Scientists studying a shared genetic mechanism across three vastly different species—axolotls, mice and zebrafish—have uncovered fresh clues that could one day support limb regeneration in humans. The findings, detailed this week in the Proceedings of the National Academy of Sciences, point toward the possibility of developing gene-based therapies aimed at restoring lost limbs.
“This work brought together multiple labs and model organisms to understand regeneration in a comparative way,” said Josh Currie, Assistant Professor of Biology at Wake Forest University. He noted that the study reveals common genetic programs that drive regeneration across species as different as salamanders, fish and mammals.
The research also involved David A. Brown of Duke University and Kenneth D. Poss of University of Wisconsin-Madison, who specialise in regeneration studies in mice and zebrafish respectively.
Globally, more than one million amputations are carried out each year due to conditions such as diabetes, trauma, infections and cancer, according to Global Burden of Disease estimates. With ageing populations and rising diabetes cases, this number is expected to increase further, intensifying the search for solutions that go beyond prosthetics.
Researchers involved in the study are aiming to develop therapies that could restore not just the structure but also the function of lost limbs—something prosthetic technology still cannot fully replicate.
Their focus turned to a group of genes known as SP genes, which appear to play a crucial role in regeneration and are shared across the three species examined.
Therapy makes up for missing gene
The choice of species was deliberate, reflecting different regenerative abilities in nature.
The axolotl, a type of salamander, is known for its extraordinary capacity to regrow entire limbs, as well as parts of vital organs including the heart and brain.
Zebrafish, meanwhile, are widely used in research because their tail fins regenerate rapidly and repeatedly. They can also repair tissues in organs such as the heart and spinal cord.
Mice, representing mammals, offer a closer comparison to humans. While their regenerative ability is limited, they can regrow the tips of their digits. Humans share a similar, though restricted, ability when fingertip injuries preserve the nail bed.
The researchers found that regenerating skin tissue in all three species expressed two key genes—SP6 and SP8. This prompted further investigation into how these genes function.
The study also involved contributions from doctoral student Tim Curtis Jr. and undergraduate researcher Elena Singer-Freeman at Wake Forest.
Emulating the abilities of salamander genes
In salamanders, the SP8 gene plays a central role in enabling limb regrowth. Using CRISPR gene editing, researchers removed SP8 from the axolotl genome. The result was a clear disruption in limb regeneration, particularly in bone formation.
A similar outcome was observed in mice when both SP6 and SP8 were absent, confirming the genes’ importance across species.
Building on these findings, Brown’s lab developed a viral gene therapy using a regeneration enhancer identified in zebrafish. This therapy introduced a molecule called FGF8—normally activated by SP8—into mice.
The treatment partially restored bone regrowth in mouse digits, effectively compensating for the missing genes and demonstrating what researchers describe as a “proof of principle”.
While humans lack this level of regenerative ability, the findings suggest it may be possible to mimic such processes through targeted therapies.
“We may be able to design treatments that replicate this regenerative skin environment in humans,” Currie said, highlighting the long-term potential of the approach.
Building the foundation for human therapies
Despite the breakthrough, researchers caution that translating these findings into human treatments will require extensive further study. Moving from digit regeneration in mice to full limb regrowth in humans remains a complex scientific challenge.
Currie described the work as a foundational step toward future therapies that could address limb loss caused by injury or disease.
He added that gene therapy represents just one pathway among several being explored, including stem cell research and bioengineered scaffolds. A combination of approaches is likely to be needed to achieve full limb regeneration.
The collaborative nature of the study, involving different organisms and research disciplines, was key to its success.
“Scientists often work within narrow models, focusing on a single species,” Currie said. “What sets this research apart is the integration across multiple systems, which offers a much broader understanding of regeneration.”
The findings underscore a growing shift in regenerative medicine—from isolated breakthroughs to cross-species insights that could eventually reshape how the human body heals.