Optimal genetic manipulations in batch bioreactor control

Advances in metabolic engineering have enabled bioprocess optimization at the genetic level. Large-scale systematic models are now available at a genome level for many biological processes. There is, thus, a motivation to develop advanced control algorithms, using these complex models, to identify optimal performance strategies both at the genetic and bioreactor level. In the present paper, the bilevel optimization framework previously developed by the authors is coupled with control algorithms to determine the genetic manipulation strategies in practical bioprocess applications. The bilevel optimization includes a linear programming problem in the inner level and a nonlinear optimization problem in the outer level. Both gradient-based and stochastic methods are used to solve the nonlinear optimization problem. Ethanol production in an anaerobic batch fermentation of Escherichia coli is considered in case studies that demonstrate optimization of ethanol production, batch time, and multi-batch scheduling.