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Need a Hand? Or Three?

In Spider-Man comics, scientist Curt Connors injects himself with a serum based on lizard DNA and re-grows his amputated arm. He also transforms into a giant humanoid lizard and becomes evil. Unfortunate side-effects aside, the Lizard’s story reflects a real and longstanding scientific quest – to understand the extraordinary regenerative powers of animals, and duplicate them in humans.

If I cut my arm off, I will end up with a permanent stump that’s covered in scar tissue. By contrast, if a newt or salamander loses its leg, it will grow a new one. The wound will close and, over time, it will create new bones, muscles, nerves and skin.

Healing powers of this kind were first discovered in 1740, when Abraham Trembley discovered that a green pond animal could regenerate its tentacle-crowned head if it was amputated. He called it Hydra after the head-renewing monster from Greek mythology. Since then, scientists have discovered more animals with regenerative powers. Lizards restore lost tails. Starfish grow dismembered arms back. Some flatworms can rebuild their entire bodies from a single cell.

But despite centuries of research, we’re a long way from even understanding how regeneration works, much less replicating the feat in our own bodies. The latter should be possible, according to James Monaghan, who studies regeneration biology at Boston’s Northeastern University, although he adds that “we are not even close, and putting a timeframe on it is difficult.”

Partly, this is because the field has only ever attracted a small cadre of scientists, with little coordination between them. Largely, it’s because the list of animals that are easy to keep and work with in a lab – so-called “model organisms” – is very different from the list of animals that regenerate well. Chickens, mice, flies and roundworms have been mainstays of lab science and have helped scientists to understand how a ball of cells can develop into a fully-formed embryo. But they’re not great at renewing lost limbs. Salamanders are the ideal choice, since they regenerate very well and have limbs with the same basic structure as ours. But they make for poor laboratory subjects. “It can take a month for the limb to regenerate,” says Ashley Seifert, who studies tissue and organ regeneration at the University of Florida. “That really slows down your experimental progress.”

Making things worse, salamander genomes are oddly bloated. They have ten times the amount of DNA as ours, and no one has ever fully sequenced them. And until very recently, scientists had no ways of adding foreign genes into a salamander, or knocking out one of its existing set. Without these powerful techniques, salamanders – and the science of regeneration – were left behind by the molecular biology revolution.


Healing acts
Despite these hurdles, we know the basic steps that a regenerating limb must go through. After an amputation, cells from the outermost layer of skin climb over to seal the wound. At this point, humans would lay down lots of scar tissue, and that would be that. But in salamanders, the new cells transform into a structure called the wound epidermis, which sends chemical instructions to those below it. In response, nerves in the stump to start to grow again, while mature cells such as muscles and connective tissues revert to an immature mass called a blastema. This is what restores the limb. Regeneration is about taking a few steps back to take many steps forward.

“Somehow, the cells know their positions, and they’ll only regenerate what’s missing,” says Enrique Amaya, developmental biologist at the University of Manchester. If the limb is amputated at the shoulder or hip, the blastema creates the full leg. If it’s amputated at the wrist, the blastema makes just a hand and digits. As they grow and divide, the cells take up specific positions, so they know up from down, or left from right. They fashion a miniature version of the full limb, which eventually grows to full size.

The basic outline is there, but the details have been hard to fill. Why does the wound epidermis form, and what does it do to the cells beneath it? The limb won’t regenerate if the nerves inside don’t start growing, but what exactly do the nerves do? When cells in the stump rewind their fates to become a blastema, how far back to they go?

Most importantly, how do the cells of the regrowing limb know where they are and how take on the right shape? How do they make a working limb and not a useless, deformed tube? Or even a tumour? “It’s such a difficult problem because you’re going from a complex stump into a mass of cells that all look and act the same, but that somehow recapitulate development,” says Monaghan.  “People are just starting to figure these processes out, but we don’t understand how a cell at the end of a limb is different from one at the tip.”

Instead of asking how salamanders pull off their healing acts, one might equally ask why mammals like ourselves cannot. There are no solid answers, but several guesses. Perhaps cancers are more of a problem for mammals? The same checkpoints that stop our cells from growing uncontrollably into tumours might also stop a blastema from forming. Amaya wonders if it’s because we are warm-blooded. “If an amphibian chews off one of its arms, it could hide away for weeks without eating and regenerate,” he says. “That’s out of the question for an animal whose high metabolic rate requires it to feed constantly. It has to heal quickly and dirtily.”

Not all mammals flunk the regeneration test, though. Just last year, Seifert discovered that African spiny mice escape from predators by jettisoning huge chunks of their own skin. Miraculously, they can regenerate these flayed patches in record time. They even seem to form blastemas when wounds close up in their ears. This suggests that mammal regeneration may not be as distant a hope as many had feared.


Body patterns
But even if we could understand and replicate the mouse’s powers, Seifert doubts we will ever have an injectable cocktail of molecules that triggers regeneration. There’s too much complexity in the transition from wound to blastema to new limb, he says. It will also be a lengthy process. While the comic-book Lizard can regenerate a fresh limb in minutes, one of Seifert’s small salamanders took 400 days to grow back a leg that’s less than 4 millimetres across. The largest ones need more than a decade to finish the job. “Even if a human could grow a limb back, it might take 15-20 years,” says Seifert. A finger might be more realistic.

Would that be worth it? While the study of animal regeneration has been slow, other areas of medicine have sped ahead. Stem cell research and tissue engineering promise to make lab-grown organs from a patient’s cells, and both have attracted hordes of researchers with big budgets. With such breakneck progress, is it still relevant to chip away at the healing powers of salamanders and other animals?

Seifert thinks so. “For one thing, there are a lot of unintended benefits,” he says. Regeneration in salamanders has many similarities to wound healing in mammals. We may never be able to sprout new arms in comic book fashion, but we may learn how to close an injury more quickly. Doing so without scarring would also be a boon. Many nasty human diseases, from heart attacks to cirrhosis, involve some sort of fibrosis, where the body deals with injuries by laying down connective tissue. “Fibrosis is the antithesis of regeneration,” says Seifert. Understanding how animals avoid it could tell us how to stop scar tissue from building up on our vital organs.

And forget the science-fiction aspects. The study of regeneration is ultimately about how our bodies produce patterns – how our cells know where they are, and how they organise themselves to make organs. That knowledge will be invaluable, no matter what technique is used to produce new body parts. “I’d argue that stem cell researchers need the kind of work that we do,” says Amaya,  “we’re still damn ignorant about how cells behave, and how to control their behaviour.”


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