A central goal of my research is to uncover new regulatory mechanisms in signaling systems, to understand how these mechanisms are damaged in disease states, and to devise new strategies to repair their function. One focus of the laboratory has been on morphogenetic pathways, such as Hedgehog and WNT, that regulate the formation of most tissues during development. These same pathways control tissue stem-cell function and organ regeneration in adults, and defects in these systems cause degenerative conditions and cancer. Our efforts have elucidated how the Hedgehog signal is transmitted across the membrane, processed in specialized organelles called primary cilia and eventually conveyed to the nucleus to influence gene expression programs. We have shown that reception of the Hedgehog signal in vertebrates requires precisely regulated protein trafficking events and spatially localized biochemical interactions in primary cilia, solitary hair-like projections found on most cells in our bodies that function as critical hubs for signaling. Over fifty human genetic diseases, called “ciliopathies,” are caused by defects in cilia, and our work has helped elucidate the molecular pathogenesis of a subset of these syndromes. In a separate effort, we have used a combination of classical pharmacology and crystallography to discover that both oxysterols and cholesterol can directly activate the Hedgehog membrane transducer Smoothened and to characterize conformational changes that drive Smoothened activation, as well as its inactivation by anti-cancer drugs used in the clinic. Most recently, we have uncovered novel pathways that can regulate the sensitivity of target cells to morphogenetic signals and thus alter the important relationship between signal strength and cell fate. We continue to tackle unsolved mysteries in signal transduction and to study emerging regulatory principles, such as the signaling function of endogenous lipids and the role of protein phase transitions, in cell-cell communication systems important in development, physiology and disease.