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Synthetic biology applications have the potential to have lasting impact; however, there is considerable difficulty in scaling up engineered genetic circuits. One of the current hurdles is resource sharing, where different circuit components become implicitly coupled through the host cell's pool of resources, which may destroy circuit function. One potential solution around this problem is to distribute genetic circuit components across multiple cell strains and control the cell population size using a population controller. In these situations, perturbations in the availability of cellular resources, such as due to resource sharing, will affect the performance of the population controller. In this work, we model a genetic population controller implemented by a genetic circuit while considering perturbations in the availability of cellular resources. We analyze how these intracellular perturbations and extracellular disturbances to cell growth affect cell population size. We find that it is not possible to tune the population controller's gain such that the population density is robust to both extracellular disturbances and perturbations to the pool of available resources., National Science Foundation (Award 1521925)

© 1963-2012 IEEE. The ability of cells to sense and respond to their environment is encoded in biomolecular reaction networks, in which information travels through processes such as production, modification, and removal of biomolecules. Recent advances in biotechnology have made it possible to reengineer these physical processes to the point where synthetic biomolecular circuits can be inserted into cells to program cell behavior for useful functionalities. These circuits are often designed in a bottom-up fashion with smaller components connected to form complex systems. In a bottom-up approach to design, it is highly desirable that circuit components behave modularly, that is, the input-output behavior of a module characterized in isolation remains unchanged when the context changes. Unfortunately, due to the physical processes by which information is communicated from one biomolecular circuit module to the other, the lack of modularity is often a problem. In fact, the input-output behavior of a module depends on both direct connectivity to other modules, due to loading effects, and indirect connectivity arising from loads applied to shared cellular resources. In this paper, we summarize the published work illustrating how the means of molecular communication lead to these problems. Specifically, we review the concept of retroactivity, which has been proposed to capture loading problems within a 'signals and systems' framework, allowing for engineering solutions that restore modularity.

The ability to engineer genetic circuits in living cells has tremendous potential in many applications, from health, to energy, to bio-manufacturing. Although substantial efforts have gone into design approaches that make circuits robust to variable cellular context, context dependence of genetic circuits remains a significant hurdle. We review intra-cellular resource competition, one culprit of context dependence, and summarize recent efforts toward design approaches to mitigate it. We classify these approaches into two main groups: global control and local control. In the former, the pool of resources is regulated to meet the demand, and in the latter, individual modules are regulated to be robust to variability in the pool of resources. Within each group, we highlight both feedback and feedforward implementations., National Science Foundation (Award 1521925)