Diversity training for signal transduction: leveraging cell-to-cell variability to dissect cellular signaling, differentiation and death

•Cell-to-cell variability is ubiquitous in genetically identical cells.•Variability exists at multiple levels: genes, proteins, signaling and phenotypes.•New methods have been developed to connect different levels of variability.•Variability provides insight into cells’ function, individually and in populations.•Computational modeling maps out variability that in turn helps improve models.

Populations of ‘identical’ cells are rarely truly identical. Even when in the same state of differentiation, isogenic cells may vary in expression of key signaling regulators, activate signal transduction at different thresholds, and consequently respond heterogeneously to a given stimulus. Here, we review how new experimental and analytical techniques are suited to connect these different levels of variability, quantitatively mapping the effects of cell-to-cell variability on cellular decision-making. In particular, we summarize how this helps classify signaling regulators according to the impact of their variability on biological functions. We further discuss how variability can also be leveraged to shed light on the molecular mechanisms regulating cellular signaling, from the individual cell to the population of cells as a whole.

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