The medical field can often perform miracles, using medicines and surgeries to bring people back from the brink of death. Diseases can be cured, but there are limits to what can be fixed. If someone loses a limb, then while the wound left behind may heal, the limb itself won’t magically return. The ability to fully restore parts of a body would be akin to magic, but science has been making steady inroads into the field for years. We’ve known about some species that have the ability to regrow lost body parts, such as with salamanders, but being able to show the same sort of regrowth in a species model that has regeneration capabilities similar to humans would be something else entirely.
Millions of people every year suffer from limb loss for one reason or another, often the result of violence and physical trauma. And while the technology behind prosthetics has seen incredible leaps in capability over the past two decades, we are still far from returning the full working levels of a person’s natural limbs. The fields of regeneration are also intertwined with other medical prospects like the growth of new organs and so advancements in one can help inform how to proceed in others. Particularly understanding how tissue regeneration can be promoted on a genetic level. Now researchers at Tufts University have made their own contribution to this expansion of knowledge and unveiled their successful regrowth of a frog’s limb to almost complete functionality.
The Broad Picture of Regeneration
There have been a number of attempts to stimulate limb regeneration in test animals, ranging from using electricity to transplanting stem cell-like tissue to just manipulating genes involved in growth and development pathways. And they’ve all met with some, but not extensive, success. The only ones that have explicitly succeeded have done so in animal species that already have the capability to some extent to regenerate, such as axolotls, and often in animals at immature ages rather than adults. The researchers at Tufts saw that while these approaches tried to focus on individual aspects of regeneration, it was the bigger picture of where regenerative medicine has been successful that mattered. The developmental cascades of growth require a diverse set of electrochemical responses signaling for growth to occur and continue in order to have a full limb be reformed.
Because of this, they decided to take advantage of new achievements in biomimetics, the ability to replicate biochemical processes technologically, to create a specialized environment around the cut off limb site to make the body develop the limb anew as if it was doing so from an embryonic state in the womb. To test this, they chose to use the species Xenopus laevis, also known as the African clawed frog, because it has a similar regeneration profile to mammals, having some small amount of natural tissue regeneration and the use of pluripotent stem cells for facilitating that process. And the key was to ensure that adult frogs were used, as the tadpole stage for most frogs has much stronger regenerative capabilities. Of course, this also meant that there could be comparisons made between the two stages to further observe what was happening in the adult vs the tadpole and what impacts the biochemicals used were having on the frog’s physiology and genetics.
They started by using a device from 2010 called a BioDome, which is a bioreactor for carrying out contained biological reactions that can be fitted and worn by an animal on a part of their body. In this case, the limb stump would be covered by the device. This then allowed them to fill the BioDome with specialized chemicals to facilitate certain cellular responses, specifically preventing the wound from closing up and turning into scar tissue like it would under normal healing processes. Using information from other regeneration studies, they put together a cocktail of five chemicals used in the body for repair, including restoring motor function neurons, application of pituitary signals for regeneration, inhibiting the overproduction of collagen that would otherwise cause the healing system of fibrosis to start, a hypoxia factor for maintaining oxygen availability in the environment being repaired, and controlling the amount of inflammation caused to promote tissue growth, but not to an excessive degree.
As you can see from the list, promoting full limb regeneration is like walking a fine tightrope to ensure cells keep forming for all the different types needed, but in a way that actually creates a functional limb and without accidentally causing the wound end to heal over. The scientists amazingly found that just a 24 hour exposure of the wound site to the BioDome caused a regeneration response that lasted for an entire year and resulted in a complete limb at the end that had almost full functionality again. Further tests involving longer and shorter term exposure and how those impact regeneration are in the works for future studies. There are also many other biochemicals they want to try to see if they assist in the process and perhaps even speed up the rate of regeneration.
In addition to their repeat studies with their frog model to better improve their design of limb regeneration, the Tufts researchers also plan on moving onto a mammal model next to see if the same regrowth and repair can be done in a species that is that much closer to us humans. And they want to look into how the immune response pathways play a role in regeneration and if they can be altered to further improve the chances of successful regrowth. Since the complexity of regrowing a human limb to the same degree and the fine motor control that would be needed to truly consider it to have restored functionality is another level above just this experiment. There’s much more research to be done, but this study is another huge step toward the science fiction future we always read about with medical technologies that can truly cure anything.
Photo CCs: Krallenfrosch Xenopus laevis from Wikimedia Commons