A set of shared genes in salamanders, zebrafish and mice is giving researchers a new lead on something that still sounds like science fiction, regrowing lost limbs.
The study, published in the Proceedings of the National Academy of Sciences, identified a group of genes known as SP genes that appear to help drive regeneration across the three species.
“This significant research brought together three labs, working across three organisms to compare regeneration,” said Wake Forest Assistant Professor of Biology Josh Currie, whose lab studies the Mexican axolotl salamander.
“It showed us that there are universal, unifying genetic programs that are driving regeneration in very different types of organisms, salamanders, zebrafish and mice.”
The project also involved Duke University plastic surgeon David A. Brown, who studies digit regeneration in mice, and Kenneth D. Poss of the University of Wisconsin-Madison, whose research focuses on fin regeneration in zebrafish.
According to Global Burden of Disease statistics, more than 1 million amputations happen each year around the world because of diabetes-related vascular disease, traumatic injuries, infections and cancer. Researchers expect that number to rise as populations age and diabetes becomes more common.
The researchers chose axolotls, zebrafish and mice because each species can regenerate tissue in ways that help answer different questions. Axolotls can regrow entire limbs, along with tails, spinal cord tissue and parts of organs including the heart, brain, lungs, liver and jaw. Zebrafish can repeatedly regrow damaged tail fins and can also repair the heart, brain, spinal cord, kidneys, retinas and pancreas. Mice were included because they are mammals, and they can regenerate the tips of their digits.
Currie said the team found that regenerating epidermis, or skin tissue, in all three species activated two genes called SP6 and SP8.
Researchers then tested how those genes affect regeneration. In salamanders, they found SP8 was especially important for limb regrowth. Using CRISPR gene-editing technology, Currie’s team removed SP8 from the axolotl genome. Without it, axolotls could not properly regenerate limb bones.
Scientists saw similar problems in mice when SP6 and SP8 were missing from regenerating digits.
Using those results, Brown’s lab designed a viral gene therapy based on a tissue regeneration enhancer previously identified in zebrafish. The therapy delivered a signaling molecule called FGF8, which is normally activated by SP8.
In mice, the treatment encouraged bone regrowth in damaged digits and partly restored some regenerative ability lost when the SP genes were absent.
“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.
The researchers said the work is still at an early stage and that much more study will be needed before findings in mice could lead to treatments for people.
“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 said the study shows the value of comparing very different animals.
“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.”
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