While a treatment that regrows lost limbs in humans remains many years away, the research of Wake Forest University’s Josh Currie has brought the goal one step closer.

Currie, an assistant professor of biology, studies how and why Mexican axolotls so readily regenerate tissue. These salamanders with the frilly gills can regrow everything from toes to tails to parts of the brain.

His research has significant potential for improving human health. Injury, cancer, vascular disease like peripheral artery disease (PAD), and congenital conditions have left more than 57 million people across the globe without a limb as of 2017. A therapy to regrow a finger or a toe—or even an arm or a leg—could change many lives.

Here, Currie explains what he has learned about limb regeneration in axolotls so far and how it might apply to humans in the future.

First, why axolotls? What can salamanders tell us about regrowing limbs in humans?

My lab researches how tissue is able to regenerate in certain organisms and not so well in other organisms. Axolotls are one of the only limbed animals that can regenerate fully functioning limbs. And we use the axolotl because it is this gold-standard model of regeneration. Every time an axolotl loses a limb, it grows back just the missing pieces. 

We’re trying to understand what are the molecules, what are the genes, what is the constellation of events that takes place to make regeneration happen perfectly?

When an axolotl loses a limb, it heals that injury pretty much like any other injury that you or I would have. But then a really amazing thing happens: Cells start to accumulate under the skin that healed over and they form this mass of cells. That mass of cells will start to redevelop the missing pieces, and it will reconstitute only the parts that were lost.

What do we know about how axolotls regrow tissues like legs, tails and organs?

With my lab’s most recent research (published in the Proceedings of the National Academy of Sciences), we focused on a specific shared gene and how it works during limb generation in the axolotl. We use a technique called CRISPR genome editing. 

CRISPR is a really great, new technique that allows us to very specifically target and cut out parts of the axolotl genome. We knocked out—meaning we removed parts of—the axolotl genome surrounding a gene called SP8. 

We were surprised to see that SP8 was absolutely critical for limb regeneration. When you get rid of SP8, the axolotls try to regrow tissue, but they’re disorganized in what they can regenerate.

Your latest study also included zebrafish and mice. Why?

We wanted to do work with mice because they’re mammals like us. They have a very limited ability to regenerate, like we do. The axolotl and the zebrafish are both really good regenerators, but they obviously are quite evolutionarily distant. 

David Brown’s lab at Duke University looked at the digit tip regeneration of mice and Ken Poss’ lab at the Morgridge Institute and University of Wisconsin-Madison looked at zebrafish fin regeneration. We were able to show that there are specific genes shared among the regeneration in all three of these organisms. 

Specifically, there are genes expressed in the skin that heals over during regeneration. We were able to show that these shared genes are actually essential. If you’re missing them, regeneration doesn’t work properly.

Did you figure out how to regrow tissue? How?

After discovering that SP8 was shared across fish and mice and axolotls, and learning that it’s critical for limb regeneration in the axolotl, we wanted to translate this research towards a clinical outcome. 

We designed a gene therapy, meaning a virus that delivered a payload of a gene called FGF8 that targeted just the site of the regenerating mouse digit. FGF8 is controlled by SP8.

With this gene therapy delivering a pro-growth, pro-regeneration molecule, the mouse was able to regenerate a partial digit tip in the absence of the SP genes. That really sets the stage for being able to ask, “Can we bring this therapy in other contexts of injury? And can we bring other payloads that might be more potent in spurring regeneration?” 

This will help us deliver pro-regenerative molecules in places where we know regeneration is not going to happen naturally, and maybe to spur on a true regeneration outcome.

How long before we might see a therapy for regrowing limbs in humans?

Mice can regenerate the very tips of their fingers. Humans actually have the same regenerative potential. If you were to lose your fingertip, anything past the nail bed, there’s a good chance it would regrow. 

But there are a lot of steps that have to occur before actually applying what we found in our research to humans. We still know very little about what is essential for regeneration to take place, and there’s still a large divide between knowing why regeneration happens sometimes and in other times it doesn’t. 

I think iterations of these kinds of gene therapies will allow us to push further towards regeneration in humans.

Being able to apply the principles of limb regeneration to things like postoperative healing, to muscle injuries that you might get on a basketball court, to actually changing the lives of patients with limb loss or limb differences—all of those things can be impacted by learning about how regeneration works in an animal that has figured it out, like the axolotl.

Learn more

See the On Topic page to hear more Wake Forest University experts discuss relevant topics and new research.