Axolotls can regrow limbs. Could they one day help us do the same?
A better understanding of how these amphibians grow new appendages may lead to better wound healing—or even new limbs—in humans.
When a sharp shrub severs a salamander tail or it loses an arm in a predator fight, the animal sits back and waits. Within weeks, the missing body part regrows good as new.
For years scientists have wondered how these amphibians work this magic, and whether humans might one day follow suit. A study published June 10th in Nature Communications takes a giant step in understanding the phenomenon, detailing the biology by which axolotls regrow the exact missing limb in its proper place.
Retinoic acid, a substance also abundant in the human body—as well as in many skin creams—has long been known to be a major player. Now it’s clear that a particular enzyme (which humans have too) finely tunes levels of the retinoid at the animal’s wound site to ensure the correct part appears. At the same time, a gene controls the size of the appendage’s development.
“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,” says James Monaghan, chair of biology at Northeastern University in Boston and the study’s lead author. Monaghan has researched axolotl regeneration for several decades and says he was initially skeptical humans might ever achieve this. The latest science has made him a believer.
“Now we have the blueprint, and we have the genes to grow a limb,” he says. Today’s increasingly sophisticated gene-editing technology could direct those genes to turn on and off. “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.”
Although more work is needed, “understanding the mechanisms that regulate and control cell growth and differentiation is an important part of future wound care management,” says Sam Arbabi, a surgeon who works on burn patients at the University of Washington, who was not involved in the research but calls wound care today a “major disappointment in medicine.”
(These pioneering therapies are treating hard-to-heal wounds.)
Retinoic acid plays an important role
An axolotl (pronounced ak-so-la-tul, accent on the third syllable) is a youthful-looking pink salamander with external gills on its head that resemble a Troll doll’s hair. They’re named after the Aztec god of fire, Xolotl, and were once abundant in Mexico. They’re now endangered in the wild, even as they have become popular plush toys and video-game characters.
Captive-bred axolotls, which live a decade or longer, have become stars in dozens of laboratories around the globe for both their eternal youthfulness and their power to regenerate both their organs and their limbs.
(How axolotls stop aging after four years.)
A wounded axolotl can regenerate an entire lost leg or only its pinky toe. How the mass of cells that migrate to the wound site, known as a blastema, knows exactly what’s needed is a key question the new paper helps answer.
“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,” Monaghan says, referring to the gene Shox, which initially creates and then recreates the long bones needed to make an arm or leg.
Monaghan also found an enzyme called CYP26B1 reduces the amount of retinoic acid at the site to exactly the level needed for a particular body part. It’s the quantity of the retinoid that tells the cells what it is building, the researchers found. So the mass of cells capable of forming an entire arm has more than those making a hand or, at even lower amounts, a finger.
In humans as well as other animals, retinoic acid is integral to cell differentiation and growth. Its role in human development is so important that women are urged to avoid the oral acne retinoid medication isotretinoin during pregnancy so as not to interfere with natural levels—although recent research found no increased risk of birth defects or disabilities.
Rather than create the retinoic acid, the enzyme assesses current levels and reduces it to the desired amount. This was unexpected, Monaghan says, and crucial to understanding the process humans might one day use to regenerate limbs, too.
Could humans one day regrow missing limbs?
Somewhere back in our evolutionary tree, humans and other mammals lost the ability to regrow severed appendages, a trade-off that comes with our more complex, higher-functioning parts. (One exception: newborn babies can regrow fingertips.)
Scientists are hopeful these regenerative capacities remain hidden in our biology. If so, “we can learn to unlock them, potentially restoring greater regenerative potential than we currently see,” says Thomas Rando, director of the Broad Stem Cell Research Center at the University of California, Los Angeles, who was not involved in this study.
Rando believes even the manipulation of human stem cells he and others are studying may benefit from the axolotl research.
“In mammals, we rely on skin stem cells to make skin, bone stem cells to make bone, and muscle stem cells to make muscle,” he says. What isn’t known is how to make these cells produce multiple tissues at once, which is necessary to regenerate a functioning limb. Learning how amphibians successfully do this could yield treatments that entice stem cells to mimic those actions.
(The ability to reverse damage to your lungs and heart is tantalizingly close.)
Monaghan hopes for an even more direct application, with people ultimately regenerating limbs similar to the way his beloved amphibian does.
After all, he notes, it’s now clear that both have all the genetic material involved in the process. The difference is “simply the accessibility of the genes.”
