A balanced perspective on unbalanced growth and thymineless death

Philip C. Hanawalt

The early history of the esoteric phenomenon of thymineless death (TLD) is recounted, from the pioneering discovery by Seymour Cohen and Hazel Barner, through my graduate studies at Yale and postdoctoral research in Copenhagen. My principal contribution was the discovery that restricted synthesis of protein and RNA permits cultures of Escherichia coli to complete their DNA replication cycles without initiating new ones, and that cells held in this physiological state are immune to the lethality of thymine deprivation; unbalanced growth is not the fundamental cause of TLD. The successful synchronization of the DNA replication cycle contributed to formulation of the replicon concept. Studies at Stanford revealed a specific requirement for transcription and led to the discovery of a TLD-resistant mutant in a new gene, termed recQ, with important homologs in humans and most other organisms. The lessons learned from research on TLD underscore the value of basic research in bacterial systems that can have profound implications for human health.