Do Distinct Subpopulations Signify Modes of Behavior in a Noisy Single Cell?

Population-level distributions of fluorescence or molecule counts are often taken to reflect the behaviors of individual cells within that population. In this article, we argue that counting sub-populations can be a misleading proxy for identifying the number of behavioral modes accessible to individual cells within a system. We show that definitions of behavioral modes based on deterministic modeling can fail when fluctuations in a system’s state—or noise—become significant. In such cases, peaks in the probability distribution—emerging from stochastic descriptions—are often interpreted as substitutes for deterministically defined stable modes. However, we demonstrate that this interpretation can break down: it is possible to construct counterexamples in which two subpopulations arise from a system that supports only a single mode of behavior, driven by non-equilibrium transient dynamics. Better understanding the role of noise in transient biological randomness may allow for the discovery of novel mechanisms of regulation that are not apparent in steady state behaviors.