Gardiner has studied salamander regeneration for decades, seeking the underlying mechanism of the superpower. Human regeneration, he said, is likely still in the future, but not too far off — it’s possible one of his current graduate students or postdoctoral researchers will crack it, and limb regeneration will be a part of the medical toolkit.
That’s because, in theory, regrowing a human limb should be possible. In skin, for instance, if the cuts aren’t deep, there will be no scarring due to the healing process that regenerates skin cells. It’s also possible for humans to regenerate the very tips of the fingers if the cells under the fingernails are still intact. Bones will knit together if you rejoin the pieces, say, with a screw or a cast. Human livers can also grow to fill the space and rebuild some of the structure that was damaged.
Growing an entire limb
But limb regeneration (of the kind salamanders do) is more than just replacing tissue. For a limb to regenerate, you need bone, muscle, blood vessels and nerves. There are adult stem cells, a kind of undifferentiated cell that can become specialized, that regenerate muscle, but they don’t seem to activate. “You can regenerate blood vessels and even nerves,” Gardiner said. “But the whole arm can’t [regrow].”
Stéphane Roy, director of the laboratory for tissue regeneration in vertebrates at the University of Montreal, noted that skin, liver and bone don’t regenerate in the same sense that salamanders do it.
“Humans can only replace the superficial layer of skin, (which is, in fact, a continuous process referred to as homeostasis),” he said in an email. “Most of the dust in a house is dead skin cells that we lost.”
“Liver is also quite different than limb regeneration in salamanders,” Roy said. “Liver regeneration is really compensatory hyperplasia, which means that what is left will grow in size to compensate for what is lost.” So the liver tissue that is there will grow larger, but if the entire liver were lost, it couldn’t regenerate.
“What has been lost will not regrow, and hence you cannot re-amputate the liver, as opposed to limbs in a salamander, which can be amputated multiple times and each time a new limb will regenerate.”
Humans have the ability to regenerate
Gardiner, however, said humans build entire organ systems in the womb; from just some genetic information a human embryo develops into a complete person in nine months. So there is a limited ability to regrow things, and that makes evolutionary sense — humans have to be able to heal, he said.
On top of that, the underlying genetic machinery in a human and a salamander is not that different, even though our last common ancestor diverged during the Devonian period, some 360 million years ago. “There’s no special genes for regeneration,” Gardiner said. “There are these steps they go through and at least one of those steps doesn’t work in humans.”
To regrow a limb, the cells need to know where they are — are they at the very tip of a limb by the fingers, or are they at the elbow joint? — and they need to build the right structures in the right order. Salamanders do have certain genes that are “turned off” in humans, Gardiner said. Perhaps those genes enable regeneration, or at least help control the process. Something in humans’ evolutionary past selected against expressing those genes the way salamanders do. Nobody knows what that something was, he said.
In 2013, an Australian scientist, James Godwin, at Monash University may have solved part of that mystery. He found that cells, called macrophages, seem to prevent the buildup of scar tissue in salamanders. Macrophages exist in other animals, including humans, and are part of the immune system. Their function is to stop infections and cause inflammation, which is the signal to the rest of the body that repair is needed. Salamanders lacking macrophages failed to regenerate their limbs, and instead formed scars.
Gardiner said Godwin’s work was a step toward understanding limb regeneration. Ordinarily salamanders don’t develop scar tissue at all. When a human tears a muscle or gets a deep-enough cut, damaging connective tissue, scar tissue forms. This scar tissue doesn’t offer the same functionality as the original stuff.
“If I could get a salamander to scar that would really be something,” Gardiner said, because that would shed light on the mechanism that makes humans unable to regrow a limb or organ. So macrophages might be part of the story, but not all of it.
Neotony and limb regeneration
The ability to “stay young” may add another insight into the mystery of limb regeneration. Mexican salamanders, called axolotls, or Ambystomamexicanum, are neotenic, meaning they retain juvenile features into adulthood. This is why axolotls retain gills as they mature, whereas other salamander species don’t.
Humans possess neoteny, too, which is why adults look more like our baby selves than is the case with other primates, and why we take longer to mature than, say, chimps do. There’s some connection, perhaps, with neoteny and regeneration. Gardiner notes that younger people seem better able to heal than older ones.
In addition, researchers at Harvard Medical School found that a gene called Lin28a, which is active in immature animals (and humans), but shuts down with maturity, has a hand in enabling mice to regenerate tissue — or at least to regrow the tips of their toes and ears. Once the animals were more than 5 weeks old, they weren’t able to regrow those parts, even when Lin28a function was stimulated. Lin28a is part of the animal’s control system for metabolism — when stimulated, it can make an animal generate more energy, as though it were younger.
But the exact nature of the connection isn’t understood yet. Whereas all salamanders can regenerate limbs, only axolotls are neotenic, Roy noted.
Salamanders, especially axolotls, can recruit stem cells to start regrowing limbs, and the kinds of cells that react to a wound site also appear connected to whether limbs can grow again. Gardiner was able to get salamanders to grow extra limbs by stimulating the growth of nerve cells in a wound site.
“It may have to do with a strong immune response, or the specific release of some growth factors, or a combination of both. It could be partly a question of biophysics: Salamander limbs are much smaller than humans; however, frogs cannot regenerate their limbs, so it may not be just a question of size,” Roy said.
This mystery remains one – at least for now.