Saturday, May 28

From a stump to a functional leg in 18 months: scientists manage to regenerate limbs in adult frogs


A group of researchers has managed to regrow lost limbs in adult frogs over the course of 18 months. They have done it using a cocktail of five drugs applied to the stump of the study subjects. Frogs, like humans, are unable to naturally regenerate large and complex structures of their organisms.

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The achievement has been published this wednesday in the magazine Science Advances. It is the work of scientists from Tufts University and the Wyss Institute at Harvard University, both in the United States.

The researchers triggered the regeneration process in African Clawed Frogs (Xenopus laevis) covering the wound with a silicone cap –which they call BioDome–, which contains a gel with the cocktail of five drugs.

Each of the drugs performs a different function: reducing inflammation, inhibiting the production of collagen that would cause scarring, and promoting the growth of new nerve fibers, blood vessels, and muscles.

The plug is technically a bioreactor (a device that houses and maintains an active biological or chemical process). Along with the cocktail of five drugs, the bioreactor provided both biochemical signals and a controlled and stable environment that managed to reverse the natural scarring of the stump and force the regenerative process.

“Spectacular” growth

The researchers observed “spectacular” tissue growth in many of the treated frogs, recreating a nearly fully functional leg. The new limbs had an extended bone structure with characteristics similar to the bone structure of a natural limb and several “fingers”, which grew from the end of the limb, although without the support of the underlying bone.

The regenerated limb moved and responded to stimuli such as the touch of a stiff fiber, and the frogs were able to use it to swim through the water, moving much like a normal frog would, they say in the release.

Millions of people lose members annually for reasons ranging from diabetes to trauma

Many creatures have the ability to fully regenerate at least some limbs, such as salamanders, starfish, crabs, and lizards. Flatworms can even be cut into pieces, with each piece rebuilding an entire organism.

Humans are able to close wounds by growing new tissue, and our livers have a remarkable ability, almost similar to that of flatworms (flatworms), to regenerate to full size after 50% loss. But in mammals the loss of a large and structurally complex limb – an arm or a leg – cannot be restored by any natural regeneration process.

“In fact, we tend to cover major injuries with an amorphous mass of scar tissue, which protects them from further blood loss and infection and stops them from growing,” the note says. Millions of people lose members each year for reasons ranging from diabetes to trauma.

“It’s exciting to see that the drugs we selected helped create a nearly complete limb,” says Nirosha Murugan, a researcher affiliated with the Allen Discovery Center at Tufts and first author of the paper. “The fact that only a brief exposure to the drugs was necessary to kick-start a months-long regeneration process suggests that frogs, and perhaps other animals, have latent regenerative abilities that can be kick-started.”

The regenerated limb moved and responded to stimuli such as the touch of a stiff fiber, and the frogs were able to use it to swim through the water, moving much like a normal frog would, they say in the statement.

The researchers explored the mechanisms by which this limited intervention has led to long-term growth. In the first days after treatment, they detected the activation of molecular pathways that are already known and that normally play a role in embryonic development.

Activation of these pathways could allow tissue organization to be managed by the limb itself, similar to how it occurs in an embryo, rather than requiring ongoing therapeutic intervention over the many months of limb growth.

How does the silicone stopper work?

Animals with natural regenerative capacity mostly live in an aquatic environment. The first stage of growth after limb loss is the formation of a mass of stem cells at the end of the stump called a blastema, which is used to gradually rebuild the lost body part. The wound quickly becomes covered with skin cells in the first 24 hours after injury, protecting the rebuilding tissue underneath.

“Regenerating mammals and other animals often have their wounds exposed to the air or in contact with the ground, and it can take days to weeks for them to close with scar tissue,” said David Kaplan, professor of engineering at Tufts and co-author of the study. . “Using the BioDome plug in the first 24 hours helps to mimic an amniotic-like environment which, along with the right drugs, allows the reconstruction process to proceed without interference from scar tissue.”

Previous work by the Tufts team showed a significant degree of limb growth caused by the use of the silicone plug and a single substance: a hormone, progesterone. However, the resulting limb grew spike-shaped and was a far cry from the more normally shaped functional limb achieved in the current study.

“We are going to test how this treatment could be applied in mammals”

Michael Levin
University of Tufts

The five-drug cocktail represents “an important milestone” in restoring fully functional frog limbs, and suggests that further exploration of drug and growth factor combinations could lead to even more fully recovered limbs since the functional point of view, with normal fingers and webs and more detailed skeletal and muscular features.

“We are going to test how this treatment could be applied in mammals,” says another of the authors, Michael Levin, a professor in the Tufts School of Arts and Sciences. “Covering the open wound with a liquid environment under the BioDome plug, with the appropriate drug cocktail, could provide the early signals needed to kick-start the regenerative process.”



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