Predicting and Controlling Collective Fate in Multicellular Systems

Abstract Collective behavior is a defining property of multicellular systems, where coordinated outcomes emerge from local cell–cell interactions. Yet the quantitative rules linking single-cell decision-making to tissue-scale organization remain poorly resolved. Here, we develop a quantitative framework that defines an order parameter predicting when initially disordered colonies undergo a transition to ordered fate alignment and when minimal, localized inputs can redirect their collective state. This analysis reveals a distinct control regime in which multicellular assemblies become susceptible to a single engineered “guide” cell. We validate these predictions by introducing guide cells that integrate into unperturbed colonies and redirect fate patterns within the theoretically defined control windows. Together, these results connect single-cell decision rules to emergent tissue-level organization and establish a generalizable biological control strategy in which a minority engineered subset can reliably redirect the developmental trajectory of a much larger multicellular population. Abstract Figure Summary figure: Emergence, Scaling, and Control of Multicellular Collective Order. ( A ) Cell-number–dependent collective order. Sparse colonies lack coordination and yield disordered fate distributions; dense colonies exhibit coordinated, ordered outcomes. ( B ) Collective order rises with colony compactness (∝ cell density) and collapses across colony radii R onto a single curve. ( C ) Once coordination emerges, a single “guide cell” can steer fate-analogous to a sheepdog guiding a flock. The herding efficacy exhibits a biphasic window versus cell number.