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Published On August 6, 2021

BASIC RESEARCH

The Search for a Regeneration Switch

Can studying salamanders and spiny mice help humans grow new limbs? Answer: It’s complicated.

An axolotl is hard to call cute, exactly. Paired off in rows of numbered tanks in a Harvard lab, the pale salamanders look out with pinprick eyes, and feathery red gills wave at each end of their wide smiles. Their primary appeal to scientists such as Jessica Whited, an assistant professor with the Harvard Stem Cell Institute, is their shocking ability to regrow not only severed limbs but also to repair damaged internal organs such as the heart, lungs and ovaries.

That ability is shared by a handful of other species, and it is Whited’s very long-term goal to help humans grow new limbs, too. In the nearer term, she hopes that a better understanding of regeneration in the axolotl might lead to a fresh look at human injuries and diseases, and at how medicine might nudge or amplify self-healing processes in people.

“I don't like to talk about these animals having a special regenerative ‘capacity,’” says Whited. “That suggests humans don't have the capacity to regenerate limbs—and I think humans do. It's just that our cells need special instructions and the right environment to do it.”

Whited is far from the only person whose research focuses on the regenerative abilities of salamanders, which have been studied since the late 1700s. In recent decades, scientists like her have made considerable advances in identifying cell types, biological factors and signaling pathways that are necessary for regeneration. They have also clarified key steps in the initial formation at a wound site of a “blastema,” a mass of adult stem cells specific to the tissues that need to be regrown.

Over the past decade, with the increasing accessibility of sequencing technology, regeneration research has largely turned to identifying sections of DNA that are activated through the various stages of regeneration. The axolotl genome, first sequenced by European scientists in 2018, turns out to be huge, made up of 32 billion nucleotide base pairs, compared to 3 billion or so in humans. Finding a human “key” to regeneration would depend, in part, on whether axolotls and humans share common regeneration genes. If they do, the next step would be to figure out how to activate the version that humans have. But even if regeneration genes aren’t present in the human genome, says Whited, it might still be possible to identify proteins created by axolotl genes and see whether they could be introduced to an existing biochemical pathway in the human body.

In a September 2020 paper in Science, Alejandro Sánchez Alvarado and colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri, were able to pinpoint one possible regeneration regulator. Inhibin beta A is active during the regeneration of fin and heart tissue in zebrafish and killifish. The scientists also found a non-coding stretch of DNA called an enhancer sequence that influences the gene’s activity. Deleting the sequence, or replacing it with a human version, hindered fin and heart regeneration.

Sánchez Alvarado found that inhibin beta A was also active during regeneration of ear tissue in the African spiny mouse. A rare mammal with regenerative abilities, this gerbil relative can completely regenerate skin, cartilage, hair follicles and fur after a hole is punched out of its ear, creating a seamless “patch.” It can also rapidly regrow skeletal muscle, restore function to damaged organs such as the liver and shows minimal scarring after spinal injury. (None of this is true for its relative Mus musculus, the common lab mouse.)

Other work with adult spiny mice appears to show an uncanny ability for cardiac repair. In a recent preprint on bioRxiv that is currently under revision for publication, researchers found that after an induced heart attack, the animals rapidly developed new blood vessels, which preserved heart muscle and stabilized heart function. Ashley Seifert, an associate professor of cell and developmental biology at University of Kentucky is part of a collaborative team that led that research. He says that the next step is to figure out what’s missing in Mus musculus, which has been exhaustively studied and shares 85% of its coding DNA with humans. “Studying regeneration in a mammalian system will, we hope, offer special insight into problems that we have in human injury and self-repair,” Seifert says.

While the discoveries of regeneration genes shared by warm- and cold-blooded animals has stirred a flurry of interest, the field is “still squarely in basic science mode,” Whited says. But even short of regrowing whole limbs, there could be practical applications in humans.  Whited’s lab, for instance,  is focused on brachial plexus injuries—in which large nerves that run from the neck area to the arms are damaged, through traumatic injury or to a newborn during childbirth, often resulting in lifelong limb impairments. “Even though humans can regrow the peripheral nervous system to some extent, that regrowth usually isn’t perfect, and becomes less so as you get older,” Whited says. “There can be a benefit in knowing how salamanders so successfully develop peripheral nerves.”

Findings from axolotl, spiny mice and other species could also inform new approaches to scar-free healing, perhaps through novel topical treatments. There could be other translational benefits from studying axolotls’ “wound epidermis,” a special kind of skin that covers the wound surface at the start of regeneration. “When axolotls lose a leg, they’re still swimming around in the water that they’re eating and going to the bathroom in, and they don’t get infected,” Whited says. “There are all kinds of antimicrobials ripe for the picking that no one has really characterized.”

Another question is how the cells of regenerating species can aggressively grow and proliferate without damaging DNA. Human stem cells cultured in vitro can experience chromosomal rearrangements and other damage, which renders them useless. The question is also relevant in studying cancer, in which cellular proliferation runs amok. In a 2020 paper, Whited’s lab identified a specific DNA damage response pathway that is activated following limb amputation in axolotls. Her team concluded that such a mechanism is required for successful regeneration.

Although final answers to many of these questions may be far off—and the frontier of human limb regeneration more distant still—current discoveries have ensured that Whited’s and Seifert’s labs, among others, will continue to study the self-healing abilities of the axolotl and the spiny mouse. “These and other model organisms have been great at advancing our understanding of regeneration,” says Seifert.