Around this time, Cairns was recruited away from the Australian National University in Canberra to become the director of the CSHL in New York from 1963 to 1968. Despite having to spend the majority of his time fund-raising to rescue the CSHL from bankruptcy, Cairns achieved another molecular biology milestone. At the time, only one DNA polymerase had been isolated from E. coli, by the Kornberg lab. It was generally assumed that this polymerase was responsible for duplication of the entire E. coli genome, and Cairns set out to determine whether or not this assumption was correct. Not only was his answer surprising to the molecular biology community but also his experimental approach was stunning. Cairns and his assistant, Paula De Lucia, carried out what is known as a brute-force mutant hunt. Thousands of individual cells were isolated from a mutagenized E. coli culture, and each cell was separately incubated to spawn a culture containing a billion bacterial cells that was then analyzed for DNA polymerase content. The first 3,477 cultures tested had normal DNA polymerase levels; the 3,478th culture had virtually none (the mutated gene was named polA as a subtle nod to Paula De Lucia’s contribution). The fact that cells deficient in this enzyme could grow normally de facto demonstrated that this polymerase was not required for duplication of the E. coli chromosome. It was this discovery that stimulated Kornberg and others to search for additional polymerases and ultimately led to the identification of a large multi-protein replication machine responsible for copying the entire E. coli genome.
When James Watson was recruited to take over as director of the CSHL in 1968, Cairns became an American Cancer Society Professor, the most prestigious award conferred by the society, and he turned his attention to reading and thinking about issues related to cancer. One product of these endeavors was a Perspective in Nature proposing that rapidly proliferating epithelial cells might be organized to minimize the accumulation of mutations, and that stem cells might always inherit daughter DNA molecules containing the original parental DNA strands. This became known as the ‘immortal strand hypothesis’, and subsequent studies have strongly supported this model of DNA strand segregation in certain kinds of epithelial stem cells. Another product was the highly influential and now classic book entitled Cancer Science and Society, which presented numerous meticulously researched, thought-provoking arguments about cancer; this book became essential reading for biologists and epidemiologists alike working on cancer, as it seamlessly integrated basic biology with the global epidemiology of cancer. Finally, during this period of thinking about issues related to cancer, Cairns was appointed in 1973 as director of the Imperial Cancer Research Fund’s Mill Hill laboratories in London. Over the next 7 years, Cairns fostered basic biological research using model organisms such as bacteria, flies, slime molds, amphibians and mice to understand fundamental biological pathways that were likely to be relevant to the transformation of normal cells into cancer cells. Cairns created and fostered an exceptionally stimulating, interactive, nurturing and cutting-edge research environment that launched the careers of many students and postdocs who had the privilege of training in the rarified atmosphere that surrounded Cairns wherever he went. In his own lab at Mill Hill, Cairns discovered new pathways for DNA repair in E. coli exposed to the kinds of alkylating agents that are commonly used for cancer chemotherapy; all of the DNA-alkylation-repair pathways identified in E. coli turned out to also exist in humans and to be important players in both cancer susceptibility and cancer treatment.
