Alfred G. Knudson (1922–2016)

An iconic, visionary giant in medical science, Alfred G. Knudson, Jr., M.D., Ph.D. died July 10, 2016, one month short of his 94 birthday. Often referred to as the ‘‘Mendel of cancer genetics’’—Al was widely known for his groundbreaking ‘‘two-hit’’ hypothesis of cancer development and his prediction of recessiveacting tumor suppressor genes. His revolutionary two-hit hypothesis envisaged that cancer occurs when both copies of such a gene sustain mutations. The first hit may be hereditary, and the second occurs somatically. This theory, originally based on studies of hereditary and nonhereditary forms of retinoblastoma, was later shown to be applicable to many cancers. His elegant mathematical models, borrowed from physics and probability theory, served as the foundation for understanding the relationship between hereditary and sporadic cancers. Proof of his prescient ideas took more than a decade, with the emergence of recombinant DNA technologies that permitted validation of the model by Webster Cavenee and colleagues and subsequent cloning of the first tumor-suppressor gene, RB1, by Stephen Friend and