Regeneration Makes Scientists Ax-a-lotl Questions

Understanding the Miracle of Salamander Limb Regeneration

Reptiles and amphibians are famed for their bizarre abilities to regrow lost tails. Although not all species are capable of regeneration, the creatures that can effectively provide their own medical attention have caused a lot of head scratches in scientist circles for centuries. One unassuming salamander is at the root of this complex scientific phenomena.

Axolotl (Ambystoma mexicanum)

Believe it or not, the name ‘axolotl’ is possibly the least strange thing about this animal. Living in a perpetual stage of adolescence known as neoteny, the axolotl reaches sexual maturity before metamorphosis. The axolotl also possesses the power to regenerate a scary array of body parts including its jaw, spinal cord, skin and much more. This regeneration process happens extremely quickly, placing the axolotl at the centre of much Aztec mythology. In fact, the word ‘Axolotl’ comes from ‘Atl’ meaning water and ‘Xolotl’ which was an Aztec deity that assumed the appearance of a dog. The axolotl can only be found in lakes and rivers in Xochimilco and is very likely extinct in the wild, as numbers of this species decimated very quickly with only a handful of live animals being recorded in recent years.

Their regenerative abilities have been known for over 200 years now and yet there is still much mystery surrounding this process. One thing is certain, the axolotls regenerated limbs are perfect. This is practically unheard of, where no scarring or morphological difference appears at all. In a 2006 paper written by Stéphane Roy et al, she states “The vast majority of vertebrates including mammals, birds, anuran amphibians, and reptiles are incapable of regenerating complex structures such as limbs. Thus, scarring or fibrosis seems to be a universal response in dealing with wounds that span the three layers of the skin in vertebrates. Even the sea cucumber, which has the amazing capacity to regenerate a large portion of its viscera, is incapable of healing its skin wounds perfectly.”

In fact, it is the medical potential of the axolotl that caused the species to be such a common sight in pet shops across the world. Bred initially for science purposes, their ease to keep and willingness to breed meant that they quickly become popular, requiring a similar level of care to a conventional goldfish. In fact, in Japan, axolotls are bred so prolifically that some restaurants serve them as food.

Keeping an axolotl

For such an incredible animal with a complex natural history, axolotls can be found in pet shops across the world. Their care is extremely simple, and they make very interesting alternatives to a goldfish. Providing a 60x45x45cm tank with a suitable filter filled part-way with room temperature water, fine grain sand and large rocks will house an axolotl comfortably for its entire life. Lighting should be kept minimal, as these animals live in murky water. Feeding bloodworms, lob worms and the occasional de-frosted shrimp a few times a week will ensure a healthy and happy animal. Beyond this, there is very little care involved in looking after an axolotl. As they are voracious feeders, ensure that the axolotl is housed on its own or with the same species of the same size as tank mates will likely be eaten immediately.

How axolotl regeneration works

When an axolotl loses a limb, the surviving cells go through a complex process of rebuilding. After the trauma, the axolotl’s cells will cover the amputation to stop bleeding etc forming a cover which is referred to as a ‘wound epidermis’. As these cells continue to divide and multiply, the amputated limb grows a ‘blastema’ which appears as an extended stump from the wound site. The cells that make up this stump (blastema) are thought to be bone, muscle and cartilage cells that have lost their identity to appear similar to stem cells, which can typically become any cell. Unlike stem cells, blastema cells must retain their original identity. For example, a blastema cell that was previously a bone cell can only become bone matter. Eventually as these cells continue to multiply, the blastema begins to form a perfect replica of the original limb, including connections to nerves and blood vessels.

What does this mean to us?

Mammals do not have the ability to regenerate limbs and organs. Instead, we scar and heal. These are two very distinct processes, but scientists believe there is much potential in understanding the relationship between the two. By identifying the key differences between our healing process and that of the axolotl, scientists could potentially discover a breakthrough that could change the lives of millions of people across the globe.

In 2006, Stéphane Roy wrote: “Genomic studies have consistently shown that developmentally important genes are strongly conserved across vast evolutionary distances. Much of what we know of vertebrate development and molecular genetics has been derived from studies on Drosophila and other invertebrates. Interestingly, parallels between tissue repair in Drosophila and mammals have led others to state that the fruit fly embryo is as good a model for wound healing as the mammalian embryo. Therefore, it is not unreasonable to expect that the same genes involved in the limb regeneration of amphibians are conserved in humans, though their activity may be either suppressed or neutralized by inhibitory factors in humans or enhanced in amphibians.”

Since then, we have come much further in identifying what some of these inhibitory factors are. Garrett Dunlap graduated from the Biological and Biomedical Sciences Ph.D. program at Harvard University in 2019 after conducting an independent research project on limb regeneration in axolotls. He writes: “the immune system was found to be an important player in the limb regeneration process. Injecting a drug to get rid of macrophages in an axolotl’s limb before amputation leads to the accumulation of scar tissue instead of regrowth. This scarring, which happens when a protein called collagen becomes disordered, is a normal part of wound healing in humans, but it is unusual in axolotls. This result suggests that macrophages may be essential for regeneration. Tweaking the nervous system has also been shown to interfere with regeneration. Scientists have observed that surgically removing a limb’s nerves prior to amputation can hinder regeneration, though work is still being completed to better understand why this happens.”

To most of us, this will not mean much. However, a greater understanding of what causes and promotes regeneration in salamanders creates a lot of potential for future medical endeavours. In a more accessible blog post on The Harvard University website, Garrett writes: “Aided by tools that allow scientists to see the fine genetic details of the regeneration process, we are slowly inching closer to understanding what makes regeneration tick. To test this, scientists are working diligently to develop new tools that will allow them to identify other targets and begin transferring these insights to mammals like mice, meaning that perhaps one day, the millions living with lost limbs will have a new avenue for treatment: regeneration.”

Breaking the mould

Axolotls are close relatives of the tiger salamanders of North America. As such, it is possible, in very rare instances, for the axolotl to metamorphose into a terrestrial salamander. Cases of this happening have almost always been a result of science experiments involving hormone injections, but that is not to say that there have not been some naturally occurring phenomena cases.

Axolotls which metamorphose before they reach sexual maturity can develop relatively successfully. They will have a much shorter life expectancy than those that do not metamorphose but can usually feed and survive. Axolotls that are forced into metamorphosis after they have reached sexual maturity will almost always die within the space of a year. This is usually due to hormone imbalances or because they will go off their appetite entirely.

Cultural significance

Already famed for its neoteny, the axolotl has been under the microscope of key thinkers for centuries. When Julian Huxley found he could prompt an axolotl to metamorphose by feeding it sheep thyroid in 1920, it was reported he had discovered ‘The Elixr of Life’. This had a great cultural impact as it prompted his brother, the celebrated author and philosopher Aldous Huxley, to treat the axolotl as a metaphor for mankind. Much of his seminal literature became ‘neoteny-boosters’, prompting future philosophers to focus on the idea of retaining a perpetual youth.  This shift in philosophical thinking has created ripples affecting the society we live in today.

The fact an unassuming, baby salamander with a comedic grin has had such a large impact on cultures from Mayan civilizations to modern societies is truly impressive. The axolotl also potentially holds the key to major breakthroughs in medicine which could change the evolutionary path of mankind. Rarely displayed in zoos and frequently overlooked in pet shops, the axolotl serves as a reminder that even the most basic animals to care for can often be the most impactful.

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