When an axolotl—a small, wide-eyed salamander with feathery gills sprouting from its head—loses a limb, it doesn’t panic. It simply waits. In a matter of weeks, that missing arm or leg regrows, fully formed and fully functional, as if nothing ever happened. This natural superpower has long fascinated scientists who wonder, could humans ever do the same?
Now, a groundbreaking study published June 10th in Nature Communications brings us one step closer to understanding this biological magic and perhaps even replicating it. Researchers at Northeastern University in Boston have uncovered how these remarkable amphibians achieve their regenerative feats, revealing a delicate orchestration of enzymes, genes, and molecular signals that instruct their bodies precisely what to regrow and where.
At the heart of this process lies retinoic acid, a familiar molecule known to many as a common ingredient in skincare products. Retinoic acid also plays a critical role in development and cell differentiation across many species, including humans. But while its presence has long been noted, scientists hadn’t fully grasped how axolotls fine-tune their levels during regeneration until now.
James Monaghan, chair of biology at Northeastern and lead author of the study, has spent decades studying axolotl regeneration. “Salamanders have been famous for their ability to regenerate arms for centuries,” Monaghan told The Washington Post.
Initially skeptical that humans might ever unlock similar abilities, Monaghan’s recent findings have dramatically shifted his outlook.“The paper gives us insight into how a limb knows what to grow back, which was a mystery in the field for a long time,” Monaghan explained.
“Now we have the blueprint, and we have the genes to grow a limb. I could imagine for sure decades down the road having a patch on a wound that can program the cells that would normally make a scar into turning on the appropriate regeneration program.”
Retinoic acid essentially serves as a biological GPS, guiding cells to rebuild the proper structure in the correct place. Monaghan’s research uncovered that axolotls maintain a gradient of retinoic acid across their limbs. In areas like the shoulder, levels of retinoic acid are higher, while lower levels are found near the hand.
This gradient works in tandem with an enzyme called CYP26B1, which helps break down the molecule, fine-tuning its concentration. Fibroblast cells, the architects of regeneration, read these chemical cues to determine what to rebuild and how much to rebuild.
“The cells can interpret this cue to say, ‘I’m at the elbow, and then I’m going to grow back the hand’ or ‘I’m at the shoulder. I have high levels of retinoic acid, so I’m going to then enable those cells to grow back the entire limb.’”
To test the system’s flexibility, Monaghan conducted what he calls some “pretty Frankensteiny” experiments by artificially adding retinoic acid to an axolotl’s hand, triggering the growth of an extra limb. The results confirm just how central these chemical instructions are to the regeneration process.
According to Monaghan, the axolotls were sedated before the treatment, and their vitals were meticulously monitored. “Importantly, they don’t show signs of pain or distress after limb amputation the way mammals might, and they regenerate fully within weeks,” he said.
Yet the puzzle doesn’t end with retinoic acid. Understanding which genes are activated during regeneration is equally critical. Monaghan has zeroed in on one gene in particular, the short homeobox gene, or shox. This gene plays a vital role in determining limb length.
When retinoic acid signaling was elevated, shox activity increased. When Monaghan used CRISPR-Cas9 gene editing to knock out shox entirely, the axolotls grew severely shortened arms with normally sized hands, a phenomenon strikingly similar to what happens in humans with shox mutations.
“Evidence suggests it’s the access to the appropriate genes after an injury that enable them to regenerate an arm so they can turn on those programs that built the arm in the first place.”
Essentially, the axolotl’s body reactivates the same genetic programs it once used to build the limb during embryonic development.
This extraordinary ability doesn’t just apply to limbs. Axolotls can regenerate organs, tails, and even parts of their hearts and spines. Remarkably, they can also halt the aging process after approximately four years, maintaining their youthful appearance and regenerative abilities for most of their decade-long lives in captivity.
While axolotls are accomplishing these feats in labs around the world, humans remain frustratingly limited. Somewhere along the evolutionary journey, mammals lost the ability to regrow complex structures. Scientists believe this trade-off may have accompanied our shift toward more specialized and higher-functioning systems. However, a few remnants of these regenerative powers still linger, such as newborn babies who can regrow fingertips.
The tantalizing question that remains is whether we could someday coax our own cells to follow the axolotl’s lead? Researchers believe that with the rise of gene-editing technologies, such as CRISPR, and advances in stem cell manipulation, that future is not entirely out of reach.
“I could imagine for sure, decades down the road, having a patch on a wound that can program the cells that would normally make a scar into turning on the appropriate regeneration program. It could help with scar-free wound healing but also something even more ambitious, like growing back an entire finger. It’s not out of the realm [of possibility] to think that something larger could grow back like a hand.”
Thomas Rando, director of the Broad Stem Cell Research Center at UCLA, who was not involved in the study, shares this cautious optimism. “In mammals, we rely on skin stem cells to make skin, bone stem cells to make bone, and muscle stem cells to make muscle,” Rando told National Geographic. What we don’t know is how to make these cells produce multiple tissues simultaneously, the way a limb does. Studying amphibians like axolotls may help scientists crack that problem.
The implications of such breakthroughs extend far beyond simply regrowing lost limbs. Wound care remains one of modern medicine’s great frustrations. Sam Arbabi, a surgeon at the University of Washington who treats burn patients, sees enormous potential in this approach. “Understanding the mechanisms that regulate and control cell growth and differentiation is an important part of future wound care management,” he said, calling the current state of wound healing a “major disappointment in medicine.”
Should scientists eventually figure out how to replicate the axolotl’s regenerative precision in humans, the potential applications could span organ repair, heart and lung regeneration, and treatments for degenerative diseases.
Monaghan believes the difference between humans and axolotls isn’t a matter of lacking the necessary ingredients; it’s about unlocking access to the genetic instructions already within us. The genetic material is there in both cases, he believes. The difference is “simply the accessibility of the genes.”
“If we can find ways of making our fibroblasts listen to these regenerative cues, then they’ll do the rest. They know how to make a limb already because, just like the salamander, they made it during development.”
The axolotl has captivated the human imagination for centuries, even outside the laboratory. Named after the Aztec god Xolotl, these unusual creatures were once widespread in Mexico’s lakes but are now endangered in the wild. Yet they’ve become familiar to many as viral internet pets, plush toys, and video game characters, an odd fate for an animal that may one day unlock some of the most revolutionary advances in human medicine.
As science continues to decode the axolotl’s secrets, researchers hope that one day, the pink, wide-smiling amphibian may not just charm us with its unusual appearance but offer us a second chance at healing what was once thought to be permanently lost.
“This species is special. They’ve really become the champion of some extreme abilities that animals have.”
Moumita Basuroychowdhury is a Contributing Reporter at The National Digest. After earning an economics degree at Cornell University, she moved to NYC to pursue her MFA in creative writing. She enjoys reporting on science, business and culture news. You can reach her at moumita.b@thenationaldigest.com.
