Nearly complete limb develops over 18 months, raising exciting possibilities for human patients
A frog has regrown a lost leg after being treated with a cocktail of drugs in a significant advance for regenerative medicine.
The African clawed frog, which is naturally unable to regenerate its limbs, was treated with the drugs for just 24 hours and this prompted an 18-month period of regrowth of a functional leg. The demonstration raises the prospect that in the future drugs could be used to switch on similar untapped abilities for regeneration in human patients to restore tissues or organs lost to disease or injury.
“It’s exciting to see that the drugs we selected were helping to create an almost complete limb,” said Nirosha Murugan of Tufts University in Massachusetts 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.”
Many creatures are able to fully regenerate at least some limbs, including salamanders, starfish, crabs and lizards. Flatworms can even be chopped into pieces, with each piece reconstructing an entire organism.
Humans have some regenerative capabilities – the liver can regrow to full size after being halved and children can regrow the tips of their fingers. However, the loss of a large, complex limb cannot be restored by any natural process in mammals. The rapid formation of scar tissue protects us from blood loss and infection, but also prevents regrowth.
In the latest research, published in the journal Science Advances, the scientists amputated a frog’s hind-leg and enclosed the wound in silicone cap containing a five-drug cocktail. The drugs each had a different purpose, including reducing inflammation and the production of collagen to stop scar tissue growing. The drugs also aimed to promote the growth of new nerve fibres, blood vessels and muscle.
The experiment was repeated in dozens of frogs and many of those treated had a dramatic regrowth of tissue, with many re-creating an almost fully functional leg, including bone tissue and even toe-like structures at the end of the limb.
The regrown limb moved, responded to touch and the frogs were able to make use of it for swimming.
In the first few days of treatment scientists observed the activation of molecular pathways that are normally used to map out limbs in the developing embryo. They believe that adult humans still retain the information needed to make body structures and that, in theory, it should be possible to tap into this dormant ability.
“Covering the open wound with a liquid environment under the [silicone cap], with the right drug cocktail, could provide the necessary first signals to set the regenerative process in motion,” said Michael Levin, Vannevar Bush professor of biology and director of the Allen Discovery Center at Tufts. The team now plan to test the technique in mammals.
Bob Lanza, head of Astellas Global Regenerative Medicine, who was not involved in the research, described the advance as an “amazing achievement”.
“The study has extremely exciting ramifications for regenerative medicine,” said Lanza. “Although frogs have much greater regenerative capacity than humans, this is a very important first step. With the right combination of drugs and factors a similar approach could potentially spur regeneration and restore lost function in humans.”
Michael Schneider, a professor in cardiology at Imperial College London, said that the findings could have applications in other areas of regeneration, such as the possibility of scarless healing, after a heart attack. “The results are highly intriguing for human regenerative medicine, beyond just their implications for the limb,” he said. “As the authors acknowledge, a crucial step to be made before any human testing will be proof that this approach, possibly with further refinements, also can be applied to mammals.”