Automated design of gene circuits with optimal mushroom-bifurcation behaviour

Abstract

Recent advances in synthetic biology are enabling exciting technologies, including the next generation of biosensors, the rational design of cell memory, modulated synthetic cell differentiation and generic multi-functional bio-circuits. These novel applications require the design of gene circuits leading to sophisticated behaviours and functionalities. At the same time, designs need to be kept minimal to avoid compromising cell viability. Bifurcation theory of dynamical systems provides powerful tools to address complex nonlinear dynamics and multifunctionality, linking model topology and kinetic parameters with circuit behaviour. However, the challenge of incorporating bifurcation analysis to automated design has not been accomplished so far. In this work we present an optimisation-based method for the automated forward design of synthetic gene circuits with specified bifurcation diagrams, allowing us to find minimal topologies optimizing the required functionalities and taking into account additional requirements and/or context specifications. We apply the method to design of gene circuits exhibiting the so called mushroom bifurcation, a relatively unexplored multi-functional behaviour of particular relevance for developmental biology. Using the results of the optimisation analysis we explore the capabilities of the resulting circuits for possible applications in advanced biosensors, memory devices, and synthetic cell differentiation.