Talk about the implications of your work outside of the context of
medicine. Is this going to help us make better yogurt?
We've all been sick; we're all afraid of infection. I think the
easiest application to help people understand what quorum sensing is
and why it's important to study is to tell them that if we could
make the bacteria either deaf or mute, we could create new
antibiotics.
But, what many people generally don’t know is that bacteria also do
all these amazing, fantastic things. In fact, we mostly don't get
sick. Most often, bacteria are keeping us well.
So, on the flipside of trying to make antagonists - molecules that
suppress quorum sensing - my lab spends lots of time trying to make
agonists, molecules that make bacteria talk better. If we could beef
up the conversation of the bacteria that live in us or on us that
are keeping us healthy, it might be even better than developing an
anti-quorum sensing molecule.
We want to manipulate these bacterial conversations both positively
and negatively. But we don't know yet if it's better to enhance the
conversation for mutualists or to suppress it in the case of harmful
bacteria. There's a place for each of these technologies, and we're
trying to get them both to work.
How exactly they're deployed will
come later.
Would a drug that comes from this research technically be called an
antibiotic?
Current antibiotics work in only a few ways - they pop membranes,
they prevent DNA replication -- but the bottom line is, they either
kill bacteria or they stop bacterial growth.
An anti-quorum sensing-type compound would simply prevent bacteria
from counting one another. In essence, the bacteria would "think"
they were alone when they are actually in a group. Alone, they don't
initiate virulence cascades. So, if the bacteria can't count
themselves and thus, can’t carry out these group virulence
activities that are critical for enabling them to stay in the host,
the immune system just gets rid of them.
Such a drug would not be an antibiotic. It would simply give your
immune system a little extra time to do what it's supposed to do:
constant surveillance, and get rid of harmful invading microbes. But
I don't know what you'd call it - it's a funny question. Many
scientists are investigating different bacterial traits that could
be similarly exploited.
Behavior modification drugs? Maybe that's
what I should call them.
Of the many molecules bacteria might have evolved to use for
signaling, why these?
We don’t actually understand this yet, but we have some ideas.
First, these molecules are cheap and easy to make. The molecules
come from core, central metabolites. They're made from leftover
molecules that bacteria must produce in order to stay alive. After
putting a bell or whistle on these leftovers, they become signals.
For this reason, we don’t think it costs the bacteria very much to
evolve these signaling capabilities.
Second, we are also now beginning to understand that there is extra
information encoded in the molecules in the form of their physical
properties. For example, the molecules used for intra-species
communication are hydrophobic - they don’t like water.
On the other
hand, the molecule I showed on my slide - the one used for
inter-species communication - is hydrophilic and loves water. A
hydrophobic molecule doesn't travel very far. A hydrophilic molecule
goes really far. In this way, I think bacteria can use the blends of
molecules to measure space. There are also long-lived and
short-lived signals. I think the bacteria can use them to measure
time.
These features are in addition to using the molecules to count
numbers of other cells in the vicinity.
Does this process ever "go to sleep," or are the bacteria just
constantly chugging along, creating these signaling molecules?
The bacteria are constantly producing the signal molecules. As I
mentioned, these molecules are not expensive to make.
The real energy in quorum sensing isn't spent making the signaling
molecules. What really "costs" the bacteria something, is turning on
and off hundreds of genes in a precise order, to switch from the
"alone" program to the program related to collective behavior in
response to the signal molecules.
Maybe then it would make sense then for bacteria to "cheat." That
is, it might seem ideal for a bacterium to produce the signal
molecule only, and let the neighboring cells turn on and off the
hundreds of genes as a consequence. But if there were cheaters, that
is, members of the gang didn’t participate in the quorum sensing
behaviors, there would be no benefit because it takes the whole
group acting together to make quorum sensing behaviors successful.
Consistent with this notion, as far as we can tell, this kind of
cheating doesn’t happen.
Rather, we see that, if a particular
bacterium initiates the quorum sensing- program, one of the first
genes that gets turned on in response to the signal molecule is the
gene responsible for making the signal molecule itself. This
"positive feedback loop" floods the environment with even more
signal molecule and ensures that all the surrounding cells enter the
program.
We think this feedback step acts as a sort of molecular
police that imposes synchrony.
I wouldn't say any of these ideas are obvious, but after hearing
about them, they seem to make so much sense.
I spend half my time thinking, "My God, I can't believe they do
this!" and then the other half thinking, "Why did it take me so long
to figure this out? Of course they do this!" I agree, it's obvious
in retrospect.
I often think,
"Why is it that my lab that's doing this?"
