University of California, Berkeley
Dr. Vance is also a professor of immunology and pathogenesis at the University of California, Berkeley.
Innate Detection of Bacterial Infections by the Immune System
Russell Vance, the son of two biochemists, had just earned a degree in biochemistry when a rebellious streak took hold of him. "I didn't want to do what my parents had done," he says. So the young radical decided to become a philosopher.
After earning a master's degree in philosophy, however, Vance found he missed biology. He was soon back in the lab, unsure of his next move. In what turned out to be a life-changing discussion, Vance's supervisor argued that immunology might be "the most philosophical of the biological sciences." Maybe studying immunology would be a way for Vance to combine his two passions. "I hadn't thought about immunology. I didn't even really know what it was," he says. Yet the idea quickly appealed to Vance. Soon he was pursuing a PhD in the discipline at the University of California, Berkeley. The gamble paid off. Over the past decade, Vance has worked at the interface of immunology and microbiology to deliver deep insights about how the immune system detects bacteria.
Graduate school gave Vance a strong basis in immunology, but he wanted a better understanding of what the immune system must defend against. "Immunologists have to get in the 'mind' of the pathogen, to understand things from the pathogen's point of view," he says. This desire for a new perspective led Vance to a postdoctoral fellowship in John Mekalanos's lab at Harvard University, where he immersed himself in microbiology. In 2003, Vance took a second postdoctoral fellowship at Harvard, this time in the laboratory of William Dietrich, a geneticist and HHMI investigator at the time who was studying the interaction between the immune system and Legionella pneumophila, the bacterium responsible for a form of pneumonia called Legionnaires' disease. Colleagues told Vance that taking a second postdoc in another field might be career suicide, but he ignored the naysayers. "My hope was that I could bring my knowledge of immunology and microbiology to the lab and try to work at the interface," he says.
Dietrich had recently discovered that a class of molecules called neuronal apoptosis inhibitory proteins—or NAIP proteins—seemed to play a critical role in immune defense. But no one knew how these proteins worked. Vance and another postdoc speculated that NAIP might be a sensor that detects microbial invaders. To figure out what NAIP might be sensing, the pair performed a genetic screen to identify Legionella mutants that could evade NAIP. The key, they found, was in the bacterial tail. All of the mutants that evaded NAIP carried mutations in the gene that codes for flagellin. The flagellin proteins arrange themselves to form the whip-like appendages, or tails, that many bacteria use to motor around. "The results were really dramatic," Vance says, "and strongly suggested to us that NAIP sits in the cytosol, the fluid interior of the cell, acting as a sensor of flagellin."
In 2006, Vance established his own laboratory at Berkeley. Since then he and his colleagues have gained insights into how this flagellin sensor works. NAIP activation triggers the formation of a protein complex called an inflammasome, which prompts infected immune cells to self-destruct. That prevents the infection from spreading. Vance and his colleagues have also discovered that different NAIP proteins respond to different bacterial components. But NAIP is just one of many sensors housed within the cytosol of cells to detect bacteria. He and his colleagues are working to identify others.
The human body is rife with bacteria, and Vance thinks these sensors in the cytosol might help the immune system distinguish harmful from harmless. Only pathogens invade the cell cytosol, Vance says. Harmless microbes tend to hang out in the spaces between cells. "So having your sensors in the cytosol is actually a really good strategy for selectively responding to pathogens," he says.
Thinking about the guiding principles that govern the immune system takes Vance right back to his early days. "Philosophical thinking is important, even in biology," he says, arguing that immunologists need to do more than just accumulate data. "We have to figure out the underlying concepts that allow the immune system to work." But philosophy can also sometimes be frustrating. "Philosophers can't even agree on the first principles of what is knowledge," he says. Scientists like Vance are busy accumulating it.