Revisiting a Breathtaking Publication in the History of Molecular Biology

I will tell the story of how three pioneers of molecular biology made breathtaking insights into the nature of the genetic material based on simple experiments with a bacterial virus (phage) called T4. Using T4, Seymour Benzer brought the genetic material down to the level of nucleotides and defined the gene as a functional unit (cistron). Building on the work of Benzer, Francis Crick, Sydney Brenner and their collaborators deduced that the genetic code is read in units of three bases, is non-overlapping and is read from a fixed starting point. These remarkable insights were made using two genes of phage T4 called rIIA and rIIB and simple experiments based on whether or not the mutants could form zones of clearing (plaques) on a lawn of bacteria growing on an agar plate. Fast forward a quarter of a century with the invention of DNA sequencing, our host Larry Gold and his research team revisited these classic experiments by sequencing the rIIA and rIIB mutants. Seen from the lens of these nucleotide sequences, Crick and Brenner were correct in their conclusions but not for the reasons that are widely believed.