Extra eyeball. Manipulating the voltages in embryonic frog cells led to the formation of a functioning eye (arrow) on the gut.

Michael Levin and Sherry Aw

My, Your Eyes Are So Electric

A decade ago, Michael Levin made a bizarre discovery. Subjected to an electrical pulse, cells in a developing frog gut or tail would form what looked like normal eyes. At the time, the developmental biologist at Tufts University in Medford, Massachusetts, was too busy with other projects to follow up on the discovery. But now he and colleagues have shown that a natural electrical current jump-starts normal eye development in frogs. The discovery comes as a surprise to some biologists, but it may eventually help clarify why certain human eye defects arise and lead to ways to repair damaged or diseased eyes.

Most people think only nerve cells have electrical pulses, but almost all cells have membranes perforated with molecular channels and pumps that let charged particles move in and out—the essence of an electrical current. Typically, cells are slightly polarized, with a negative charge inside. A rush of ions into or out of cells changes the voltage inside. Scientists have shown that this voltage change can trigger a cascade of biochemical reactions that relay messages to the cell nucleus, changing gene activity and altering cell growth and differentiation.

Ten years ago, convinced that bioelectricity plays an important role in development, Levin and his colleagues systematically altered the number of ion channels in cells in different parts of a frog embryo. One result was the formation of lens and retinal tissue outside the head. "We didn't know if this was something that was used naturally in the embryo to make eyes," Levin recalls. About a year ago, Levin began thinking about that old work when a Tufts developmental biologist, Dany Adams, was determining voltage patterns in the embryonic frog head and observed that cells destined to become eyes had a large negative charge, suggesting a role for electricity in normal eye development.

To verify that these pre-eye cells were electrically different from the surrounding embryonic cells, Levin's team used a dye that fluoresces brighter the more negative charge there is in a cell. Where they saw a telltale glow, they also found gene-regulating proteins, such as Pax6, that help drive eye development. Labeling studies then showed that those cells ended up in the retina and lens. Other cells make Pax6, but only cells with a large negative charge became eyes, Levin notes. The researchers also made the cells electrically neutral, forcing open their ion channels so that a negative charge couldn't build up inside. In those cases, the eye-creating proteins were absent, and about half the embryos failed to form normal eyes, Levin and his colleagues report online today in the journal Development.

Working with frog embryos at the four-cell stage, Levin and his colleagues then used several methods to disrupt the normal voltages of the cells, making them more or less negatively charged. The frogs didn't grow eyes in their heads, but entire eyes did form in other parts of the body, including the gut. Shining light on these extra eyes prompted changes in the animal's behavior, indicating that the eyes can at least detect light, and the group is now assessing how the brain processes visual signals coming from unexpected locations in the body.

Much of the recent research into eye development has focused on the cascade of genes that turn on at different times to coordinate the process, but researchers thought electricity didn't play a role. "This is, indeed, a surprising and exciting finding," says Norann Zaghloul, a developmental geneticist at the University of Maryland School of Medicine in Baltimore. "This opens the door to an entirely different aspect of [the] cellular environment that we had not previously considered in eye development."

Calling the work "beautiful," James Coffman, a developmental biologist at the Mount Desert Island Biological Laboratory in Salisbury Cove, Maine, says it shows that "bioelectrical information is both necessary and sufficient for inducing development of the vertebrate eye." He and other biologists wonder whether electricity might trigger the development of other organs as well.

Levin says that one of his goals in characterizing the role of electricity in development is to learn how to regrow damaged tissues or keep development from going awry. The new work involved very young frog embryos, so it's unclear how it might be applied to adult humans in need of eye repair, cautions Michael Zuber, a developmental biologist at SUNY Upstate Medical University Syracuse in New York. "However, if [electricity] can be successfully used to direct cultured cells to [form] a retinal or lens lineage, for example, it might have wide application in cell-replacement therapies," he says. "Implications in this study for regeneration of eye tissue are profound."

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