Towards next-generation cell factories by rational genome-scale engineering

Metabolic engineering holds the promise to transform the chemical industry and to support the transition into a circular bioeconomy, by engineering cellular biocatalysts that efficiently convert sustainable substrates into desired products. However, despite decades of research, the potential of metabolic engineering has only been realized to a limited extent at the industrial level. To further realize its potential, it is essential to optimize the synthetic and native metabolic networks of cell factories at a system and genome-wide level. Here we discuss the tools and strategies enabling system-wide (semi-) rational engineering. Recent advances in genome-editing technologies enable directed genome-wide engineering in a growing number of relevant microorganisms. Such system-wide engineering can benefit from machine learning and other in silico design methods, and it needs to be integrated with efficient screening or selection approaches. These approaches are expected to realize the promise of next-generation cell factories for efficient, sustainable production of a wide range of products.