Homogenizing bacterial cell factories: Analysis and engineering of phenotypic heterogeneity

Biotechnology; Cells; Cytology; Forestry; Gene expression; Nutrients; Physiology; Artificial environments; Bioprocess optimization; Biotechnological production; Cell-to-cell variation; Competitive environment; Environmental heterogeneity; Large scale bioreactors; Multi-species communities; Cell engineering; Review

Abstract :

[en] In natural habitats, microbes form multispecies communities that commonly face rapidly changing and highly competitive environments. Thus, phenotypic heterogeneity has evolved as an innate and important survival strategy to gain an overall fitness advantage over cohabiting competitors. However, in defined artificial environments such as monocultures in small- to large-scale bioreactors, cell-to-cell variations are presumed to cause reduced production yields as well as process instability. Hence, engineering microbial production toward phenotypic homogeneity is a highly promising approach for synthetic biology and bioprocess optimization. In this review, we discuss recent studies that have unraveled the cell-to-cell heterogeneity observed during bacterial gene expression and metabolite production as well as the molecular mechanisms involved. In addition, current single-cell technologies are briefly reviewed with respect to their applicability in exploring cell-to-cell variations. We highlight emerging strategies and tools to reduce phenotypic heterogeneity in biotechnological expression setups. Here, strain or inducer modifications are combined with cell physiology manipulations to achieve the ultimate goal of equalizing bacterial populations. In this way, the majority of cells can be forced into high productivity, thus reducing less productive subpopulations that tend to consume valuable resources during production. Modifications in uptake systems, inducer molecules or nutrients represent valuable tools for diminishing heterogeneity. Finally, we address the challenge of transferring homogeneously responding cells into large-scale bioprocesses. Environmental heterogeneity originating from extrinsic factors such as stirring speed and pH, oxygen, temperature or nutrient distribution can significantly influence cellular physiology. We conclude that engineering microbial populations toward phenotypic homogeneity is an increasingly important task to take biotechnological productions to the next level of control. © 2017 International Metabolic Engineering Society

Disciplines :

Biotechnology

Author, co-author :

Binder, D.; Institute of Molecular Enzyme Technology, Heinrich-Heine-University Düsseldorf, Forschungszentrum Jülich, Jülich, Germany

Drepper, T.; Institute of Molecular Enzyme Technology, Heinrich-Heine-University Düsseldorf, Forschungszentrum Jülich, Jülich, Germany

Jaeger, K.-E.; Institute of Molecular Enzyme Technology, Heinrich-Heine-University Düsseldorf, Forschungszentrum Jülich, Jülich, Germany, Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich, Jülich, Germany

Delvigne, Frank ; Université de Liège - ULiège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Microbial, food and biobased technologies

Wiechert, W.; Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich, Jülich, Germany, RWTH Aachen University – Computational Systems Biotechnology (AVT.CSB) –, Aachen, Germany

Kohlheyer, D.; Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich, Jülich, Germany, RWTH Aachen University – Microscale Bioengineering (AVT.MSB) –, Aachen, Germany

Grünberger, A.; Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich, Jülich, Germany, Multiscale Bioengineering, Bielefeld University, Universitätsstr. 25, Bielefeld, Germany

Language :

English

Title :

Homogenizing bacterial cell factories: Analysis and engineering of phenotypic heterogeneity

Publication date :

2017

Journal title :

Metabolic Engineering

ISSN :

1096-7176

eISSN :

1096-7184

Publisher :

Academic Press Inc.

Volume :

Pages :

145-156

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

BMBF - Bundesministerium für Bildung und Forschung
HGF - Helmholtz Association of German Research Centres

Available on ORBi :

since 02 July 2018

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