Controllability of cell population in bioreactor is mainly determined by the fitness cost associated with phenotypic switching

¹Terra research and teaching centre, Microbial Processes and Interactions (MiPI), Gembloux Agro-Bio Tech, University of Liège, Gembloux, Belgium

²Microsystems in Bioprocess Engineering, Institute of Process Engineering in Life Sciences, Karlsruhe Institute of Technology, Karlsruhe, Germany

*Corresponding author: F.Delvigne@uliege.be

Clonal population of cells can cope with stress conditions by switching to alternative phenotypes. Even if it can lead to increased fitness in a natural context, this feature is typically unwanted for a range of applications (e.g., bioproduction, synthetic biology, biomedicine...) where it tends to decrease the controllability of the cellular response. However, little is known about the diversification profiles that can be adopted by a cell population. We characterized the diversification dynamics for 6 different biological systems involving Gram-negative and Gram-positive bacteria, as well as eukaryotes and for different phenotypes (utilization of alternative carbon sources, general stress response and more complex development patterns). Interestingly, our results suggest that the diversification dynamics and the fitness cost associated with cell switching are coupled. Furthermore, we used a cell-machine interface (Segregostat) to demonstrate that the phenotypes associated with these diversification regimes exhibit different levels of controllability, enabling applications involving more precise cellular responses.

Keywords: phenotypic switching, population control, automated flow cytometry, biological noise, bet hedging, information theory