What If There Were Biological Time Machines?

Cellular reprogramming could reverse aging and revolutionize medicine, but it is still in its early stages.

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By Lillian Zou

Aging is an irrevocable fact of life. Or is it? For a few hopeful billionaires, including Jeff Bezos, getting older is something that could be engineered away with the latest cutting-edge biotechnology. This isn’t science fiction; it’s a concerted effort to figure out how to keep humans from aging and rejuvenate their cells. Altos Labs, the research company backed by billionaire Yuri Milner, Shinya Yamanaka, and other decorated scientists, is poised to jump into the field by investigating methods of biological reprogramming.

Cellular reprogramming is like a factory reset for cells—they go from producing specific proteins tailored to their functions to being stem cells capable of differentiating into any cell type. This is achieved through the removal of epigenetic marks from DNA. These marks, such as the methyl groups attached to DNA, are changes that affect gene expression without altering the genetic code. They may be caused by environmental factors, such as exposure to toxins, or result from development and aging. 

The most dramatic period of reprogramming occurs during embryonic development. When an egg is fertilized, the epigenetic marks on parental genes block embryo development. Reprogramming occurs to remove the methyl groups, altering parental DNA’s expression so that the embryonic cells become totipotent—having the ability to divide into a complete organism with any type of cell. While DNA methylation is heritable, reprogramming makes the embryo’s cells generic and nearly uninfluenced by outside factors. Such cells are described as having an “epigenetic age” of zero, or being in a state as little affected by epigenetic marks as possible. 

In 2006, Yamanaka discovered a set of transcription factors that could be used to artificially create stem cells with an epigenetic age of zero from older cells. These transcription factors aid in the transcription of DNA to mRNA to produce proteins specific to regulating the life cycles of stem cells. When the OSKM Factors Yamanaka discovered—Oct4, Sox2, Klf4, and c-Myc—are produced in older cells, those cells transition into pluripotent stem cells. Pluripotent cells can differentiate into any type of cell. 

In his 2006 experiment, Yamanaka used the OSKM factors to transform mouse embryonic fibroblasts, which normally help create connective tissue, into pluripotent cells. In 2007, Yamanaka proved that by coding for the OSKM factors in human fibroblasts’ DNA, the same result of pluripotent cells can be achieved. Before this, pluripotent cells had never been created without the aid of extra stem cell material. The results of Yamanaka’s research are akin to turning back the biological clock: expressing OSKM Factors stimulates demethylation to a state only found in embryos, resetting older cells’ epigenetic age to zero so that they function like brand-new ones. 

In the following years, more leaps were made in the field of reprogramming. In a 2016 study, partial activation of OSKM Factors was shown to reduce signs of aging in mice, limiting muscle aging and the breakages in DNA double helices that occur after many cell divisions.  The same study showed that when OSKM Factors are tested on mice with genetic diseases that cause premature aging, they reduce aging and extend the mice’s lifespans. In 2020, the OSK factors (excluding c-Myc) were shown to boost retinal cell regeneration in mice with crushed optic nerves, suggesting the possibility of future treatments to improve human eyesight.

These studies sought to eliminate the biggest issue with induced pluripotent stem cells: cancerous tumors. Naturally-occurring stem cells must be able to divide almost indefinitely because they are responsible for growing a bundle of cells into a fetus. When stem cells are created in the lab with the OSKM factors, their goal is not to become an organism, but rather to improve the functioning of certain parts of a mouse or human. However, induced stem cells have the indefinite growth potential that leads to teratoma tumors, which are masses composed of different cell types.

Altos Labs’ supporter and PayPal co-founder Peter Thiel said, “Death will eventually be reduced from a mystery to a solvable problem.” Cellular reprogramming is not yet at that point, though. None of the reprogramming therapies designed by anti-aging biotech companies have made it to clinical trials on humans because of mixed results in early testing on mice. It is essentially a goldilocks issue; researchers must find a way to safely alter human cells to reduce the amount of methylation on DNA without causing those cells to lose their identity or become cancerous. 

Besides the cancerous cell issue, there are many other concerns associated with biological reprogramming. In order for the OSKM Factors to be expressed in cells, their code must be transferred into cellular nuclei. One way this can be done is by creating special viruses that infect host cells to transfer OSKM Factor information instead of replicating viral genetic information. However, sometimes viral DNA gets integrated into the cell instead. It is always risky to introduce foreign pieces into cellular DNA for risk of disrupting an important part of the genetic code. 

The ethical issues that would result from making age reversible and possibly age-related death preventable are even more troubling. The science of cellular reprogramming is still underway, though it will probably be 50 years before humans can take advantage of it. When the time comes, reprogramming is sure to be prohibitively expensive like all new medicines; with the unprecedented power of being able to prevent something once unavoidable—aging—it is no doubt that the uber wealthy will maintain exclusive access to its benefits. Limited time and death are currently the great social equalizers because nobody can opt out of their inevitability. There is something very sinister about the privileged few being able to buy more time, not by maintaining a healthy lifestyle but by reversing their cellular age. Such circumstances would unduly drain Earth’s resources as the human lifespan was extended. If humans lived unnaturally long, the population growth rate would drastically outpace the death rate, with devastating consequences.