That’s what led Levin and his colleagues to start tinkering with the resting potential of cells. By changing the voltage of cells in flatworms, over the last few years they produced worms with two heads, or with tails in unexpected places. In tadpoles, they reprogrammed the identity of large groups of cells at the level of entire organs, making frogs with extra legs and changing gut tissue into eyes — simply by hacking the local bioelectric activity that provides patterning information.
And because the brain and nervous system are so conspicuously active electrically, the researchers also began to probe their involvement in long-distance patterns of bioelectric information affecting development. In 2015, Levin, his postdoc Vaibhav Pai, and other collaborators showed experimentally that bioelectric signals from the body shape the development and patterning of the brain in its earliest stages. By changing the resting potential in the cells of tadpoles as far from the head as the gut, they appeared to disrupt the body’s “blueprint” for brain development. The resulting tadpoles’ brains were smaller or even nonexistent, and brain tissue grew where it shouldn’t.
Unlike previous experiments with applied electricity that simply provided directional cues to cells, “in our work, we know what we have modified — resting potential — and we know how it triggers responses: by changing how small signaling molecules enter and leave cells,” Levin said. The right electrical potential lets neurotransmitters go in and out of voltage-powered gates (transporters) in the membrane. Once in, they can trigger specific receptors and initiate further cellular activity, allowing researchers to reprogram identity at the level of entire organs.
This work also showed that bioelectricity works over long distances, mediated by the neurotransmitter serotonin, Levin said. (Later experiments implicated the neurotransmitter butyrate as well.) The researchers started by altering the voltage of cells near the brain, but then they went farther and farther out, “because our data from the prior papers showed that tumors could be controlled by electric properties of cells very far away,” he said. “We showed that cells at a distance mattered for brain development too.”
Then Levin and his colleagues decided to flip the experiment. Might the brain hold, if not an entire blueprint, then at least some patterning information for the rest of the body, Levin asked — and if so, might the nervous system disseminate this information bioelectrically during the earliest stages of a body’s development? He invited Herrera-Rincon to get her scalpel ready.
Making Up for a Missing Brain
Herrera-Rincon’s brainless Xenopus laevis tadpoles grew, but within just a few days they all developed highly characteristic defects — and not just near the brain, but as far away as the very end of their tails. Their muscle fibers were also shorter and their nervous systems, especially the peripheral nerves, were growing chaotically. It’s not surprising that nervous system abnormalities that impair movement can affect a developing body. But according to Levin, the changes seen in their experiment showed that the brain helps to shape the body’s development well before the nervous system is even fully developed, and long before any movement starts.