Douglas E Brash, PhD
Senior Research Scientist in Therapeutic Radiology and in Dermatology and Clinical Professor of Therapeutic RadiologyCards
About
Titles
Senior Research Scientist in Therapeutic Radiology and in Dermatology and Clinical Professor of Therapeutic Radiology
Biography
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.
Appointments
Therapeutic Radiology
Senior Research ScientistPrimaryDermatology
Senior Research ScientistSecondaryTherapeutic Radiology
Clinical ProfessorSecondary
Other Departments & Organizations
Education & Training
- Postdoctoral
- Harvard Medical School (1984)
- Postdoctoral
- Harvard School of Public Health (1981)
- PhD
- Ohio State University, Biophysics (1979)
- BS
- University of Illinois, Engineering Physics (1973)
Research
Overview
The story thus far, from photons up to cells: UV leads to mutations at the site of DNA photoproducts (rather than elevating genomic instability); the important photoproducts are cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts, which join adjacent cytosines or thymines; only the cytosine mutates; these unique properties create a characteristic "mutation signature" for UV that can be seen in tumors decades later; sunlight mutates the P53 and PTCH genes in non-melanoma skin cancer; P53 is required for UV-induced apoptosis, which prevents mutations; apoptosis is signaled by DNA photoproducts in actively transcribed genes and by a product of UV-irradiated melanin; another cause of apoptosis is exposure of melanin to sunlight, particularly the melanin found in blonde and red hair; and our sun-exposed skin carries about 60,000 tiny clones of P53-mutant keratinocytes. Expansion of single mutant cells into clones is due to physiology, not a 2nd mutation: UV-induced apoptosis deletes normal progenitor cells while sparing the mutant ones. UV also tilts the progenitor cell's fate decision toward self-renewal rather than differentiation. Recently, we found two novel properties of CPDs: They can also be created in the dark by a novel physical chemistry process termed "chemiexcitation" that excites electrons in the skin pigment melanin, after which the energy transfers to DNA. They occur 100-fold more frequently at specific sites in the DNA that we term "hyperhotspots". Now, the lab is in the midst of some practical applications:
- Using UV-sensitive DNA targets, for CPDs and mutations, to determine an individual's past UV exposure and predict future skin cancer risk. Early detection in at-risk individuals can lead to survival rates approaching 100%.
- Blocking chemiexcitation as an "after-sun" approach to preventing skin cancer.
- Determining whether chemiexcitation also happens during wound healing and in diseases such as Parkinson's.
Medical Subject Headings (MeSH)
Academic Achievements & Community Involvement
News & Links
Media
- Clone of p53-mutated keratinocytes in a 3D confocal image of an epidermal whole-mount of normal human skin.
News
- May 16, 2022
BRCA Experts Rally to Research DNA Repair for Better Breast, Ovarian and Other Cancer Treatments
- November 12, 2019
Yale study finds ‘hyperhotspots’ that could predict skin cancer risk
- November 24, 2015
Douglas E. Brash, PhD receives the Yale Cancer Center Basic Science Research Prize
- June 15, 2015
Shedding light on skin cancer