How bacteria talk Bonnie Bassler

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’re one cell and they have the

special property that they only have one

piece of DNA so 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 so

they just grow and divide and grow and

divide so 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 and so this man is

supposed to represent a generic human

being and all of the circles in that man

are all the cells that make up your body

so there’s 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 ten 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 so of course it’s the DNA that

counts so here’s all the 80 G’s and C’s

that make up your genetic code and give

you all your charming characteristics so

you have about 30,000 genes well it

turns out you have a hundred times more

bacterial genes playing a role in you or

on you all of your life and so at the

best your 10% human we’re more likely

about 1% human depending on which of

these metrics you like so I know you

think of yourself as human beings but I

think of you as ninety or ninety two

point nine percent bacterial and these

bacteria are not passive writers 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

keep in our 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

insert 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 from

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

soaring sort of boring life where they

grow and divide and they’ve always been

to consider to be these a social

reclusive organisms and so it seemed to

us that they’re 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 the bacteria live and the

clue to this came from another marine

bacterium and it’s a bacterium called

Vibrio fischeri

and so 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

and this bacterium has the special

property that it makes light so it makes

bioluminescence like fireflies make

light so 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 and 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 and so 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 and what we

figured out is that the way that they do

that is that they talk to each other and

they talk with a chemical language so

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 ours

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

that molecule increases in proportion to

cell number and when the molecule hits a

certain amount that tells the bacteria

how many neighbors they are they

recognize that molecule and all of the

bacteria turn on light in synchrony and

so that’s how bioluminescence works

they’re talking with these chemical

words and the reason that Vibrio

fischeri is doing that comes from the

biology so again another plug for the

animals in the ocean the real fish fry

lives in this squid what you’re 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 how’s the Vibrio

fischeri cells they live in there at

high cell number that molecule is there

and they’re making light and the reason

the squid is willing to put up with

these shenanigans is because it wants

that light and so the way that this

symbiosis works is that this little

squid lives just off the coast of Hawaii

so just in a sort of shallow knee-deep

water and 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 and so on bright

nights when there’s 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 and what the squid has developed

is a shutter they can open and close

over this specialized light organ

housing the bacteria and 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 squids back so the

squid doesn’t make a shadow so it

actually uses the light from the

bacteria to counter illuminate itself in

an anti predation device and so it so

predators can’t see its shadow calculate

its trajectory and eat it and so this is

like the stealth bomber of the ocean but

then if you think about it this squid

has this terrible problem because it’s

got this dying stick 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% of the bacteria and

so now the bacteria are dilute that

little hormone molecule is gone so

they’re not making light but of course

squid doesn’t care it’s asleep in the

sand and as the day goes by the bacteria

doubled they release the molecule and

then light comes on at night exactly

when the squid wants it and so first we

figured out how and 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 and so 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 and

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 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

launched their virulence attack together

they’re going to be successful at

overcoming an enormous host so bacteria

always control pathogenicity with quorum

sensing

and so that’s how it works we also then

went to look at what are these molecules

so these were the red triangles on my

slides before and so this is the Vibrio

fischeri molecule this is the word that

it talks with and then we started to

look at other bacteria and these are

just a smattering of the molecules that

we’ve discovered and what I hope you can

see is that the molecules are related so

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 and what that does

is to confer exquisite species

specificities to these languages so each

molecule fits into its partner receptor

and no other so these are private secret

conversations these conversations are

for interest species communication each

bacteria uses a particular molecule

that’s it like its language that allows

it to count its own siblings and so once

we got that far we thought we were

starting to understand that bacteria

have these social behaviors but we

started what we’re 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 found now

is that in fact bacteria are

multilingual so 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 and so what

