Control Engineering Inspired Design Tools for Synthetic Biology

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James Arpino, Dr Edward Hancock, Dr Ye Yuan, Dr Guy-Bart Stan, Dr Karen Polizzi, Dr Antonis Papachristadolou

Imperial College London, United States

Synthetic Biology aims to design new in vivo biological systems or to redesign existing ones for new or improved functionality and performance. The development of proof-of-concept experimental applications has revealed that, when constructed in the laboratory, most designs do not work as predicted and need to be fine-tuned on a case-by-case basis. Here we use firm engineering principles to establish a redesign framework that reliably generates synthetic bio-systems that behave in a predictable fashion. The framework is based on a systems-engineering, bio-inspired design cycle. We illustrate the application of this cycle on the toggle switch, for which we investigate its quantifiably robust and predictable implementation. We first produce a detailed mathematical model for the system that captures its most important biochemical properties. Combining prior knowledge reported in the literature with experimental data, we show how the model and its parameters can be systematically refined. Based on the models obtained and their robust control analysis, and taking into account model uncertainties and stochastic effects, we propose modifications to biological parts that can be “easily” implemented experimentally (called “dials”), so as to achieve a (re-) design objective which has been specified a priori. We show how the modified systems can be constructed using a “plug-and-play” plasmid that allows direct insertion or modification of any biological part in the system. We then show how experimental data from the implemented prototype systems can be used to refine the models and improve the design through successive iterations.