The Physical Structure of Intracellular Feedback Loops

Christopher V. Rao, Department of Chemical Engineering, University of Illinois, 600 South Matthews Ave., 211 Roger Adams Laboratory, Box C-3, Urbana, IL 61801

The parallels between the feedback control mechanisms used in cells and manufacturing processes have long been noted. Both need to function robustly in response to dynamics changes in supply/demand and also in response to unforeseen disturbances. To deal with these challenges, natural and synthetic systems employ feedback control. As a general control theory for synthetic systems has already been developed, one can imagine that the same tools may be applicable for the analysis and design of natural systems. However, one challenge in applying concepts from synthetic systems to natural one is that with the latter a natural decoupling between the process and control system often does not exist. Moreover, natural systems physical encode their control systems in a number of different ways. Understanding this encoding is often necessary for elucidating the mechanism and associated degrees of freedom. In this work, we explore two biological control examples, one involved in sugar metabolism and the other in antibiotic resistance, where the relative location and orientation of the regulators encoded within the genome plays a critical role in the feedback mechanism. We demonstrate experimentally that perturbations to the genetic encoding of the feedback dramatically alter its behaviors. These results suggest that the physical instantiation of the feedback needs to be accounted for in any theory of biological control.