happens is that bacteria are able to

count how many of me and how many of you

and they take that in for

Meishan 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 and so then

again we turn to chemistry and we

figured out what this generic molecule

is so that was the pink ovals on my last

slide this is it it’s a very small five

carbon molecule and what the important

thing is that we learned is that every

bacterium has exactly the same enzyme

and makes exactly the same molecule so

they’re all using this molecule for

interspecies communication so this is

the bacterial Esperanto and so once we

got that far we’ve started to learn the

bacteria can talk to each other with

this chemical language but what we

started to think is that maybe there’s

something practical that we can do here

as well so I’ve told you the bacteria do

you have all these social behaviors that

they communicate with these molecules

and of course I’ve also told you that

one of the important things they do is

to initiate pathogenicity using quorum

sensing so we thought what if we made

these bacteria so they can’t talk or

they can’t hear couldn’t these be new

kinds of antibiotics and of course

you’ve just heard and you already know

that we’re running out of antibiotics

bacteria are incredibly multi

drug-resistant right now and that’s

because all of the antibiotics that we

use kill bacteria so they either pop the

bacterial membrane they make that

bacterium so it can’t replicate its DNA

we kill bacteria with traditional

antibiotics and that selects for

resistant mutants and so now of course

we have this global problem in

infectious diseases so we thought well

what if we could sort of do behavior

modifications just make these bacteria

so they can’t talk they can’t count and

they don’t know to launch virulence and

so that’s exactly what we’ve done and

we’ve sort of taken two strategies the

first one is we’ve targeted the intra

species communication system so we’ve

made molecules that look kind of like

the real molecules which you saw but

they’re a little bit different and so

they lock into those receptors and they

Jam recognition of the real thing and so

by targeting the red system what we are

able to do is to make species specific

or disease specific anti quorum sensing

molecules we’ve also done the same thing

with the pink system we’ve taken that

universal molecule and turned it around

a little bit so that we’ve made in

goodness of the interspecies

communication system and these the hope

is that these will be used as

broad-spectrum antibiotics that work

against all bacteria and so to finish

I’ll just show you the strategy and this

one I’m just using the interspecies

molecule but the logic is exactly the

same so what you know is that when that

bacterium gets into the animal in this

case a mouse it doesn’t initiate

virulence right away it gets in it

starts growing it starts secreting its

quorum sensing molecules it recognizes

when it has enough bacteria that now

they’re going to launch their attack and

the animal dies and so what we’ve been

able to do is to give these virulent

infections but we give them in

conjunction with our anti quorum sensing

molecules so these are molecules that

look kind of like the real thing but

they’re a little bit different which

I’ve depicted on this slide and what we

now know is that if we treat the animal

with the pathogenic bacterium a

multidrug-resistant pathogenic bacterium

in at the same time we give our anti

quorum sensing molecule in fact the

animal lives and so we think that this

is the next generation of antibiotics

and it’s going to get us around at least

initially this big problem of resistance

so what I hope you think is the bacteria

can talk to each other they use

chemicals as their words they have an

incredibly complicated chemical lexicon

that we’re just now starting to learn

about and of course what that allows

bacteria to do is to be multicellular

right and so in the spirit of Ted they

are doing things together because it

makes a difference right so what happens

is that bacteria have these collective

behaviors and they can carry out tasks

that they could never accomplish if they

simply acted as individuals and what I

would hope that I could further argue to

you is that this is the invention of

multicellularity bacteria had been on

the year on the earth for billions of

years humans a couple hundred thousands

so we think bacteria made the rules for

how multicellular an organization works

and and we think by studying bacteria

we’re going to be able to have insight

about multicellularity in the human body

so we know that the principles and the

rules if we can figure them out in these

sort of primitive organisms the hope is

that they will be applied to other human

diseases and human behaviors as well

I hope that what you’ve learned is that

bacteria can distinguish self from

others so by using these two molecules

they can say me and they can say you and

again of course that’s what we do both

as Malec in in a molecular way and then

also in an outward way but I think about

the molecular stuff this is exactly what

happens in your body it’s not like your

heart cells and your kidney cells get

all mixed up every day and that’s

because there’s all of this chemistry

going on these molecules that say who

each of these groups of cells is and

what their tasks should be and so again

we think that bacteria invented that and

then you’ve just evolved a few more

bells and whistles but all of the ideas

are in these simple systems that we can

study and then the final thing is again

just to reiterate that there’s this

practical part and so we’ve made these

anti quorum sensing molecules that are

being developed as new kinds of

therapeutics but then to finish with a

plug for all the good and miraculous

bacteria that live on the earth we’ve

also made Pro quorum sensing molecules

so we’ve targeted those systems to make

the molecules work better and so

remember you have these ten times or

more bacterial cells in your on you

keeping you healthy what we’re also

trying to do is to beef up the

conversation of the bacteria that live

as mutualist with you in the hopes of

making you more healthy making those

conversations better so bacteria can do

things that we want them to do by in

here better than they would be on their

own and then finally I wanted to show

you this is my gang at Princeton New

Jersey everything I told you about was

discovered by someone in that picture

and I hope when you learn things like

about how the natural world works I just

want to say that whenever you read

something in the newspaper you get to

hear some talk about something

ridiculous in the natural world it was

done by a child so science is done by

that demographic there all of those

people are between 20 and 30 years old

and they are the engine that drives

scientific discovery in this country and

it’s a really lucky demographic to work

with I keep getting older and older and

they’re always the same age and it’s

just Anna crazy delightful job and I

want to thank you for inviting me here

it’s a big treat for me to get to come

to this conference

you