Can we domesticate germs Paul Ewald

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 it’s and when

evolutionary biologists talk about

design they are they really mean

designed 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 yeah but I’m not just doing this to

be cute I really think that the subtitle

explains what somebody like me is sort

of a Darwin wannabe how they are to look

at one’s role in sort of coming into

this field of Health Sciences in

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 and may

actually be very resistant to try to

resistant when one tries to introduce

ideas so all of the talk today is going

to deal with two general questions one

is it why are some disease organisms

more harmful in a very closely related

question which is how can we take

control of this situation once we

understand the answered the first

question how can we make the harmful

organisms more mild and I’m really

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 germs

point of view germ side view and in

particular to think about a fundamental

idea which I think makes sense out of

tremendous amount of variation in the

variation in the harmfulness of disease

organisms and that idea is that from the

germs my 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 soup theory tells us that

natural selection

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 the competition will be the

milder organisms so if the pathogen

doesn’t need the host to be healthy and

active natural 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 are tend to be the winners so I’m

going to begin by applying this idea to

diarrheal diseases sterile disease

organisms get transmitted in basically

three ways they can be transmitted from

person 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 got

a sick person in bed somebody is 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 into the 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 you should look at all

diarrhea 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

and I put those names in there just for

the bacteria buffs but the main point

here is is that the lot of them here I

can tell the main point here is that

those data points are show a very strong

positive association between the degree

to which the disease organism is

transmitted by water and how harmful

they are how how much death they caused

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 in 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 that graph but it

doesn’t tell you how long I mean if 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 we we just suggest 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

alt or bio type 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 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 the internal chamber of our

intestine and then that fluid goes on

when we 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 produces a lot of toxin after a

few days of infection you end up having

you have to fecal material really isn’t

it’s 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 diarrhea organisms if if the

organism produced a lot of toxin you

might find ten million or 100 known it

didn’t prove a lot of this toxin then

you might find a smaller number so the

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 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 of some possible

experiments one would be to take a lot

of different strains of this organism

something

a lot of toxins something produced a

little and take those strains and spew

them out in different countries some

countries that might have clean water

supplies they so 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 yeah I hope I was I was

hoping to hear a few gasps at least that

makes me worried a little bit but anyhow

the laughter can makes me feel a little

bit better and this ethical problems a

big problem just to emphasize this this

is what we’re really talking about

here’s a girl’s almost dead she got

rehydration therapy she’s being cooked

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 1991 this cholera

organism got into Lima Peru and within

two months it had spread to the

neighboring areas now I didn’t have I

don’t know how that happened and I

didn’t have anything to do with that I

promise you I don’t think anybody knows

but I’m not averse to 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 those at

Krueger Foundation I got a lot of

strains from these different countries

and I met we measure 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 upper left

hand side of this graph you see a lot of

variation in their toxin production each

dot corresponds to an isolate from a

different person a lot of variation on

which natural selection act 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 caller on average reported from Chile

every two years so it’s controlled

apology that’s not much we have in

America a 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’ve got to look at some

of those other countries make sure that

this organism doesn’t just always evolve

towards mildness well improve it didn’t

and in Ecuador remember this is the

place where there’s 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 that

people are living in and I think that

the only realistic explanation is that

it’s the the degree of waterborne

transmission favored the harmful strains

in one place in mild strains in another

so this is very encouraging it suggests

that something that we might want to do

anyhow if he 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

could be infected of mild strains that

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

the people are going to be symptomatic

high proportions people going to be

going to get antibiotics you 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 are knocking out the

harmful strains anymore so you’ve got a

higher level of Maryland 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 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 but we’ve got a lot of

