Co-evolution of strain design methods based on flux balance and elementary mode analysis

More than a decade ago, the first genome-scale metabolic models for two of the most relevant microbes for biotechnology applications, Escherichia coli and Saccaromyces cerevisiae, were published. Shortly after followed the publication of OptKnock, the first strain design method using bilevel optimization to couple cellular growth with the production of a target product. This initiated the development of a family of strain design methods based on the concept of flux balance analysis. Another family of strain design methods, based on the concept of elementary mode analysis, has also been growing. Although the computation of elementary modes is hindered by computational complexity, recent breakthroughs have allowed applying elementary mode analysis at the genome scale. Here we review and compare strain design methods and look back at the last 10 years of in silico strain design with constraint-based models. We highlight some features of the different approaches and discuss the utilization of these methods in successful in vivo metabolic engineering applications.