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  • Bacteria are the oldest living organisms on the earth.

  • They've been here for billions of years,

  • and what they are are single-celled microscopic organisms.

  • So they are one cell and they have this special property

  • that they only have one piece of DNA.

  • They have very few genes,

  • and genetic information to encode all of the traits that they carry out.

  • And the way bacteria make a living

  • is that they consume nutrients from the environment,

  • they grow to twice their size, they cut themselves down in the middle,

  • and one cell becomes two, and so on and so on.

  • They just grow and divide, and grow and divide -- so a kind of boring life,

  • except that what I would argue is that you have

  • an amazing interaction with these critters.

  • I know you guys think of yourself as humans, and this is sort of how I think of you.

  • This man is supposed to represent

  • a generic human being,

  • and all of the circles in that man are all of the cells that make up your body.

  • There is about a trillion human cells that make each one of us

  • who we are and able to do all the things that we do,

  • but you have 10 trillion bacterial cells

  • in you or on you at any moment in your life.

  • So, 10 times more bacterial cells

  • than human cells on a human being.

  • And of course it's the DNA that counts,

  • so here's all the A, T, Gs and Cs

  • that make up your genetic code, and give you all your charming characteristics.

  • You have about 30,000 genes.

  • Well it turns out you have 100 times more bacterial genes

  • playing a role in you or on you all of your life.

  • At the best, you're 10 percent human,

  • but more likely about one percent human,

  • depending on which of these metrics you like.

  • I know you think of yourself as human beings,

  • but I think of you as 90 or 99 percent bacterial.

  • (Laughter)

  • These bacteria are not passive riders,

  • these are incredibly important, they keep us alive.

  • They cover us in an invisible body armor

  • that keeps environmental insults out

  • so that we stay healthy.

  • They digest our food, they make our vitamins,

  • they actually educate your immune system

  • to keep bad microbes out.

  • So they do all these amazing things

  • that help us and are vital for keeping us alive,

  • and they never get any press for that.

  • But they get a lot of press because they do a lot of

  • terrible things as well.

  • So, there's all kinds of bacteria on the Earth

  • that have no business being in you or on you at any time,

  • and if they are, they make you incredibly sick.

  • And so, the question for my lab is whether you want to think about all the

  • good things that bacteria do, or all the bad things that bacteria do.

  • The question we had is how could they do anything at all?

  • I mean they're incredibly small,

  • you have to have a microscope to see one.

  • They live this sort of boring life where they grow and divide,

  • and they've always been considered to be these asocial reclusive organisms.

  • And so it seemed to us that they are just too small to have an impact

  • on the environment

  • if they simply act as individuals.

  • And so we wanted to think if there couldn't be a different

  • way that bacteria live.

  • The clue to this came from another marine bacterium,

  • and it's a bacterium called Vibrio fischeri.

  • What you're looking at on this slide is just a person from my lab

  • holding a flask of a liquid culture of a bacterium,

  • a harmless beautiful bacterium that comes from the ocean,

  • named Vibrio fischeri.

  • This bacterium has the special property that it makes light,

  • so it makes bioluminescence,

  • like fireflies make light.

  • We're not doing anything to the cells here.

  • We just took the picture by turning the lights off in the room,

  • and this is what we see.

  • What was actually interesting to us

  • was not that the bacteria made light,

  • but when the bacteria made light.

  • What we noticed is when the bacteria were alone,

  • so when they were in dilute suspension, they made no light.

  • But when they grew to a certain cell number

  • all the bacteria turned on light simultaneously.

  • The question that we had is how can bacteria, these primitive organisms,

  • tell the difference from times when they're alone,

  • and times when they're in a community,

  • and then all do something together.

  • What we've figured out is that the way that they do that is that they talk to each other,

  • and they talk with a chemical language.

  • This is now supposed to be my bacterial cell.

  • When it's alone it doesn't make any light.

  • But what it does do is to make and secrete small molecules

  • that you can think of like hormones,

  • and these are the red triangles, and when the bacteria is alone

  • the molecules just float away and so no light.

  • But when the bacteria grow and double

  • and they're all participating in making these molecules,

  • the molecule -- the extracellular amount of that molecule

  • increases in proportion to cell number.

  • And when the molecule hits a certain amount

  • that tells the bacteria how many neighbors there are,

  • they recognize that molecule

  • and all of the bacteria turn on light in synchrony.

  • That's how bioluminescence works --

  • they're talking with these chemical words.

  • The reason that Vibrio fischeri is doing that comes from the biology.

  • Again, another plug for the animals in the ocean,

  • Vibrio fischeri lives in this squid.

  • What you are looking at is the Hawaiian Bobtail Squid,

  • and it's been turned on its back,

  • and what I hope you can see are these two glowing lobes

  • and these house the Vibrio fischeri cells,

  • they live in there, at high cell number

  • that molecule is there, and they're making light.

  • The reason the squid is willing to put up with these shenanigans

  • is because it wants that light.

  • The way that this symbiosis works

  • is that this little squid lives just off the coast of Hawaii,

  • just in sort of shallow knee-deep water.

