MIT engineers have challenged a core idea in biology by showing that epigenetic memory is not simply binary.
Their research reveals cells don’t just lock genes in an “on” or “off” state. Instead, they can freeze expression at many points along a spectrum, opening new questions about how cells define their identity.
For decades, scientists believed DNA methylation fixed genes in permanent on or off states. This process enables cells to “remember” who they are and prevents, for example, a skin cell from morphing into a neuron.
Domitilla Del Vecchio, professor of mechanical and biological engineering at MIT, said her team saw something unexpected. “The textbook understanding was that DNA methylation had a role to lock genes in either an on or off state. We thought this was the dogma. But then we started seeing results that were not consistent with that.”
Her group engineered hamster ovarian cells to express a target gene at different levels. Some cells glowed brightly due to high activity, others dimmed with weaker expression, while some switched off entirely.
When researchers introduced a short burst of DNA methylation, they expected gene activity to drift toward one of the extremes. Instead, cells held their initial setting.
“Our fluorescent marker is blue, and we see cells glow across the entire spectrum, from really shiny blue, to dimmer and dimmer, to no blue at all,” Del Vecchio said. “Every intensity level is maintained over time, which means gene expression is graded, or analog, and not binary.”
In-between states matter
Earlier work hinted that some cells might “freeze” in partial expression.
Many scientists assumed this was a temporary condition. But MIT researchers showed the in-between levels persisted for more than five months.
Sebastian Palacios, a lead author, explained the shift in thinking. “We found there was a spectrum of cells that expressed any level between on and off. And we thought, how is this possible?”
The findings suggest that cells may adopt more varied, stable states than previously thought.
Del Vecchio believes these overlooked cell identities could play roles in health and disease. “Our finding opens the possibility that cells commit to their final identity by locking genes at specific levels of gene expression instead of just on and off. The consequence is that there may be many more cell types in our body than we know and recognize today.”
Implications for medicine and biology
The discovery adds a new dimension to understanding cancer and therapy resistance, where cells often evade treatment by shifting states. It also gives synthetic biologists new tools to design tissues and organs with precision.
Michael Elowitz, professor at Caltech, who was not part of the study, praised the work. “Del Vecchio and colleagues have beautifully shown how analog memory arises through chemical modifications to the DNA itself. As a result, we can now imagine repurposing this natural analog memory mechanism, invented by evolution, in the field of synthetic biology.”
Palacios called the discovery “mind-blowing.” He added, “I think we’re going to find that this analog memory is relevant for many different processes across biology.”
The research received support from the National Science Foundation, MODULUS, and a Vannevar Bush Faculty Fellowship through the U.S. Office of Naval Research.