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>> So now what we understand is that
all bacteria can talk to each other.

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They make chemical words, they recognize
those words, and they turn on group behaviors

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that are only successful when all
of the cells participate in unison.

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And so now we have a fancy name for this.

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We call it "quorum sensing".

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They vote with these chemical votes.

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The vote gets counted, and then
everybody responds to the vote.

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And what's important for today's talk is that
we know that there are hundreds of behaviors

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that bacteria carry out in
these collective fashions,

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but the one that's probably the
most important to you is virulence.

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So it's not like a couple bacteria get in you,
and then they start secreting some toxins.

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You're enormous.

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That would have no effect on you.

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You're huge.

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But what they do, we now understand,
is they get in you; they wait.

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They start growing.

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They count themselves with these
little molecules, and they recognize,

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when they have the right cell number,

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that if all of the bacteria launch
their virulence attack together,

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they're going to be successful
at overcoming an enormous host.

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[ Applause ]

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>> Hi! I'm delighted to be back
to give you a little progress

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about what we've been doing in quorum sensing.

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And so today, I want to tell you one story
about how we're taking what we learned

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about these bacteria talking together and
trying to interfere with that conversation,

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to make a fundamentally new kind of antibiotic.

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And so the story I'll tell you about concerns
this pathogen, Pseudomonas aeruginosa.

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This is the bacterium that kills
people who have cystic fibrosis.

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It kills immune-compromised
people, and it causes infections

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when you get a catheter, a
stent or a breathing tube.

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And the reason Pseudomonas is so virulent is

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because of this chemical
communication, this quorum sensing.

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What Pseudomonas does is that as it grows,
it makes and releases small molecules,

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which are the red triangles on this slide.

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And so as the cells grow, these
molecules that are outside

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of the cells increase in
proportion to cell number.

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And as you heard on the clip, when the
bacteria detect that those molecules are there,

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they interpret that that means
there's other cells around.

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And then, as a collective, all of
the bacteria together make a biofilm,

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which is how they sit on
surfaces and cure to tissue.

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And then the group together secretes the
poisons, the toxins that make us sick.

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So that's quorum sensing.

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And so we want to be able to
interfere with that conversation.

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And so we know what the molecule
is that Pseudomonas talks with.

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It's the one that's on the
left side of this slide.

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And so what we did, using chemistry, is
we changed the structure of that molecule

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to make the one that's on the right.

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And so what that chemistry did was
it changed the signal molecule,

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the word, into an inhibitor.

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So we changed the molecule
that turns on quorum sensing

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into a molecule that shuts down quorum sensing.

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So what happens if you have such a molecule?

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So first, I'll talk about biofilms.

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So in this petri plate, what we've done
is we've put Pseudomonas in the middle

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of the petri plate, and what
I hope you can see is

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that the bacteria have spread out to the edges.

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That's this biofilm formation.

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As a group, they move out over the plate,
and that could be like your tissues.

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But we have this inhibitor.

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So now if we do the experiment, and
we put the Pseudomonas in the plate,

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and we add the inhibitor, what you can
see is that the Pseudomonas can't move.

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So that's good.

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That's step one in the infection.

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It seems like our inhibitor can
shut down biofilm formation.

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The next question for us is,
what about these poisons,

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these toxins, that Pseudomonas secretes?

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So now you're looking at an experiment,

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and in the lefthand test tube,
that's wild-type Pseudomonas.

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It's doing quorum sensing, and
it's secreted these toxins.

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And when it secretes those
toxins, the bacteria turn green.

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In the middle test tube, that's
a mutant that we've made,

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where we've knocked out its
quorum-sensing system.

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So that mutant has no communication.

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And what you can see is that
the bacteria are colorless.

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They can't secrete the toxin,
so they don't turn green.

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The righthand test tube shows you wild-type
Pseudomonas that we've added our inhibitor.

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And what I hope you can see is that the
inhibitor greatly decreases the ability

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of Pseudomonas to secrete that green poison.

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So now we're in business.

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It looks like at least in the
lab, we can shut down biofilms,

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and we can shut down toxin secretion.

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So what about in an infection?

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So in this experiment, you're looking
at an animal model system that we have

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for Pseudomonas infection in the lab,

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and all we do is measure whether
the animals are alive or dead.

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And so on the line that you
looking at, obviously,

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if we don't add pseudomonas,
the animals are perfectly fine.

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If we give a Pseudomonas infection, now what
you can see is that all of the animals die

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within the first day after the infection starts.

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But if we do that, we give the Pseudomonas
infection, and we give that inhibitor molecule

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that I showed you, what you
can see with the third line is

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that we can greatly improve
the outcome for the animal.

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So in fact, we think now that there must
be merit to this idea of interfering

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with chemical communication, and that
maybe this could form the foundation

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of a new type of therapeutic.

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And so what we're doing in the lab, right now,
is we're taking the molecule that I showed you,

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and we have to make it more
medicine-like we have to build in potency,

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and we have to make that molecule safe.

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The second thing is that we got inspired by
that biofilm experiment that I showed you,

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and we're working with engineers now to try,

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to try to embed those inhibitor
molecules into materials.

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And the idea is that maybe we could
make infection-resistant catheters,

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or stents or breathing tubes.

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And then finally, I'm just telling you one
little vignette that's about Pseudomonas.

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We work on lots of globally-important
pathogens in my lab,

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and we're having similar success doing these
kinds of strategies in other bacteria as well.

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And then to finish, I just want to show you the
two students who did the work, Colina Loflin

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and [inaudible] Drescher [phonetic].

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They both work in the lab, and I'm lucky
to get to work with them every day.

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Thanks for having me back.

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[ Applause ]

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>> So interesting.