Genetically engineered control systems

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. 

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.

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. 

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.