27th January 2022
Scientists regrow frog’s missing leg
Scientists at Tufts University and Harvard University’s Wyss Institute have regrown the missing legs of adult frogs, which are naturally unable to regenerate limbs, using a five-drug cocktail applied in a silicone wearable bioreactor.
Credit: Pouzin Olivier, CC BY-SA 3.0, via Wikimedia Commons
For millions of patients who have lost limbs – for reasons ranging from diabetes to trauma – the possibility of regaining function through natural regeneration remains out of reach. The regrowth of legs and arms remains limited to animals such as salamanders and the realm of science fiction.
However, a new study published in the journal Science Advances, by scientists at Tufts University and Harvard University’s Wyss Institute, has brought us a step closer to the goal of regenerating human limbs.
On adult frogs, which are naturally unable to regenerate limbs, a research team succeeded in triggering regrowth of a lost leg using a five-drug cocktail applied in a silicone wearable bioreactor dome that seals over the stump for just 24 hours. That brief treatment sets in motion an 18-month period of regrowth that eventually restores a functional leg.
Various creatures have the ability of full regeneration of at least some limbs – including salamanders, starfish, crabs, and lizards. Flatworms can even be cut up into pieces, with each piece reconstructing an entire organism. Humans are capable of closing wounds with new tissue growth, and our livers have a remarkable, almost flatworm-like capability of regenerating to full size even after a 50% loss.
But the loss of a large and structurally complex limb – an arm or leg – cannot be restored by any natural process of regeneration in humans, or other mammals. In fact, we tend to cover major injuries with an amorphous mass of scar tissue, protecting it from further blood loss and infection and preventing further growth.
For this study, scientists triggered a regenerative process in African clawed frogs. After being anesthetised, each animal had a leg removed and its wound enclosed in a silicone cap, called a BioDome, containing a silk protein gel loaded with the five-drug cocktail.
Credit: Murugan, et al. (Science Advances, 26 January 2022)
Each drug fulfilled a different purpose – including tamping down inflammation, inhibiting the production of collagen (which would lead to scarring), and encouraging new growth of nerve fibres, blood vessels, and muscle. This drug combination and the bioreactor provided a local environment and molecular signals that tipped the scales away from the natural tendency to close off the stump, and toward the regenerative process.
The researchers observed a dramatic growth of tissue in many of the treated frogs, re-creating an almost fully functional leg. The new limbs had bone structure extended with features similar to a natural limb’s bone structure, a richer complement of internal tissues (including neurons), and several “toes” that grew from the end of the limb.
The regrown limb even moved and responded to stimuli such as a touch from a stiff fibre, and the frogs were able to make use of it for swimming through water, moving much like a normal frog would.
“It’s exciting to see that the drugs we selected were helping to create an almost complete limb,” said Nirosha Murugan, research affiliate at the Allen Discovery Center at Tufts and first author of the paper. “The fact that it required only a brief exposure to the drugs to set in motion a months-long regeneration process suggests that frogs and perhaps other animals may have dormant regenerative capabilities that can be triggered into action.”
Credit: Murugan, et al. (Science Advances, 26 January 2022)
The researchers explored the mechanisms by which the brief intervention could lead to long-term growth. Within the first few days after treatment, they detected the activation of known molecular pathways that are normally used in a developing embryo to help the body take shape. Activation of these pathways could allow the burden of growth and organisation of tissue to be handled by the limb itself, similar to how it occurs in an embryo, rather than require ongoing therapeutic intervention over the many months it takes to grow the limb.
Animals naturally capable of regeneration are mostly found in aquatic environments. The first stage of growth after loss of a limb is the formation of a mass of stem cells at the end of the stump called a blastema, which is used to gradually reconstruct the lost body part. The wound is rapidly covered by skin cells within the first 24 hours after the injury, protecting the reconstructing tissue underneath.
“Mammals and other regenerating animals will usually have their injuries exposed to air or making contact with the ground, and they can take days to weeks to close up with scar tissue,” explained David Kaplan, Professor of Engineering at Tufts and co-author of the study. “Using the BioDome cap in the first 24 hours helps mimic an amniotic-like environment which, along with the right drugs, allows the rebuilding process to proceed without the interference of scar tissue.”
The five-drug cocktail is a major milestone toward the restoration of fully functional frog limbs. Further exploration of drug and growth factor combinations could lead to regrown limbs that are even more functionally complete, with normal digits, webbing, and more detailed skeletal and muscular features.
“We’ll be testing how this treatment could apply to mammals next,” said corresponding author Michael Levin, associate faculty member of the Wyss Institute.
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