Bonnie Bassler
When Bonnie Bassler talks about bacterial conversations, electrical current seems to surge through her body. Arms gesticulate and fingers point. Words percolate. She zaps her audience with the conviction that she is explaining the coolest thing ever. Miniscule, primitive creatures are communicating with one another to perform tasks that none of them could accomplish on their own.
Bassler’s achievements have earned her a MacArthur “genius” grant, membership in the National Academy of Sciences, and a prestigious appointment as a Howard Hughes Medical Institute investigator. Her TED talk has garnered more than two million views. But success has not come easily. Tenacity and relentless curiosity buoyed her as she hit multiple waves of skepticism about her work’s significance and financial uncertainty loomed.
When Bassler was in high school, her mother impressed upon her the idea that professional opportunities for women had exploded since the elder Bassler had come of age. “When I went to college, a woman could be a teacher or a nurse, but you can be anything,” Bassler recalls her mother saying. “And I thought, ‘I can be anything.’ It was a toss-off conversation, but it has stuck with me for my entire life.” Bassler tears up. “She gave me this tiny little confidence nugget that I could be anything and then she never got to see what I became.”
As long as Bassler can think about how bacteria talk to one another, as long as her mind can chew on riddles the microbes present, she thrives. “I’m just so lucky to have this career that lets you live in your mind so much of the time,” she says.
Bassler began college aiming to be a veterinarian, but recoiled when she encountered anatomy. “I’m not a memorizer; I’m a puzzle solver,” she says. She enjoyed classes that challenged her to crack mysteries using basic information in new ways. “It was such a remarkable feeling when you worked problems,” she says. “In real time, you figured out the answer.”
In spring of her junior year, her mother was diagnosed with cancer. That August, she died. Bassler returned to school in a fog.
She saw a bulletin board notice about two research opportunities in a single lab—one on cancer and one on bacteria. “Now I have my life goal,” she told herself. “I’m going to cure cancer.”
The professor put her on the bacterial project. “I’ll show him,” she recalls thinking. “I’ll be really earnest and then he’ll transfer me” to the cancer project. Instead, Bassler got hooked on microbiology—the daily “surprises in the incubator and the molecular thinking.” In graduate school at Johns Hopkins University, she explored other topics, but returned to her tiny workhorses.
As she was tying up her Ph.D. work, a seminar by Michael Silverman bewitched her. He described how bacteria called Vibrio fischeri count themselves. They wait until they reach a critical population density before investing in activities that require a group to succeed. A single bacterium that generates a light-producing protein, for instance, remains invisible, but when many bacteria make the same protein in a confined space, they create a discernible glow. To achieve this feat, the bacteria churn out a particular chemical that is detected by their brethren. They luminesce only when enough of them—reflected by the chemical’s concentration—have amassed to emit useful light.
Bassler was struck by this cooperative behavior, which scientists later dubbed “quorum sensing.” “I can’t convey how fringe that idea was,” she says. Conventional wisdom held that bacteria were social recluses. Cells of complex organisms communicated with one another to accomplish “the fancy stuff—signaling, development,” says Bassler. “Now quorum sensing is in textbooks, but when I went to that talk, this was not the way people thought about bacteria.”
Bassler joined Silverman’s lab as a postdoctoral fellow in 1990 and set about untangling the light-producing quorum-sensing system of a different marine bacterium, Vibrio harveyi. Some regulator must turn on luminescence when V. harveyi congregates, and she aimed to find it. To that end, she sought bacteria that carry a genetically tweaked version of the presumptive control molecule by searching for creatures that do not properly respond to crowding. Try as she might to track down genetic changes that demolish the microbe’s ability to luminesce at high population density, she couldn’t find such mutations. Every “dark” mutant carried a defective gene for luciferase, the enzyme that generates light. Bassler’s scheme was not pointing toward genes that govern luciferase manufacture; it was repeatedly leading her to luciferase itself.
One day, while Bassler was feeling like a washout geneticist, insight hit. If two signals stimulate the luciferase gene, obliterating only one of them through her experimental strategy would lead to the results she had obtained. With the other signal intact, the bacteria would continue to glow when they accumulated unless a genetic anomaly destroyed the light-producing enzyme. Guided by this rationale, she suddenly understood her observations and devised a new plan. In 1993 and 1994, she discovered that two systems converge to control light production in V. harveyi.
Simultaneously, other researchers were finding that unrelated bacteria utilize population density-sensing systems to promote diverse processes such as virulence, antibiotic synthesis, and DNA transfer. Each of these species seemed to speak its own chemical dialect. “It was this amazing moment when it was clear that collective behavior was widespread in the bacterial world,” says Bassler. Suddenly, scientists began realizing that her work held relevance for a wide range of microbes, “not just crazy glow-in-the-dark bacteria,” she says.
