Research themes:

Synthetic gene regulation

How do cells turn genes on or off, and how do we engineer them to turn genes on or off? How are cell type-specific gene expression programs initiated and sustained? We develop tools to engineer synthetic control of mammalian gene expression using CRISPR and other components inspired by natural transcriptional regulation processes. We gain insights into those fundamental processes from lessons learned while developing these genome perturbation tools that may have useful properties as therapeutic modalities. Some areas of interest include discovering and engineering the molecular control of cell type-specific transcription, cell differentiation state, and epigenetic memory.

Combinatorial genetics

The human genome contains ~20,000 coding genes and >500,000 predicted non-coding regulatory elements. A major challenge in understanding and engineering the genotype-to-phenotype relationship is that genetic elements often do not function as isolated units, but rather in combinations to contribute to natural and engineered biological phenotypes. The potential combinatorial space of genetic elements is enormous, especially at higher-order (>3-plex) combinations, posing a major hurdle for systematic perturbative analyses. To address this challenge, we develop scalable tools and conceptual frameworks that enable efficiently exploring numerous higher-order combinations of genetic perturbations using high-throughput CRISPR experiments.

Functional genomics of tissue biology

In metazoans, cells do not exist alone, but rather as complex cellular communities within tissues. Tissue-level properties that emerge from cell-cell interactions are critical for normal and disease physiology, such as tissue regeneration after environmental insult, and immune recognition of normal or cancer cells. We are developing tools and strategies that enable studying and engineering such emergent tissue-level phenotypes using high-throughput CRISPR perturbations, with emphasis on compressed and combinatorial genetic screens. We aim to establish these approaches in mouse models and human tissues and organs. In these endeavors, we collaborate with long-standing basic science experts in immunology, cancer biology, and tissue regeneration, as well as clinicians and surgeons.