Michael West: brief cellular reprogramming may not be enough to repair damaged tissues

Michael West: brief cellular reprogramming may not be enough to repair damaged tissues

In an August 22 post, aging researcher Michael West suggested that repairing the brain after a stroke or the heart muscle after a myocardial infarction may require cells to remain reprogrammed for weeks or months.

Partial reprogramming briefly activates the Yamanaka factors, proteins that regulate gene activity. The goal is to shift a cell away from its aged state while preserving its specialized identity, so a heart cell remains a heart cell. Complete or excessive reprogramming can produce teratomas, tumors containing multiple tissue types.

In a 2016 mouse experiment, researchers continuously activated OSKM, the four Yamanaka factors. In mice carrying one DNA construct for OSKM activation, weight loss and high mortality appeared after only four days. In mice carrying the same construct, a schedule of two days of activation followed by a five day pause preserved body weight and survival for 35 cycles. Short cycles therefore became a way to limit the toxicity of this regimen.

One week earlier, a debate between West and Aubrey de Grey examined why a single measurable cellular feature cannot establish whether a cell retains its specialized identity during a short regimen. The new post adds a separate question: whether a large area of damaged tissue can recover within such a short period.

West extends the problem from individual cells to the brain after a stroke and the heart muscle after a myocardial infarction. He hypothesizes that repairing these tissues requires a longer regimen during which the cells remain reprogrammed. He writes:

“This will probably require cells to remain continuously in a reprogrammed state for weeks to months.”

West proposes searching for genes that, according to his hypothesis, could reverse age related cellular changes and initiate regeneration. He associates these genes with stages after pluripotency, the state in which a cell can develop into different tissue types.

A regimen lasting several weeks is already being tested on a different scale. In the phase 1 study of ER-100, the investigational gene therapy is administered to one eye, and doxycycline activates the three OSK factors for 56 days. The investigators plan to enroll up to 18 participants in sequential groups to assess the safety of treating optic nerve diseases. West frames a broader problem: how to maintain cells in the required state throughout a large area of damaged tissue and then end the regimen safely.