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Human amputees often experience a phenomenon known as “phantom limb,” where the missing arm or leg aches or itches.
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It turns out the opposite may also be true: Intact limbs can mirror major injuries or amputations that happen on the other side of the body — at least in young frogs.
In a new study, researchers have found that frog amputees flash an electric signal at the time of amputation both at the site of injury and in their opposite, healthy leg, mirroring the location of the cut limb.
Although so far these distant signals of injury have only been seen in young frogs, the idea that bodies can reveal information about far away wounds is intriguing, said Michael Levin, Ph.D., leader of the Allen Discovery Center at Tufts University and senior author on the study, published this week in the journal Development.
“It opens up this idea of surrogate site diagnostics, the idea that you could learn something about what’s going on in one part of the body by looking at a completely different part of the body,” Levin said. “We’ve really just scratched the surface of what kind of information that’s propagated and how far.”
The idea that a localized injury could have far-ranging effects in the body has not been well explored, Levin said. Researchers who study wound response and healing tend to focus on the site of injury and the cells and tissues immediately surrounding it, with the exception of those who have studied changes in blood hormone levels following major injury.
In fact, Levin and his colleagues found the mirroring signal serendipitously. They were originally studying electrical signals in the body after amputation in tadpoles who can regenerate their limbs and those who cannot (in certain stages of their development, young frogs can regenerate amputated limbs, while older frogs lose that ability). They were only looking at the young frogs’ healthy legs as a comparison — they should have been a blank, uninteresting background against which to measure the electrical changes in the injured leg.
Sera Busse, first author on the study and a recent Tufts college graduate, was soaking the froglet amputees in a special liquid that lights up under a fluorescent microscope in response to electrical activity. She was looking at the amputated legs, she said, and then noticed that the healthy leg, which she expected would not light up under the microscope, was glowing just as strongly.
“Within the first two days, I kept seeing that the opposite limb was also staining,” Busse said. “I took it to Mike and said, ‘This is probably nothing; I just wanted to see if this was normal — do you know what’s going on here?’”
Levin was so excited about the unexpected finding that he told Busse to drop her original project and focus on the healthy limb signals. They found that the uninjured leg not only flashes electricity to signal that the opposite limb has been amputated, but that it also marks the site of amputation. They also saw that less severe injuries cause a corresponding flash on the uninjured side, and they could tell the type of injury from the bioelectric signal. They also found that the same signaling doesn’t happen for all paired structures, such as a missing eye or kidney.
Next, Levin said, they want to understand more details about where the signal comes from and what it means. They’re not sure how the healthy leg knows what is happening to its injured partner, but they wonder if the electrical signal might spread through the blood or the skin. They’re also not sure if the signal is exclusive to frogs who are able to regenerate their limbs; they’d need to test more stages of the frogs’ lives to answer that question.
They want to ask whether they can influence healing or wound response to the damaged leg by treating the healthy leg, an avenue of research that, Levin believes, could open new doors into understanding wound healing and treatment. What if we could treat an injury deep in the body — say, a tumor — from a distant site?
From this point, there are a lot of questions to answer.
“A lot of what people study when they study injury response is local. They look right at the wound; they look at the cells right next to the wound,” Levin said. “How much do other tissues in the body know that this has happened? Do they influence what has happened and what’s going to happen? To what extent is the body a large, integrated system?”