variation in antibiotic sensitivity and

Chile pruin active our know trend across

the years but if we look at the end of

the 1990s just half a decade later we

see that in Ecuador they started having

a resistance problem antibiotic

sensitivity was going down and in Chile

you still had antibiotic sensitivity so

it looks like Chile dodged

two bullets they got the organism

involved the mildness and they got no

development of antibiotic resistance now

these ideas should apply across the

board as long as you can figure out why

some organisms evolve to virulence and I

want to give you just one more example

because we’ve talked a little bit about

malaria in the example I want to deal

with this or the idea I wanted to deal

with a question is what can we do to try

to get the malaria organism evolve to

mildness now malaria is transmitted by

mosquito and normally if you’re infected

with malaria and you’re feeling sick it

makes it even easier for the mosquito to

to bite you and you can show just by

looking at data and literature that

vector borne diseases are more harmful

than non vector borne diseases but I

think there’s a really fascinating

example of what one can do

experimentally to try to actually

demonstrate this in the case of

waterborne transmission we’d like to

clean up the water supplies see whether

or not we can get those organisms to

evolve towards mildness in the case of

malaria what we’d like to do is

mosquito-proof houses and and the logic

is a little more subtle here if your

mosquito-proof houses when people get

sick they’re sitting in bed or the skete

above hospitals they’re sitting in a

hospital bed and the mosquitoes can’t

get to them so if you’re a harmful

variant in a place where you’ve got

mosquito proof housing then you’re a

loser

the only pathogen to get transmitted are

the ones that are detecting people to

feel healthy enough to walk outside and

get mosquito bites so if you were to

mosquito-proof houses you should be able

to get these organisms to evolve to

mildness and there’s a really wonderful

experiment that was done that suggest

that we really should go ahead and do

this and that experiment was done in

northern Alabama just to give you a

little perspective and this I’ve given

you a star at the intellectual center of

the United States which is right there

in Louisville Kentucky and this really

cool experiment was done about 200 miles

south of there in northern Alabama by

the Tennessee Valley Authority they had

dammed up the Tennessee River that

caused the water to back up these

electric hydroelectric power and when

you get stagnant water you got

mosquitoes they found in the in the late

30s ten years after they’d made these

dams that the people in northern Alabama

were infected with malaria about a third

of the third to half of them are

infected with malaria guys it shows the

positions of some of these dams okay so

the Tennessee Valley Authority was a

little bit of a bind

there wasn’t DDT there wasn’t chloric

winds what did they do well they decided

a mosquito poof every house northern

Alabama so they did they divided

northern Alabama in 11 zones and within

three years about $100 per house they

mesquite approved every house and these

are the data every row across here

represents one of those 11 zones and the

asterisks represent the time at which

the mosquito proofing was complete and

so what you can see is that just the

mosquito proofing housing and nothing

else caused the eradication of malaria

and this was incidentally published in

1949 in the leading textbook of malaria

called Boyd’s malaria ology but almost

no malaria experts even though it exists

this is important because it tells us

that if you have moderate biting

densities you can eradicate malaria by

mosquito proofing houses now I would

suggest that you could do this in a lot

of places like you know sub tear and

just as you get into the malaria zone

it’s up to in Africa but as you move to

really intense biting right areas like

Nigeria you’re probably not certainly

not going to Radek eight but that’s when

you should be favoring evolution towards

mildness so to me it’s just an

experiment that’s waiting to happen if

it confirms the prediction then we

should be you should have a very

powerful tool in a way much more

powerful than the kind of tools we’re

looking at because most of what’s being

done today is to rely on things like

anti malarial drugs and we know that

although it’s great to make those anti

malarial drugs available in really low

cost and high high frequency we know

that with when you make no highly

available you’re going to get resistance

to those drugs and so it’s a short-term

solution this is this long-term solution

what I’m suggesting here is we could get

evolution working in the direction we

want it to go rather than always having

to battle evolution is a problem that

stymies our efforts to control the

pathogen for example with anti malarial

drugs so this table I’ve given just to

emphasize that I’ve only talked about

two examples but as I said earlier this

kind of logic applies across the board

for infectious diseases and it ought to

because when we’re dealing with

infectious diseases we’re dealing with

living systems we’re dealing with living

we’re dealing with systems that evolve

and so if you do something those systems

they’re going to evolve one way or other

and all I’m saying is that we need to

figure out how they’ll evolve so that we

need to adjust our interventions to get

the most bang for the intervention buck

so that we can get these organisms to

evolve in the direction we want them to

go so I don’t really have time to talk

about those things but I did want to put

them up there just to give you a sense

that there really are solutions to

controlling the evolution of harmfulness

of some of the nasty pathogens that were

confronted with and and this this links

up with a lot of the other ideas have

been talked about so for example earlier

today we you know there’s a discussion

of how do you really lower sexual

transmission of HIV what this emphasizes

is that we need to figure out how to

lower it maybe get lowered if we alter

the economy of the area it may get

lowered if we intervene in ways that

encourage people to stay more faithful

departments and so on but the key thing

is to figure out how to lower it because

if we lower it we’ll get an evolutionary

change in the virus and the data really

do support this that you actually do get

the virus evolving towards mildness and

that will just add to the effectiveness

of our control efforts so the other

thing I really like about this besides

the fact that it brings a whole new

dimension into the study of control of

disease is that often the kinds of

interventions that you want to that it

indicates should be done are the kind of

Vengeance interventions that people want

anyhow but people just haven’t been able

to justify the cost so this is the kind

of thing I’m talking about if we know

that we’re going to get extra bang for

the buck from providing clean water then

I think that we can say let’s push the

effort into that aspect of the control

so that we can actually solve the

problem even though if you just look at

the frequency of infection you would

suggest that you can’t solve the problem

well enough just by cleaning up water

supply you know oh in there and thank

you very much

you