Automatic design of gene regulatory mechanisms for spatial pattern formation.

Gene regulatory mechanisms (GRMs) control the formation of spatial and temporal expression patterns that can serve as regulatory signals for the development of complex shapes. Synthetic developmental biology aims to engineer such mechanisms for understanding and producing desired multicellular patterns. However, the design of synthetic GRMs that can produce a target spatial gene expression pattern is a current challenge due to the nonlinear interactions and feedback loops present in genetic circuits. Here we present a methodology to automatically design GRMs that can produce any given spatial pattern. The proposed approach uses two orthogonal morphogen gradients acting as positional information signals in a multicellular tissue area or culture, which constitutes a continuous field of engineered cells implementing the same designed GRM. To efficiently design both the circuit network and the interaction mechanisms-including the number of genes required for the formation of the target pattern-we developed an automated algorithm based on high-performance evolutionary computation. The tolerance of the algorithm can be configured to design GRMs that are either simple to produce approximate patterns or complex to produce precise patterns. We demonstrate its performance by automatically designing GRMs for a diverse set of synthetic spatial expression patterns. The proposed method offers a versatile approach to systematically design and discover pattern-producing genetic circuits.