KAIST finds molecular 'lock' that traps cells in abnormal states — and a way to reverse it

A new possibility has emerged for returning cells locked into abnormal states — such as cancer cells — to their normal condition.

KAIST announced Friday that a research team led by Professor Cho Kwang-hyun of the Department of Bio and Brain Engineering has identified the core circuit within a cell's molecular network that prevents state changes from being reversed, and has developed a foundational control technology called ROOT to manipulate that circuit and restore cells to their prior state.

Cells in the human body respond to external stimuli by altering their properties and functions. In some cases, however, the changed state persists even after the stimulus disappears — a phenomenon known as "irreversibility."

Irreversibility plays a necessary role in normal biological processes, such as when cells differentiate into specialized types. But it can also drive disease progression, as in epithelial-mesenchymal transition, or EMT, the process by which cancer cells acquire the ability to migrate and invade surrounding tissue.

Inside cells, thousands of "positive feedback loops" exist in which one molecule activates another, which in turn activates the first. These loops allow cells to sustain a changed state even after the original stimulus is gone, as the molecules continue to activate one another. Identifying which among those thousands of circuits actually locks a cell into a state of no return had long proved difficult.

ROOT models the interactions among a cell's molecules as a computer logic model and simulates the full process of an external stimulus appearing and then disappearing. Through this, it identifies the "irreversibility kernel" — the set of core circuits that hold a cell in its changed state.

In simple terms, it finds, among thousands of tangled wires, only the ones actually keeping the door locked.

Building on this, the research team also proposed two control strategies for reversing cell states. "Resetting control" returns a cell to its state before the change while preserving its irreversible properties. "Reversing control" eliminates the underlying cause of irreversibility itself, allowing the cell to move freely between different states.

The research team applied ROOT to a range of biological models, including B-cell differentiation, EMT in lung cancer, and the differentiation of intestinal cells and beta cells based on single-cell transcriptome data.

As a result, the team identified causal circuits consistent with the key factors previously known to determine cell state and differentiation. The team also proposed control strategies capable of reversing cell states within molecular networks built from actual experimental data.

The findings are expected to inform new treatment strategies that go beyond simply eliminating cells locked in abnormal states due to cancer or aging — targeting instead the core circuits that hold cells in those states and restoring them to normal.

"The core of this research is that we identified the causal circuits behind cells that change and never revert, and developed a technology to control those circuits and return cells to their previous state," Professor Cho said. "We expect this to be used in developing new treatment strategies that restore abnormally fixed cell states — in cancer, aging and beyond — back to normal."

The findings were published in the Proceedings of the National Academy of Sciences.