Bacteria talk when they walk- Quorum sensing. ( A Chemical Conversation)

According to -- Bassler BL. - Department of Molecular Biology, Princeton University, Princeton, 08544-1014, USA. bbassler@molbiol.princeton.edu -        That - Control of gene expression or the Quorum sensing,  n response to cell density, is used by both gram-negative and gram-positive bacteria to regulate a variety of physiological functions it involves the production and detection of extracellular signalling molecules called autoinducers.involves the production and detection of extracellular signalling molecules called autoinducers-

Bonnie Bassler on TED.com | Main | A trickster's theory of everything: Emily Levine on TED.com » say that 

The TED Blog interviewed Bassler over the phone to talk about this secret, social life of bacteria. She told us why the chemical language evolved the way it did, what the applications of her research outside of medicine might be, and what the daily life of a scientist is like. Here’s a snippet:

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 thatan 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.

alk 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.