Microbes that live in dirt often engage in their own deadly turf wars, producing a toxic mix of chemical compounds (also called “small molecules”) that can be a source of new antibiotics. When he started out in science more than a decade ago, Michael Fischbach studied these soil-dwelling microbes to look for genes involved in making these compounds.
Eventually, Fischbach, who is now at the University of California, San Francisco, came to a career-altering realization: maybe he didn’t need to dig in dirt! He hypothesized an even better way to improve human health might be found in the genes of the trillions of microorganisms that dwell in and on our bodies, known collectively as the human microbiome.
Fischbach is most interested in bacteria living in the human gut, especially the many species that generally live in harmony with us. These microbes produce thousands of small molecules, some so abundantly that they are absorbed into the bloodstream at levels comparable to a drug. Concentrations of these small molecules can vary dramatically from person to person, but researchers still don’t know exactly why.
Fischbach has received a 2016 NIH Director’s Pioneer Award to conduct research aimed at gaining a better understanding of the small molecules made by the human gut microbiome. He will begin by creating a “Top 100” list of its most-abundant molecules. Armed with this information, Fischbach’s team will set about assembling and growing beneficial communities of bacteria in the lab, with the ultimate aim of repopulating a sick person’s gut with a collection of microbes that make health-promoting small molecules. He thinks such a strategy could help to prevent or even treat gastrointestinal problems and possibly even a wide range of other conditions, from obesity to heart disease.
To create his “Top 100” small-molecule catalog, Fischbach will analyze stool samples collected from male and female volunteers representing a broad cross-section of ages, races, and ethnicities. His group will then culture the predominant bacterial strains and apply state-of-the art analytical chemistry to determine the chemical structure of the molecules that they produce.
The team will then attempt to determine which particular bug, and which of that bug’s genes, makes each small molecule. That ambitious work will enable Fischbach’s team to knock out the function of each gene, transplant the genetically engineered bacteria into the guts of laboratory mice, and then study how the lack of each particular bacterial gene affects the health of the mice.
Fischbach stresses that his current work is just the first step in a complicated effort to develop the biological knowledge and computational tools necessary to delve deeper into the biochemistry of the human gut microbiome. In a few years, he hopes to have constructed his first “synthetic community” of gut bacteria and to be gearing up for clinical trials to test its safety and ability to improve human health.
Human Microbiome Project (Common Fund)
Fischbach Group (University of California, San Francisco)
Video: Michael Fischbach Faculty Profile (University of California, San Francisco)
Fischbach Project Information (NIH RePORTER)
NIH Director’s Pioneer Award Program (Common Fund)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; Common Fund