A Half-Century of Inspiration: An Interview with Hamilton Smith

In 1962, Hamilton Smith abandoned a career in medicine to follow his passion for the emerging field of molecular biology; within six years, he had made the discovery of a lifetime. As a new Johns Hopkins faculty member, Smith, together with his first graduate student, Kent Wilcox, geared up to study recombination in vitro but instead discovered the restriction enzyme “R” in Haemophilus influenzae. By cobbling together crude techniques, Smith, along with Wilcox and later Tom Kelly, showed that R cleaves DNA at a specific recognition sequence, a palindromic site, yielding blunt-ended DNA fragments. Now known as HindII, R proved to be the first of an enormous class of Type II restriction enzymes, and as such, presaged gene cloning, allowed DNA to be reproducibly fragmented and then sequenced, and enabled physical mapping of genomes. Smith went on to discover DNA methylases that constitute the other half of the bacterial host restriction and modification systems, as hypothesized by Werner Arber of Switzerland. Together with Arber and his Hopkins colleague Daniel Nathans, who first used the enzyme on SV40 DNA and demonstrated discrete bands on a tube gel, Smith shared the Nobel Prize for Physiology or Medicine in 1978.