From bacteria to humans: Lessons learned from a reductionist's view of ultraviolet light-induced DNA lesions

What follows is a personal remembrance of how Dr. Richard Setlow influenced me as a young postdoctoral fellow at Oak Ridge National laboratory between 1963 and 1966. The narrative tries to place my "maturation" as a young, in experienced scientist in the context of the cultural upheaval caused by the Vietnam war, of a Northerner facing a "culture-shock" living in the South and in a revolution in molecular and radiation biology taking place at Oak Ridge National Laboratory at that time. The unique historic juxtaposition o f Dr. Setlow's contribution of the discovery of UV-induced pyrimidine dimer s in bacterial DNA, being potentially the molecular lesion responsible for cell killing and mutagenesis, occurring as I was at Oak Ridge, and the wond erful working relationship I had with William Carrier, his technician, led to our discovery with James Regan that normal human cells repaired these le sion from their DNA. Amazingly, because of Dr. Setlow's challenge to me abo ut my thoughts of the implications of his findings in bacteria, the chance visit to Oak Ridge National Laboratory by Dr. James Cleaver and my backgrou nd as a human geneticist provided me the extraordinary opportunity to carry out a collaboration to test if human cancer prone syndromes might be defic ient in the repair of these UV-induced DNA lesions. With our finding that t he direct demonstration of a lack of repair of UV-induced pyrimidine dimers in cells from the skin cancer prone syndrome, xeroderma pigmentosum, opene d up a new paradigm for the understanding of the molecular mechanism of car cinogenesis of both radiation and chemical carcinogenesis. From this invest igator's vantage point in the history of the understanding of carcinogenesi s, which has led us to the present point of "oncogenes" and "tumor suppress or genes", the old adage by Newton, "I only saw further because I stood on the shoulder of giants", is so applicable here. Dr. Setlow's shoulders were indeed among those of all of us that have made some small contribution in trying to understand this extremely complex process of human carcinogenesis . (C) 2001 Wiley-Liss, Inc.