KAIST researchers develop ROOT method to reverse irreversible cell-state transitions

Researchers at the Korea Advanced Institute of Science and Technology (KAIST) have developed a computational method called ROOT, short for Revelation Of the Original circuit of irreversible Transition, that identifies the molecular circuits responsible for locking cells into irreversible states. Led by Professor Kwang-Hyun Cho of the Department of Bio and Brain Engineering, the team published their findings in the Proceedings of the National Academy of Sciences.

Cells often fail to return to their original state after an external stimulus disappears because positive feedback loops in their molecular networks sustain the new condition. While this irreversibility is essential for normal processes such as differentiation, it also drives diseases including cancer, where epithelial–mesenchymal transition enables tumor cells to invade surrounding tissue. Until now, pinpointing which of the thousands of feedback loops actually causes the lock-in has been extremely difficult.

The ROOT framework represents intracellular regulatory processes as logic-based computational models and analyzes them using systems biology techniques. By simulating how cells maintain signals after a stimulus is removed, the method isolates a set of core circuits the researchers term the "irreversibility kernel." In tests on models of B-cell differentiation, epithelial–mesenchymal transition in lung cancer, and enterocyte and beta-cell differentiation based on single-cell transcriptome data, ROOT accurately identified causal circuits matching known cell-fate determinants.

Beyond identification, the team proposed two control strategies. "Resetting control" restores a cell to its pre-transition state while leaving the underlying irreversible property intact, analogous to unlocking a door without disabling the lock. "Reversing control" removes the source of irreversibility itself, allowing the cell to move freely between states, comparable to disabling the mechanism that automatically locks the door.

Professor Cho said the core achievement is identifying the causal circuits behind cells that do not revert on their own and developing technology to control those circuits and restore the previous condition. The researchers expect the approach to enable new treatment strategies that restore abnormally fixed cell states — such as those seen in cancer and aging — back to normal, rather than relying solely on removing the affected cells.

The study, authored by Jongwan Kim and colleagues, appears in PNAS with DOI 10.1073/pnas.2600800123. The work remains at the computational and model-validation stage; further experimental and clinical research would be needed to translate the control strategies into therapies.