João Pedro de Magalhães: reprogramming must be tested at every level, from cells to the whole organism

João Pedro de Magalhães: reprogramming must be tested at every level, from cells to the whole organism

On August 9, biogerontologist João Pedro de Magalhães responded to a National Geographic report that discussed the ER-100 trial in one eye alongside plans to rejuvenate the entire body. He argued that results in cells, individual tissues, and whole organisms should be considered separately. In the current first phase of the ER-100 trial, the treatment is administered to only one eye. At this stage, researchers are determining the dose and monitoring safety.

In his August 9 post, de Magalhães stated the distinction in one sentence:

“Rejuvenating cells is not the same as rejuvenating an organism.”

Cellular reprogramming aims to return an adult cell to some aspects of a younger pattern of gene activity while preserving its specialized identity. This is done by temporarily delivering factors that control gene activation into the cell. A retinal cell must remain a retinal cell, and a liver cell must remain a liver cell.

In a 2020 study in mice, researchers activated three such factors, OSK, in retinal ganglion cells, the neurons that carry visual signals to the brain. They observed younger patterns of DNA methylation, which consists of chemical marks that regulate gene activity. They also found that neuronal projections regenerated after injury and that vision improved in a glaucoma model.

The choice of factors and the length of time they remain active affect the outcome. In the same study, continuous activation of the complete set of four factors, OSKM, frequently caused teratomas in mice. These are tumors formed from cells that have lost their normal specialized identity. In other cases, the mice died within several days. For this reason, when testing local OSK delivery, the authors separately assessed the incidence of retinal tumors.

ER-100 is testing this approach in humans. The first phase of the study is expected to enroll up to 18 adults with optic nerve diseases. A modified virus delivers OSK to cells in one eye, after which participants take doxycycline for 56 days to activate these factors. Local delivery to the eye confines the intervention to one region and allows researchers to monitor visual outcomes.

Applying this method throughout the body would require researchers to determine, separately for many tissues, how to deliver the factors, how long to activate them, and how to preserve the specialized identity of the cells.