Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch

TL;DR

This paper demonstrates that a stochastic bistable switch can serve as a biochemical mechanism for long-term cellular decision-making, linking short-term molecular dynamics with phenotypic changes over years.

Contribution

It introduces a mathematical model showing how stochastic bistable switches can reliably operate over long time scales, exemplified by follicle growth initiation in ovaries.

Findings

Model explains long-term follicle depletion dynamics

Stochasticity enables reliable decision-making over decades

Applicable to other physiological binary decision processes

Abstract

Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.