In 1994, Bassler moved to Princeton as a faculty member. She and colleagues followed up on earlier descriptive work to establish that some bacteria—including several that inhabit the intestines—spew a molecular signal that activates V. harveyi’s second quorum-sensing system. This result hinted at the possibility of a universal language. For years, however, Bassler couldn’t find the V. harveyi chemical that provokes its second light-producing pathway nor the gene that manufactures it. “It was driving me bananas,” she says.
The break came in the late 1990s, when her team discovered that a common E. coli laboratory strain does not create the luminescence-stimulating substance. The researchers found a V. harveyi gene that makes this E. coli produce the second signal. Bassler and postdoctoral fellow Michael Surette entered the sequence of this gene, luxS, into a computer program that searches for similarity with known DNAs.
The screen started scrolling. More than a dozen unrelated bacteria—including inhabitants of the environment and various parts of the human body—possessed luxS. “I got goosebumps,” Bassler says. She turned to Surette and said, “Oh my god, they’re talking to each other.” In that moment, she realized that the second signaling system “was everywhere and it was way bigger than we had been thinking and it was unified. It was in about 50 percent of all sequenced bacteria. When there are 10,000 genomes, 5000 will have it. When there are a million, half a million will have it.”
Still, the signaling molecule’s identity eluded her. She could obtain “gobs” of the substance in a test tube, but never in pure form, she says. She always wound up with a pot of chemically rearranged versions of one another and didn’t know which one made V. harveyi “brighter than the sun.”
Bassler, X-ray crystallographer Frederick Hughson, and colleagues devised an innovative approach to tackle the challenge. They combined the jumble with the protein that senses the second chemical signal, hoping that the protein “would reach into this complicated mix and pull out the active molecule,” she says. Then they used X-ray crystallography to discern the structure of the two molecules stuck together.
This procedure yielded clear data, but the analysis hit a wall when the researchers tried to translate it into an atomic structure with carbon, which composes the standard backbone of organic molecules, at all the key junctures. They proposed a structure in which carbon was bound to four oxygens. When they showed it to a chemist colleague, he said, “That molecule may exist at the core of the sun, but it doesn’t exist on earth,” Bassler says. Forced to consider unusual solutions, they realized that boron—an element that is rare in biological molecules—plays a central role in the signaling molecule.
Despite her productivity during that period, Bassler struggled to secure funding. She wrote proposals on bacteria relevant to human health, but “I could not for the life of me get an NIH [National Institutes of Health] grant,” says Bassler. Reviewers doubted her interpretations. Perhaps, one suggested, the supposed signaling molecules were just “waste products.”
In 2002, she published the structure of the second signaling molecule, won a MacArthur fellowship, and received her first NIH grant when a program officer reached into a slush fund to support her work. She also teamed up with researchers who study Vibrio cholerae, which causes severe diarrheal disease, and showed that quorum sensing dampens its virulence-factor production. A few years later, she and her colleagues mimicked this effect with a synthetic version of a V. cholerae signaling molecule.
This finding suggested that quorum sensing could be manipulated for clinical benefit. Most disease-causing bacteria, however, ramp virulence-factor production up—not down—at high population density. A more widely applicable strategy that harnesses quorum sensing to fight disease would therefore depend on agents that quash rather than enhance the process.
With this idea in mind, she and her colleagues identified small molecules that hinder quorum sensing in other disease-causing bacteria. Some of these compounds block the organisms’ lethal effects in animals and lab-grown human cells. Such chemicals offer a tantalizing alternative to traditional antibiotics, which block bacterial growth or kill the microbes, Bassler and others posit. Resistant cells—those with genetic glitches that allow them to ignore these medicines’ effects—can take over. In contrast, a bacterium that evades a medicine that targets quorum sensing should not replicate particularly well. It will switch into quorum-sensing mode when its kin accrue, but nearby bacteria will not. The group behavior thus won’t occur and the drug-resistant bacterium will squander its resources. Bassler’s lab and many others are testing and working toward this dream.
When Bassler was growing up, “none of us [in my family] understood what a scientist does and how brain candy it is,” she says. Her mother would have been thrilled to know “how wonderful it is to make this thing called knowledge,” Bassler adds. “She was out trying to change the world,” canvassing for Hubert Humphrey because she cared about civil rights. “She would have been so happy that a woman could do these things. She would’ve said, ‘that’s progress.’”
Author: Evelyn Strauss, Ph.D.