The recipe of the axolots
Text by: Alejandra Ortiz
When the sun and the moon ceased to move and the fate of the world was in jeopardy, the gods decided to offer themselves in sacrifice. This marked the beginning of the fifth sun. But a cowardly god cheated death and tried to elude his destiny. Xólotl, Quetzalcóatl’s twin brother fled his executioner, turning into a corn plant at first, then into a maguey leaf, and finally into an aquatic monster, which is the form he was found in and sacrificed. This last form – the god of bad luck – is that of the axolotl, which preserves the power of transformation to escape death based on the Aztec myth.
There are 17 species of the genus Ambystoma in Mexico; mole salamanders are endemic to North America. Many of these species are neotenic, namely, they reach sexual maturity at a nymph stage and can maintain this state their whole life, endowing them with their peculiar aspect of external gills and tadpole tail. This developmental arrest has been widely studied and might be one of the characteristics that the axolotl is best known for. However, the Ambystoma mexicanum has a trait that stands out even more than perpetual adolescence: its regenerative capacity.
All animals possess a certain regenerative capacity. Healing is an example. Urodela, which are amphibians from the group of the axolotl, can regenerate entire structures such as the tail, jaw, skin, limbs, including the spine, as many times as necessary. In addition, this regeneration leaves no scar: tissue regenerates perfectly. This incredible regenerative power does not include any ingredient that humans do not have; the genes, proteins and tissues involved are present not only in humans, but in all mammals. What changes is the formula.
When the axolotl looses a limb, the surviving cells begin a process of dedifferentiation, they return to a previous state where their cellular identity (be it an Epithelium, muscular, or bone cell, among others) is not yet completely defined. The least differentiated cells in nature are stem cells, which have the potential to turn into any type of cell. Until recently, it was believed that the axolotls had the capacity to create stem cells at any moment and place in time, and that because of this, they could regenerate tissue. Now we know that the dedifferentiation of cells during the regeneration of this animal is not that extreme; instead the surviving cells preserve a certain memory of their past, based on which they build the new tissue. For example, skin cells can produce cartilage and tendons but not muscle.
A blastema is a mass of cells capable of regenerating new limbs; it is not only present in axolotls, but in all vertebrates. The difference lies in the moment when the blastemas are formed: in humans and all mammals, it occurs during the embryonic development. In axolotls, blastemas are formed every time an amputation occurs, which implies cellular reprogramming where, although it does not return to a state of stem cells, it goes back a few steps in cellular differentiation. The mechanics of what buttons are activated and what ones are turned off for this to occur, remains a mystery. However, certain indications exist that suggest what processes and molecules are associated to the regeneration. Once again, they’re not composed of a new ingredient.
When we get hurt, an immune response is activated to repair the wound. After two to four days, macrophages, which are specialized cells in charge of engulfing pathogenes or any other infectious particles, then cause swelling by secreting molecules to fight the infection, and finally generate anti-inflammatory signals to initiate tissue repair. As a result of this last stage, the wounded tissue is replaced by fibrous tissue, leaving a scar.
In axolotls, the new tissue is identical to the previous one; therefore there is no scar. Macrophages appear in the animals’ wound in less than 24 hours, and the anti-inflammatory response, which is a sign of recovery in mammals, occurs simultaneously. If macrophages are removed experimentally, the regeneration of the axolotls stops and they scar just as we do. In addition, the lack of macrophages prevents the activation of the TGF-β1 protein (transforming growth factor beta), which in axolotls has been observed to increase their activity during the formation of blastema. In humans, TGF-β1 is associated with cellular proliferation and differentiation, playing and important role in the immune response and cancer.
Just like the Xólotl god, humans seek to find a way to transform themselves into axolotls and escape their own destiny, creating therapies that allow for better scarring, for the formation of new tissues, organs and limbs. There is even talk of finding a cure for cancer through the study of axolotls. In spite of this potential, the Ambystoma mexicanum is an endangered species, due primarily to the loss of its habitat and the introduction of tilapias (a species of fish) in Xochimilco that compete against them for the same resources. Axolotls used for biomedical research are bred in captivity; if environmental decay continues in the future, it is most likely to be the only place where these animals will be found.
We share the ingredients and tools that allow for an extraordinary regenerative capacity with these amphibians. Will it be possible one day to find their formula? Xólotl’s death did not restore the movement of the stars. We can learn many things from the axolotls and surely new therapies will emerge from their research; however, I believe that their regenerative power will remain a unique quality to their specie.