As a physician-scientist caring for patients with chronic diseases, I am acutely aware of the burden caused by these conditions and the need for improved treatment options. Regenerative medicine offers enormous hope for the treatment of many conditions either through directed differentiation of pluripotent stem cells or through the activation of endogenous tissue stem cells. My laboratory has been specifically focused on developing model systems to define basic mechanisms underlying stem cell regulation and lineage development in self-renewing tissues. My laboratory identified an elusive intestinal stem cell (ISC) and is now investigating the mechanisms regulating slowly and rapidly cycling ISCs in response to physiological (fasting) and pathological (irradiation, inflammation) stress. We are also defining the role of ISCs in intestinal regeneration and cancer initiation and their potential for directed differentiation. We discovered that in slowly cycling ISCs, PTEN is an important regulator of the quiescent state and regulates nutrient sensing and that JAK/STAT-1 regulates the response to inflammation. I founded the Intestinal Enteroid Core of the Harvard Digestive Diseases Center. This effort led to a number of discoveries including the description of a major mechanism underlying C. diff. colitis and a strategy to directly convert mouse gastrointestinal stem cells into functional insulin-producing beta cells, ex vivo. My laboratory is also focused on mechanisms underlying lineage development within endocrine tissues. We are testing the hypothesis that terminally differentiated cells undergo transdifferentiation in response to hormonal feedback. To investigate this, we are studying the adrenal cortex, which is composed of functionally distinct concentric layers that develop postnatally. We discovered that adrenocortical zonation results from cell fate conversion between differentiated cells, which may provide a paradigm for homeostatic cellular renewal in other tissues. This mechanism also underlies pathological states such as hyperaldosteronism (a major cause of hypertension) and adenoma formation.