Turn.Bio – OSKMLN

Summary

Epigenetic alterations are one of the hallmarks of aging, and in December 2016, a team of researchers from the Salk Institute discovered that the intermittent expression of genes normally associated with an embryonic state could reverse some aspects of aging in cells [1]. In particular, they found that they were able to reverse the epigenetic alterations that our cells experience as we age, thus switching their gene expression from an unhealthy, aged profile back to a healthy, youthful one.

They achieved this astonishing feat in living mice, opening the door for the possible reversal of cellular aging in people. They effectively reset aging in the cells of these mice with just four factors, Oct4, Sox2, Klf4, and c-Myc (OSKM). These four factors, known as the Yamanaka factors, are expressed by genes during development and are the same ones currently used in stem cell research to create induced pluripotent stem cells (iPSCs).

When iPSCs are created, their cellular identities are reset along with their cellular ages, allowing researchers to roll them back to a flexible state known as pluripotency. In this state, a cell can become any kind of specialized cell in the body, and researchers can use the technique to produce any desired cell type for therapies or studies.

However, completely resetting all our cells so that they forget what type of cells they are would be a seriously bad idea. Imagine if heart cells forgot what they were doing and stopped being heart cells! Fortunately, there may be a way to both have our cake and eat it by separating the aging reset from the cell identity erasure.

It turns out that the aged state of cells is wiped before their identities are reset, so while iPSCs experience a full cellular reprogramming process, it is also possible to halt the process before the second part happens, thus resulting in partial reprogramming, which resets cell age but not identity.

Earlier this year, the Turn.Bio team published a study showing the potential of using transient mRNAs to trigger partial cell reprogramming [2]. The approach activates the same OSKM factors but in a slightly different way using transient mRNAs. In order to facilitate a better partial reprogramming of the cells, the researchers also added two more factors, LIN28 and Nanog, to the original Yamanaka lineup, making OSKMLN.

Turn.Bio is now on the road to bringing partial cellular reprogramming therapies to human trials, and in July 2019, Kizoo Technology Ventures announced that it was supporting the biotech to help it to develop its technology to that end. We also interviewed Professor Vittorio Sebastiano of Turn.Bio at the Undoing Aging 2019 conference in Berlin about this research.

References

[1] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.

[2] Sarkar, T. J., Quarta, M., Mukherjee, S., Colville, A., Paine, P., Doan, L., … & Rando, T. A. (2019). Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells. bioRxiv, 573386.

Website: Turn.Bio

Articles:

An Interview with Prof. Vittorio Sebastiano of Turn.Bio

Partial Cellular Reprogramming to Reverse Cellular Aging