Abstract: Synthetic biology is an emerging field of research aimed to engineer biological systems by inserting programmed DNA molecules into living cells. These DNAs encode the production and subsequent interactions of biomolecules that allow the cells to have novel sensing, computing, and actuation capabilities. However, most success stories to date rely heavily on trial and error. This is mainly because genetic devices are context-dependent: the expression level of a synthetic gene often depends not only on its own regulatory inputs, but also on the expression of other supposedly unconnected genes. This lack of modularity leads to unexpected behaviors at the system level, making it difficult to engineer larger and complex systems that function predictably and robustly in practice.

In this talk, I will present my work to characterize context dependence, and to engineer robust, context-independent genetic devices using control theoretic approaches. I will first present a model to describe resource competition as a major source of context dependence, which results in a hidden layer of unintended interactions among genetic devices. These hidden interactions lead to failure of the composed system in experiment. I will then introduce a set of biomolecular controllers – designed to solve an output regulation problem in vivo – that can decouple a genetic device’s output from its context. I will describe challenges applying classical control theory to engineer such controllers due to the physical constraints in living cells, and then present novel theory-guided engineering solutions based on the principle of timescale separation. Finally, I will point to additional design considerations when regulating multiple devices using multiple controllers in a single cell, and pose mathematical conditions to guarantee the regulated devices’ robustness. These works have the potential to enhance the modularity of future synthetic biological systems and to fully unleash their power to address pressing societal needs in environment, energy, and health.

Biosketch: Yili Qian is a PhD candidate in the Department of Mechanical Engineering at the Massachusetts Institute of Technology, in the lab of Prof. Domitilla Del Vecchio. He received his MS degree from MIT in 2015, and dual BS degrees from Shanghai Jiaotong University and Purdue University in 2013, all in Mechanical Engineering. His current research focuses on applying and creating new systems and control theories to engineer robust biomolecular systems. He is broadly interested in nonlinear dynamical systems, networked systems, and model reduction. He also works with synthetic genetic circuits in bacteria in lab. He is a recipient of MIT Ho-Ching and Han-Ching Award (2017), Wunsch Award (2017), and the Chinese National Scholarship (2010).