AsianScientist (Nov. 14, 2026) – Cells can sometimes remain in a new state even after the signals that caused the change are gone. In many cases, these changes are permanent, meaning that cells do not return to their original state after the signal disappears. This is known as an irreversible transition.
Some permanent changes inside cells are normal and necessary. For example, when a cell develops into a specialised cell type, it needs to remain in that state to perform its function. But permanent changes can also be harmful. In cancer, for example, a process called epithelial-to-mesenchymal transition (EMT) can make cancer cells more invasive and aid their spreading to other parts of the body.
Scientists know that feedback loops, in which molecules repeatedly activate or reinforce one another, can make these changes difficult to reverse. Cells contain thousands of interconnected molecules, creating numerous such loops. The challenge is to determine which specific loops are responsible for keeping a cellular change permanent.
Now, Korean researchers have developed a computer-based tool called ROOT – Revelation Of the Original circuit of irreversible Transition – to identify these key feedback loops.
The results were published in the Proceedings of the National Academy of Sciences of the United States of America.
Previous studies have examined simple feedback loops or focused on individual processes such as cell division, EMT and programmed cell death. Other studies have examined how common feedback loops are across large cellular networks.
However, these approaches generally cannot identify the small number of loops that actually keep a particular cellular change permanent. Also, they do not provide clear ways to reverse these processes.
ROOT uses a simplified computer model in which genes and other molecules are represented as switches that can be either “on” or “off.”
It examines how these switches affect one another and identifies the key feedback loops that keep a cell locked in a particular state. The researchers call these key loops “irreversibility kernels.”
ROOT can also suggest two ways of interfering with these processes: resetting, i.e., temporarily changing the system so that the cell returns to the state it was in before the permanent change; and reversing, i.e., making a more lasting change so that the cell is no longer locked into one state and can move between states again.
The researchers tested ROOT on several biological systems, including B-cell development and lung cancer EMT. They also used data from individual cells to study intestinal cell and pancreatic beta-cell development.
In these cases, ROOT identified key regulators and feedback loops that were consistent with mechanisms identified in previous research and experiments, and suggested ways of resetting the cells.
The researchers compared the irreversibility kernels identified by ROOT with another type of feedback structure called conditionally stable motifs (CSMs), i.e, feedback loops that can keep a cell in a particular state but depend on certain other molecules being switched on or off.
They found that many of the feedback loops identified by ROOT were among the most important loops for keeping cells in their new state. These loops were also located relatively close to where outside signals enter the cellular network, suggesting they may act early in the process of locking a cell into a new state.
According to the researchers, ROOT could eventually be useful in cell reprogramming and disease research.
Reversing could be useful when a cell has entered a harmful state because of mutations or abnormal gene activity. Instead of permanently switching off genes, this approach could change the cell’s internal system while allowing it to continue responding to signals from its surroundings.
“The core achievement of this study is identifying the causal circuits behind cells that, once changed, do not return to their original state, and developing a technology to control these circuits and restore cells to their previous condition,” said Kwang-Hyun Cho, professor in the Department of Bio and Brain Engineering at the Korea Advanced Institute of Science and Technology (KAIST).
“We expect this technology to be used in developing new treatment strategies that restore abnormally fixed cell states — such as those seen in cancer and aging — back to normal,” he added.
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Source: Korea Advanced Institute of Science and Technology (KAIST) ; Imgae: Jolanta Mosakovska/shutterstock
This study can be found at The structural origin of irreversible transitions in biological networks
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.
