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Humans Already Have the Ingredients to Regrow Limbs, Scientists Find
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Axolotls are known for their ability to grow back just about any body part that is bitten off by a predator, but the trigger for this regeneration was a mystery until now.
It turns out that retinoic acid and the enzyme CYP26B1 are heavily involved in regrowing missing limbs, determining what goes where before forming new tissue.
Future technology inspired by axolotls could possibly help humans regenerate limbs—we have what is needed, but need to find out how to make those pieces communicate like they do in axolotls.
In the 1995 cyberpunk film Virtuosity, the genes of android villain SID 6.7 are merged with snake DNA, giving him the superhuman ability to regrow lost limbs. Axolotls can do that without even trying—in fact, it is possible for an axolotl to lose virtually any body part (even its brain and internal organs) and fully regenerate it.
Mysteries surrounding these virally adorable amphibians' regenerative powers have fueled the sci-fi dreams (and frustrations) of scientists for almost two centuries, but not until recently did anyone understand the mechanism behind this ability. Now, molecular biologist James Monaghan of Northeastern University has made a breakthrough that has allowed us to identify the driving force of regeneration—and maybe, one day, we will be able to give this power to humans.
Positional memory means that an axolotl somehow knows if it needs to grow back a lost finger, hand, or entire arm. This was already known to be the basic mechanism behind vertebrate regeneration, but what Monaghan found was that it begins with retinoic acid and the enzyme CYP26B1. Neither of these chemicals are exclusive to axolotls—both are also found in the human body. It is just a matter of axolotls being able to use them differently. Larger limbs at proximal sites closer to the body, such as arms, contain more retinoic acid and less CYP26B1 (which breaks the retinoic acid down). And in smaller sites further from the body, like hands, there is less retinoic acid and more CYP26B1.
'Regenerating limbs retain their proximodistal (PD) positional identity following amputation. This positional identity is genetically encoded by PD patterning genes that instruct blastema cells to regenerate the appropriate PD limb segment,' Monaghan and his team said in a study recently published in the journal Nature Communications.
When a predator bites an arm (or anything else) off of an axolotl, retinoic acid is synthesized in the middle layer of skin and spreads to the limb bud. This helps generate fibroblasts, which are connective tissue cells in humans, but regenerative cells in these creatures. Fibroblasts form blastema, or limb progenitor cells, which then grow and differentiate to recreate the particular limb that is missing. Blastema mirror the behaviors of limb buds that grow as an embryo develops, and in both embryos and adult axolotls that have been injured, positional information is exchanged between stem cells in the blastema and other cells in this budding limb to ensure that the appropriate tissues regenerate where they are supposed to grow.
The gene Hoxa13 activates CYP26B1, which breaks down retinoic acid where it is not needed and uses it to create a pattern for the limb being regenerated. This breakdown determines how much retinoic acid is at an amputation site and, consequently, the position and structure of the limb which is regrown. Higher levels of retinoic acid activate the Shox gene—a transcription factor that both gives directions for producing a protein that regulates what other genes do and is involved with forming the skeleton.
As Monaghan found out, defects such as skeletal abnormalities can occur if this process is disrupted. Raising levels of retinoic acid in an axolotl's hand caused it to grow not just another hand, but a whole new arm. Eliminating Shox with CRISPR-Cas9 resulted in normal hands but short arms, with bones that did not harden properly. This also occurs in humans with Shox mutations.
What is especially amazing about axolotls is that they regenerate the limb in the exact same form it took before amputation. Some other animals that regenerate, like lizards, may grow back the end of a missing tail, but in a simpler form than the original. Much more research will be needed to transfer this ability to humans, but the materials are there. Healing wounds without scarring might even be possible in the near future. What we need to do next to make that future a reality is find out what happens inside blastema cells during regeneration, and which parts of these cells are targeted by retinoic acid.
'If we can find ways of making our fibroblasts listen to these regenerative cues, then they'll do the rest,' Monaghan said in a recent press release. 'They know how to make a limb already because, just like the salamander, they made it during development.'
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