When introduced into a cell, the Yamanaka factors rapidly strip it of the outer layer of its DNA, known as the epigenome.

 

Our epigenome,

is the key to cellular reprogramming and also, frankly, life itself...!

If you've ever wondered how the cells in your heart know to be heart cells and not skin, bowel or some other cells, you can thank your epigenome.

 

It's what gives every cell its identity.

 

Our DNA starts out alike in almost every cell. But almost immediately, tiny clumps of molecules known as methyl groups start attaching themselves like mollusks to the outside of various genes, with different configurations in different cells.

 

Depending on the number and patterns of these molecules, the genes beneath will be able to receive biochemical signals telling them to turn on, or they won't.

 

This process, called methylation, is probably the most important part of our epigenome.

 

Methylation continues throughout our lives and reflects those lives, for better and worse. Smoking strongly influences methylation patterns. So does exercise, although in almost opposite fashion.

 

Ditto for stress, nutrition, parenting, illness, air pollution and many other choices and conditions.

 

Through methylation, our epigenome functions, in effect, as our bodies' diary, with the tiny molecular doodles on our DNA recording what we've been doing with ourselves.

 

But nothing affects methylation as much as aging. The patterns of methylation during infancy are distinctly different than during childhood, adulthood and old age.

 

Many longevity researchers believe these changes in methylation don't just record our aging process, they drive it, meaning our evolving epigenome may be responsible for aging itself.

In petri dishes, cellular reprogramming works just as expected.

 

Add the Yamanaka factors to skin cells from a wrinkled centenarian - as scientists have done - and many of the cells will shed their methyl marks and turn back into newborn cells, or what scientists call pluripotent stem cells.

 

With no cellular memory of having been skin, these cells can become almost any type of cell, with the right coaxing.

 

Pluripotent stem cells from donated human cells are routinely used today for tissue engineering and other medical and research purposes.

 

But the process isn't efficient or benign. In a dish containing millions of elderly cells, many will become youthful stem cells after exposure to Yamanaka factors.

 

But many others won't, for reasons that remain mysterious.

Some resist the process.

 

Some die.

 

And some, almost invariably, transform into huge, rapidly dividing growths known as teratomas or monster tumors.

These develop when a stem cell doesn't know what to become and turns into the wrong kind of cell.

 

With a teratoma, teeth cells can wind up growing in a pelvis or bone cells in an eyeball. Although rarely malignant, teratomas often swell to massive sizes.

The three remaining factors were genetically engineered to grow active only in the presence of the antibiotic doxycycline.

 

The scientists then gave the mice water containing the antibiotic on a controlled schedule of two days with the drug and five days without for two months.

 

The plan was to reprogram cells in the optic nerve only partially, removing much but not all of their methylation. That way, the cells would retain their fundamental identity, even as they grew functionally younger.

 

In this scenario, teratomas wouldn't present an obstacle, because the affected cells would never regress fully into stem cells.

 

Instead, they'd be the same cells but sprightlier, younger and hopefully more capable of healing the injured optic nerve.

 

 

 

 

The Harvard mouse study results, published in Nature in December 2020, under the cover line, "Turning Back Time?" seemed positive.

 

The researchers noted epigenetic changes in the cells and regrowth of the damaged optic nerves in many of the mice who'd received the treatment.

 

They reported no teratomas.

"It was quite exciting," said David Sinclair, a Harvard geneticist, senior author of the mouse eye study and a controversial figure among longevity researchers.

Sinclair resigned last March as president of the Academy for Health and Lifespan Research, a prestigious organization of longevity researchers, after other prominent scientists in the group disputed his claim that a canine supplement developed by a company he co-owned could "reverse" aging in dogs.

 

Under fire from colleagues who said that assertion was irresponsible and unsupported by evidence, Sinclair revised the wording and said he regretted not being more precise, while standing by the underlying research.

 

In his interview with The Washington Post, Sinclair declined to comment on the incident.

 

In 2021, Sinclair and Harvard licensed his lab's version of partial cellular reprogramming to the biotech company, Life Biosciences. (Sinclair retains equity.)

 

In April 2023, the company reported at an ophthalmology conference that they had successfully used this version of partial cellular reprogramming in the eyes of monkeys with a type of optic nerve strokes.

 

The company said the experiment restored aspects of the monkeys' lost vision and altered some of the nerve cells' epigenomes - meaning the cells resembled those of younger animals.

 

It was the first time partial reprogramming had been attempted in primates. The company reported no tumors or other side effects in its presentation, but the results haven't yet been peer reviewed or published.

 

In December 2023, company representatives met with FDA officials to discuss their plans to use partial cellular reprogramming in the eyes of people with optic nerve strokes, Rosenzweig-Lipson said.

