As a young scientist-in-the-making, Bonnie Bassler imagined she would grow up to cure cancer. An undergraduate at the University of California, Davis, Bassler joined the lab of Fredrick Troy, who, in the early 1980s, was conducting two major research projects: one on cancer and one on bacterial carbohydrates. "I thought, surely he'll put me on the important project: the cancer one," recalls Bassler. "Of course he signed me up to work with bacteria. I was furious," she says. "But then I just fell in love with them. During that time I learned that bacteria are like these stripped-down versions of us and that you could actually do amazing science with them. And I've never looked back."
Now, two decades later, Bassler-a professor at Princeton University and a MacArthur Foundation fellow-is credited with discovering the ability bacteria have to communicate across species using a small molecule called autoinducer-2 (AI-2). This simple sugar, produced by scores of microbes including Escherichia coli, Salmonella, Vibrio cholera, and several species of bioluminescent marine bacteria, allows bugs to assess the density of the local prokaryotic population and to adjust their behavior accordingly: throwing off light, spewing out toxins, or forming slimy biofilms. "I am synonymous with the term 'autoinducer-2,' laughs Bassler. "You can boil down 15 years of my life into this one little five-carbon molecule."
The idea that bacteria use chemical signals to convey information about population density-a phenomenon called quorum sensing-has been around for decades. In the early 1970s, microbiologist Woody Hastings noticed that V. fischeri, an organism that resides inside the light organs of squid and other marine life, glows only when its ranks swell. But few scientists appreciated how widespread quorum sensing would turn out to be. "Initially it was thought, well, just a couple of obscure marine organisms are doing this," says Princeton's Ned Win?green, Bassler's colleague and collaborator. Now people realize it's incredibly important; it's central to the life cycle of all these bacteria. Bonnie, more than anyone else, has driven that science from the fringe to the center."
In the Navy
Like her entree into the world of bacterial physiology, the path Bassler followed from the outer reaches to center stage was largely serendipitous. In graduate school at Johns Hopkins in the late 1980s, Bassler took up residence in a lab that had a small grant from the Navy to study how marine bacteria recognize and adhere to sugar molecules, allowing them to form biofilms that coat the underside of boats. Toward the end of her tenure, as she was wondering what she'd do for her postdoc, Bassler attended a small meeting for other Naval grantees. There she met Michael Silverman-the man who unraveled the genetic circuit that V. fischeri use to talk amongst themselves.
"He gave this talk about these cockamamie glow-in-the-dark bacteria that are communicating with each other"-using small molecules to coordinate when, as a community, they should luminesce. "I could hardly understand his talk; there were all these genetic terms I didn't know," she says. "But, I could understand that these bacteria were talking to each other with chemicals, and that all you had to do to figure out what was going on was make mutants that couldn't turn on or off lights. And I thought, 'I can do that. I have no idea what this guy's talking about, but that I can do.'"
So in 1990 Bassler joined Silverman's lab at the Agouron Institute in La Jolla, Calif., where she steeped herself in the world of quorum sensing-and where she stumbled across the interspecies communication system that revolves around AI-2. Bassler set out to repeat Silverman's work in V. harveyi, a free-living microbe that she refers to as the "E. coli of the ocean." These bugs, she thought, might harbor a more sophisticated means of communication than V. fischeri because they live in complex, mixed microbial communities and have to cope with the changing environment of the open sea. Indeed, Bassler soon discovered, V. harveyi possess two parallel systems for keeping track of its neighbors: one that V. harveyi use to talk with other V. harveyi and a second they use to exchange information with other bacterial species-the microbial equivalent of Esperanto.
The problem that solved itself
The work was not as straightforward as Bassler had originally imagined. She had planned to mutate her V. harveyi and look for colonies that no longer glowed. Silverman had used a similar approach in V. fischeri to discover LuxI and LuxR-the enzyme that produces autoinducer-1 and the receptor that recognizes it. But all Bassler's "dark mutants" turned out to have lost their luciferase, the enzyme that actually produces light. "I thought, 'I can't be too dumb to do this,'" she says. Then came an insight that wound up being pivotal. "One day it dawned on me: There had to be two systems. If you knocked out one, the other would still function." That's why Bassler had not found any mutants missing V. harveyi's version of LuxI/LuxR-because she hadn't produced any mutants that were defective in both systems. With that in mind, Bassler was able to isolate mutants in the second system, the interspecies communication network that involves AI-2.
