Seung Kim Laboratory

Understanding organ development and achieving functional restoration of diseased organs is a broad goal motivating intensive effort in biomedical research. Many vital organs derive from the endodermal and mesodermal germ layers to form the gastrointestinal and respiratory tracts, yet little is known about the molecular and cellular programs that coordinate steps culminating in proper organ morphogenesis and axial position, cell differentiation, proliferation and physiologic function. Replacement or regeneration of pancreatic islets of Langerhans, endocrine organs that secrete insulin and glucagon, has emerged as a paradigm for organ restoration in recent years. Deficiency of insulin-producing islet ß-cells underlies the pathogenesis of diabetes mellitus, a disease with devastating autoimmune (type 1) and pandemic (type 2) forms. However, islet replacement in diabetes is ultimately limited by our inadequate understanding of mechanisms controlling islet formation and growth. Thus, islet replacement is a specific challenge to the consensus that knowledge about solid organ development and expansion can be used to restore organ function in human diseases.

To meet this challenge, my group has pioneered new approaches to create, expand, and regenerate islets. We discovered Drosophila endocrine cells, including insulin-producing cells, that are functional orthologs of mammalian islet cells, and generated novel genetic screens to identify evolutionarily conserved programs that control the development, expansion and reprogramming of islet cells. We identified new FACS-based methods to purify specific classes of cells that generate the pancreas and islets in mice and humans, including definitive endoderm and native pancreatic progenitor cells, providing a powerful platform to accelerate use of pancreatic and embryonic stem cells for islet studies and replacement. We elucidated new molecular pathways that control proliferation of ß-cells in physiological settings or islet tumors. We envision that modulation of these pathways will be useful for stimulating expansion of functional islets for diabetes, and for treating neuroendocrine cancer. Below, we summarize our major research efforts and describe how our unique approaches to islet and pancreas biology should culminate in diagnostic and therapeutic paradigms for human diseases.