Bacteria
have been intensively studied for 400 years. How could this have
been missed for nearly 390 of those years? I guess there was this
sort of snobbery - among bacteriologists and among scientists in
general - that because bacteria seemingly live this mundane
primitive life, and they have so few genes, and are so tiny, that we
could not imagine they possessed this level of complexity and
sophistication.
But think about multicellularity on this Earth. Every living thing
originally came from bacteria. So, who do you think made up the
rules for how to perform collective behaviors? It had to be the
bacteria.
Again, even after we knew about intra-species quorum sensing, when
we discovered the cross-species signaling molecule, we were shocked.
But in retrospect, of course they have to signal across species! It
doesn't do bacteria any good to only count their siblings if there
are all kinds of other species around. It all makes total sense,
right? But you can't know that until you figure it out.
The bottom
line is that we are always underestimating them.
Do you often have these sorts of "Whoa!" moments?
I remember the day we found the gene for the inter-species signaling
molecule like it was yesterday.
We got the gene and we plugged it
into a database. And we immediately saw that this gene was in an
amazing number of species of bacteria. It was a huge moment of
realization. We had wondered for so long what this second molecule
was for, and the database told us in an instant this must be about
cross-species communication.
It's a manic-depressive life. You run in here, you open your
incubator, your experiment makes no sense, you think,
"I hate this
job." Then ten minutes later you think, "Well, now, maybe I'll try
this or I'll try that."
You do it because you know there will be an
"a-ha!" day. Those a-ha! days make it all worthwhile and they have
to last you a long time.
One thing that is really good is that now there are 18 of us in this
lab. The people in my lab get to see people who've come before them
who are successful. We see one another have the a-ha! moment and you
think you can figure something out too and that you’re a-ha! day
will come.
Luckily, I get to be a part of all of the a-ha! days that
happen for the group.
Craig Venter has talked about a species of bacteria that creates
gasoline. Is this sort of industrial technology at all in your daily
thinking, or on your road map?
Yes. There are very clear medical and industrial applications.
Let's talk about anti-quorum sensing molecules, for example.
Researchers want to embed them in the plastic wrap used to package
foods to monitor for bacteria and keep food fresher longer.
They
want to put anti-quorum sensing molecules in the plastic that
catheters are made from so we don’t get infections in hospitals.
They want to put them in paints so they can paint cooling towers in
industrial plants and keep the towers from getting gunked up and
made unusable.
They want to put them in toothpaste so you don't get
the bacterial films on your teeth that give you cavities.
What if these quorum sensing-based technologies open another
Pandora's Box?
Oh, indeed they will - no question, the bacteria will figure a way
around this new strategy. When antibiotics first came out, nobody
could have imagined we’d have the resistance problem we face today.
We didn't give bacteria credit for being able to change and adapt so
fast.
Basically bacteria do evolution on a 20-minute time scale. It
takes humans about 20 years to make an offspring; but bacteria are
dividing every 20 minutes, testing out new mutations for selective
advantages.
When antibiotics became industrially produced following World War
II, our quality of life and our longevity improved enormously. No
one thought bacteria were going to become resistant. This is the
problem with underestimating bacteria that I mentioned earlier.
People thought the bacterial problem was solved.
Researchers moved
on to other important diseases:
cancer and heart disease.
Antibiotics were put into tremendous use both for health and
agriculture - and now we have this resistance problem. Compounding
the problem is that because we thought the bacterial problem was
gone, little effort was placed on studying bacteria, learning
resistance mechanisms, and developing new antibiotics. So we're way
behind in this game.
The fantasy is, since an anti-quorum sensing drug won't kill
bacteria, it won't select as readily for resistance.
Even if some
bacterium is fortuitously resistant, it won't get the growth
advantage that comes when its siblings die as happens with
resistance to a traditional antibiotic. The hope is that an
anti-quorum sensing therapeutic will have a long shelf-life, that
is, it will take bacteria a long while to evolve ways around the
anti-quorum sensing therapy.
That, in turn, gives scientists time to
develop more new ways to combat harmful bacteria or to enhance good
bacteria.
Have you come to see the everyday world differently, working in this
microscopic world all the time?
I would say mostly no. Just like you, I can’t see bacteria either.
So what’s funny is that, in the lab most everything we work on looks
like water or grains of sand in tubes and bottles. It's in our heads
that we make up pictures of what's going on in that invisible world
inside those tubes and bottles.
What I do think I have is an appreciation for nature’s complexity.
It's a really lucky life to be tuned into a world that's completely
invisible to everyone else.
