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  • What I'd like to do is just drag us all down into the gutter,

  • 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