and actually all the way down into the sewer

because I want to talk about diarrhea.

And in particular, I want to talk about

the design of diarrhea.

And when evolutionary biologists talk about design,

they really mean design by natural selection.

And that brings me to the title of the talk,

"Using Evolution to Design Disease Organisms Intelligently."

And I also have a little bit of a sort of smartass subtitle to this.

But I'm not just doing this to be cute.

I really think that this subtitle explains

what somebody like me, who's sort of a Darwin wannabe,

how they actually look at one's role in

sort of coming into this field of health sciences and medicine.

It's really not a very friendly field for evolutionary biologists.

You actually see a great potential,

but you see a lot of people who are sort of defending their turf,

and may actually be very resistant, when one tries

to introduce ideas.

So, all of the talk today is going to deal with two general questions.

One is that, why are some disease organisms more harmful?

And a very closely related question, which is,

how can we take control of this situation once we understand

the answer to the first question?

How can we make the harmful organisms more mild?

And I'm going to be talking, to begin with, as I said,

about diarrheal disease organisms.

And the focus when I'm talking about the diarrheal organisms,

as well as the focus when I'm talking about any organisms

that cause acute infectious disease,

is to think about the problem from a germ's point of view,

germ's-eye view.

And in particular, to think about a fundamental idea

which I think makes sense out of a tremendous amount of variation

in the harmfulness of disease organisms.

And that idea is that from the germ's-eye point of view,

disease organisms have to get from one host to another,

and often they have to rely on the well-being of the host

to move them to another host.

But not always.

Sometimes, you get disease organisms

that don't rely on host mobility at all for transmission.

And when you have that, then evolutionary theory tells us

that natural selection will favor the more exploitative,

more predator-like organisms.

So, natural selection will favor organisms

that are more likely to cause damage.

If instead transmission to another host requires host mobility,

then we expect that the winners of the competition

will be the milder organisms.

So, if the pathogen doesn't need the host to be healthy and active,

and actual selection favors pathogens

that take advantage of those hosts,

the winners in the competition are those that exploit the hosts

for their own reproductive success.

But if the host needs to be mobile in order to transmit the pathogen,

then it's the benign ones that tend to be the winners.

So, I'm going to begin by applying this idea to diarrheal diseases.

Diarrheal disease organisms get transmitted in basically three ways.

They can be transmitted from person-to-person contact,

person-to-food-then-to-person contact,

when somebody eats contaminated food,

or they can be transmitted through the water.

And when they're transmitted through the water,

unlike the first two modes of transmission,

these pathogens don't rely on a healthy host for transmission.

A person can be sick in bed and still infect tens, even hundreds

of other individuals.

To sort of illustrate that, this diagram emphasizes that

if you've got a sick person in bed,

somebody's going to be taking out the contaminated materials.

They're going to wash those contaminated materials,

and then the water may move into sources of drinking water.

People will come in to those places where you've got

contaminated drinking water,

bring things back to the family,

may drink right at that point.

The whole point is that a person who can't move

can still infect many other individuals.

And so, the theory tells us that

when diarrheal disease organisms are transported by water,

we expect them to be more predator-like, more harmful.

And you can test these ideas.

So, one way you can test is just look at all diarrheal bacteria,

and see whether or not the ones that tend to be

more transmitted by water, tend to be more harmful.

And the answer is -- yep, they are.

Now I put those names in there just for the bacteria buffs,

but the main point here is that --

(Laughter)

there's a lot of them here, I can tell --

the main point here is that those data points

all show a very strong, positive association between

the degree to which a disease organism is transmitted by water,

and how harmful they are,

how much death they cause per untreated infection.

So this suggests we're on the right track.

But this, to me, suggests that we really need

to ask some additional questions.

Remember the second question that I raised at the outset was,

how can we use this knowledge

to make disease organisms evolve to be mild?

Now, this suggests that if you could just block waterborne transmission,

you could cause disease organisms to shift from

the right-hand side of that graph to the left-hand side of the graph.

But it doesn't tell you how long.

I mean, if this would require thousands of years,

then it's worthless in terms of controlling of these pathogens.

But if it could occur in just a few years,

then it might be a very important way to control

some of the nasty problems that we haven't been able to control.

In other words, this suggests that we could

domesticate these organisms.

We could make them evolve to be not so harmful to us.

And so, as I was thinking about this, I focused on this organism,

which is the El Tor biotype of the organism called Vibrio cholerae.

And that is the species of organism that is responsible

for causing cholera.

And the reason I thought this is a really great organism to look at

is that we understand why it's so harmful.

It's harmful because it produces a toxin,

and that toxin is released when the organism

gets into our intestinal tract.

It causes fluid to flow from the cells that line our intestine

into the lumen, the internal chamber of our intestine,

and then that fluid goes the only way it can, which is out the other end.

