Modelling host biosynthetic limitations and dynamics for engineering cell factories

Engineering microbes for chemical or protein production is a time-consuming iterative process of theoretical design, experimental construction, evaluation and redesign. A key cause of the failure of many initial designs is lack of consideration of host physiology. Here we summarise the key aspects of host physiology which are perturbed during metabolic engineering and synthetic biology projects and outline the implications of such host biosynthetic constraints and growth dynamics on engineered processes. We review how these phenomena can be captured in different modelling frameworks from traditional genome-scale approaches used for metabolic engineering to coarse-grain “host-aware” methods used in synthetic biology. We describe recent advances in whole-cell modelling. We give examples as to how these frameworks can be used to simplify the engineering biology design cycle and offer some open challenges in developing computer-aided design tools for engineering microbes.