the
U.S.
was about 80 billion annually,
for resistance,
and the economic burden for the
planet is probably about a
trillion.
 
It's a big problem.
 
So basically I'm going to just
put--I'm not going to read all
the way through this.
 
Okay?
 
Basically what this says is
people move back and forth
between hospitals and nursing
homes, and when they move,
they move the bacteria with
them.
And so however you're managing
it in the hospital,
you have to deal with a
situation where it could be
coming back in.
 
And I can tell you that if you
operate a nursing home,
you're just deathly afraid that
one of your patients in the
nursing home is going to come up
with a multiply resistant strain
of bacterium,
because in old people that can
go through and just wipe them
out.
You'll get incurable pneumonia
very quickly occurring.
This idea--well let me just go
back here.
In this context of the ecology
of hospitals and nursing homes,
there's been some fairly
sophisticated thought given to
how should we manage the use of
antibiotics.
The kind of simple-minded way,
which has often been used,
is that well we'll just cycle
the antibiotics.
We'll use Antibiotic A for
three weeks in the hospital,
and then we'll replace it with
Antibiotic B;
and that way every time they
start to evolve resistance to
Antibiotic A,
they get hit with Antibiotic B,
and so forth.
 
It turns out that produces a
selection regime which is
extremely effective at causing
the rapid evolution of multiple
resistance;
happens again and again and
again.
 
Turns out the best way to
really screw up the bacteria is
to assign antibiotics at random,
to individual patients within
the hospital,
and change them about every two
days.
 
Well that would drive the
nursing staff crazy;
I mean, that's just hard to
manage.
Right?
 
But that's the most effective
method.
Well if we apply that to
chemotherapy,
what we notice when we look at
the community of oncologists is
that many of them aren't aware
that a cancer is a genetically
heterogeneous population of
cells.
I mean, the whole thing that
gets a cancer going is an
optimum mutation rate,
and those cells continue to
mutate;
so they become quite
genetically heterogeneous.
 
It takes seven to nine
mutations to turn a stably
differentiated cell into a
cancer cell, one after the
other.
 
And those cells then--and by
the way, the mutations that do
it are often mutations to the
DNA repair apparatus.
So cancer cells tend to have a
pretty elevated mutation rate,
and they become- a cancer
becomes very genetically
heterogeneous.
 
So if you start prescribing one
chemotherapy,
and wait until it fails,
and then start another one,
you are applying a selection
pressure that very effectively
selects for resistance to
chemotherapy.
So if a more sophisticated
strategy were used,
it's been calculated that the
lifespan of cancer patients
might be prolonged by well
several times;
it all depends on the cancer.
 
But say take something like
breast cancer,
instead of perhaps having a ten
or twenty year potential
survival,
you might be able to manipulate
the chemotherapy to have a
thirty to forty year potential
survival;
which for many women would get
it to their normal lifespan.
 
So this is a place where
evolutionary models can actually
really help to better manage the
use of antibiotics.
Okay, virulence.
 
Now I've used Ebola,
HIV and malaria to symbolize
the three different stages in
the evolution of virulence when
a disease emerges and moves into
the human population,
and then starts to become
adapted to it.
So the first phase,
which would be Ebola,
Lyme disease,
bird flu, SARS,
rabies, it's accidental;
it's an accidental infection.
It's coming in from another
species, it's not adapted to us
yet, and sometimes these things
are just incredibly virulent.
By the way, they aren't always.
 
We probably don't even notice
the thousands that come into us
and never take root and die off
quickly,
because they simply pass
without having caused any major
disease.
 
But the point,
the reason that some of them,
some perhaps small proportion,
are highly virulent is that
they've never had any
evolutionary experience in
humans,
and they're not adapted to the
level of virulence that's best
for them.
They kill us too quick;
they kill us so quickly they
can't get out.
 
Ebola is essentially a
self-snuffing disease.
It won't spread out of one
village, because everybody's
dead too quickly for it to
transmit.
Phase Two would be one in which
the parasite's been established,
but it's still far away from
its optimal virulence.
Okay?
 
So this is probably the case
with HIV.
The virulence of HIV is
probably still evolving.
It's been in humans,
we think, about seventy,
eighty years,
something like that.
And the Myxoma virus that was
used on rabbits in Australia.
So it evolved its virulence
downward in Australia,
because it was killing rabbits
too fast.
Then in Phase Three you're
dealing with a parasite that's
well established,
it's been in that host for a
very long time.
 
It's probably at its optimal
level of virulence.
Okay?
 
So yes, it will kill some
people, but it doesn't kill them
too fast.
 
It kills them at a rate where
most of it can still get out and
get into another individual,
before the first host dies.
And that's probably the case
with malaria and tuberculosis.
So let's take something which
is in Phase Two,
and put it to work.
 
So here's where virulence
evolution actually becomes part
of a medical technology.
 
Microbiologists have been using
serial passage to produce
attenuated vaccines for a long
time.
And what an attenuated vaccine
is, is a pathogen that would
cause a serious disease,
but it's been evolutionarily
changed, so that it's
attenuated.
It will infect you but it won't
make you sick,
and it will therefore elicit a
very strong immune response,
which is also effective against
the unattenuated relatives.
And that's been used to produce
the Sabin oral polio vaccine;
the measles,
mumps, rubella,
yellow fever and chickenpox
vaccines;
one flu vaccine;
and a TB vaccine and a typhoid
vaccine.
 
So this is actually showing you
that rapid evolution of
virulence is a medical
technology, and has been now for
fifty years.
 
