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Some unusual creatures have an innate ability to regrow a limb: salamanders, starfish, crabs, lizards and newts.
Such extraordinary powers elude most animals, including humans, although scientists have long sought to understand and replicate them in a quest to regenerate limbs for millions of patient amputees, including diabetics and victims of trauma.
Now, researchers in the United States said Wednesday they were able to trigger the regrowth of an amputated leg in a type of African clawed frog (Xenopus laevis), in what they described as a “step closer to the goal of regenerative medicine.”
The technique used by the team of scientists, based at Harvard University’s Wyss Institute and Tufts University, involved applying a mix of five drugs to the test frogs’ spike-like stump, sealed in with a small silicone dome. The cocktail was only applied for 24 hours, but after 18 months, the limb was almost fully functional. The frogs, which live in water, were able to swim and respond to touch. They also grew several toes but not the webbing between them.
The research was published in the journal Science Advances on Wednesday.
The results were “impressive” and “exciting,” said James Monaghan, an associate professor in the department of biology at Northeastern University. He wasn’t involved in the research.
“Xenopus frogs are somewhere in between a salamander that regrows a limb nearly perfectly and a mammal that generates a scar after amputation. Adult Xenopus frogs regenerate a spike after amputation, but the spike lacks any pattern like a limb,” Monaghan explained.
“This study is significant because it shows that patterning, albeit not perfect, can be induced in a limb that typically regenerates only a spike,” Monaghan said via email.
Activating cell growth and organization
The team said that the fact that only a brief exposure to the drugs set in motion a monthslong regeneration suggested that frogs – and perhaps other animals – have dormant regenerative capabilities that can be triggered into action.
“An immediate translation of this strategy to humans is unlikely because a regenerative spike does not occur in humans as it does in Xenopus frogs. Yet, this work is exciting because it shows that endogenous regenerative processes can be enhanced by a short application of a drug cocktail,” Monaghan said.
The strategy the team used relied on triggering dormant mechanisms in the frog’s body rather than try to “micromanage its growth,” said study author Mike Levin, Vannevar Bush Professor of Biology and director of the Allen Discovery Center at Tufts.
“I think the way to really achieve regenerative medicine is to exploit the collective intelligence of the body’s cells. They already know how to build all of these organs. They did it during embryonic development. All that information is still there,” Levin said.
“For me, the goal is to identify triggers, very simple kinds of stimuli, that will kick-start the cells and convince them to build whatever it is that you want them to build.”
The drugs included molecules important for limb development or that have anti-inflammatory properties. Levin said it was the first cocktail they tested, and it was possible that a different combination of drugs and growth factor could have better results.
“It has the girth and the kind of features of a normal limb, some bumps that are becoming toes. It does not yet have all of the correct terminal structure. It doesn’t have the long toes, the webbing – we didn’t get that far; we may have if we let it go longer,” he said.
Regenerative medicine vs. prostethtics
The research team used the technique on more than 100 frogs, but the results were “not perfect in every case.” Levin said that the frogs were not largely identical like lab mice, which could be a factor, or there were inconsistencies in the surgery conducted to attach the dome. The next stage of the research would test the technique on mammals such as mice.
Levin and his colleagues have also used frog stem cells to create self-replicating living robots, which they call xenobots. The shared thread between the two streams of research is understanding the signals required for cells to organize into complex tissues that form a structure such as a limb, or an entire organism.
Ashley Seifert, an associate professor of biology at the University of Kentucky who studies animal regeneration but was not involved in the research, said that advancements being made with prosthetics offered more hope than limb regeneration for people with amputated limbs lost through trauma or illness like diabetes.
“Will we one day be able to regenerate a human digit or even a limb? Probably, but how long we need to wait is impossible to predict,” Seifert said.
“One step in that direction will be when regenerative biology fully embraces new regenerative models, particularly certain species of mammals. This and comparative studies will help us understand how and why regeneration fails in some contexts and succeeds in others.”