KAIST

< Top right: Dr. Jongwan Kim (co-first author), Department of Bio and Brain Engineering, KAIST. Group photo (from left in the back row): Dr. Jonghoon Lee (co-author), Dr. Seong-Hoon Jang (co-first author), Corbin Hopper, Ph.D. student (co-author); (front row): Professor Kwang-Hyun Cho. >

Once a cell has locked into an abnormal state — the way cancer cells do — can it ever be restored back to normal? A KAIST research team has identified the ‘molecular lock’ that keeps cells trapped in an altered state, opening a new path toward releasing that lock and reversing a cell’s fate.

KAIST (President Choongsik Bae) announced on the 21st of August that a research team led by Professor Kwang-Hyun Cho of the Department of Bio and Brain Engineering has, for the first time, identified the causal circuits responsible for irreversibility in intracellular molecular networks and developed a fundamental control technology called ROOT that can regulate these circuits and restore biological states to their original condition.

Cells in the human body change their state in response to external stimuli. In many cases, however, these state changes are irreversible, in the sense that cells do not return to their original state even after the stimulus disappears.

< [Figure 1] The ROOT framework for identifying and controlling the cause of irreversible cell-state transitions >

Irreversibility is essential for maintaining normal biological processes, such as a cell differentiating into one with a specific function. At the same time, it can also drive disease progression — for example, in epithelial–mesenchymal transition, which gives cancer cells the ability to migrate into and invade surrounding tissue.

Complicating matters, the circuits that maintain these state changes inside a cell are highly intricate: more than a thousand positive feedback loops are woven throughout the network, in which one molecule activates a series of other molecules that in turn reactivate the original molecule. This is similar to the feedback screech produced when a microphone is placed next to a speaker, where a sound repeatedly amplifies itself. Even a change that starts with an external stimulus can persist after the stimulus is gone, simply because the cell’s own molecules keep reinforcing one another. Until now, it has been extremely difficult to determine which of these countless circuits is actually responsible for locking a cell into an irreversible state.

To solve this problem, the team developed ROOT technology, short for Revelation Of the Original circuit of irreversible Transition, which works by representing intracellular regulatory processes as computational logic models and analyzing them through systems biology techniques. Using ROOT, the research team successfully simulated the process in which cells maintain a signal even after an external stimuli is removed, allowing them to identify a set of core circuits that cause irreversibility, which they defined as the “irreversibility kernel.”

Going beyond identifying the cause, the team also proposed two groundbreaking control strategies.

< [Figure 2] Process of identifying the irreversibility kernel and deriving control strategies using ROOT >

The first, “resetting control,” restores a cell to its state before the change while leaving the cell’s underlying irreversible property intact — comparable to leaving the lock itself in place, but opening the locked door and returning to the starting point.

The second, “reversing control,” removes the source of irreversibility itself, allowing a cell to move freely between different states — comparable to disabling the mechanism that automatically locks a door each time it closes, so that afterward the door can be opened and closed again.

The team applied the new technique to various biological models, including B-cell differentiation, epithelial–mesenchymal transition in lung cancer, and enterocyte and beta-cell differentiation models based on single-cell transcriptome data, in which the ROOT method accurately identified causal circuits that matched known cell-fate determinants. The team also proposed more effective resetting control strategies, demonstrating that the method can be broadly applied even to models built from real experimental data.

Rather than simply removing cells that have become fixed in an abnormal state, as in cancer or aging, the technology is expected to help identify and control the core circuits that keep cells trapped in that state, enabling new treatment strategies that restore cells to a normal condition.

Professor Kwang-Hyun Cho said, “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.” He added, “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.”

< [Figure 3] Analysis of irreversibility in hematopoietic stem cell differentiation using ROOT >

This study was co-led by Dr. Jongwan Kim and Dr. Seong-Hoon Jang of KAIST’s Department of Bio and Brain Engineering as co-first authors, with participation from Dr. Jonghoon Lee and Ph.D. student Corbin Hopper. The research was published on August 13 in Proceedings of the National Academy of Sciences of the United States of America (PNAS), one of the world’s leading scientific journals.
Paper title: The structural origin of irreversible transitions in biological networks,
DOI: https://doi.org/10.1073/pnas.2600800123

This research was supported by the Mid-Career Researcher Program and the Basic Research Laboratory Program of the National Research Foundation of Korea, funded by the Ministry of Science and ICT.