Fitness cost associated with cell phenotypic switching drives population diversification dynamics and controllability

Isogenic cell populations 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 various systems (bacteria and yeast) 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. For quantifying the contribution of the switching cost on population dynamics, we built a stochastic model that allowed us to reproduce the dynamics observed experimentally and identified three diversification regimes i.e., constrained (at low switching cost), dispersed (at medium and high switching cost), and bursty (for very high switching cost). Furthermore, we used a cell-machine interface (Segregostat) to demonstrate that the phenotypes associated with these diversification regimes have different levels of controllability, enabling applications involving more precise cellular responses.