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The future of self-selecting and stable fermentations

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 cel...

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Autores principales: Rugbjerg, Peter, Olsson, Lisbeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695646/
https://www.ncbi.nlm.nih.gov/pubmed/33136197
http://dx.doi.org/10.1007/s10295-020-02325-0
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author Rugbjerg, Peter
Olsson, Lisbeth
author_facet Rugbjerg, Peter
Olsson, Lisbeth
author_sort Rugbjerg, Peter
collection PubMed
description 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.
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spelling pubmed-76956462020-12-02 The future of self-selecting and stable fermentations Rugbjerg, Peter Olsson, Lisbeth J Ind Microbiol Biotechnol Fermentation, Cell Culture and Bioengineering - Mini Review 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. Springer International Publishing 2020-11-02 2020 /pmc/articles/PMC7695646/ /pubmed/33136197 http://dx.doi.org/10.1007/s10295-020-02325-0 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Fermentation, Cell Culture and Bioengineering - Mini Review
Rugbjerg, Peter
Olsson, Lisbeth
The future of self-selecting and stable fermentations
title The future of self-selecting and stable fermentations
title_full The future of self-selecting and stable fermentations
title_fullStr The future of self-selecting and stable fermentations
title_full_unstemmed The future of self-selecting and stable fermentations
title_short The future of self-selecting and stable fermentations
title_sort future of self-selecting and stable fermentations
topic Fermentation, Cell Culture and Bioengineering - Mini Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695646/
https://www.ncbi.nlm.nih.gov/pubmed/33136197
http://dx.doi.org/10.1007/s10295-020-02325-0
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