Douglas E Brash, PhD

Dr. Brash received his BS in Engineering Physics from the University of Illinois, minoring in Physiological Psychology. After receiving a PhD in Biophysics, he began elucidating the steps leading from ultraviolet light photons to human skin cancer. As a postdoc at Harvard, he found that UV-induced mutation hotspots in E. coli occur at the same gene positions as (6-4) photoproducts and cyclobutane dimers: UV wasn't elevating random genomic instability. At the National Cancer Institute, he proved these photoproducts were mutagenic. Upon moving to Yale, his lab used the distinctive UV mutation pattern to identify genes mutated by sunlight in causing skin cancer: p53 in squamous cell carcinoma and its actinic keratosis precursor, and p53 and PTCH in basal cell carcinoma. They then showed p53 to be a key element of UV-induced apoptosis, preventing damaged cells from becoming mutants. Because the multiple-genetic-hit model of cancer predicts that our bodies harbor cells mutated in just one or another of the genes needed for cancer, the lab then sought p53-mutant cells in normal skin. These cells were not only present but were already proliferating as clones and were astonishingly common – many people carry 60,000 clones, occupying almost 5% of their epidermis. Switching to mice revealed that clonal expansion is driven by physiology, not by adding mutations. One mechanism is the mutant's resistance to UV-induced apoptosis. Another is UV's ability to tilt a clone's balance of progenitor cells and differentiating cells toward self-renewal of the progenitors. Recently the lab discovered that chemical excitation of electrons, "chemiexcitation", is a new mode of disease that uses the pigment melanin to create UV-like carcinogenic lesions even after UV exposure has ended. These results contribute to what is perhaps the best picture available of how a human carcinogen works. Another current project is identifying UV-hypersensitive genome regions for use as "genomic dosimeters" to assess a person's past sun exposure and future skin cancer risk.