Outlining Some of the Science Behind Partial Reprogramming at Turn.bio

Turn.bio is an early venture in the new field of in vivo cellular reprogramming, though it is unclear as to whether the partial reprogramming approach they are taking will eventually be used directly in patients, versus in cell cultures prior to transplantation for cell therapy. The publicity materials here cover some of the work undertaken by one of the scientific founders of Turn.bio in recent years, including the transplantation of partially reprogrammed muscle cells into old mice to restore muscle function.

Cells can be reprogrammed into pluripotent stem cells via expression of a small number of genes - the Yamanaka factors. When applied to old cells, this process has been shown to produce numerous beneficial effects along the way. In cells from old tissues it resets many of the epigenetic changes characteristic of aging, and restores mitochondrial function, for example. So while reprogramming most likely cannot meaningfully address issues such as nuclear DNA damage or accumulated molecular waste that cannot be effectively broken down, even by young cells, it may prove to be a useful basis for therapies to treat aging.

This is all a fairly straightforward proposition when applied to cells outside the body and intended for transplantation. When considering in vivo use, however, the challenge lies in reprogramming to a sufficient degree to produce these benefits, versus reprogramming too much, to the point at which tissue is disrupted and cancer arises. The Turn.bio approach is a partial application of reprogramming, to find the point at which cells are shocked into restoring more youthful function, but not so far as to otherwise change their cell type and function. This is a fine balancing act, likely different for different tissues in the body, and still in a comparatively early stage of development.

Old human cells rejuvenated with stem cell technology

Researchers make induced pluripotent stem cells from adult cells, such as those that compose skin, by repeatedly exposing them over a period of about two weeks to a panel of proteins important to early embryonic development. They do so by introducing daily, short-lived RNA messages into the adult cells. The RNA messages encode the instructions for making the Yamanaka proteins. Over time, these proteins rewind the cells' fate - pushing them backward along the developmental timeline until they resemble the young, embryonic-like pluripotent cells from which they originated.

During this process the cells not only shed any memories of their previous identities, but they revert to a younger state. They accomplish this transformation by wiping their DNA clean of the molecular tags that not only differentiate, say, a skin cell from a heart muscle cell, but of other tags that accumulate as a cell ages. Recently researchers have begun to wonder whether exposing the adult cells to Yamanaka proteins for days rather than weeks could trigger this youthful reversion without inducing full-on pluripotency. In fact, researchers found in 2016 that briefly expressing the four Yamanaka factors in mice with a form of premature aging extended the animals' life span by about 20%. But it wasn't clear whether this approach would work in humans.

wondered whether old human cells would respond in a similar fashion, and whether the response would be limited to just a few cell types or generalizable for many tissues. They devised a way to use genetic material called messenger RNA to temporarily express six reprogramming factors - the four Yamanaka factors plus two additional proteins - in human skin and blood vessel cells. Messenger RNA rapidly degrades in cells, allowing the researchers to tightly control the duration of the signal. The researchers then compared the gene-expression patterns of treated cells and control cells, both obtained from elderly adults, with those of untreated cells from younger people. They found that cells from elderly people exhibited signs of aging reversal after just four days of exposure to the reprogramming factors. Whereas untreated elderly cells expressed higher levels of genes associated with known aging pathways, treated elderly cells more closely resembled younger cells in their patterns of gene expression.

When the researchers transplanted old mouse muscle stem cells that had been treated back into elderly mice, the animals regained the muscle strength of younger mice, they found. Finally, the researchers isolated cells from the cartilage of people with and without osteoarthritis. They found that the temporary exposure of the osteoarthritic cells to the reprogramming factors reduced the secretion of inflammatory molecules and improved the cells' ability to divide and function. The researchers are now optimizing the panel of reprogramming proteins needed to rejuvenate human cells and are exploring the possibility of treating cells or tissues without removing them from the body.

Comments

I hope they test in primates soon then do a long follow up cancer study.

If it proves safe, it could perhaps have a cosmetic function in the skin.

Posted by: Jimofoz at March 25th, 2020 5:42 PM

We need a replacement stem cell technology to deal with the nuclear DNA damage (if its a real problem).

Posted by: Abelard Lindsey at March 26th, 2020 10:12 AM

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