Sounds like a rock group, but hellbenders are mute, cryptic, and uglier than any band! I imagine some American pioneer naming them after turning over a rock in a mountain stream and recoiling in horror at the sight of something looking like it crawled out of H***. But hellbenders are among nature’s innocents (despite their jaws) and, like the Elephant Man, they should draw our sympathy because we, too, would want to hide under a rock if we had the ugliest mugs in the world.

Credit: Pearson Scott Foresman (Public domain)

A hellbender’s body extends two to three feet behind its slimy head, sprouting two pairs of stumpy legs before reaching the tail. They live in rivers like the Greenbrier and Cheat in West Virginia that drain pristine water from the mountains and harbor the diet of crayfish (“crawdads”). Hellbenders are giant salamanders, and the Appalachian mountain chain is the redoubt of more of their species than anywhere else in the world, over seventy in all, mostly small, dainty, and colorful.

I have never found a Big Sal under a rock, but Nick and Tim grab one on their excursion to West Virginia in this video.  They are slippery characters that are best left alone like other protected species with dwindling numbers.

Elk River, WV. Hellbender homeland

Hellbenders like a quiet life, but their home stretches can quickly change temper after a storm, turning a gentle stream into a raging torrent that tosses slimy torsos against rocks, crushing and tearing their flesh. And yet deep skin wounds almost never go septic in salamanders because they evolved ways of repairing traumas and consequently live for 30 to 50 years, longer than almost every other animal in the forest except some large birds.

A family of small peptides called defensins help to protect them against infection by latching on before bacteria, fungi and viruses snuck into cells. We, too, have defensins for boosting our innate immunity by drinking our mother’s milk during the most vulnerable weeks of our young lives.

There are related peptides encoded in our genome, but they are shams because their pseudogenes have premature stop codons that produce truncated peptides that don’t work for us throughout life. Perhaps they were useful long ago, but we now depend on cells in the immune system to guard against microbes, and for the past eighty years have counted on the penicillin family when needed. I say “past” because overuse of these drugs is creating microbial resistance that could turn us back to the pre-antibiotic era. If defensins help to preserve salamanders in a turbulent environment perhaps we can synthesize analogous molecules as backups for penicillin.

These four-legged aquatic animals with a long tail look too alien to inform medical science, but their body plan and tissue architecture are not so foreign to our own. There is one huge, enviable difference. They have an amazing ability to regenerate amputated limbs that we lost way back in evolution along with the services of some defensins. If we could mimic their biology millions of patients could throw away prosthetic hands, arms and legs, and repair damaged internal organs by drawing on the regenerative potency that rests unbidden inside our bodies.

When part of a salamander’s body is lost a blastema forms at the site of injury containing stem cells and other cells that lose their specialized character as they ready themselves for a reconstruction job. Careful anatomical studies have shown that when limbs are regrown they become perfect copies of the originals. This process fails in us because of an absence of blastemas and scar tissue getting in the way.

But we are getting accustomed to surprises in biology, and there are grounds for hoping that the plasticity of cells can be harnessed one day for regenerating our bodies. If you see a salamander squatting in a glass tank in a lab you may think it is a scientist’s pet or a grotesque throw-back to the Cretaceous Era, but perhaps you are looking at the future, at something that will help to improve human lives, and revise your judgment of the beasts from Hell.

Next Post: Cover Crop and No Till

An Axolotl with a Tale for Regenerative Medicine

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?

Mexican axolotl
Axolotl by th1098 (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons
Axolotls are the kind of weird creature you might expect Alice to find in Wonderland. The first one I knew was an albino called Axel. It was a pet in an Edinburgh University aquarium belonging to a colleague who was an expert on the brains of octopuses (not octopi!). Although that was many years ago, I still remember how at the end of day he would wander into my office unannounced and bearing a plate of fried octopus legs leftover from his latest experiment. It was hard to look other octopuses in the eye when I visited his lab, so I hurried over to say hello to Axel, who always had a faint smile of Buddha-like intelligence curved over his chin.

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.

Lost a fingertip? Call an axolotl.
Lost a fingertip? Call an axolotl.

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.

Next Post: Artificial Gametes