The Fountains Of Youth Are NOT For Peasants...,

nautil.us |  What impact will your work have on aging research?

I’m studying whether we can separate the process of functional reprogramming of cells from the process of aging reprogramming of cells. Typically these two processes happen at the same time. My hypothesis is that we can induce cellular rejuvenation without changing the function of the cells. If we can manage to do this, we could start thinking about a way to stall aging.

What is the difference between functional and aging reprogramming?

The function of a skin cell is to express certain proteins, keratins for example that protect the skin. The function of a liver cell is to metabolize. Those are cell-specific functions. Reprogramming that function means that you no longer have a liver cell. You now have another cell, which has a totally different function. Age, on the other hand, is just the degree of usefulness of that cell, and it’s mostly an epigenetic process. A young keratinocyte cell is younger than an older keratinocyte but it is still a keratinocyte. The amazing thing is that if you take an aged cell that is fully committed to a certain function, and you transplant its nucleus into an immature egg cell called an oocyte, then you revert its function to a pluripotent, embryonic one, which means it can become any other cell of the body—and you also revert the age of that cell to the youngest age possible. It’s mind-blowing to me.

This could be a paradigm shift in the way we approach aging.

How can you make a pluripotent cell in the lab?

Historically, the way pluripotency was induced from non-pluripotent cells was by doing the procedure I’ve just described: so-called “somatic cell nuclear transfer.” You take a non-pluripotent cell, let’s say a liver cell or a fibroblast or any other cell. You isolate its nucleus and transplant it into an egg, an oocyte, which was previously deprived of its own nucleus. This produces what is known as a reconstituted embryo, in which the cytoplasm is the original egg’s cytoplasm, and the nucleus is the nucleus of the cell that you isolated. The egg has this amazing ability to reprogram the nucleus to an embryonic-like state. Since embryonic cells are naturally endowed with a pluripotency program, if you then take that embryo and put it in culture, you can establish pluripotent stem cell lines. Shinya Yamanaka, a Japanese researcher that got a Nobel prize for his work three years ago, demonstrated another technique, called induced pluripotent stem cells, or iPS. He showed that if you simply boost the expression of four particular transcription factors inside a non-pluripotent cell for a few weeks, you also could create an embryonic-like program. The factors also somehow wipe off the epigenetic memory of the cell, making them younger.

How close are we to using pluripotency induction in therapies?

iPS in mice was described in 2006, and in humans in 2007, so it’s been already 10 or 11 years. The first clinical trials using iPSCs are just about to get to early phase I and phase II. There has been a lot of hope and promise but it’s been a little slow. The reason being that when it comes to clinical applications, you have to consider a number of complications. You need to know how to make the cells very efficiently, and then they need to be safe. There will be more clinical trials coming up based off iPSs. For example, I am collaborating with an iPS-based platform for the cure of a skin disease called epidermolysis bullosa. We’re trying to move this to the pre-clinical stage over the next few years, and then if we pass that, we will potentially start moving into a phase I clinical trial. Things are moving forward pretty fast now.