Genetically engineered control systems
A genetic control system must contend with many challenges, including uncertainty in the toplogy and parameters of the biomolecular process to be controlled, persistent environmental disturbances, and strong dependence on in the highly variable cellular context in which the controller functions. On top of that, the molecular controller must function reliably in the extremely noisy environment of the cell including the noise generated from its own molecular reactions. The resulting genetic feedback control systems implemented are autonomous, highly dynamic, and generally stochastic in nature. We are developing the foundations of a control theory needed to analyze and design such biomolecular controllers. In the lab, we are constructing these controllers in E. coli, yeast, and mammalian cells.
A Universal Integral Control System for Robust Perfect Adaptation
We proved mathematically that there is a single fundamental biomolecular controller topology that realizes integral feedback and achieves robust perfect adaptation in arbitrary intracellular networks with noisy dynamics. This toplogy requires the interaction of two antagnistic molecules closing the feedback loop. We call this strategy antithetic integral control.
On the basis of this concept, we genetically engineered the first synthetic integral feedback controller in living cells and demonstrated its tunability and adaptation properties. A growth-rate control application in E. coli shows the intrinsic capacity of our integral controller to deliver robustness and highlights its potential use as a versatile controller for regulation of biological variables in uncertain networks.
High Performance Genetic Controllers for Mammalian Cells
Tunable induction of gene expression is an essential tool in biology and biotechnology. We introduced a novel family of miRNA gene expression control systems of varying complexity with significantly enhanced performance. We demonstrated the benefits of these controllers in two applications in a culture of CHO cells for protein manufacturing and in human-induced pluripotent stem cells.
Molecular Circuits for Dynamic Noise Filtering
The invention of the Kalman filter is a crowning achievement of filtering theory that has revolutionized technology. A similar protocol to deal with noise in synthetic biology has been missing. We developed an optimal filtering theory for noisy biochemical networks and showed how the resulting filters can be implemented at the molecular level. We experimentally demonstrated our findings in vitro and in vivo.
Integral Control for Optimal Productivity in a Biofuel Metabolic Pathway
The production of complex biomolecules by genetically engineered organisms is one of the most promising applications of metabolic engineering and synthetic biology. We showed that an antithetic integral control strategy achieves robust perfect adaptation and a high robust rate of production of extracellular biofuel, even when the parameters of the model and controller are poorly known and implemented.