Exploiting bacterial growth laws to characterize indirect mechanisms for generating phenotypic heterogeneity from isogenic populations

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From the time of Jacob and Monod, a dominant theme running through microbiology and bacterial physiology is the idea that the information encoded in DNA can be connected to the physiological state of the organism through a multi-scale assembly of simple elements: the gene within an operon, the operon within a network and the network within the cell. This bottom-up approach to the understanding (and, more recently, the synthesis) of genetic networks is analogous to the engineering principles of electrical circuit design - a fruitful analogy that has lead to significant conceptual advances particularly in the burgeoning field of systems biology. But the limitation of this analogy is, of course, that electrical circuits do not grow and divide. There is an increasing appreciation that genetic networks must be understood within the context of the growing organism; that core metabolic processes leading to rapid cell proliferation impose constraints on gene expression involved in auxiliary tasks. Recently, I have uncovered empirical relationships (called 'growth laws') that allow the interdependence between growth-rate and gene expression to be understood quantitatively. In the present proposal, I examine the consequences of these growth laws, specifically as a mechanism for generating distinct sub-populations in a culture that shares identical DNA. With focus on a simple synthetic inducible protein-expression system in Escherichia coli, I propose to determine the extent to which growth-mediated feedback effects are responsible for establishing observed phenotypic heterogeneity. The results of the investigation have immediate implications for the industrial optimization of protein expression systems to synthesize expensive therapeutics in bacteria, and for the treatment of virulent bacterial infections. In a broader context, the study highlights the importance of a holistic view of the regulation of gene expression in bacteria, where cell growth and protein synthesis are intimately interconnected, and provides insight into a new class of gene regulation through indirect feedback.