  • The squid is nocturnal, so during the day

  • it buries itself in the sand and sleeps,

  • but then at night it has to come out to hunt.

  • On bright nights when there is lots of starlight or moonlight

  • that light can penetrate the depth of the water

  • the squid lives in, since it's just in those couple feet of water.

  • What the squid has developed is a shutter

  • that can open and close over this specialized light organ housing the bacteria.

  • Then it has detectors on its back

  • so it can sense how much starlight or moonlight is hitting its back.

  • And it opens and closes the shutter

  • so the amount of light coming out of the bottom --

  • which is made by the bacterium --

  • exactly matches how much light hits the squid's back,

  • so the squid doesn't make a shadow.

  • It actually uses the light from the bacteria

  • to counter-illuminate itself in an anti-predation device

  • so predators can't see its shadow,

  • calculate its trajectory, and eat it.

  • This is like the stealth bomber of the ocean.

  • (Laughter)

  • But then if you think about it, the squid has this terrible problem

  • because it's got this dying, thick culture of bacteria

  • and it can't sustain that.

  • And so what happens is every morning when the sun comes up

  • the squid goes back to sleep, it buries itself in the sand,

  • and it's got a pump that's attached to its circadian rhythm,

  • and when the sun comes up it pumps out like 95 percent of the bacteria.

  • Now the bacteria are dilute, that little hormone molecule is gone,

  • so they're not making light --

  • but of course the squid doesn't care. It's asleep in the sand.

  • And as the day goes by the bacteria double,

  • they release the molecule, and then light comes on

  • at night, exactly when the squid wants it.

  • First we figured out how this bacterium does this,

  • but then we brought the tools of molecular biology to this

  • to figure out really what's the mechanism.

  • And what we found -- so this is now supposed to be, again, my bacterial cell --

  • is that Vibrio fischeri has a protein --

  • that's the red box -- it's an enzyme that makes

  • that little hormone molecule, the red triangle.

  • And then as the cells grow, they're all releasing that molecule

  • into the environment, so there's lots of molecule there.

  • And the bacteria also have a receptor on their cell surface

  • that fits like a lock and key with that molecule.

  • These are just like the receptors on the surfaces of your cells.

  • When the molecule increases to a certain amount --

  • which says something about the number of cells --

  • it locks down into that receptor

  • and information comes into the cells

  • that tells the cells to turn on

  • this collective behavior of making light.

  • Why this is interesting is because in the past decade

  • we have found that this is not just some anomaly

  • of this ridiculous, glow-in-the-dark bacterium that lives in the ocean --

  • all bacteria have systems like this.

  • 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.

  • 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.

  • 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.

  • It's not like a couple bacteria get in you

  • and they start secreting some toxins --

  • you're enormous, that would have no effect on you. You're huge.

  • 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 are going to be successful at overcoming an enormous host.

  • Bacteria always control pathogenicity with quorum sensing.

  • That's how it works.

  • We also then went to look at what are these molecules --

  • these were the red triangles on my slides before.

  • This is the Vibrio fischeri molecule.

  • This is the word that it talks with.

  • So then we started to look at other bacteria,

  • and these are just a smattering of the molecules that we've discovered.

  • What I hope you can see

  • is that the molecules are related.

  • The left-hand part of the molecule is identical

  • in every single species of bacteria.

  • But the right-hand part of the molecule is a little bit different in every single species.

  • What that does is to confer

  • exquisite species specificities to these languages.

  • Each molecule fits into its partner receptor and no other.

  • So these are private, secret conversations.

  • These conversations are for intraspecies communication.

  • Each bacteria uses a particular molecule that's its language

  • that allows it to count its own siblings.

  • Once we got that far we thought

  • we were starting to understand that bacteria have these social behaviors.

  • But what we were really thinking about is that most of the time

  • bacteria don't live by themselves, they live in incredible mixtures,

  • with hundreds or thousands of other species of bacteria.

  • And that's depicted on this slide. This is your skin.

  • So this is just a picture -- a micrograph of your skin.

  • Anywhere on your body, it looks pretty much like this,

  • and what I hope you can see is that there's all kinds of bacteria there.

  • And so we started to think if this really is about communication in bacteria,

  • and it's about counting your neighbors,

  • it's not enough to be able to only talk within your species.

  • There has to be a way to take a census

  • of the rest of the bacteria in the population.

  • So we went back to molecular biology

  • and started studying different bacteria,

  • and what we've found now is that

  • in fact, bacteria are multilingual.

  • They all have a species-specific system --

  • they have a molecule that says "me."

  • But then, running in parallel to that is a second system

  • that we've discovered, that's generic.

  • So, they have a second enzyme that makes a second signal

  • and it has its own receptor,

  • and this molecule is the trade language of bacteria.

  • It's used by all different bacteria

  • and it's the language of interspecies communication.

  • What happens is that bacteria are able to count

  • how many of me and how many of you.

  • They take that information inside,

  • and they decide what tasks to carry out

  • depending on who's in the minority and who's in the majority

  • of any given population.

  • Then again