Current Projects:
Translating human genetics to functional biology
We identify and characterize disease-associated genetic variants—using deep molecular profiling, genotyped cohorts, clinical phenotypes, base editing in primary cells, high-fidelity cellular models, and knock-in animal models—to understand gene function in relevant cell types and processes and ultimately reveal disease mechanisms and develop therapeutic hypotheses.
Most recently, we coupled single-cell and spatial transcriptomics with functional studies of an HGFAC variant conferring risk of inflammatory bowel disease to dissect a healing response in the intestinal epithelium (Nakata et al. Sci Transl Med., 2023)
Determining the influences of the gut microbiome on health and disease using human cohorts and computational models
We combine analyses of multi-omic data from human cohorts—including patients with autoimmune and inflammatory diseases as well as early childhood and centenarian cohorts—with computational approaches to define homeostatic and pathological interactions between the gut microbiome and the immune system and to link the enzymatic activities of gut microbes to human physiology. We further identify and functionally analyze immunomodulatory products of disease-associated microbes.
Analyzing the microbiome during the first three years of life, we demonstrated that maternal microbes shape the functional potential of infant microbiomes through horizontal transfer of genes, many of which impact immune and nervous system development (Vatanen et al. Cell. 2022). We discovered cholesterol-metabolizing Oscillibacter species that were linked to better cardiovascular health humans by generating and analyzing metagenomic and metabolomic profiles from participants in the Framingham Heart Study (Li et al. Cell. 2024). Moreover, we identified a phospholipid from the cell membrane of Akkermansia muciniphila that functions in homeostatic immunity (Bae et al. Nature. 2022).
Generating systems-wide maps within the gut that capture immune features and metabolic states at single-cell resolution
We create single-cell and spatial maps of the healthy and inflamed gut to expose cellular, transcriptomic, and spatial dynamics that contribute to pathology. We also develop computation approaches to uncover patterns of human and microbial pathway activation during disease.
Recently, we charted the spatial and cellular landscape of the murine intestine in steady and perturbed states and determined that intestinal regionalization is characterized by robust and resilient structural cell states and that the intestine can adapt to environmental stress in a spatially-controlled manner (Mayassi et al. Nature. 2024). We also developed an algorithm that uses deep learning to integrate latent structural features of protein antigens with immunopeptidomes restricted to diverse HLA-II alleles, which revealed bacterial and viral antigens driving heterogeneous protective and pathological T cell responses (Stražar et al. Immunity. 2023).
Leveraging chemical biology to test therapeutic hypotheses and inform drug discovery programs
We integrate human genetics and functional genomics with computational and chemical biology to identify disease-relevant proteins and sites on these proteins that can be selectively targeted by small molecules and molecular glues.
In collaboration with Stuart Schreiber, we recently combined chemical inducers of proximity (CIPs)—molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities—with a DNA-encoded library to screen for CIPs that recruit FKBP12 to the Crohn’s disease risk variant ATG16L1 T300A, identifying a compound that reverses the cellular defects characteristic of the variant (Tan et al. Cell Chem Biol. 2025).
Contact: rxavier [at] broadinstitute.org (rxavier[at]broadinstitute[dot]org) | Lillian Blizard, lblizard [at] mgb.org (lblizard[at]mgb[dot]org)
Location: MGH / The Broad Institute