This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Which genes need to be controlled to guide a stem cell toward a desired cell type or modulate an immune cell's inflammatory response? A Korean research team has developed a general-purpose computational framework that identifies the key targets needed to steer a cell toward a desired state with a single temporary intervention, without permanently altering its genes.
A research team led by Professor Kwang-Hyun Cho from the KAIST Department of Bio and Brain Engineering has developed NUDGE, a foundational technology that redirects cell fate in a desired direction through a minimal, temporary intervention by harnessing the gene regulatory dynamics already present within cells. The work is published in the journal Proceedings of the National Academy of Sciences. Technologies that redirect cell fate have drawn attention as key tools for treating intractable diseases and advancing regenerative medicine because they can differentiate stem cells into cells with specific functions or return diseased or aged cells to a near-normal state.
Differentiation, for example, refers to the process by which a stem cell becomes a specific cell type with a distinct function, such as a cardiomyocyte or neuron. However, existing methods for controlling cell fate have relied mainly on permanent interventions, such as keeping specific genes locked in an "on" or "off" state. While this approach can produce the desired cell state, it has limitations.
It can reduce plasticity, the flexibility that allows cells to adapt to future changes in their environment, and give rise to abnormal cell states that do not exist in nature. Rather than forcing a cell into a fixed state, the research team devised a 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.
NUDGE (natural dynamics control of gene regulatory networks), the technology the team developed, uses a computational logic model to examine how key genes inside a cell influence one another and determine which state the cell ultimately reaches as a result. It then mathematically decomposes the logical functions that describe these gene interactions to identify the minimal combination of control factors needed to convert a cell from its current state to the desired one. For example, if the goal is to differentiate a stem cell into a cardiomyocyte, NUDGE functions as a "blueprint for minimal intervention" that identifies which molecular targets need to be temporarily activated or inhibited.
A key strength of the framework is that its exact method is mathematically guaranteed to identify all minimal control combinations that lead to the desired phenotype within the model. The team also presented an efficient approximation method that extends the framework to large-scale molecular networks. NUDGE does more than identify which factors to stimulate.
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