Our past studies revealed that gene expression evolved to be remarkably precise. For example, using precision measurements we developed to globally quantify protein synthesis, our lab uncovered two unifying principles that govern expression stoichiometry among co-regulated genes. First, nearly all components of multiprotein complexes are synthesized at rates proportional to the complexes’ structural stoichiometry. This “proportional synthesis” is observed from bacteria to humans, is independent of post-synthesis control, and predisposes cells to proteotoxic stress under gene copy-number variations, such as aneuploidy. Second, many biosynthetic pathways adhere to a similar principle, with exact enzyme ratios broadly conserved across distant phyla despite vastly different mechanisms controlling synthesis ratios. We have demonstrated both experimentally and theoretically that slight deviations from optimal stoichiometries can have devastating consequences. Therefore, natural genomic sequences contain largely unappreciated but highly quantitative instructions for protein synthesis rates that are critical for life.

A major focus of our laboratory is to interpret these quantitative instructions in bacteria, which are relatively simple but have important impact on human health. We develop high-precision methods to manipulate and measure the effects of nucleotide sequences on the rates of transcription, translation, and mRNA decay. We believe in the power of precision measurements as a discovery engine. For example, our global quantitative mapping of transcription termination in Bacillus subtilis led us to discover “runaway transcription” as an alternative central-dogma paradigm for many Gram-positive bacteria, whose uncoupled transcription-translation defines a previously unrecognized gene-regulatory landscape, shaping how cells respond to antibiotics and other stress. Through these discoveries, our ultimate goal is to create a generative model for protein synthesis as a demonstration of the depth of our understanding of the central dogma, and pave a path forward for predictive biology in non-model and higher organisms. Our current focal areas include sequence determinants of transcription termination, mRNA decay, and translation.