The Yamanaka Factors

It looks like science-fiction, but it’s actually fact-based science. Shinya Yamanaka got the Nobel prize in 2012 by turning differentiated cells (also called somatic cells) back into stem cells. This opened a whole new R&D universe to explore, whose practical applications should be starting to appear in the very next years.

Crash course in Cellular Biology

For accessibility purposes, I’ll make some approximations here, because I want the content to be easy to understand, so that everyone gets how disruptive this major scientific breakthrough is. Please don’t kill me if you’re an expert in microbiology 🙂

Stem cells are undifferentiated cells (similar to the ones that grow once a sperm and an ovocyte met). As the foetus grows, the inner structure grows more an more complex, and mechanisms we do not fully understand today contribute to the specialization of stem cells into neurons, muscle, skin, etc… During our lifetime, stem cells continue to exist though, disseminated everywhere in our bodies, ready to take over in case of accidental or systemic cell damage. When this happens, stem cells follow a complex process of migration and differentiation, which ultimately allows them to replace the damaged tissue.

Once a stem cell specializes into a somatic cell, that cell will fulfil its function, live and probably die at some point. It’s a one way ticket decided by Mother Nature for that cell, which will normally never return into a stem cell again.

The DNA of a stem cell differs from the one of a somatic cell by what called the methylation of the DNA, which is a mechanism by which some portions of the DNA become “blocked” or unreadable and only the portions of DNA which are relevant to that specific category of cells will be expressed again. It makes total sense, as you want a neuron to behave like a neuron, and not like a skin cell, or the other way around, etc.

This is a very simplified version of how Mother Nature works.

The Yamanaka Factors

Yamanaka discovered that there are 4 genes, called the Yamanaka Factors (Oct3/4, Sox2, Klf4, c-Myc), which, when over-expressed to different degrees and combinations, result in any differentiated “adult” cell turning back into a stem cell. That stem cell can then be multiplied at will, and then be differentiated again into any other kind of somatic cell. In plain words, this means taking for example a skin cell, turning it back into a stem cell, and then turning it into a neuron – for example. Mind blowing!

Ongoing Research Projects related to the Yamanaka Factors

There are numerous ongoing projects, I’ll just give a couple of examples, just to barely scratch the surface of such an extensive and fascinating field of research:

– stem cells based therapies. The idea is either to inject stem cells in damaged issue, so that it regenerates faster and better. Another idea is to extract somatic cells, turn them into stem cells, then turn them into specialized cells, and then again provide them locally where they’re most needed. Although not yet approved in US & EU, meet 40 world-class athletes who are using or have used stem cells therapies (Rafael Nadal, Cristiano Ronaldo, etc.)

– create and grow organs in a flask, and then transplant them into human bodies. The process begins with your own cells, which are then differentiated into specialized cells, then multiplied, through a complex process as you can imagine, and then ultimately grown into full sized functional working organs. All of this would have never been possible without using the Yamanaka Factors. For example, meet your future heart if at some point you’ll need a new one.

– last but not least, it seems possible to apply a partial “mild” activation of some of the 4 Yamanaka factors, so instead of totally reverting a somatic cell from its current state all the way back to a stem cell, that cell is just partially rejuvenated. It keeps its specialization, it does not become a stem cell, but instead of being old and damaged, it is just gets youthful again. This is called “epigenetic reprogramming” and is currently the most promising field in aging research. Altos Labs (arguably the best founded longevity company today, sponsored by Jeff Bezos amongst others) is working specifically on this cellular reprogramming technology, and they’re betting big on it.

Caveats and current limitations

The main problem today, when it comes to reverting somatic cells to stem cells, is that during this process, some of the resulting stem cells become cancer cells, quickly multiplying and creating tumors.

One other problem is that while scientists know how to take a single cell and manipulate it “in-vitro” with regard to these Yamanaka Factors, doing the same thing with multiple cells, and making sure that each and everyone of them corresponds to the expected differentiation stage, is a challenge. Doing so “in-vivo” is even more of a challenge.

However, when it comes to practical applications to come, there are so many companies, and so much money has been invested into this technology, that it is one of the most (if not THE most) promising research domains today, the hottest topic in the field.

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