Reconstructing and exploring uniquely humaN Biology

1: Integrated Tissue Systems: We apply and develop single-cell genomic methods to reconstruct differentiation trajectories, trace lineages, perturb gene networks, and spatially map cell states in three-dimensional (3D) tissues engineered from human stem cells (often-called “organoids”). We compare these in vitro systems to real, primary tissues to understand the extent to which organoids recapitulate natural processes that occur during organ development and physiology. We work across organs including the brain, retina, liver, and gut in order to identify mechanisms that are common and specific to each tissue. We collaborate to engineer next-generation human models that include vascular and immune competency in order to gain access to more relevant human physiology.

2: Disease Trajectories and Therapeutics: We are using 3D organoid and other human model system technologies to understand human disease and to develop therapies. We are establishing high-throughput, high-information content experiments to quantify phenotypic spaces or landscapes (“Phenospace”/”Phenoscape”) using multimodal readouts in each of our human model systems grown in a variety of perturbation conditions. We are developing computational pipelines to understand and explore these data. Our major goal is to develop accurate and personalized models of various disorders, and assist with the development of novel corrective therapies.

3. Experimental Evolutionary Physiology: We are generating cell atlases of great ape organs in order to understand similarities and differences between humans, chimpanzees/bonobos, gorillas, and orangutans. In parallel, we are generating stem cell-derived organoids from each of these species in order to understand and model organ development across primates. These efforts aim to identify how human cells have diverged from our closest living and extinct relatives. We use comparative genomic screens to identify genetic changes that are specific to humans, and use CRISPR-Cas9 editing to explore the molecular mechanisms that led to uniquely human phenotypes.