ExplorING uniquely humaN development

1: Organ development: We apply and develop new single-cell genomic tools to reconstruct differentiation trajectories, trace lineages, perturb gene networks, and spatially map cell states in three-dimensional (3D) tissues engineered from human pluripotent stem cells (so-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 with multiple organ systems including the brain, retina, lung, and gut in order to identify developmental mechanisms that are common and specific to each tissue. We are also working with collaborators to engineer next-generation vascularized organoid systems that can be perfused in vitro to study cellular maturation and crosstalk between epithelilal, endothelial, mesenchymal, immune, and neuronal cell lineages.

2: Genetic disease: We are using 3D organoids to understand how human genetic diseases disrupt organ development, with a particular focus on the visual system. Using isogenic and patient-derived iPSC lines, we are working to recapitulate retinal malformations in controlled culture environments, and using single-cell genomics and imaging to understand the disease mechanisms. Our major goal is to develop accurate and personalized models of retina developmental disorders, and assist with the development of novel corrective therapies.

3. Great ape organoids and Neandertalized cells: We engineer cells and tissues from chimpanzees and other great apes to identify how human cells have diverged from our closest living relatives. We use comparative genomic screens to identify genetic changes that are specific to humans, and use CRISPR-Cas9 editing to ancestralize human cells to study the molecular mechanisms that led to uniquely human phenotypes. We are also working with groups at the Max Planck Institute for Evolutionary Anthropology to study the function of Neandertal DNA that has introgressed into the modern human lineage, with a particular focus on analyzing Neandertal-derived gene expression over developmental processes .