Mechanical and Civil Engineering Seminar

Synthetic biology offers tremendous potential for tackling pressing societal problems from energy, to environment, to medicine. The success of the field hinges on the critical ability to design genetic circuits that perform as intended once interacting with each other inside the cell.  Today, this ability is largely lacking. Genetic circuits rarely perform as specified because they are poorly robust to context: a circuit's input/output behavior is affected by surrounding systems, in ways that can be very subtle.   Control theory has been instrumental for nearly a century in achieving the level of robustness required for real life applicability of physical devices from electronic amplifiers to aircrafts.  It is therefore natural to address the lack of robustness of genetic circuits to context by taking a control theoretic standpoint. In this talk, I will summarize how this natural, yet novel, approach has allowed us to develop an experimentally validated mathematical framework to describe, reason about, and mitigate problems of context-dependence in synthetic biology. Specifically, I will focus on two main sources of context-dependence: direct connectivity of a circuit module to other systems (retroactivity) and competition among different circuit modules for limited cellular resources. For the latter problem, I will introduce a new mathematical description of genetic circuits, which allows resource-aware design. I will then propose a decentralized feedback control approach for decoupling circuit modules from the effects of resource competition. A key element of this strategy is a quasi-integral controller to reject disturbances. Finally, I will transition to application and introduce our preliminary work towards establishing a control theoretic framework for gene-based cell fate reprogramming, specifically for stem cell reprogramming.