We are aware that the classical biochemical view is centered

We are aware that the classical biochemical view is centered on the local concentrations of specific ion and molecules rather than on cell electric potentials. However, important downstream processes can be influenced by acting locally on these potentials because they regulate the conductance of the specific channels involved in the transference of signaling molecules and ions. Moreover, it has been shown [[7], [8], [9]] that rescue and recapitulation of pattern phenotypes can result from Vmem changes implemented by diverse ion channels – in some cases, what matters is the bioelectrical state and not which specific ion was involved in reaching it. In addition, the dynamic intercellular coupling provided by voltage-gated gap junctions between Colchicine can induce dynamic and complex systems-level physiological behavior [10]. As it is usual for emerging approaches to significant scientific problems, there is room for additional interpretations and future conceptual frameworks derived from novel forthcoming data in this field. We believe that by presenting the bioelectrical concepts involved, further exchange of diverse viewpoints on this important topic will be facilitated.
Bioelectrical regulation: experimental examples The bioelectric roles of ion channel-mediated signaling in regulating cell-level responses, including differentiation, proliferation, migration, and apoptosis, are summarized elsewhere [28,42]. Importantly, the molecular machinery involved in transduction of membrane potential changes to transcriptional cascades, as well as numerous genetic targets of bioelectric signaling (including Notch, BMP, Wnt, and Hedgehog pathways), are becoming increasingly identified [6,43]. The frontier of this field is in cracking the bioelectric code –understanding how global dynamics of ionic signaling interplay with biochemical and genetic processes to underlie large-scale order. Next, we briefly review several examples of endogenous bioelectric control, made possible by novel techniques for tracking [[44], [45], [46]] and modulating [47,48] endogenous patterns of membrane potentials in different model species (see Fig. 1). The following four examples highlight ways in which bioelectric signaling operates during the patterning control observed in regeneration, embryogenesis, and carcinogenesis. (1) An important parameter in any patterning system is the size and scale of the pre-pattern and of the subunits whose morphogenesis is described by it. In a healthy body, cells obey biochemical and bioelectrical cues that orchestrate their activity toward creation and maintenance of complex pattern on the scale of the entire organism. Before discussing the role of bioelectrics in normal patterning, it is important to consider the function of bioelectric signals in the context of a lack of patterning – the disease state known as cancer. One view of cancer is as a disease state in which the boundary of the “self” shrinks to the level of individual cells, which revert to an ancient unicellular program and treat the rest of the body as an environment within which they grow uncontrolled [49,50]. Consistent with this view, it has long been known that one of the earliest signs of carcinogenesis is shutting down of gap junctions to isolate cells from the bioelectric cues of local and remote regions [51]. Indeed, bioelectric disruption in the absence of chromosome damage, oncogene expression, or carcinogens can be sufficient to initiate metastatic conversion on a genetically normal background [52,53] via serotonergic signaling (Fig. 1A–K). Conversely, artificial reversion of cancer cells with an aberrantly depolarized bioelectric signature (Fig. 1J–K), for example using optogenetic reagents such as ChR2D156A (a blue-light activated cation channel) or Arch (a green-light activated proton pump), can normalize cells [11,54]. Importantly, the effect is non-local: the state of quite remote cells can affect the incidence of tumors occurring from KRAS oncogene misexpression [55] via an epigenetic mechanism that involves bacteria-derived butyrate [54,56]. Having considered the role of bioelectricity in single-cell decisions, we next discuss the roles of bioelectric signaling in coordinating complex coherent patterns during normal embryogenesis and regeneration.