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.
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.