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Salamanders can regrow their limbs, and so could we one day?
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Losing a limb is a tragic event for any human being, but it's no news that salamanders couldn't care less if the same thing happens to them. They have the ability to regenerate fully functional new ones - so why couldn't we learn from them and do the same?

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Recent studies have shed a new light on the regeneration mechanism that these reptiles are gifted with, offering a glimpse of hope that one day our own cells and tissues could be reprogrammed to do the same.
          Starfish, lobsters, earthworms or even snails are some of the creatures that show extremely powerful regenerative abilities, being able to grow back their own missing limb, or even organ. Some mammals, like two spiny mice species from Africa, are also equipped with regenerative abilities, although to a lesser extent – they can regrow fur, cartilage or sweat glands. So why can’t humans grow a new heart, or kidney, or even an arm? This mystery has been puzzling scientists for years, since solving it could hold the key to massive developments in the treatment of patients with amputated limbs, or even in the case of internal organs damage.

         Humans do have their own regenerative abilities in fact, but not on the same level. Compared to salamanders, we are quite limited beginners, in fact. Our bodies can in fact reconstruct themselves, but only on a cellular level. Our organisms have the power to fix damage to some extent, and this is the reason why wounds heal – a survival mechanism that we shouldn’t underestimate. Growing back a lost limb is out of the question, but an article published in Nature in 2013  showed evidence that sometimes children can regain a lost fingertip, and adult bodies have the capacity to rebuild a damaged portion of the liver.


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         Before birth, humans are built bit by bit in the mother’s womb. The mechanism of this gradual development lies in embryonic stem cells, which are able to differentiate into numerous types of specialized cells , from neurons, muscle cells and blood cells to skin cells and light-sensitive receptors in the retina, and then divide into millions. At birth, these cells are replaced with adult stem cells, which, much to the scientists’ frustration, lose most of their ability to divide and regrow. They do have some regenerative abilities, such as helping skin tissue “fill up” wounds with new layers, growing scar tissue to close them. Stem cells in bone marrow can also produce new blood cells. But this is quite modest if we compare ourselves to the salamanders.
          The reason why salamanders and other lucky creatures can regenerate complex structures like parts of their eyes, hearts, tails or even spinal cords lies precisely in these stem cells. Unlike human stem cells, those of salamanders maintain their regenerative abilities throughout the entire life cycle. When, for example, a salamander loses its leg, stem cells are triggered into forming a blastema – a fast-growing mass of initially undifferentiated cells that later differentiate into specific cells needed to create the structure of the missing limb.

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         James Goodwin, of the Australian Regenerative Medicine Institute (ARMI) at Monash University in Melbourne, studied the aquatic salamander axolotl, or Ambystoma mexicanum, and investigated the regeneration mechanism on a cellular level. "We need to know exactly what salamanders do and how they do it well, so we can reverse-engineer that into human therapies", the researcher stated. Results of the study showed that macrophages, a type of immune cells, are crucial to the early stages of limb regeneration, and removing them made the process impossible, leading to scarring. This could lead to new, innovative ways to deal with scar tissue in humans. In mammals, the same type of cells also play an important role when the immune system responds to injury. It takes two to four days for macrophages to arrive at the wound, where they proceed to digest infectious particles, bacteria and pathogens. They are also responsible of generating the inflammatory/anti-inflammatory signals of healing. Yet they have a long way ahead before they could show the same capacities that the salamanders’ macrophages have.

         Godwin and his team discovered that only one day after the amputation, salamander wound areas showed both inflammatory and anti-inflammatory signs at the same time, whereas in mammals, the anti-inflammatory signals would normally arrive only later in a healing wound. A large number of macrophages were detected in the area for four to six days after the injury. To show their essential role in the limb rebuilding process, researchers injected a chemical to partially or fully annihilate the macrophages, so that they can study how regeneration will go in their absence. Results were impressive – with all their macrophages removed, salamanders were no longer capable of regenerating a limb at all. Those that only had some of their macrophages removed still managed to regenerate their limbs, but at a much slower pace. Once salamanders “refilled” their macrophage supplies, researchers once again amputated the same limbs, or their stubs. Remarkably, salamanders then fully regenerated their lost limbs at a normal rate. Conclusions were obvious – the immune cells are the true wonder behind these creature’s self-healing superpowers, playing an essential part in this unique biological process. As researcher Godwin says, tissue regeneration capabilities have been basically turned off in many creatures as a normal part of evolution, but there is a chance the process could be reactivated, opening new doors for potential future treatments of heart or liver disease, post-surgery recovery or even scarring prevention.
         Salamanders are the only adult vertebrates that have the capacityy to regenerate full limbs, and their re-growing abilities are almost limitless. They can regrow not only limbs, but almost any other component of their body. Moreover, the process works perfectly at any age, as they can regenerate fully functional limbs in their old days just as easily as in their youth. And a more recent study digs even deeper, analyzing the precise proteins that cause this almost miraculous regrowth to happen on a molecular level.

          Lead by Dr Max Yun from the University College London (UCL)’s Institute of Structural and Molecular Biology, the study focused on the red-spotted newt, or Notophthalmus viridescens. The team identified a biological pathway that must be constantly active in salamanders for muscle cells regeneration to be possible, and this process never occurs in the same way in mammals. This molecular pathway is called ERK, or MAPK/ERK, which stands for mitogen-activated protein kinases, or extracellular signal-regulated kinases. The ERK is a protein chain within a cell, and its function is to communicate a signal from the receptor on the cell surface to the DNA in its nucleus. As the signaling molecule binds to the receptor, it triggers the chain, ending with the DNA releasing a protein and producing a change in the cell. One of such changes is cell division, and this is where things get really interesting. While mutations in this protein chain is often an early step in the development of many types of cancer, leading to uncontrolled cell growth, this is also the biological basis that allows salamanders to regrow their lost limbs, tails, eyes or even internal organs so easily.

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         As the UCL study revealed, the ERK pathway is not fully active in the cells of adult mammals. Comparing salamander and mammalian muscle cells, researchers found that cells of mammals can activate the ERK pathway to some extent, but fail to keep it “on”. However, in a salamander missing a limb, this pathway is “switched on” permanently until the new tissue has formed, and this protein determines adult stem cells in the stump to reestablish their growth cycle and proliferate, then differentiate in order to replace the missing tissue. “Manipulating this mechanism could contribute to therapies directed at enhancing regenerative potential of human cells”, says lead scientist Yun. The UCL team used a piece of DNA to force mammalian cells to produce a protein that keeps the pathway activated, and discovered that this sustained artificial activation can aid cells in developing a much stronger regeneration and reprogramming potential. However, this process depends on different adult cells’ ability to lose their natural identity and undergo reprogramming and reassignment.
         This may be a happy end, but it is not the finish line for the UCL team, as they already plan further research focusing on the regulation of this important pathway during limb regeneration, and on identifying other molecules that play key roles in the process.


While these fascinating findings provide key information on why only a limited number of creatures are lucky enough to have regenerative abilities, they also offer a massive development, bringing medicine a step closer to therapies that can push human regeneration further. There is still a long road ahead, but with the help of new DNA or molecules that can stimulate this crucial pathway, human bodies might just have a chance at learning how to rebuild lost complex structures.



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Published by Andreea Dobre


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