Tuesday, 8 September 2009

Deep Inside Bacteria, a Germ of Human Personality

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Deep Inside Bacteria, a Germ of Human Personality

Scientists Hope to Fight Infections by Blocking the Social Creatures' Ability to Sense When They Have Sufficient Numbers to Attack

Bacteria are the oldest living things on earth, and researchers have long felt that they must lead dull, unfussy lives. New discoveries are starting to show just how wrong that notion is.

For a simple, single-cell creature, a bacterium is surprisingly social. It can communicate in two languages. It can tell self from nonself, friend from foe. It thrives in the company of others. It spies on neighbors, spreads misinformation and even commits fratricide.

"Really, they're just stripped-down versions of us," says Bonnie Bassler, microbial geneticist at Princeton University, who has spent two decades peeking at the inner lives of bacteria. Dr. Bassler and other scientists are using this information to devise new ways to fight infections and reduce antibiotic resistance.

Bacterial society is based on a chemical language called quorum sensing. To detect how many of its own species, or members of another bacterial species, are in the immediate vicinity, each bacterium secretes a certain molecule into the environment. The greater the number of molecules it can sense, the more fellow bacteria it knows are out there.

This is often a trigger to act. Some bacteria will attack a person or any other host only after establishing that there is a quorum -- a large-enough army to overcome the host's immune defenses. The strategy helps explain the virulence of a number of human ailments, including cholera, pneumonia and food poisoning.

Dr. Bassler was the first to identify the molecule that bacteria use to communicate with members of other species. She hopes the finding will lead to a new kind of drug that won't succumb to antibiotic resistance.

Resistance is a serious and growing health risk across the world. It occurs because most antibiotics are designed to kill bacteria. But some bugs survive the attack and pass on their resistant genes to their progeny, strengthening future generations and making the antibiotic less effective.

Instead of killing bacteria, Dr. Bassler wants to simply jam their communication lines -- the quorum-sensing mechanism. She figures that if the bugs can't signal each other, they can't properly assess the size of their growing army and might never attack. Another benefit: Because bacteria aren't killed, the approach could delay the onset of resistance.

In a study published in July in the journal Molecular Cell, Dr. Bassler and her colleagues identified a compound that disrupted bacterial small talk. The compound stopped worms from dying from a bug that also infects humans. The next step is to test it on mice. Says Dr. Bassler: "We plan to tinker with the molecule to make it stronger and stronger."

Labs are developing similar drugs to fight other bacterial maladies, including cholera, pneumonia and septicemia. Last year, University of Iowa researchers used a human protein to destroy a particular bacterium's messenger molecule, protecting fruit flies from infection-related death. The bacterium is the same one that causes some infections in hospitalized patients, burn victims and people with cystic fibrosis. Microbiologist Richard Novick of New York University has applied a similar technique for fighting staph infections in animal models. And the U.S. National Institutes of Health's Human Microbiome Project aims to catalog and understand all the microbes humans carry, and their role in nutrition, development and physiology.

Though the drugs are promising, they are a long way from being tried on humans.

At first glance, bacterial life is humdrum. A microbe eats nutrients, doubles in size, then divides in two. The colony grows.

But scientists are learning that microbes interact with humans in complex and often-useful ways. For starters, humans have one trillion cells of their own, but 10 trillion cells of bacteria. "At best," says Dr. Bassler, "you're only 10% human."

While some bacteria cause disease, other "good" bacteria keep people alive. They digest plant products in the gut, educate the immune system, and help to produce vitamins B-12 and K. Some 1,000 species live on human skin alone.

Equally remarkable is how bacteria band together and behave like sophisticated, multicellular animals. They sometimes organize into deeply structured "slime cities," or biofilms. The whitish layer that forms on the teeth every morning is actually a tightknit community of 600 bacterial species. Brush it away, and a new layer will form in exactly the same way by the next morning.

In the 1970s, scientists puzzled over why a colony of bioluminescent bacteria begins to glow only after it reaches a certain size. Over the years, they found the answer. By releasing a chemical into their environment, the bacteria constantly communicate with each other in order to assess the size of their population. Once the chemical level reaches a certain threshold, the bacteria individually -- and simultaneously -- turn on their lights.

In the deep ocean where light is scarce, the angler fish makes clever use of bacteria's ability to shine through quorum-sensing. A spine of the fish's dorsal fin has evolved to stick out like a fishing rod; its tip is home to a colony of bioluminescent bacteria. Attracted by the glowing lure, prey swim towards the angler fish and are devoured in its toothy jaws.

In the early 1990s, Dr. Bassler discovered that bacteria use a second chemical language to talk to other species, a sort-of microbial Esperanto. "The molecule simply says 'I'm the other,'" says Dr. Bassler. "But there must be molecules that tell the bacteria who the other is. We haven't found those yet."

Today, quorum sensing is a fast-growing area of research, with dozens of labs involved and scores of papers published.

During a recent tour of her lab in Princeton, N.J., Dr. Bassler asked a visitor to peer through a microscope. A dozen or so tiny worms, known as c. Elegans, writhed on a glass plate. The worms were the subject of the experiment that was recently reported in Molecular Cell.

In the experiment, Dr. Bassler was looking for a drug that would disrupt a bacteria's quorum-sensing system. As an opponent, she chose a bacterial species, C. violaceum, whose relatives include salmonella and E. coli. Though it rarely infects humans, violaceum can easily kill other creatures, including c. Elegans.

When its population reaches a certain critical mass, E. violaceum produces an easy-to-see purple dye, making it a good subject to study in the lab. To communicate with its brethren, it uses a molecule called acyl-homoserine lactone, or AHL. Dr. Bassler hoped to block AHL.

She had researchers at Broad Institute in Cambridge, Mass., screen 35,000 chemicals to see whether any might do the trick. They narrowed the possibilities to 15 compounds, then picked the most promising one and tweaked its molecular structure to make it more powerful.

It worked. The researchers found that the chemical interfered with the bacteria's quorum-sensing mechanism and prevented infected worms from dying. The worms suffered no noticeable ill effects.

Write to Gautam Naik at gautam.naik@wsj.com

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