For the finale of our three-part cellular reprogramming series on Science to Save the World, we discuss restoring vision through cellular reprogramming along with the problems involved in bringing partial cellular reprogramming to humans.
Script
Can cellular reprogramming restore vision?
In late 2020, researchers, including Dr. David Sinclair, published a study that showed they could restore lost vision to old mice and mice with damaged retinal nerves, using partial cellular reprogramming, or PCR. To reduce cancer risk, they opted to try PCR, leaving out one of the Yamanaka factors.
Dr. Yuancheng Lu, a study author, was looking for a safer way to rejuvenate aged cells, as there was concern that using c-Myc could cause cancer under certain circumstances.
In the end, they opted to use only Oct4, Sox2, and Klf4 (OSK). The good news was that even OSK alone was able to rejuvenate the damaged eye nerves in mice and restore vision.
It also worked to improve age-related vision impairment in treated mice, and in mice that experienced increased eye pressure, an emulation of glaucoma.
Study co-author, Dr. Sinclair, said in an article in Nature, “We set out with a question: If epigenetic changes are a driver of ageing, can you reset the epigenome?” In other words, “Can you reverse the clock?” The answer to that appears to be a resounding yes.
In January, 2021 researchers showed that PCR rejuvenates human cells by about 30 years, making old, worn-out cells function like the cells of a person of 25.
They used an approach that exposed cells to enough reprogramming factors to push them beyond the limit at which they were considered somatic rather than stem cells – but only just beyond.
The fibroblasts that were reprogrammed in this way retained enough of their epigenetic cellular memories to return to being fibroblasts once again.
The team used a doxycycline-activated lentiviral package to expose the cells to the OSKM factors, as previous animal studies had done. According to the 2013 Horvath multi-tissue clock, after 13 days of PCR, sample cells that were nearly 60 years old became epigenetically equivalent to cells that were approximately 25 years old. The 2018 Horvath skin and blood clock showed that cells that were approximately 40 years old were also epigenetically returned to a 25-year-old state.
It seems that reprogrammed cells revert to an epigenetic age of about 25, suggesting this is a peak of cellular prime, or the optimal functional age for cells.
The biggest hurdle to translating PCR to humans is to find a way to activate the Yamanaka factors in our cells without having to engineer our bodies to react to a drug such as doxycycline. This may require us to develop drugs capable of activating OSKM, editing every cell in our body to respond to a particular compound like doxycycline, which would be extremely challenging, though plausible.
Another possibility is editing the germline so that children are born with a modification to respond to a chosen compound, an idea that currently is both technically challenging and an ethical nightmare. Whatever the solution, it needs to be practical.
Another major hurdle is to find a durable treatment, one that does not require constant upkeep. In mice, signs of aging returned rapidly when treatment stopped.
Humans are not mice; we have superior repair systems and different metabolism. Still, it is likely that aging would return if treatment ended. The challenge is to find a cost-effective way to sustain treatment, perhaps using drugs, or transient gene therapy.
If we can overcome these challenges, PCR could hold great promise for preventing, or even curing, diseases of aging.
One might envision an early, first-pass, preventative use of this approach in the young.
Older people could receive PCR to halt or significantly slow their aging, reducing their risk of developing age-related diseases. Used in a more focused, refined manner, PCR could repair a certain organ or tissue damaged by injury or disease.
In another scenario, gradual whole-body rejuvenation of older people might completely prevent age-related diseases and keep people healthy, active and vibrant, enjoying a longer life.
Well-funded companies such as Altos Labs and Alphabet’s Calico are also investigating ways to achieve PCR without using Yamanaka factors. This new research direction may prove more practical, and safer.
The rapid progress of medical technology could mean that PCR therapies may be available sooner than you think.