Over the past few years, the microbial world’s reputation has been turned on its head. Since Louis Pasteur proved the so-called germ theory of disease in almost 150 years ago, we humans have diligently tried to purge bacteria from our lives. But scientists today are telling us at that the story isn’t so simple, and that the bacteria that colonize our bodies – more than one hundred trillion of them – are actually our coevolutionary partners, crucial to maintaining human health.
Sarkis Mazmanian, a microbiologist at the California Institute of Technology (Caltech) in Los Angeles, was among the first to foray into this new field. His research in the last decade has begun to define just how our microbial squatters keep our immune systems healthy – and how a skew in their population may be linked to diseases as diverse as inflammatory bowel disease, multiple sclerosis and autism. Among numerous other awards, in 2011 he received the Burroughs Wellcome Fund’s Investigators in the Pathogenesis of Infectious Disease award. In 2012, his work was honored with a MacArthur Foundation “genius” grant.
His lab’ most recent findings, published in March this year, showed that mice infected with a common food-borne pathogen called Listeria monocytgenes could not fight off the bug efficiently if their bodies didn’t contain the normal complement of gut bacteria – called microbiota – because without the microbiota their bodies produced only half the numbers of a key immune system cell. Adding the gut bacteria back to the mice made them healthy again, demonstrating their immune-boosting role. The research team then did a parallel experiment in which they gave mice a course of antibiotics to deplete their naturally-occuring microbioata, and then exposed them to Listeria, and found that the antibiotic treatment made the animals more susceptible to getting ill from the bug.
Doctors often give antibiotics to people who are at high risk of developing infection, even before they contract one. Mazmanian says his mouse results hint that this strategy may be doing more harm than good. “I think this work suggests that there’s an unintended and previously unanticipated drawback to that,” he says. “Maybe what you’re actually doing is making it more likely the person will get an infection.”
Mazmanian’s initiation into the teeming world of pathogens was somewhat accidental. As a young man he had no great love of science, and started college at the University of California, Los Angeles (UCLA), as an English major. But something just wasn’t clicking, he says, so he groped around for another field of study. Biology classes really resonated: Not only did he love the material, but he also became fascinated by the process of science. “As I was reading the text books,” he recalls, “I started thinking, ‘How did this information come to be? How did scientists ever come to these conclusions and define them to the extent that they are in a text book?”
Mazmanian took this interest as an arrow pointing him towards research. At UCLA, the most research-oriented of the biology departments at the time was widely considered to microbiology, so that’s where he headed. But after diving into this microscopic world, he says, “I’ve never looked back.”
After spending a post-graduate year working as a technician in the lab of Olaf Schneewind (now at the University of Chicago), Mazmanian signed on to do a PhD in Schneewind’s lab. His research there focused on identifying virulence factors by which Staphylococcus aureus, a major human pathogen, causes infection. Auspiciously, his very first scientific paper – which identified an enzyme in this bacterium that allows it to glom onto tissues in the host and suggested blocking it represents a novel approach to treat infection – was published in Science in 1999.
Some ten publications later, Mazmanian found himself facing the end of his doctoral work and wondering where to go next. “I loved microbiology, but I wanted to do something different and off the beaten path – not just study the next bad bug,” he says. A brief opinion article by Jeffrey Gordon at Washington University in St Louis – still a powerhouse in the field – about how bacteria living in our gut give us a nutritional boost set him on course. “A lightbulb just went off in my head, and I thought, ‘That’s what I have to do,’” Mazmanian says.
So in 2002, he joined the lab of Dennis Kasper at Harvard University. Kasper was studying a microbe called Bacteroides fragilis, and his team had recently discovered that it contained a molecule called plysacharide A (PSA), which induced the body’s immune system to produce a chemical that fights inflammation. He wanted Mazmanian to study how exactly PSA modulates the immune system of the humans it infects – a topic right up the young scientist’s newly-chosen alley.
Mazmanian spent his first year and a half in Kasper’s lab figuring out how to work with so-called germ-free mice, which have absolutely no bacteria in their bodies from birth. Starting with a bacterially blank slate, he figured he could add bacteria back in one at a time to begin to understand how they functioned. In 2005 study that has since become a classic in the field, Mazmanian reported that in germ-free mice, immune cells just didn’t develop properly. Colonizing the animals with B fragilis restored their immune system function – an effect he traced directly to PSA. Other high-profile studies followed, including one suggesting a protective effect of PSA in inflammatory bowel disease. “He was obviously a really talented young man,” says Kasper. “I’m very pleased that we were on the front end of the explosion in the field.”
In 2006, Sarkis set off to Caltech to start his own lab, which grew to 10 members within just six months. Initially, the group continued their work on PSA, focusing mostly on inflammatory bowel disease and also started exploring the role of gut bacteria in multiple sclerosis and autism. B fragilis quelled inflammation in the nervous system of mice in which auism-like symptoms had been induced, they found, but not due to PSA; instead, the bacterium seems to prevent metabolites that are toxic to the nervous system from leaching out of the gut and causing autism-like behavioral symptoms. “We were throwing wet noodles at the wall for five years before we figured that out,” says Sarah McBride, Mazmanian’s lab manager and a researcher on the autism project.
Wet noodle-throwing is a fairly common methodological approach in the lab because there’s just so much still unknown about this new field, says McBride, adding that Mazmanian’s enthusiasm and quirks keeps the group’s morale high. “Sarkis likes to say, ‘It’s not called “search,” it’s called “research” -- as in you do it over, and over, and over again,’” she says. “I have a whole list on my computer of what we call is ‘Sarkisms.’”
Since coming to Caltech, Mazmanian has begun to travel annually to Armenia, where his family is from, to teach microbiology at the Institute of Molecular Biology in the city of Yerevan. The building is in sad shape, with tiles missing from the floor and windows cracked and broken, “but the will of the students and their desire to learn is incredible,” he says. He’s toying with the idea of somehow supporting life science in his country of origin. “I feel very fortunate and grateful to be in a position to help people who are not as educationally fortunate as students in this country,” he says.
Meanwhile, his lab is continuing to ride the wave of microbiome research. One recent focus is trying to understand exactly which beneficial molecules our gut bacteria produce, so that they can be given as medicine to people who must take antibiotics, or to those with immune disorders. And judging by Mazmanian’s track record so far, there are many awards still to come.