In a study published in the journal Nature Communications yesterday, scientists used axolotls genetically engineered to glow in the dark to understand the molecular underpinnings of this amazing trait.
“This species is special,” said James Monaghan, a Northeastern University biologist who led the research. They’ve “really become the champion of some extreme abilities that animals have”.
Although critically endangered in the wild in Mexico, axolotls have been kept and studied in labs since the 19th century.
They are known for being, naturally, forever young.
Unlike other amphibians, such as frogs, axolotls never go through full metamorphosis, instead retaining into adulthood certain juvenile characteristics such as external gills and webbed feet that make them look so weirdly cute to their human admirers.
The species is also a comeback king, able to regrow not only lost limbs but also tissue in the heart, lungs, and even the brain.
One marvel is that to enable a body part to grow back, the cells responsible for that growth need to somehow register where they are on the body.
If an amputation is at the upper arm, for example, they have to re-create the upper arm, then the lower arm and, finally, the hand.
But if it’s at the lower arm, the cells have to know to grow back just the lower arm and hand.
“Salamanders have been famous for their ability to regenerate arms for centuries,” Monaghan said.
“One of the outstanding questions that has really plagued the field is how a salamander knows what to grow back.”
For their study, Monaghan and his colleagues investigated a tiny molecule called retinoic acid that seems to be responsible for this careful choreography.
A derivative of vitamin A, it is known for its regenerative ability and is related to retinol found in skin-care products.
“Anyone that watches TV for 30 minutes watches a skin commercial with retinol,” Monaghan said.
His team worked with axolotls that had been genetically engineered so that their tissue glows in the presence of the acid, allowing real-time tracking.
Then, in the name of vitally important science, the researchers did something that might strike some axolotl fans as shocking: They severed axolotl arms.
Monaghan said his team anesthetised the axolotls before the procedure and closely monitored their health.
“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.
When given a drug that blocks an enzyme responsible for breaking down retinoic acid, the axolotls regrew their missing limbs incorrectly, with an upper arm sprouting out where a forearm should be. A control group of animals that did not receive the drug regenerated normally.
The work suggests that retinoic acid acts like a GPS device, helping cells to determine their location: the higher the concentration of the acid, the closer to the centre of the body.
The chemical appears to activate a gene or genes within the cells to regulate limb growth.
“While we are still far from regenerating human limbs, this study is a step in that direction,” said Prayag Murawala, an assistant professor at MDI Biological Laboratory in Maine.
His lab helped Monaghan produce the genetically engineered animals used in the study, but was otherwise not involved in the research.
“Better understanding of gene regulatory circuit is essential if we have to re-create this in humans,” Murawala said.
When it comes to human limb regeneration, Monaghan noted that every cell already contains in its DNA the blueprints to rebuild body parts.
“We all have the same genes,” he said. “We’ve all made these limbs when we were embryos.”
The question now is figuring out the right chemical signals to unlock those early developmental instructions in humans after birth, as axolotls are able to do.
“It’s one of the oldest questions in biology, but it’s also the most futuristic-looking,” he said.
When Monaghan began his research two decades ago, “most people didn’t know what an axolotl was”.
But for the past decade, the animal has been an obsession for kids, boosted in popularity after debuting in the video game Minecraft in 2021.
“It’s a little surreal,” he said. “You just see axolotls at the airport, axolotls at the mall. My kids are coming home with axolotl toys all the time, because people know what I do.”
