The microbiome carries out extraordinary feats of biology: it produces hundreds of molecules, many of which impact host physiology; modulates immune function potently and specifically; self-organizes biogeographically; and exhibits profound stability in the face of perturbations. Our lab studies the mechanisms of microbiome-host interactions. Our approach is based on two technologies we recently developed: a complex (119-member) defined gut community that serves as an analytically manageable but biologically relevant system for experimentation, and new genetic systems for common species from the microbiome. Using these systems, we investigate mechanisms at the community level and the strain level.
1) Community-level mechanisms. A typical gut microbiome consists of 200-250 bacterial species that span >6 orders of magnitude in relative abundance. As a system, these bacteria carry out extraordinary feats of metabolite consumption and production, elicit a variety of specific immune cell populations, self-organize geographically and metabolically, and exhibit profound resilience against a wide range of perturbations. Yet remarkably little is known about how the community functions as a system. We are exploring this by asking two broad questions: How do groups of organisms work together to influence immune function? What are the mechanisms that govern metabolism and ecology at the 100+ strain scale? Our goal is to learn rules that will enable us to design communities that solve specific therapeutic problems.
2) Strain-level mechanisms. Even though gut and skin colonists live in communities, individual strains can have an extraordinary impact on host biology. We focus on two broad (and partially overlapping) categories:
Immune modulation: Can we redirect colonist-specific T cells against an antigen of interest by expressing it on the surface of a bacterium? How do skin colonists induce high levels of Staphylococcus-specific antibodies in mice and humans?
Abundant microbiome-derived molecules: By constructing single-strain/single-gene knockouts in a complex defined community, we will ask: What are the effects of bacterially produced molecules on host metabolism and immunology? Can the molecular output of low-abundance organisms impact host physiology?
3) Cell and gene therapy. We have begun two new efforts in mammalian cell and gene therapies. First, we are developing methods that enable cell-type specific delivery of genome editing payloads in vivo. We are especially interested in delivery vehicles that are customizable and easy to manufacture. Second, we have begun a comprehensive genome mining effort with an emphasis on understudied or entirely novel enzyme systems with utility in mammalian genome editing.