In the swamp of the blind, the frog with one eye surgically attached to its back is king. Researchers have found a way to transplant an eyeball onto a blind tadpole's spine that confers some degree of vision—the first evidence that functional sight can occur so far from the brain. Such research promises to give scientists a better understanding of how transplanted tissue connects to the nervous system, paving the way for improved regenerative therapies in humans.
Scientists have moved frog eyes around before. In 2003, researchers transplanted them at various points around the head. The out-of-place organs extended information-transmitting nerve fibers known as axons into the animal's brain. But scientists haven't been able to determine whether such transplanted eyes are fully functional.
Now, developmental biologists from Tufts University in Medford, Massachusetts, have created a novel way to test whether transplanted eyes see as well as to determine how far away from the brain visual ability can extend. The study's lead author, Michael Levin, and his colleague Douglas Blackiston took tadpoles of the African clawed frog (Xenopus laevis) whose eyes had been surgically removed and transplanted "donor" eyeballs—one per tadpole—along various points on the back. In total, the researchers operated on 230 tadpoles and compared their performance in a light reaction test with similar numbers of intact tadpoles and blinded tadpoles without transplants.
To determine how the animals reacted to changes in light, the team placed the tadpoles individually into petri dishes that could be illuminated by either red or blue light. While under red light, the tadpoles were docile and swam slowly. Under blue light, though, they moved much more rapidly.
Here, the researchers found something strange. The blind tadpoles with no eyes still reacted when the light changed. "You have a flashlight and you shine it on the [blind] tadpoles and they take off, they zoom around the dish," Levin says. Eyes, it seemed, were unnecessary for responding to light.
Because changing the light's color couldn't indicate whether the tadpoles' transplanted eyes were functional, the researchers turned to a more sophisticated experiment. They made the petri dishes half red and half blue. Tadpoles that ventured into the red portion received a mild electric shock, and Levin and Blackiston recorded which animals eventually learned to avoid the red side.
Although they could react to changes in light, the blind tadpoles never learned to avoid being shocked. For them, Levin thinks "there's a kind of twitchy program going on" in which photosensitive cells—the researchers aren't sure which ones—bypass the brain and directly spur the muscles into movement. Thus, these automatic impulses can't help blind animals learn.
In contrast, about 10% of tadpoles with transplanted eyes were able to learn to avoid the red side of the petri dish, compared with about 40% of the tadpoles with intact eyes. Looking closer at the transplant recipients, Levin and Blackiston noticed differences in the ways the eyes formed axonal connections. When new tissue is introduced, Levin explains, it sends out axons to make connections with host tissue. In these tadpoles, the eyes' axons almost universally connected with either the spinal cord or the gut. Only tadpoles whose transplanted eyes formed connections with their spinal cord managed to learn ; eyes that instead connected to the gut were apparently useless. The researchers report their findings online today in The Journal of Experimental Biology.
Levin says the research is an important step in scientists' understanding of what makes a transplanted organ functional and how information flows between these organs and the nervous system, including the brain. There are obvious differences between a human's spinal cord and a frog's, he says, but "there are no fundamental differences, meaning I don't see any reason [similar experiments] would not eventually work [in humans]," Levin says. Humans might not want spare eyeballs on their backs, but the same technique could be useful for growing new organs to replace damaged ones, or for developing therapies to repair damaged nerve connections.
Levin's and Blackiston's findings are important because they demonstrate for the first time that animals can learn from sensory information provided by an organ transplanted to a non-native position, says Karen Echeverri, a developmental biologist at the University of Minnesota, Twin Cities, who primarily studies limb regeneration in salamanders. "That the animals do show a learned response is very interesting," she says. "It's pretty convincing."
William Harris, a neuroscientist at the University of Cambridge in the United Kingdom, adds in an e-mail that through studies like this one, scientists "can learn to understand weird inputs," which is critical to building technologies like bionic hands.