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

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

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

And so now we have a fancy name for this.

We call it "quorum sensing".

They vote with these chemical votes.

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

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

that bacteria carry out in
these collective fashions,

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

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

You're enormous.

That would have no effect on you.

You're huge.

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

They start growing.

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

when they have the right cell number,

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

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

[ Applause ]

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

about what we've been doing in quorum sensing.

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

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

to make a fundamentally new kind of antibiotic.

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

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

It kills immune-compromised
people, and it causes infections

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

And the reason Pseudomonas is so virulent is

because of this chemical
communication, this quorum sensing.

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

which are the red triangles on this slide.

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

of the cells increase in
proportion to cell number.

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

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

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

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

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

So that's quorum sensing.

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

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

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

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

to make the one that's on the right.

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

the word, into an inhibitor.

So we changed the molecule
that turns on quorum sensing

into a molecule that shuts down quorum sensing.

So what happens if you have such a molecule?

So first, I'll talk about biofilms.

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

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

that the bacteria have spread out to the edges.

That's this biofilm formation.

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

But we have this inhibitor.

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

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

So that's good.

That's step one in the infection.

It seems like our inhibitor can
shut down biofilm formation.

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

these toxins, that Pseudomonas secretes?

So now you're looking at an experiment,

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

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

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

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

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

So that mutant has no communication.

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

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

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

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

of Pseudomonas to secrete that green poison.

So now we're in business.

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

and we can shut down toxin secretion.

So what about in an infection?

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

for Pseudomonas infection in the lab,

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

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

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

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

within the first day after the infection starts.

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

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

that we can greatly improve
the outcome for the animal.

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

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

of a new type of therapeutic.

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

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

and we have to make that molecule safe.

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

and we're working with engineers now to try,

to try to embed those inhibitor
molecules into materials.

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

or stents or breathing tubes.

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

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

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

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

and [inaudible] Drescher [phonetic].

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

Thanks for having me back.

[ Applause ]

>> So interesting.