The reason it works is that
pathogens evolve rapidly.
And the results demonstrate
that there really are widespread
tradeoffs in performance on
different hosts.
This tradeoff right here,
that you do well on one host
and poorly on another--that a
jack-off-all trades is a master
of none;
the master of one doesn't do
well on another--limits host
range and constrains the
emergence of new diseases.
 
So these kinds of data,
which basically were directly
technically related to the
production of vaccines,
are indirectly telling us a lot
about pathogen evolution and
ecology.
 
Here's the way it works.
 
What you do is you get a nice
genetically homogenous mouse,
which is not going to be any
kind of a genetic challenge to
the parasite.
 
So you give it a sitting
duck--except it's a sitting
mouse--and you inject it with
parasite;
parasite grows exponentially,
and while it's still in
exponential growth phase,
you take some of it out.
You remove its transmission
costs.
You take away any tradeoff it
might have had with
transmission.
 
Okay?
 
So it's going to become really
bad at transmission,
but boy does it get good at
growing in this thing.
You extract it,
you re-inject it,
and you let it go through
exponential phase--you just keep
it in exponential phase the
whole time.
You're killing mice like crazy.
 
This is what happens.
 
This is a passage through mice.
 
This is the percentage of dead
mice.
This is salmonella.
 
So you start it in a new host,
and it gets more and more
virulent in that host.
 
As it specializes on its new
host, it gets really good at
growing in that host.
 
This is what happens through
passages in cell culture.
And this is the number of
monkeys being killed for polio
virus.
 
And this is actually Sabin's
original data.
Okay?
 
So he's passaging polio through
cell culture.
So it's really good at living
in cell culture.
It's getting really lousy at
living in monkeys,
and the longer it lives in cell
culture,
the fewer monkeys it kills,
until after 50 passages in cell
culture it isn't deadly at all,
in monkeys;
and at that point they began a
clinical trial and put it into
humans.
 
Okay, so the point of that--I
mean, there are a number of
points in that whole story about
manipulating virulence.
One is, virulence can evolve
really quick.
Virulence has been manipulated
by medical technology,
for the last fifty years,
to produce some of the most
successful vaccines on the
planet.
That itself is an impressive
confirmation of this hypothesis,
that I've just put up there,
which is that in order to do
really well on one host,
you have to give up the ability
to infect others.
 
So if you want to produce a
vaccine that's a live,
attenuated vaccine,
that infects a human,
you take it out of the human,
you put it into something else;
you make it really good at
killing that other thing;
it becomes lousy at killing
humans, and when it gets lousy
enough at killing humans,
you can use it as a live
vaccine.
 
Now there's one more thing I
want to tell you about
evolutionary medicine,
and that's about whether
virulence will evolve in
response to vaccines.
So I've already introduced you
to the virulence transmission
tradeoff.
 
If you're too virulent,
you won't transmit,
because you will have killed
your host before you can get
out.
 
Okay?
 
This is supposed to be the most
fundamental tradeoff shaping
virulence evolution.
 
It's thought to be widespread,
and it really is thought to
drive virulence to an
intermediate level.
There's quite a bit of evidence
indicating that this is,
broadly speaking,
true.
Okay?
 
Now what happens when you make
an imperfect vaccine?
It does pretty well,
but it doesn't kill all of the
pathogens in all of the hosts.
 
Okay?
 
That's why we call it
imperfect.
Well that imperfect vaccine
will reduce the cost of
virulence by making likely that
some hosts will survive in the
presence of virulent strains.
 
So you're getting a partial
immune response.
The pathogen can persist in the
body, a longer period of time;
because, after all,
the vaccine is working a bit.
But then if the virulent
strains are the more competitive
ones,
and you've got multiple
infection, then the virulent
strains are the ones that are
going to be surviving the
longest in the bodies of people
that have an imperfect response
to the vaccine.
Okay?
 
So it turns out that this
actually happens in mice with
malaria;
you can demonstrate with mouse
malaria that this is the case.
 
And the Gates Foundation and
WHO would like to vaccinate 500
million humans against malaria.
 
All of the malaria vaccines are
imperfect;
as a matter of fact,
there isn't one that's really
very good at all yet,
but it looks like all the
malaria vaccines will be
imperfect.
And that really creates an
ethical or public health
dilemma, which is rather similar
to antibiotic resistance.
It's going to be really good
for the individual human being
to be vaccinated against
malaria.
Hundreds of millions of lives
would probably be saved.
But, as an unfortunate
byproduct of this wonderful
thing,
we are probably going to have a
situation in which the surviving
disease becomes more virulent,
and a few people are then hit
by a really nasty strain of
malaria.
 
So, as with antibiotic
resistance, it's probably a good
thing to know,
that this might happen,
so that you can start getting
ready for it.
It's not a recommendation that
you don't vaccinate,
it's a recommendation that you
understand the consequences of
vaccination,
which are evolutionary,
and be prepared to deal with
them.
So if you're interested in this
particular thing,
I've listed authors that you
can search on.
So the take-home on
evolutionary medicine basically
is that evolutionary thinking
actually provides some
interesting new illuminations of
problems in both medical
research and practice.
 
But it certainly doesn't
eliminate,
or replace, all of that other
important insight that we've
gotten from molecular medicine,
and basically from
evidence-based scientific
medicine,
up to this point.
 
There's just a tremendous
amount in physiology and
genetics and biochemistry which
is absolutely essential to know.
This, however,
also is something that is
important to know.
 
Okay, see you tonight,
if you're coming.
