To test his hypothesis, Levin has co-opted tools from neuroscience and molecular biology. By inserting new genetic material or compounds into cells, for example, he has found he can manipulate their electric potentials. For example, an injection of the appropriate genetic information leads to the creation of new pumps and channels in the cell membrane that allow ions to cross whereas certain pharmaceutical compounds can facilitate the flow of ions in and out of the cell. More recently his lab has begun publishing work that incorporates opto-genetics, which involves genes that contain the hereditary instructions for making light-sensitive proteins, allowing the researchers to control cellular changes with the flick of a lightswitch.
The approach is simple conceptually—help ions pass in or out by encouraging or constricting flow—but in practice it is more complex, requiring intricate calculations to determine what changes will produce the desired charge within and outside of the cell. "You have to think about the whole mathematics of all the pumps and channels present, and the medium inside and outside of the cell," Levin says.
In the January issue of Development Levin and colleagues describe how they identified the pattern of cellular voltages responsible for growing a frog's eyes. Tweaking those voltages during early development caused them to be malformed. Mimicking this pattern of voltages with other cell clusters in the body induced the growth of eyes in those locations, creating frogs with eyes on their tails or backs.
The work is a proof of concept with implications for regenerative biology. Levin believes one could take any cluster of cells in the body—including mature and fully differentiated cells—and override existing chemical and molecular signals by changing electric potentials. The signals would then direct growth into any shape desired, such as a new nose or eyes as well as manipulate them to repair a lost limb or correct birth defects.
What's most impressive about the study is not the outcome—scientists investigating regenerative medicine have created similar strange creatures for decades with grafts and chemical interventions—but the approach. It's possible that the electric signals serve as a master switch, meaning researchers don't need to know about the subsequent interplay of chemical and molecular signals involved in creating a new structure.
This is not to say genetics and epigenetics are not important. In fact, Levin points out that these signals are all cyclically linked and interdependent. "Genetics determines the cell's channels, for example, which in turn determines the gradient," he says. "And the bioelectric gradient can change gene expression." Precisely how these three sets of signals are intertwined in nature, however, remains unclear.
Levin's lab has also demonstrated how observing patterns of electrical potential can be used to recognize abnormal growths—a finding they believe can have important implications in cancer research. In a study to be published in the May issue of Disease Models & Mechanisms, the team details how it identified electrical signals associated with tumor formation. Levin and graduate student Brook Chernet noticed a bioelectric signature associated with tumor-like structures, which offers a novel approach to spotting cancer. In addition, they even had some success in raising the typically low electrical potentials of these cells to prevent tumor development.
But many challenges remain in understanding the possibilities of Levin's bioelectric code. Levin, for example, believes far more needs to be understood about cellular physiology, and hopes that with more data and tools he and his colleagues can begin creating a more systematic understanding of how sets of bioelectric signals relate to specific growth patterns.