Altering frog embryos' bioelectric patterns 'rescued' them from birth defects

What if we could influence an embryo’s development by changing the electrical signals in its cells?  That’s precisely what Michael Levin and his colleagues at Tufts University’s Allen Discovery Center are working on—predicting, mapping and manipulating electrical patterns, which could potentially reverse birth defects caused by substances like nicotine.

"Studies focusing on gene expression, growth factors, and molecular pathways have provided us with a better but still incomplete understanding of how cells arrange themselves into complex organ systems in a growing embryo," said Levin, director of the Allen Discovery Center, in a statement. The research center is funded by Microsoft co-founder and billionaire philanthropist Paul Allen.

"We are now beginning to see how electrical patterns in the embryo are guiding large scale patterns of tissues, organs, and limbs. If we can decode this electrical communication between cells, then we might be able to use it to normalize development or support regeneration in the treatment of disease or injury," Levin said.

Their work is based on the movement of negative and positive ions through the outer membrane of embryonic cells. Groups of cells form patterns of membrane voltage that control gene expression, as well as the changes an embryo undergoes during the course of development, the researchers said.

Previous research suggests that nicotine disturbs these patterns by promoting an influx of positive ions into embryonic cells and depolarizing them. Levin and lead author Vaibhav Pai figured this electric disruption could be the root cause of nicotine-linked problems, such as sudden infant death and brain defects, and could be targeted to reverse these effects.

They created a computational simulation platform, the BioElectric Tissue Simulation Engine, to map the voltage signatures in frog embryos. The model accurately represented the membrane voltage patterns in both healthy and nicotine-exposed embryos.

Using the platform to model how different reagents would affect the embryos’ voltage map, they found that adding the hyperpolarization-activated cyclic nucleotide gated channel (HCN2) to nicotine-exposed cells boosted their negative charge, effectively correcting the bioelectrical pattern.

And the findings weren’t just theoretical—the team discovered that expressing HCN2 in live embryos “rescued” them from the effects of nicotine and restored their normal bioelectric pattern, brain structure and markers of gene expression. The grown tadpoles had “near normal” learning capacity, they said. The study appears in Nature Communications.

"This is an important step providing a realistic model that bridges the molecular, cellular, bio-electrical, and anatomical scales of the developing embryo. Adding the bioelectrical component was critical to making a search for therapeutic strategies more tractable," Levin said.