Single isogenic cells are phenotypically heterogeneous. This is implicit in ideas such as LD50 (the drug concentration that kills 50% of cells): in the absence of variability either 100% would be killed, or none would be. The long-term objective of my research program is to determine how brief stochastic events at the molecular level generate heritable phenotypic variability in single cells and in organisms. Non-genetic heterogeneity allows microbes to survive antibiotics, tumor cells to survive chemotherapy, and results in incomplete penetrance of deleterious mutations.

Why do individual cells proliferate at different rates in the absence of genetic and environmental differences? By combining a high-throughput genome-scale microscopy screen and a novel flow-cytometry based method for isolating cells that differ only by their rate of proliferation, we identified the molecular mechanisms that generate proliferation heterogeneity in yeast. We found that reversible heterogeneity in mitochondrial state determines differences in both proliferation rates and survival in antifungal drugs. Furthermore, we found that both yeast and nematodes genetically regulate RNA polymerase fidelity, and that slow-proliferating organisms have lower fidelity, possibly using errors generated by RNA polymerase as a source of temporary heterogeneity.