And it flushes out thousands of different other competitors

that would otherwise make life difficult for the Vibrios.

So what happens, if you've got an organism,

it produces a lot of toxin.

After a few days of infection you end up having --

the fecal material really isn't so disgusting as we might imagine.

It's sort of cloudy water.

And if you took a drop of that water,

you might find a million diarrheal organisms.

If the organism produced a lot of toxin,

you might find 10 million, or 100 million.

If it didn't produce a lot of this toxin,

then you might find a smaller number.

So the task is to try to figure out

how to determine whether or not you could get an organism like this

to evolve towards mildness by blocking waterborne transmission,

thereby allowing the organism only to be transmitted

by person-to-person contact,

or person-food-person contact --

both of which would really require that people be

mobile and fairly healthy for transmission.

Now, I can think of some possible experiments.

One would be to take a lot of different strains of this organism --

some that produce a lot of toxins, some that produce a little --

and take those strains and spew them out in different countries.

Some countries that might have clean water supplies,

so that you can't get waterborne transmission:

you expect the organism to evolve to mildness there.

Other countries, in which you've got a lot of waterborne transmission,

there you expect these organisms to evolve

towards a high level of harmfulness, right?

There's a little ethical problem in this experiment.

I was hoping to hear a few gasps at least.

That makes me worry a little bit.

(Laughter)

But anyhow, the laughter makes me feel a little bit better.

And this ethical problem's a big problem.

Just to emphasize this, this is what we're really talking about.

Here's a girl who's almost dead.

She got rehydration therapy, she perked up,

within a few days she was looking like a completely different person.

So, we don't want to run an experiment like that.

But interestingly, just that thing happened in 1991.

In 1991, this cholera organism got into Lima, Peru,

and within two months it had spread to the neighboring areas.

Now, I don't know how that happened,

and I didn't have anything to do with it, I promise you.

I don't think anybody knows,

but I'm not averse to, once that's happened,

to see whether or not the prediction that we would make,

that I did make before, actually holds up.

Did the organism evolve to mildness in a place like Chile,

which has some of the most well protected water supplies

in Latin America?

And did it evolve to be more harmful in a place like Ecuador,

which has some of the least well protected?

And Peru's got something sort of in between.

And so, with funding from the Bosack-Kruger Foundation,

I got a lot of strains from these different countries

and we measured their toxin production in the lab.

And we found that in Chile -- within two months of the invasion of Peru

you had strains entering Chile --

and when you look at those strains,

in the very far left-hand side of this graph,

you see a lot of variation in the toxin production.

Each dot corresponds to an islet from a different person --

a lot of variation on which natural selection can act.

But the interesting point is, if you look over the 1990s,

within a few years the organisms evolved to be more mild.

They evolved to produce less toxin.

And to just give you a sense of how important this might be,

if we look in 1995, we find that there's only one case of cholera,

on average, reported from Chile every two years.

So, it's controlled.

That's how much we have in America,

cholera that's acquired endemically,

and we don't think we've got a problem here.

They didn't -- they solved the problem in Chile.

But, before we get too confident, we'd better look at some of those other countries,

and make sure that this organism doesn't just always evolve toward mildness.

Well, in Peru it didn't.

And in Ecuador -- remember, this is the place where it has

the highest potential waterborne transmission --

it looked like it got more harmful.

In every case there's a lot of variation,

but something about the environment the people are living in,

and I think the only realistic explanation is that it's

the degree of waterborne transmission,

favored the harmful strains in one place, and mild strains in another.

So, this is very encouraging,

it suggests that something that we might want to do anyhow,

if we had enough money, could actually give us a much bigger bang for the buck.

It would make these organisms evolve to mildness,

so that even though people might be getting infected,

they'd be infected with mild strains.

It wouldn't be causing severe disease.

But there's another really interesting aspect of this,

and this is that if you could control the evolution of virulence,

evolution of harmfulness,

then you should be able to control antibiotic resistance.

And the idea is very simple.

If you've got a harmful organism,

a high proportion of the people are going to be symptomatic,

a high proportion of the people are going to be going to get antibiotics.

You've got a lot of pressure favoring antibiotic resistance,

so you get increased virulence leading to

the evolution of increased antibiotic resistance.

And once you get increased antibiotic resistance,

the antibiotics aren't knocking out the harmful strains anymore.

So, you've got a higher level of virulence.

So, you get this vicious cycle.

The goal is to turn this around.

If you could cause an evolutionary decrease in virulence

by cleaning up the water supply,

you should be able to get an evolutionary decrease

in antibiotic resistance.

So, we can go to the same countries and look and see.

Did Chile avoid the problem of antibiotic resistance,

whereas did Ecuador actually have the beginnings of the problem?

If we look in the beginning of the 1990s,

we see, again, a lot of variation.

In this case, on the Y-axis, we've just got a measure of antibiotic sensitivity --

and I won't go into that