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Re-Engineering Cellular Electricity Allows Scientists to Dictate Embryo Development

Endogenous bioelectrical signaling coordinates cell behaviors toward correct anatomical outcomes. Lack of a model explaining spatialized dynamics of bioelectric states has hindered the understanding of the etiology of some birth defects and the development of predictive interventions.

Improper neural patterning during development leads to highly debilitating disorders, such as open neural tube defects [spina bifida, and anencephaly (small brain)], brain malformations, and susceptibility to autism and degenerative disorders like Parkinson’s and Alzheimer’s diseases.

Nicotine, a known neuroteratogen, induces serious defects in brain patterning and learning. And biologists at the Tuft’s Univeristy have now been able to explain nicotine’s effects via the disruption of endogenous bioelectrical gradients using the brains of day-old frog embryos, thereby demonstrating how HCN2 ion channels could restore the endogenous bioelectric prepatterns necessary for brain patterning.

Without the brain, the researchers found that when the embryos were exposed to chemicals that do not typically give rise to defects, they developed severe deformities. This included bent spinal cords and tails (pictured)

The research, published today in Nature Communications, suggests that targeting bioelectric states may be a new treatment modality for regenerative repair in brain development and disease, and that computational methods

can be used to find effective repair strategies.

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 Professor Michael Levin, Ph.D., corresponding author of the study and director of the Allen Discovery Center at Tufts University. “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.

To study bioelectrical signaling, Levin and his team used an open-source 2D computational simulation platform, called the BioElectric Tissue Simulation Engine (BETSE) to create a dynamic map of voltage signatures in a developing frog embryo.

Frog embryos (bottom) and bioelectric patterns (top) are shown in the figure above, with normal patterns shown left, disrupted in presence of nicotine (center), and restored when HCN2 is added, on right

Drawing from molecular data on ion channel behaviors, the BETSE model can accurately replicate the distinct pattern of membrane voltage observed in normal embryonic brain development. More importantly, voltage mapping by BETSE could measure the “flattened,” or erased, electrical pattern that is observed from nicotine exposure.

The Tufts researchers were able to use BETSE to explore the effect of various reagents on the embryo’s voltage map. One reagent in particular, the hyperpolarization-activated cyclic nucleotide gated channel (HCN2), when added to the cells in the model, selectively enhanced hyperpolarization (large internal negative charge) in areas where it was diminished by nicotine. The effect- akin to dialing up the contrast in a photo editor- effectively restored the normal electrical pattern.

Remarkably, expressing HCN2 in live embryos rescued them from the effects of nicotine, restoring a normal bio-electric pattern, brain morphology, markers of gene expression, and near normal learning capacity in the grown tadpole.

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,” said Levin.

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