Automated Design of Robust Genetic Circuits: Structural Variants and Parameter Uncertainty.

Genetic design automation methods for combinational circuits often rely on standard algorithms from electronic design automation in their circuit synthesis and technology mapping. However, those algorithms are domain-specific and are hence often not directly suitable for the biological context. In this work we identify aspects of those algorithms that require domain-adaptation. We first demonstrate that enumerating structural variants for a given Boolean specification allows us to find better performing circuits and that stochastic gate assignment methods need to be properly adjusted in order to find the best assignment. Second, we present a general circuit scoring scheme that accounts for the limited accuracy of biological device models including the variability across cells and show that circuits selected according to this score exhibit higher robustness with respect to parametric variations. If gate characteristics in a library are just given in terms of intervals, we provide means to efficiently propagate signals through such a circuit and compute corresponding scores. We demonstrate the novel design approach using the Cello gate library and 33 logic functions that were synthesized and implemented in vivo recently (Nielsen, A., et al., , , (6281), DOI: 10.1126/science.aac7341). Across this set of functions, 32 of them can be improved by simply considering structural variants yielding performance gains of up to 7.9-fold, whereas 22 of them can be improved with gains up to 26-fold when selecting circuits according to the novel robustness score. We furthermore report on the synergistic combination of the two proposed improvements.