Figuring out what all those mutant genes do would take another dozen years and a move from La Jolla to Princeton, where Bassler accepted a faculty position in 1994. There, she discovered, among other things, LuxS, the enzyme that synthesizes AI-2. And by 1997, she realized that dozens of different bacteria possess LuxS, which Bassler says indicates that interspecies chit-chat is not an anomaly, but a popular prokaryotic pastime.
However, it wasn't until Bassler and her colleagues had the AI-2 receptor in hand that she was able to isolate and characterize the signal molecule itself. The effort required collaboration with Princeton colleague Fred Hughson, who helped Bassler and her postdoc Stephan Schauder crystallize AI-2 while it was cradled in its receptor. "That's not at all the standard way of finding the structure of a molecule," notes former postdoc Karina Xavier, now at the University of Lisbon in Portugal. "But Bonnie never gave up. She's not afraid of difficult projects. And if she doesn't know the right techniques to approach a problem, she tries to find the right person to help."
Indeed, much of Bassler's success can be credited to her eagerness to enlist individuals from a variety of disciplines to "unlock the secrets of quorum sensing," says Wingreen, a physicist and active member of what he calls the Bonnie Bassler supergroup. "She's like a good general who knows how to marshal her forces and make sure her army works together in a coordinated way."
"Bonnie is willing to listen and willing to learn. She's the only one who more or less understands all of it," adds Princeton chemist and supergroup member Martin Semmelhack. And her infectious enthusiasm draws others in. "She gets very excited about the science. She's bubbly and animated and energetic. She's fun to work with."
What AI-2 switches on
At present, Bassler and her team are working to catalog the suite of genes that V. harveyi switches on in response to AI-2. Postdoc Christopher Waters chopped the bug's genome into random bits and hooked these fragments up to green fluorescent protein (GFP). "We ended up screening about 8,000 colonies that expressed GFP," he says, "and about one percent of those showed response to autoinducer-2." The collection includes genes involved in biofilm formation and central metabolism, as well as regulatory genes and a handful with unknown function.
One gene that E. coli and Salmonella turn on in response to AI-2 encodes a transporter that allows the bugs to take up and degrade the signal molecule-a trick that allows these bacteria to disrupt quorum sensing in other species. In mixed culture experiments, Xavier has found that E. coli can keep V. harveyi from shining and render V. cholera avirulent.
Such results give Bassler hope that she and Semmelhack will be able to design or discover a novel type of broad-spectrum antibiotic-a small molecule that will interrupt quorum sensing, either by blocking the AI-2 receptor or by shutting down its synthesis. Whether they'll succeed remains to be seen. "Still, it'd be nice to have something in my Christmas card saying that I helped people," says Bassler.
Even if she fails to develop such an antibiotic, Richard Losick at Harvard sees Bassler as a "rock star of microbiology." "First, she does first-rate molecular genetics. Second, she's got a wonderful instinct about the biology of microorganisms. And third, she's a gifted speaker and communicates her ideas beautifully," he says. "It took some time for everything to come together for her. But when it did, she rocketed up out of obscurity and came to be recognized as a star in her field."
Thanks in part to that relative obscurity of the work, Bassler didn't receive a National Institutes of Health grant until 2004. "This lab was held together with chewing gum and rubber bands for the first 10 years. But I'm lucky," she says. "A lot of places would have been measuring my office." Officials at Princeton, however, believed in her and in her science-a belief that was rewarded in 2002 when Bassler received a MacArthur genius award. "It's absolutely one of the best things that ever happened to me," she says. "It was a validation of my work and an external validation for everyone in my lab. It's like the world telling them they're doing something special-that they've changed how we think about bacteria."
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