Lessons from a salamander: how humans, too, might regrow lost limbs

by Marigo Farr
7/19/19 – BOSTON, MA. – James Monaghan, assistant professor in the College of Science, researches axolotl salamanders on July 19, 2019. Monaghan studies the salamanders in order to better understand complex tissue regeneration. Photo by Matthew Modoono/Northeastern University

They call her “Cinnamon,” a squirmy, slimy creature who’s been in a small tank in a windowless Northeastern laboratory for about a decade. She’s got rose-colored gills that fan in and out with each breath. Her face is reminiscent of a clumsy sketch made by an 8-year-old, with dots for eyes and a smile that takes up too much space. It’s hard to discern the logic behind her name.

But perhaps the name is as bizarre as the reason she’s in the lab in the first place.

“‘Well, what do we want to focus on, limb or tail?’” says James Monaghan, biology professor and director of the Chemical Imaging of Living Systems Institute, remembering the question his PhD advisor posed to him when he first started working with this almost mythical salamander species, the axolotl, at the University of Kentucky.

“Focus on” was a euphemism for what Monaghan and his lab would ultimately do in the name of science: amputate the arms of hundreds of axolotls.

Why would they do that to poor Cinnamon? Because the axolotl has a very rare superpower: It can regenerate its body parts after they are severed. We’re talking limbs, tails — even parts of the spinal cord. And humans, of course, can not.

“You and I make a limb when we develop, but we then turn off all the programs that were used to make that limb when we’re adults,” says Monaghan. When axolotls get injured, they don’t just close off the wound. “They then turn back on those pathways that were used in development.”

Because of this coveted trait, scientists have been obsessed with the axolotl, which comes from Mexico, for over 250 years. Monaghan’s contribution to the study of axolotls is creating visualizations of the biological phenomena behind the process of limb regeneration. He likes axolotls, but it’s not really about them. He hopes his work can lead to new ways of treating injury and disease in humans.

“I’ll freely admit, I wasn’t the kid that collected salamanders and lizards. But I was always really interested in puzzles and working with my hands and building 3D models,” says Monaghan.

Being good at puzzles is exactly what’s needed to crack the code on these creatures. First, it was a matter of mapping the entire genome of the axolotl, which was a major breakthrough in 2020 by a community of axolotl researchers.

Monaghan’s focus is isolating which of those genes are involved in regeneration and finding ways to “see” them turn on and off during the process of regeneration. It will help them answer the question: What genes are necessary for regeneration?

“We’re trying to visualize regeneration in real time and in 3D, so we look at the earliest events when an arm is regrowing,” says Monaghan. He notes that for a couple of centuries, scientists have been looking at tissues on slides. But it’s limiting, because you only get a snapshot in time and in space.

The first step is cutting off the finger of a roughly 1-inch long axolotl, and then looking at the amputated site under a microscope that is projected onto a screen.

“You’ll see it lights up like a Christmas tree when the cells are dividing,” says Monaghan, referring to the finger regrowing in real time, a process described in his team’s 2022 article in Development. “This is the first time anyone’s actually watched a regenerating appendage at this level of detail as it is happening.”

It’s not just some digital effect that makes the axolotl cells light up. These home-bred, genetically modified axolotls have a “fluorescent” protein that comes from jellyfish, zebrafish and coral. They even have part of a chicken gene.

Using the visualization, his team can see which part of the genome is “opening or closing during regeneration.” Over time, if they can understand the sequence of events that occurs when an injury happens, they can hopefully “recapitulate the system in mammals.”

Monaghan and his team have a grant through the National Institute of Health to understand how exactly the limb knows what parts to grow back, and they have identified promising genes involved in the process.

For example, if you amputate an axolotl limb at the humerus, somehow it knows to grow back the elbow, wrist and hand. The team figured out what genes are responsible for this somewhat by trial and error, taking a gene out and seeing what happened. Once the genes they suspected were responsible were removed, they noticed that the axolotls grew back truncated limbs, which is how healing happens in humans.

Now they know which genes make a complete regeneration possible. But translating this understanding into a reality for making human organ regeneration possible is a whole other step. Monaghan says the process is not about changing the sequence of human DNA.

“It’s changing the tags on the DNA that say, I’m available to turn on.”

His team, and the field in general, is hovering closely around the “how” of these processes. But Monaghan knows that the question on everyone’s mind is actually, when? Monaghan’s lab has active collaborations with researchers working with mice and human stem cells to translate their findings in axolotls to mammals.

“I don’t want to sound too optimistic, but 15 years down the road regenerating a digit is not out of the question.”

Story from the Science Media Lab.

Last Updated on July 1, 2024