February 6, Wed 2013
2:00 pm, Haworth 1005
Dr. Christian Ray
Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center
Toxic Assets in Cellular Economies
Critical points in biochemical networks emerge as an intrinsic feature of underlying molecular interactions, with potentially profound effects on global physiology. I show one such multiscale effect to arise at the interface between gene expression and metabolism in bacteria. Metabolic fluxes produce intermediates viewed as cellular assets, but saturation of consuming enzymes limits the benefit from increased intermediate production. Using mathematical models, I find that saturation of the consuming enzyme creates a critical threshold in growth rates. Below the threshold, cellular growth can be "inflationary": increases in metabolite flux are counteracted by increases in growth rate that homeostatically dilute the metabolite. Above the threshold, metabolite buildup reduces growth rates, creating runaway toxicity and, ultimately, cessation of growth. Entry into the toxic phase can be caused by noise decorrelating enzyme expression, resulting in metabolite bursts from transient flux imbalances. Therefore, some metabolic pathways may exist in a metastable state where high growth rates outcompete losses from entry into the toxic phase. I test this model and explore its implications experimentally with engineered imbalances in lactose import and catalysis. The results taken together suggest a new high risk, high reward regime for metabolic pathways, with implications for the role of critical points in evolution.