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This research shows that universal, unifying genetic programs drive regeneration in salamanders, zebrafish, and mice. Credit: Neuroscience News<\/p>\nSummary: In a monumental cross-species collaboration, scientists have identified a \u201cuniversal genetic program\u201d that drives limb regeneration. By studying axolotls, zebrafish, and mice, researchers discovered that a specific family of genes, the SP genes, is the common denominator for regrowing lost tissue.<\/p>\n
The study demonstrates that a novel viral gene therapy can partially restore regenerative powers in mammals, offering a foundational blueprint for one day regrowing human limbs.<\/p>\n
Key Findings<\/p>\n
Universal Blueprint: Regeneration isn\u2019t a collection of different tricks; it is a shared genetic program that is \u201cactive\u201d in salamanders but \u201csilent\u201d or limited in humans.A New Pillar of Treatment: While bioengineered scaffolds and stem cells are currently the focus of limb replacement, this gene-therapy approach offers a way to trigger the body\u2019s own internal repair mechanisms.Global Impact: With over 1 million amputations occurring annually due to diabetes and trauma, this research provides a biological target to move beyond mechanical prosthetics toward true limb restoration.<\/p>\n
Source: Wake Forest University<\/p>\n
Investigating a common gene in three very different species \u2013 axolotls, mice and zebrafish \u2013 scientists have discovered the potential for a novel gene therapy aimed at eventually regrowing limbs in humans, according to new research published this week.\u00a0\u00a0<\/p>\n
\u201cThis significant research brought together three labs, working across three organisms to compare regeneration,\u201d said Wake Forest Assistant Professor of Biology\u00a0Josh Currie, whose lab studies the Mexican axolotl\u00a0 salamander.<\/p>\n
This research shows that universal, unifying genetic programs drive regeneration in salamanders, zebrafish, and mice. Credit: Neuroscience News<\/p>\n
\u201cIt showed us that there are universal, unifying genetic programs that are driving regeneration in very different types of organisms, salamanders, zebrafish and mice.\u201d<\/p>\n
The research, with results appearing in the\u00a0Proceedings of the National Academy of Sciences, included David A. Brown, a plastic surgeon who studies digit regeneration in mice at Duke University, and Kenneth D. Poss, who studies fin regeneration in zebrafish at the University of Wisconsin-Madison.<\/p>\n
Each year, around the world, more than 1 million limb amputations occur because of vascular diseases such as diabetes, traumatic injuries, cancer or infections, according to annual\u00a0Global Burden of Disease\u00a0statistics. The number is expected to rise with the aging population and the increase in diabetes diagnoses.<\/p>\n
That looming challenge has inspired Brown, Currie and Poss to search for a treatment beyond prosthetics, for something that could replace the complex senses and motor skills of an actual limb.\u00a0<\/p>\n
They might have found the start of a solution in something called SP genes, which the scientists discovered are vital for limb regeneration and shared by the mouse, zebrafish and axolotl.\u00a0<\/p>\n
Therapy makes up for missing gene<\/p>\n
The scientists chose to study these three animals for specific reasons:<\/p>\n
The axolotl excels at regeneration, with the ability to regrow complete limbs; tails, including the spinal cord; parts of the heart, brain, liver, lungs and jaw.Zebrafish offer one of the best models for appendage regeneration because their tail fins regrow rapidly and have unlimited capacity for regrowth. The zebrafish also can regenerate its heart, spinal cord, brain, retinas, kidneys and pancreas.Mice represent mammals like humans, and they already can regenerate the tips of their digits. Humans, too, can regrow their fingertips when an injury preserves the nailbed. That allows regrowth of flesh, skin and bone.<\/p>\n
Currie said that once the scientists determined the regenerating epidermis, or skin, of all three species expressed the SP genes SP6 and SP8, they set out to test what the genes do and how they work.<\/p>\n
Biology Ph.D. student Tim Curtis Jr. contributed to the research in the Currie lab, with assistance from undergraduate Elena Singer-Freeman, a Goldwater Scholar and 2025 Wake Forest biochemistry and molecular biology graduate.\u00a0<\/p>\n
Emulating the abilities of salamander genes<\/p>\n
In salamanders, SP8 does the work in regenerating limbs. Using CRISPR gene-editing technology, Currie\u2019s lab removed SP8 from the axolotl genome. Without SP8, the axolotl could not properly regenerate the limb bones; a similar result occurred with the mouse digits missing SP6 and SP8.<\/p>\n
With that information in hand, Brown\u2019s lab used a btissue regeneration enhancer found in zebrafish to develop a viral gene therapy.<\/p>\n
That therapy delivered a secreted molecule called FGF8, a gene that is usually turned on by SP8, to encourage digit bone regrowth and partially restore the regenerative effects of the missing SP genes in mice.\u00a0<\/p>\n
Human limbs don\u2019t have that kind of regenerative power \u2013 but might someday, with a therapy that emulates the abilities of SP genes.<\/p>\n
\u201cWe 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,\u201d Currie explained.<\/p>\n
Building the foundation for human therapies<\/p>\n
Although it will require much more research to take the findings from mouse digits to human limbs, Currie called this study foundational in the search for therapies to regrow limbs after injury or disease.<\/p>\n
\u201cScientists are pursuing many solutions for replacing limbs, including bioengineered scaffolds and stem cell therapies,\u201d Currie explained. \u201cThe 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.\u201d<\/p>\n
He said the decision to collaborate among scientists studying such different animals made all the difference in this research.<\/p>\n
\u201cMany times, scientists work in their silos: we\u2019re just working in axolotl, or we\u2019re just working in mouse, or just working in fish,\u201d Currie said. \u201cA real standout feature of this research is that we work across all these different organisms. That is really powerful, and it\u2019s something that I hope we\u2019ll see more of in the field.\u201d<\/p>\n
Key Questions Answered:Q: If we have these genes, why don\u2019t our arms just grow back now?<\/p>\n
A: Humans have the \u201chardware\u201d (the SP genes), but our \u201csoftware\u201d turns them off shortly after birth (except in our fingertips). This research shows we might be able to use gene therapy to \u201cre-install\u201d the active version of the software used by salamanders.<\/p>\n
Q: How close are we to seeing this in human hospitals?<\/p>\n
A: This is \u201cfoundational\u201d research. It proves the concept works in mouse digits, but regrowing a full human arm, with its complex nerves, muscles, and blood vessels, is a much larger challenge that will require combining this gene therapy with other tech like bio-scaffolds.<\/p>\n
Q: Why was the zebrafish involved if they only regrow fins?<\/p>\n
A: Zebrafish have incredibly powerful \u201cenhancer\u201d sequences in their DNA, essentially high-voltage switches that turn on regeneration genes. The researchers used one of these zebrafish switches to make their gene therapy effective in mice.<\/p>\n
Editorial Notes:This article was edited by a Neuroscience News editor.Journal paper reviewed in full.Additional context added by our staff.About this genetics and limb regeneration research news<\/p>\n
Author:\u00a0Alicia Roberts<\/a>
Source:\u00a0Wake Forest University<\/a>
Contact:\u00a0Alicia Roberts \u2013 Wake Forest University
Image:\u00a0The image is credited to Neuroscience News<\/p>\n