Who would imagine that a salamander could offer clues for regenerating human limbs after amputation in an accident and on the battlefield, or even show how to thwart human cancer?
Adult axolotls grow a foot long from nose to tail. They look like giant tadpoles still sprouting the same gills they acquired in youth, like bunches of ornaments growing out of their necks for breathing in water. Once met, they are never forgotten, except perhaps when you have to spell their name, which the poet David McCord made fun of in nonsense verse. Ozelotl. Axelbottl. Ottalottal.
Biologists call them neotenous because they become sexually mature without ever undergoing metamorphosis like other amphibians. It is very rare in animals, but Axel was rarer still because he was a perversion of his kind. He was a fully-actualized axolotl, which greatly added to my fascination.
Instead of breathing through gills like a fish, Axel sucked air into his lungs like a frog, and like us. And, thus, he was no longer confined to life underwater and could climb out onto rocks to warm in the “sunshine” of a lamp under the aquarium roof. He looked like a living fossil, a relic of the first land animals in the Devonian Period.
Axel was no mutant, only the subject of a scientist’s curiosity. He arrived in the lab looking like others of his tribe, but my colleague gave him a shot of thyroid hormone which dramatically replaced his gills with a pair of lungs. It is an evolutionary enigma why axolotls don’t undergo normal metamorphosis in the wild, unless it was an adaptation to a low iodide diet in Mexican mountain lakes. Flicking the metamorphic switch with a hormone is, however, the least amazing fact of their biology. The best trick up their sleeve is regenerating a perfect limb or tail after one is amputated. They can even repair a damaged spinal cord, and the renewed organs seem biologically younger than the rest of the body. Such facts deserve serious research attention.
If my leg is cut off at the knee I don’t expect the stump to regrow bones, muscle and skin so I can walk unaided again. The ability to regenerate organs and tissues was almost completely lost long before our kind evolved. I say almost because skin wounds in human fetuses early in pregnancy are perfectly repaired without scars, and a child who loses the tip of her finger may see it regrow if some of the nail bed remains, with help from local stem cells and nerves. Of course, our deep skin wounds can be repaired after birth, albeit with scarring, but even this capacity weakens with age.
Axolotls have none of our limitations. When one of their limbs is amputated, fibroblast cells in local connective tissues turn back to a more primitive and potent stage. These stem cells multiply to create a bulge or “blastema,” the foundation of a limb bud that forms a fully-functional limb with digits. How come?
The mechanism that was active at embryonic stages for instructing cells to make a limb is switched on again. Early in the process, a family of proteins called “Wnts” activate “Frizzled” receptors which pass on the signal to “Disheveled” proteins inside cells for changing their behavior. The growth factor families FGF and TGF-beta telegraph between cells to mold the changes. I won’t test your patience with cell biology any further, except to say the most important takeaway message is that all these players still exist in humans. If only we could get our hands on the molecular levers!
As usual in science, there are more questions than answers. Two that I find particularly intriguing are why axolotls are resistant to cancer and how they avoid creating tumors when they are regenerating tissues? It seems paradoxical because we expect vigorous cell growth in response to embryonic-like signals would make them more vulnerable to runaway cell proliferation. The signals are remarkably similar in embryonic and cancer cells, and injury that repeatedly stimulates cell proliferation raises our cancer risk. There is also the related puzzle that chemicals known to trigger tumor formation in humans don’t affect axolotls—except occasionally to cause an ectopic limb to form at the site of injection. We might envy their tolerance of chemical hazards, but not at the price of generating a superfluous limb or tail!
When the tale of the axolotl is unraveled there will be lessons for regenerative medicine and repelling cancer—although I wonder what trade-offs will have to be navigated if we try to tinker with ancient, tightly-regulated cell signals. But at least we can answer whether Axel had lost the privileges of regeneration after he metamorphosed. It is reasonable to guess that regeneration is tied to the “embryonic” stage that normal axolotls remain in throughout life, and, moreover, that it can never be recovered in humans after birth. But Axel never lost that power, and although the mystery deepens the fact may timidly hold hope for us.
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