Multi-objective optimization for gene expression noise reduction in a synthetic gene circuit

Stochasticity in biological systems often referred to as gene expression noise is ubiquitous. The main sources of this noise come about in two ways. The implicit randomness of the biochemical reactions generates intrinsic noise inside the cell. Other cellular processes are themselves products that vary over time and from each cell to another, producing the so-called extrinsic noise. Controlling the mean expression level of a gene while reducing its noise is a challenge in many applications of Synthetic Biology. In previous works, we proposed a gene synthetic circuit to reduce gene expression noise while achieving a desired mean expression level. The circuit combines a negative feedback loop and a cell-to-cell communication mechanism based on quorum sensing. In this work, we use a multi-objective optimization design approach to find the best values for the tunable-in-the-lab parameters that, for a given desired mean expression value, achieve minimization of gene expression noise caused by intrinsic and extrinsic fluctuations. Our approach allows tuning the circuit parameters required to minimize noise effects, providing results which prove in accordance with genome-wide experimental data reported in the literature. Exploring different scenarios, either considering only intrinsic noise or considering both extrinsic and intrinsic ones, we find that the design strategies obtained for both cases are not transferable. Thus, designing the circuit parameters taking into account only intrinsic noise yields a sub-optimal design with decreased performance when evaluated in a scenario where both extrinsic and intrinsic noise are present