This year marks the 50th anniversary of the publication of a landmark paper in PNAS in which Till et al. proposed a remarkable model of stem cell proliferation (1). Their idea, based on assessment of colonyforming statistics in light of a mathematical model of a stochastic birth–death process, was that individual stem cell dynamics are inherently random. This surprising proposal quickly ignited a heated, and long-running, debate over stochastic and instructive models of stem cell behavior (2). In the intervening half century, many models of stem cell dynamics have been proposed, yet the mechanisms by which stem cell numbers and activity are regulated are still not completely understood. In PNAS, Lei et al. contribute an original idea to the ongoing discussion (3). Drawing on notions from evolutionary theory, they propose a general mathematical framework that views regulation of stem cell population activity as an optimization problem, which achieves best solution when there is cross-talk between genetic and epigenetic feedback mechanisms.
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