A normal African clawed frog, Xenopus laevis.
“It’s exciting to see that the drugs we selected were helping to create an almost complete limb” - Nirosha Murugan.
“It’s exciting to see that the drugs we selected were helping to create an almost complete limb” - Nirosha Murugan.
Photo: Pouzin Olivier, via Creative Commons
Discounting the account of the almost laughably fake 'miraculous' regeneration of Miguel Juan Pellicer's leg in Calanda, Spain in 1637, there are no authenticated accounts of a mammalian limb ever having regenerated or having been miraculously restores to an amputee. And yet, as scientists have now shown, the ability to regrow an amputated limb is stull present, having been inherited from remote salamander ancestors whose salamander descendants can still regenerate missing body parts. All it needs is the right cocktail of drugs to stimulate it.
Admittedly, this is only for frogs so far...
The scientists in question work at Tufts and Harvard University’s Wyss Institute. According to Mike Silver, writing in Tufts Now:
The BioDome.
An innovative device that concentrates a five-drug cocktail around the stump of a frog’s missing limb and successfully promotes regeneration of bone and soft tissues.
An innovative device that concentrates a five-drug cocktail around the stump of a frog’s missing limb and successfully promotes regeneration of bone and soft tissues.
…in a study published in the journal Science Advances, scientists at Tufts and Harvard University’s Wyss Institute have brought us a step closer to the goal of regenerative medicine.The researchers have published their work, open access, in the journal Science Advances:
On adult frogs, which are naturally unable to regenerate limbs, the researchers were able to trigger regrowth of a lost leg using a five-drug cocktail applied in a silicone wearable bioreactor dome that seals in the elixir over the stump for just 24 hours. That brief treatment sets in motion an 18-month period of regrowth that restores a functional leg.
Many creatures have the capability 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 after a 50% loss.
But loss of a large and structurally complex limb—an arm or leg—cannot be restored by any natural process of regeneration in humans or 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.
Kickstarting Regeneration
The Tufts researchers triggered the regenerative process in African clawed frogs by enclosing the wound in a silicone cap, which they call a BioDome, containing a silk protein gel loaded with the five-drug cocktail.
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.Each drug fulfilled a different purpose, including tamping down inflammation, inhibiting the production of collagen which would lead to scarring, and encouraging the new growth of nerve fibers, blood vessels, and muscle. The combination and the bioreactor provided a local environment and signals that tipped the scales away from the natural tendency to close off the stump, and toward the regenerative process.
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. 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.
Professor David Kaplan, co-author
Stern Family Professor of Engineering
Allen Discovery Center
Tufts University, Medford, MA, USA.
The researchers observed 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” grew from the end of the limb, although without the support of underlying bone.
The regrown limb moved and responded to stimuli such as a touch from a stiff fiber, 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. 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.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.
Nirosha Murugan, first author
Research affiliate
Allen Discovery Center
Tufts University, Medford, MA, USA.
Activation of these pathways could allow the burden of growth and organization 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.
How the BioDome Works
Animals naturally capable of regeneration live mostly in an aquatic environment. 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.
We’ll be testing how this treatment could apply to mammals next. Covering the open wound with a liquid environment under the BioDome, with the right drug cocktail, could provide the necessary first signals to set the regenerative process in motion. It’s a strategy focused on triggering dormant, inherent anatomical patterning programs, not micromanaging complex growth, since adult animals still have the information needed to make their body structures.
Professor Michael Levin, Corresponding author
Vannevar Bush Professor of Biology
School of Arts and Sciences
Director of the Allen Discovery Center
Tufts University, Medford, MA, USA
Associate faculty member of the Wyss Institute, Harvard University, Boston, MA, USA.
Next Steps in Frogs and Mammals
Previous work by the Tufts team showed a significant degree of limb growth triggered by a single drug, progesterone, with the BioDome. However, the resulting limb grew as a spike and was far from the more normally shaped, functional limb achieved in the current study.
The five-drug cocktail represents a significant milestone toward the restoration of fully functional frog limbs and suggests 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.
AbstractThe obvious question for creationists then, since, as the authors of this paper point out, this work suggests that frogs and maybe even mammals have the latent capacity to regenerate limbs in the form of pathways that are only active in the embryo, why is that ability there but not used, and why is it not used when it would prevent a great deal of the suffering and disability suffered by amputees?
Limb regeneration is a frontier in biomedical science. Identifying triggers of innate morphogenetic responses in vivo to induce the growth of healthy patterned tissue would address the needs of millions of patients, from diabetics to victims of trauma. Organisms such as Xenopus laevis—whose limited regenerative capacities in adulthood mirror those of humans—are important models with which to test interventions that can restore form and function. Here, we demonstrate long-term (18 months) regrowth, marked tissue repatterning, and functional restoration of an amputated X. laevis hindlimb following a 24-hour exposure to a multidrug, pro-regenerative treatment delivered by a wearable bioreactor. Regenerated tissues composed of skin, bone, vasculature, and nerves significantly exceeded the complexity and sensorimotor capacities of untreated and control animals’ hypomorphic spikes. RNA sequencing of early tissue buds revealed activation of developmental pathways such as Wnt/β-catenin, TGF-β, hedgehog, and Notch. These data demonstrate the successful “kickstarting” of endogenous regenerative pathways in a vertebrate model.
Murugan, Nirosha J.; Vigran, Hannah J.; Miller, Kelsie A.; Golding, Annie; Pham, Quang L.; Sperry, Megan M.; Rasmussen-Ivey, Cody; Kane, Anna W.; Kaplan, David L.; Levin, Michael
Acute multidrug delivery via a wearable bioreactor facilitates long-term limb regeneration and functional recovery in adult Xenopus laevis
Science Advances (2022) 8(4); eabj2164; DOI: 10.1126/sciadv.abj2164
Copyright: © 2022 The authors. Published by American Association for the Advancement of Science
Open access
Reprinted under a Creative Commons Attribution-NonCommercial 4.0 International license (CC BY-NC 4.0)
In what sense of the word, 'intelligent' is it intelligent to provide the necessary pathways to do something, then not use them? In what sense of the word 'compassionate' it is compassionate to provide the latent ability to prevent suffering, then not use it to prevent suffering?
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