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My research vision is to improve human health by identifying and targeting neurological disease mechanisms. This vision builds on my training in developmental neuroscience, where I identified the lineage and potential of adult neural stem cells and overturned dogma that stem cells are homogenous. My later work in human pluripotent stem cell (hPSC) genomics provided open-access resources for rational cell line selection, revealed recurrent mutations in p53 that profoundly impacted the fields of stem cell biology and regenerative medicine, identified a ‘reference’ hiPSC line to promote reproducibility in the field and enable large-scale studies, and showed how common genetic variants influence gene expression in a cell type- and disease state-dependent manner. I was an early adopter of CRISPR/Cas9 for hPSCs to knock out genes and introduce reporters, and employed these tools to study hPSC-derived hypothalamic POMC neurons that are key regulators of appetite. My research team showed how human POMC respond nutrients, hormones, and drugs, including the leading weight loss drug Semaglutide/Ozempic, and have revealed new potential mechanisms and drugs that suppress appetite. We pursue the fundamental biology of the three man research areas below, with the ultimate goal of developing new treatments: 1) improving the utility and reproducibility of hPSC-based disease models, 2) understanding how key appetite-regulatory hypothalamic neurons respond to metabolic signals and could be targeted to suppress appetite 3) illuminating the mechanistic links between metabolic and neurodegenerative disease to reveal novel neuroprotective strategies We achieve these goals by collaborating extensively and fostering inclusivity, curiosity, and personal development in an interdisciplinary research team. I encourage outstanding graduate students or postdoctoral candidates interested in contributing to this work to contact me at fm436[at]medschl.cam.ac.uk.
Appetite-regulatory human hypothalamic neurons, differentiated from pluripotent stem cells
