A major gene discovery in salamanders, fish, and mice could eventually assist humans in regenerating lost limbs.
Scientists examining axolotls, zebrafish, and mice have revealed a common collection of genes that may one day aid researchers in creating treatments for regrowing human limbs. The results, released in the Proceedings of the National Academy of Sciences, indicate a potential new path for regenerative medicine and gene therapy.
"This major study united three labs, operating across three species to compare regeneration," said Wake Forest Assistant Professor of Biology Josh Currie, whose lab examines the Mexican axolotl salamander. "It demonstrated that there are universal, unifying genetic programs that are driving regeneration in very different types of organisms, salamanders, zebrafish and mice."
The initiative also involved Duke University plastic surgeon David A. Brown, who investigates digit regeneration in mice, and Kenneth D. Poss of the University of Wisconsin-Madison, whose work centers on fin regeneration in zebrafish.
Globally, over 1 million amputations happen annually because of diabetes-related vascular disease, traumatic injuries, infections, and cancer, according to Global Burden of Disease data. Experts anticipate that figure will rise as populations grow older and diabetes becomes more widespread.
For years, researchers have sought methods to go beyond prosthetic limbs and toward treatments able to restore natural movement, sensation, and function. This new study indicates that a group of genes known as SP genes may play a key role in that endeavor.
Scientists chose axolotls, zebrafish, and mice because each species provides unique insights into regeneration.
Axolotls are renowned for their remarkable capacity to regrow entire limbs along with tails, spinal cord tissue, and portions of organs including the heart, brain, lungs, liver, and jaw.
Zebrafish are another potent regeneration model since they can repeatedly regrow damaged tail fins. They are also able to repair the heart, brain, spinal cord, kidneys, retinas, and pancreas.
Mice were included because, like humans, they are mammals. Mice can regenerate the tips of their digits, and humans can occasionally regrow fingertips if the nailbed remains intact after injury, allowing skin, flesh, and bone to regenerate.
Currie noted the team found that the regenerating epidermis, or skin tissue, in all three species activated two genes called SP6 and SP8. Researchers then began investigating precisely how those genes contribute to regeneration.
Biology Ph.D. student Tim Curtis Jr. took part in the work in Currie's lab, along with undergraduate Elena Singer-Freeman, a Goldwater Scholar and 2025 Wake Forest graduate in biochemistry and molecular biology.
The scientists discovered that SP8 is particularly vital for limb regeneration in salamanders. Using CRISPR gene-editing technology, Currie's team removed SP8 from the axolotl genome.
Without the gene, axolotls could not properly regenerate limb bones. Scientists noted similar issues in mice when SP6 and SP8 were absent from regenerating digits.
Using those results, Brown's lab developed a viral gene therapy based on a tissue regeneration enhancer previously identified in zebrafish.
The treatment delivered a signaling molecule called FGF8, which is normally triggered by SP8. In mice, the therapy encouraged bone regrowth in damaged digits and partially restored some regenerative abilities lost when the SP genes were missing.
Human limbs cannot naturally regenerate the way salamander limbs do, but researchers believe future treatments could potentially mimic some of the biological mechanisms controlled by SP genes.
"We can use this as a kind of proof of principle that we might be able to deliver therapies to substitute for this regenerative style of epidermis in regrowing tissue in humans," Currie explained.
Researchers warn that the work is still at an early stage, and far more studies will be needed before discoveries in mice could translate into treatments for humans. Even so, Currie described the research as a crucial foundation for future regenerative treatments.
"Scientists are pursuing many solutions for replacing limbs, including bioengineered scaffolds and stem cell therapies," Currie explained. "The gene-therapy approach in this study is a new avenue that can complement and potentially augment what will surely be a multi-disciplinary solution to one day regenerate human limbs."
Currie also stressed the importance of collaboration between scientists working on very different animals and biological systems.
"Many times, scientists work in their silos: we're just working in axolotl, or we're just working in mouse, or just working in fish," Currie said. "A real standout feature of this research is that we work across all these different organisms. That is really powerful, and it's something that I hope we'll see more of in the field."