What is in vivo reprogramming, its potential pros & cons?

Lately, we’ve been hearing more about something called “in vivo reprogramming.” It comes up frequently in the longevity space. Today’s post explains this cutting-edge area of research and its hoped-for, potential clinical applications.

What’s most intriguing about vivo reprogramming is that it could potentially regenerate or heal tissues from the inside. It’s both exciting and highly risky based on its specific pros and cons compared to other technologies.

What is in vivo reprogramming?

In essence, in vivo reprogramming is an approach to change cell identity inside the body.

It’s a related but alternative technology to the well-established idea of changing cell identity in the lab such as via reprogramming factors.

The idea of in vivo reprogramming is built on Shinya Yamanaka’s induced pluripotent stem cell or iPS cell research. Yamanaka’s work in turn was also built on previous studies. I’m thinking of research on MyoD and muscle differentiation by Hal Weintraub at The Hutch. That was also a kind of reprogramming. In my view, cellular reprogramming just means changing cell identity, not necessarily making stem cells or iPS cells. In fact, in this in vivo case, you don’t want to make iPS cells.

Still, most often in vivo reprogramming specifically refers to making cells that have an earlier or younger identity, just not all the way back to iPS cells. The end goal is to yield positive health outcomes this way.

By reprogramming cells in vivo, you’d make new cell types from existing cells already in the body. There would be no lab reprogramming step.

What is an example of in vivo reprogramming?

You might reprogram heart fibroblasts in a 70-year-old this way in a damaged heart to now have the identity and functions of early heart muscle progenitor cells. Those could potentially grow healthy new heart muscle. In contrast, if you overshoot and make iPS cells right in the heart, you might get teratoma tumors there.

So, in a model like the Waddington landscape shown above, you’d want to only take the cells back part way up the “hill”. You’d also need to keep them on the right path. For example, you wouldn’t want to accidentally make kidney cells in the heart or vice versa.

What are the pros of in vivo reprogramming?

A major pro of reprogramming cells inside the body is that it is directly done in the patient. No cell transplantation would be needed.

There may also be lower risks of lab-associated problems like some kind of contamination of lab-grown cells.

Reprogramming from within may also yield more mature, functional cells.

Even so, there are many unknowns here and no guarantees.

What are the possible cons of reprogramming cells in vivo?

My lab and many others have made iPS cells in vitro. Biotechs make iPS cells too.

During that process we can screen the mixed populations to identify true iPS cells from unwanted byproducts of the reprogramming process. Reprogramming is still not perfect. As a result, a wide variety of other cells can be generated in the process including cells that have taken a few steps toward cancer.

What this all means is that reprogramming cells in vivo would likely create unhelpful or even harm cells in the body. If not done precisely, it’s likely that researchers would inadvertently generate tumor cells or iPS cells that can grow into teratoma.

There would be no way to eliminate undesired cells or even effectively screen for them inside of patients.

What about anti-aging applications?

Firms like Altos Labs have been discussing the exciting idea of cellular rejuvenation. Some academic labs (e.g., Juan Carlos Belmonte and David Sinclair, see papers in the references section below) have also done interesting research in this space.

Many health influencers also seem interested in this technology, which has led to hype about it and confusion.

Looking ahead, precision in vivo reprogramming of cells inside the body to generate desired health outcomes like to fight aging in humans is a long way off at best. It may never happen, but I think there’s a decent chance in coming decades something of this type might be achieved for individual tissues.

Along the way it won’t be easy to convincingly address the potential risks of such reprogramming that I outlined earlier. Again, a key obstacle is the combination of not always getting the cell type you want and the inability to screen all the millions of reprogrammed cells produced inside the body.

Another challenge is the ongoing hype and drama in the longevity space, which I recently covered over at STAT.

Despite these challenges, it’s an exciting area to follow.

References and notes

• In Vivo Cellular Reprogramming: The Next Generation.
• Overview of Altos Labs.
• Belmonte Lab in vivo reprogramming mice paper
• Sinclair Lab in vivo reprogramming mice paper
• For simplicity I have not italicized “in vitro “and “in vivo” in this post.