Monostability and bistability of biological switches

TL;DR

This paper proves that simple two-molecule biological switch models modeled by ODEs can have at most two stable states, confirming a long-standing conjecture and providing criteria for monostability and bistability.

Contribution

It offers a rigorous proof that such models cannot have more than two stable equilibria, validating previous numerical conjectures and establishing a general framework for stability analysis.

Findings

Most common functions satisfy the bistability criterion

The paper characterizes parameter regions for monostability and bistability

Provides a unified framework for analyzing stability in biological switches

Abstract

Cell-fate transition can be modeled by ordinary differential equations (ODEs) which describe the behavior of several molecules in interaction, and for which each stable equilibrium corresponds to a possible phenotype (or 'biological trait'). In this paper, we focus on simple ODE systems modeling two molecules which each negatively (or positively) regulate the other. It is well-known that such models may lead to monostability or multistability, depending on the selected parameters. However, extensive numerical simulations have led systems biologists to conjecture that in the vast majority of cases, there cannot be more than two stable points. Our main result is a proof of this conjecture. More specifically, we provide a criterion ensuring at most bistability, which is indeed satisfied by most commonly used functions. This includes Hill functions, but also a wide family of convex and sigmoid functions. We also determine which parameters lead to monostability, and which lead to bistability, by developing a more general framework encompassing all our results.