Key result
NUDGE computational framework identifies minimal interventions that conserve natural dynamics and recover cardiomyocyte restoration cues.
Why the study?
Current control strategies for directing cell fate emphasize permanent interventions that cripple natural regulatory responses, undermining phenotypic plasticity and risking unexpected behavior.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Rather than forcing a cell into a fixed state, the research team devised a new strategy that lets the cell reach the desired state on its own through a single temporary stimulus. The approach nudges the gene regulatory dynamics already present inside the cell toward the target direction, much like briefly clearing a blocked channel and letting the water find its own course.”
The NUDGE computational framework provides a novel approach to identifying temporary interventions for directing cell fate while preserving natural regulatory dynamics.
It is crucial to identify cues that induce cell fate transitions for applications ranging from cell therapy to drug discovery. Computational analysis of logical models of gene regulatory networks can identify such cues, which can then be used by control strategies to direct cell fate. However, current control strategies emphasize permanent interventions that cripple natural regulatory responses, undermining phenotypic plasticity and risking unexpected behavior. We illustrate how, conversely, single-time temporary control preserves natural regulatory interactions. For this purpose we develop NUDGE: a computational framework formally guaranteed to find all minimal interventions for a desired phenotype that conserve natural dynamics, alongside an efficient approximation for large networks. We then apply our framework to existing biological networks. These case studies reveal how control of natural dynamics recovers cardiomyocyte restoration cues central to heart regeneration, resolves a mast cell fate controversy, and matches cytokine response diversity to the spectrum of anti-inflammatory macrophages. Instead of controlling cell fate at the expense of phenotypic diversity and viability, NUDGE pioneers an alternative paradigm that preserves the functionality of the system encoded by natural dynamics.
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Brahmana et al. (2026) studied this question. NUDGE computational framework was evaluated. The NUDGE computational framework identified minimal interventions for desired phenotypes that conserve natural dynamics, recovering cardiomyocyte restoration cues and resolving mast cell fate.
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