 

Optic nerve strokes are relatively uncommon in people, typically affecting about 6,000 adults a year, but can be debilitating. The loss of vision in the affected eye is sudden, often total and usually irreversible, although some eyes improve on their own.

 

There is no treatment. (In a statement to The Post, the FDA declined to comment on any interactions with Life Biosciences.)

 

If the FDA approves its application, the company will repeat the methods from the mouse and monkey experiments, Rosenzweig-Lipson said.

 

Scientists will inject volunteers' eyes with Yamanaka factors that can be turned off or on with the antibiotic doxycycline, Rosenzweig-Lipson said.

 

The hope is that the cells in people's damaged optic nerves will grow more youthful at an epigenetic level, and their vision will improve.

 

The company thinks its partial reprogramming won't result in tumors, since its protocol omits the most carcinogenic of the Yamanaka factors, Rosenzweig-Lipson said.

 

They also believe, based on their animal studies, the remaining factors won't migrate from the eyeball to other parts of the body.

 

 

 

 

Other scientists are also racing to be first to influence aging in people. The rewards - medical, societal and financial - could be enormous.

 

By the time of the Harvard study, different forms of partial cellular reprogramming were already in use at a number of labs.

 

At the Salk Institute, scientists had followed up their studies of progeric mice by creating mice that had extra copies of the four Yamanaka factors engineered onto their DNA that could be activated with doxycycline.

After several months, most of the fully reprogrammed mice were dead. The partially reprogrammed rodents were still alive and didn't experience any teratomas.

 

And in the adult animals, their kidneys and skin were biologically "younger," according to tests of their epigenomes.

None of the animals lived longer than normal, which was the main point of the experiment.

 

But the researchers saw hope in the overall results in the technique, which they call cellular rejuvenation.

 

"I am optimistic that with cellular rejuvenation, we could alter the rate of progression of aging and thereby increase overall health span,"

...said Juan Carlos Izpisua Belmonte, who was the senior scientist at the Salk Institute who oversaw the mouse cellular reprogramming research and is now the director of the Altos Labs San Diego Institute of Science, where he continues to study cellular reprogramming.

 

Reputedly the best-funded biotech start-up in history, Altos Labs opened in January 2022, with about $3 billion in seed funding from tech billionaires and others, including reportedly Jeff Bezos, the founder of Amazon and owner of The Post. (Bezos did not respond to a request for comment.)

 

Headlines and commentary at the time described the labs' founding as a high-tech quest for prolonged lifespans and even immortality by reversing aging inside every cell in the body.

 

But to start, almost all researchers and analysts agree, human experiments using cellular reprogramming, whether from Altos or other labs, will be limited in scope.

 

(A company spokesperson for Altos declined to comment about the current status of its research or the possibility of human experiments in the future.)

 

They'll focus on specific diseases related to aging, such as,

diabetes, arthritis, optic nerve stroke, glaucoma, dementia and others, not aging itself,

...since aging isn't a disease, according to the FDA, and drugs and other therapies can't be approved to treat it, although once approved, drugs can be used off-label.

 

It's unclear, though, whether treating damaged eyes or sore knees will satisfy wealthy funders who've been pouring billions into the hunt for longer lifespans.

 

At the same time, some researchers worry safety concerns remain insurmountable.

"I don't believe there can be reprogramming,"

...even partial reprogramming, in living people without serious side effects, said Charles Brenner, a diabetes and cancer researcher at City of Hope research center in Duarte, California, and frequent critic of reprogramming studies.

"Reprogrammed cells divide rapidly. Cancer cells divide rapidly. You're practically telling these cells to become cancer."

There are other open questions, too.

 

No one yet knows why some cells respond to reprogramming and others don't, how long the epigenetic changes last, or if reprogramming efforts should focus on specific organs or the whole body.

 

In an ambitious study from Stanford University published in March 2024, scientists used partial reprogramming either throughout the bodies of old mice or only inside their brains, hoping in both cases to improve brain health.

 

But the full-body experiment resulted in extra inflammation in the animals' brains, for unknown reasons, and few beneficial changes in neurons.

 

The more-targeted attempt, with reprogramming confined to the animals' brains, led to an increase in newborn neurons, but also an uptick in brain inflammation, which increases risks for neurodegeneration.

"I think there's potential" in cellular reprogramming to combat brain diseases and other conditions, said Xu, who led the brain study as a graduate researcher at Stanford, but has since left the field, in part due to concerns about the possible downsides of reprogramming.

 

"I worry about the speed" at which reprogramming researchers are moving toward human experiments, she said.

Undeterred, Life Biosciences said in a statement that,

the company believes it "remains on track" to receive approval from the FDA soon and to "initiate the first human clinical trials" of its reprogramming therapy before the end of the year...