Systems biology of stem cells: three useful perspectives to help overcome the paradigm of linear pathways

Stem cell behaviours, such as stabilization of the undecided state of pluripotency or multipotency, the priming towards a prospective fate, binary fate decisions and irreversible commitment, must all somehow emerge from a genome-wide gene-regulatory network. Its unfathomable complexity defies the standard mode of explanation that is deeply rooted in molecular biology thinking: the reduction of observables to linear deterministic molecular pathways that are tacitly taken as chains of causation. Such culture of proximate explanation that uses qualitative arguments, simple arrow-arrow schemes or metaphors persists despite the ceaseless accumulation of 'omics' data and the rise of systems biology that now offers precise conceptual tools to explain emergent cell behaviours from gene networks. To facilitate the embrace of the principles of physics and mathematics that underlie such systems and help to bridge the gap between the formal description of theorists and the intuition of experimental biologists, we discuss in qualitative terms three perspectives outside the realm of their familiar linear-deterministic view: (i) state space (ii), high-dimensionality and (iii) heterogeneity. These concepts jointly offer a new vista on stem cell regulation that naturally explains many novel, counterintuitive observations and their inherent inevitability, obviating the need for ad hoc explanations of their existence based on natural selection. Hopefully, this expanded view will stimulate novel experimental designs.