A computational approach for designing a robust bistable switch

View all posters

Abhishek Garg, Jeffrey Way, Pamela Silver

Harvard Medical School, United States

A major goal of synthetic biology is to be able to modularly engineer robust synthetic genetic regulatory circuits from a library of individually characterized parts such as promoters, RBS, genes and degradation tags. However, very often synthetic parts that are borrowed from one biological system for use in other biological system do not behave as expected when used out of their native biological context. As a result, assembled synthetic circuits rarely show the intended behavior in the first implementation as chosen parts may have the correct function but lack the required quantitative properties. This is often followed by a length process of fine-tuning of imperfect parts or testing alternate parts to resolve the observed issues in the first implementation. We have developed a modeling toolbox for computationally assembling synthetic genetic networks such that the resulting system works robustly in experiments across a wide range of Promoter strengths, RBS strengths, and mRNA/protein degradation rates. The proposed approach is currently being applied in our group to design synthetic bistable memory circuits based on the genetic components borrowed from native lambda phages. We demonstrate the practical application of our modeling approach through a case study where we simulated various combinations of Promoters, RBS and mRNA/protein degradation tags using our modeling toolbox to provide explanations for why genetic components from native lambda phage system do not show bistability when used out of context in designing synthetic bistable circuit in E. Coli. The simulation results also suggested a correct range of synthetic Promoters strengths, RBSs and mRNA/protein degradation tags that can replace their native counterparts from lambda phage such that the bistable memory circuit behaves robustly across a range of environmental conditions.