Experimental perturbations are commonly used to establish causal relationships between the molecular components of a pathway and their cellular functions; however, this approach suffers inherent limitations. Especially in pathways with a significant level of nonlinearity and redundancy among components, such perturbations induce compensatory responses that obscure the actual function of the targeted component in the unperturbed pathway. A complementary approach uses constitutive fluctuations in component activities to identify the hierarchy of information flow through pathways. Here, we review the motivation for using perturbation-free approaches and highlight recent advances made in using perturbation-free fluctuation analysis as a means to establish causality among cellular events.
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