As a child, Sarkis Mazmanian frequently took things apart to figure out how they worked. At the age of 12, he dismantled his family’s entire television set—to the dismay of his parents and the unsuccessful TV repairman.
“I wasn’t aware of this at the time, but maybe that was some sort of a foreshadowing that I would enjoy science,” Mazmanian says. “Scientists take biological systems apart to understand how they work.”
Mazmanian never thought he’d become a microbiologist, let alone a leading expert in the field. He began studying microbiology at the University of California, Los Angeles (UCLA), because it was the major that allowed him to do the most hands-on research. But as soon as he entered the field, he fell in love with the complexities of microbial organisms and the efficiency of their functions.
Microbiology is the study of microorganisms including bacteria, viruses, parasites and fungi. Researchers in the field often have a specific focus such as infectious microbes, bacterial metabolism, microorganisms in the environment, or the human microbiome (the overarching term for the genetic information of all of the microbes living in or on the human body).
After finishing his Ph.D. at UCLA in 2002, Mazmanian moved to Harvard Medical School, where he began studying the human microbiome, a virtually nonexistent field at the time.
Most people think of bacteria as dangerous creatures that cause disease, but there are many more harmless bacteria than there are harmful ones, he explains. For example, bacteria in the gut help digest food, provide Vitamin K and improve nutrient absorption.
In the early 2000s, most scientists focused on pathogenic microbes that caused disease, not those that were helpful.
“It’s my personality to go off the beaten path and try something new,” Mazmanian says. “I took this leap of faith to stay in microbiology, which I enjoyed, but to not study infectious disease. Rather, I set out to study microbes that may have potential benefits to their hosts.”
Since 2006, Mazmanian has been a professor at the California Institute of Technology, and his lab works on uncovering the mechanisms by which gut bacteria protect their hosts from various diseases, with the ultimate goal of identifying microbes with therapeutic potential.
Through his research at Harvard, Mazmanian uncovered another role that gut bacteria play in maintaining health—they send important signals necessary for the immune system to function properly. Scientists know that a mammal’s genome helps guide the development of healthy immune defenses. Mazmanian suspects that the microbiome plays a role in this important function too.
In more recent work, he found that without gut microbes, mice succumb to infectious diseases that they normally resist. These observations suggest that instructions from the microbiome work with instructions from genetic information to ensure a robust immune defense.
This idea, that the microbiome in the gut is intricately connected to the immune system, was surprising to Mazmanian and the scientific community, and garnered interest for the field.
Mazmanian and his team then focused on a disease that results from an overactive immune system, Inflammatory Bowel Disease (IBD). Characterized by chronic inflammation of the digestive tract, IBD affects at least 1 million Americans each year.
Due to the association Mazmanian had seen between bacteria and the immune system, he wondered if his team could find a bacterial strain that could rein in the excess immune response to alleviate the symptoms of IBD patients.
Through the use of mouse models, Mazmanian experimented with various bacterial strains and identified one, normally found in the gut, that could potentially prevent and treat IBD by quashing inflammation.
“The microbe, called Bacteroides fragilis, triggers the immune system to develop an anti-inflammatory or suppressive immune response,” Mazmanian says.
When designing the study, Mazmanian chose bacterial strains that are also found in humans. As a result, there is greater potential for their use in the future to help treat diseases like IBD in humans.
These findings led Mazmanian and his team to hypothesize that the absence of particular microbes—in this case, Bacteroides fragilis, with its anti-inflammatory properties—could be a risk factor for disease.
This notion is paradoxical to common wisdom that all bacteria make us sick. In fact, the research is slowly embracing the new concept that if a lack of specific beneficial bacterial is a risk factor for disease, then “microbial replacement” may be a potential therapy.
Bacterial Balancing Act
To better understand how microbes benefit their host, Mazmanian and his team set out to investigate how bacteria colonize and set up long-term residence. In 2013, Mazmanian’s team discovered that bacteria can dock and create residences in the intestines via five genes, collectively called the commensal colonization factors (ccf), that had previously been unstudied.
Mazmanian’s group found that when an antibacterial drug or infection starts to wipe out the bacterial settlements, the microbes hide away in colonic crypts with the help of the ccf genes. Once the trouble clears, the reservoirs of microbes emerge and repopulate the gut ecosystem.
These findings are important because many intestinal and inflammatory diseases are associated with a microbial imbalance in the gut. Through an increased understanding of microbe colonization and resiliency, scientists like Mazmanian are hoping to devise ways to restore normal microbe communities in the gut, and in turn, help treat diseases.
Mazmanian’s findings open up a myriad of questions about the connection between microbes and diseases that scientists are working to answer. Currently, Mazmanian’s team is investigating the connection between microbes and an entirely new subset of diseases—neurological disorders as diverse as autism and multiple sclerosis.
When mice who express certain neurological symptoms, like impaired communication and repetitive and stereotyped behaviors, are given Bacteroides fragilis, these behaviors, are reduced or eliminated. He plans to continue investigating his bold hypothesis—that the origin of certain neurological disorders lies in the intestines, not the brain.
For Mazmanian, tackling intellectual challenges in creative ways is what is most exciting.
“I think being intrepid and daring and fearless in your research results in the ability to ask questions that could be game changers,” Mazmanian says. “At the end of the day, having intellectual freedom is priceless … we follow our own interests, our own intuition and our own curiosity.”
It’s through this type of innovative thinking that scientists like Mazmanian work to advance science and improve health.