Scientists studying axolotls, zebrafish and mice have discovered a common set of genes that could one day help researchers develop treatments to regenerate human limbs. The survey results are Proceedings of the National Academy of Sciencessuggesting potential new directions for regenerative medicine and gene therapy.
“This important study brought together three laboratories and worked across three organisms to compare regeneration,” said Josh Currie, assistant professor of biology at Wake Forest. The same laboratory studies the Mexican axolotl salamander. “It showed that there is a universal, unifying genetic program that drives reproduction in very different species, such as salamanders, zebrafish, and mice.”
The project also included plastic surgeon David A. Brown of Duke University, who studies finger regeneration in mice, and Kenneth D. Poth of the University of Wisconsin-Madison, whose research focuses on fin regeneration in zebrafish.
Regenerative genes shared across species
According to the Global Burden of Disease Statistics, more than 1 million amputations occur worldwide each year due to diabetes-related vascular diseases, trauma, infections, and cancer. Researchers expect that number to increase as the population ages and diabetes becomes more common.
For years, scientists have been looking beyond prosthetics to find treatments that can restore natural movement, sensation, and function. This new study suggests that a group of genes known as SP genes may play a central role in that effort.
The researchers chose axolotls, zebrafish, and mice because each species provides unique insights into regeneration.
Axolotls are famous for their incredible ability to regenerate entire limbs, tails, spinal cord tissue, and parts of organs such as the heart, brain, lungs, liver, and jaw.
Zebrafish are another powerful regeneration model because they can repeatedly regenerate damaged caudal fins. It can also repair the heart, brain, spinal cord, kidneys, retina, and pancreas.
Mice are included because, like humans, they are mammals. Mice can regenerate fingertips, and human fingertips can regenerate if the nail bed is intact after injury and the skin, flesh, and bone can regenerate.
Curry said the team found that all three types of epidermis, or skin tissue regeneration, activate two genes called SP6 and SP8. So researchers began investigating exactly how these genes contribute to regeneration.
Biology doctoral student Tim Curtis Jr. participated in research in Currie’s lab, along with undergraduate student Elena Singer Freeman, a Goldwater Scholar and 2025 Wake Forest graduate in biochemistry and molecular biology.
CRISPR experiments reveal important role in limb regeneration
The researchers found that SP8 is particularly important for limb regeneration in salamanders. Using CRISPR gene editing technology, Currie’s team deleted SP8 from the axolotl genome.
Without this gene, axolotls could not properly regenerate bones in their limbs. Scientists observed similar problems in finger regeneration in mice lacking SP6 and SP8.
Taking advantage of these findings, Brown’s lab designed a viral gene therapy based on tissue regeneration promoters previously identified in zebrafish.
The therapy delivered a signaling molecule called FGF8, which is normally activated by SP8. In mice, the treatment promoted regeneration of damaged finger bones and partially restored some of the regenerative ability lost when the SP gene was missing.
Although human limbs cannot regenerate naturally like salamander limbs, researchers believe that future treatments may be able to mimic some of the biological mechanisms controlled by the SP gene.
“We can use this as a kind of proof of principle that we might be able to offer an alternative treatment to this regeneration style of epidermis in human tissue regeneration,” Professor Currie explained.
Building for future human limb regeneration
The researchers caution that the research is still in its early stages and that more work will be needed before the findings in mice can be translated into human treatments. Still, Professor Curry said the study was an important foundation for future regenerative treatments.
“Scientists are pursuing many solutions for limb replacement, including bioengineered scaffolds and stem cell therapy,” Professor Currie explained. “The gene therapy approach in this study is a new tool that can complement and potentially expand what will one day be a multidisciplinary solution to regenerate human limbs.”
Curry also emphasized the importance of collaboration between scientists working on very different animals and biological systems.
“A lot of times, scientists work in silos. We only study axolotls, or we only study mice, or we only study fish,” Currie said. “What really stands out about this work is that we’re working with all these different organisms. This is very powerful and I hope we’ll see more of it in this field.”
