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