“…Elizabeth and James Miller sought to find the chemical roots of cancer and showed that many dangerous chemicals, especially chemicals that cause cancer, often are chemically inert and need to be converted by metabolism, usually oxidative metabolism, to electrophiles that go on to damage cellular macromolecules as an essential first step on the pathway toward malignancy (Figure ). It is interesting that early in their careers, the Millers focused on electrophile–protein interactions because at the time it was a widely held view that proteins, because of their central roles as the purveyors of function in the cell, were likely the primary targets of carcinogens. , Once the work of Watson, Crick, Avery, MacLeod, Fraenkel-Conrat, and Schramm became mainstream, − the Millers and the balance of the field pivoted to embrace nucleic acids, especially DNA, as the target of electrophilic reagents that had the potential to change the coding specificity of information-carrying molecules. , A large field evolved in which a cohort of chemists revealed the pathways by which hundreds of compounds became bonded to DNA in ways that posed threats to genomic informational integrity. − In some cases, the chemistry of DNA adduct formation led to the use of adducts in accessible tissues as biomarkers of prior exposure, , and sometimes the presence of a particular DNA adduct correlated with mutagenic or carcinogenic end points. While useful, this developing repository of chemical information needed more in the way of a biological foundation as a next step.…”