The future of self-selecting and stable fermentations
Review article, 2020

Unfavorable cell heterogeneity is a frequent risk during bioprocess scale-up and characterized by rising frequencies of low-producing cells. Low-producing cells emerge by both non-genetic and genetic variation and will enrich due to their higher specific growth rate during the extended number of cell divisions of large-scale bioproduction. Here, we discuss recent strategies for synthetic stabilization of fermentation populations and argue for their application to make cell factory designs that better suit industrial needs. Genotype-directed strategies leverage DNA-sequencing data to inform strain design. Self-selecting phenotype-directed strategies couple high production with cell proliferation, either by redirected metabolic pathways or synthetic product biosensing to enrich for high-performing cell variants. Evaluating production stability early in new cell factory projects will guide heterogeneity-reducing design choices. As good initial metrics, we propose production half-life from standardized serial-passage stability screens and production load, quantified as production-associated percent-wise growth rate reduction. Incorporating more stable genetic designs will greatly increase scalability of future cell factories through sustaining a high-production phenotype and enabling stable long-term production.

Metabolic burden

Evolutionary stability

Production robustness

Genetic heterogeneity

Production stability

Production load

Phenotypic heterogeneity


Peter Rugbjerg

Enduro Genetics ApS

Chalmers, Biology and Biological Engineering, Industrial Biotechnology

Lisbeth Olsson

Chalmers, Biology and Biological Engineering, Industrial Biotechnology

Journal of Industrial Microbiology and Biotechnology

1367-5435 (ISSN) 1476-5535 (eISSN)

Vol. 47 11 993-1004

Subject Categories

Biomedical Laboratory Science/Technology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Other Industrial Biotechnology





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