The study of non-neural (developmental) bioelectricity went through several stages, including focus on transepithelial electric fields, extracellular ion flows (with Jaffe and Nuccitelli’s vibrating probe), and the remarkable discovery by Clarence Cone in the 1970’s that resting potential of cells regulates their plasticity and mitosis. In fact he was able to bring neurons back to mitosis by keeping them depolarized. This is the approach we took when connecting bioelectricity to modern molecular cell biology – focusing on the Vmem and the information that spatial gradients of resting potential carry and process.
I was mostly interested in resting potential because that is a key parameter via which neuronal cells bind into networks that process emergent computation in the brain. But there was also a really inspiring paper by Binggeli and Weinstein in 1986 which presciently tied together early ideas about resting potential, gap junctions, cell cycle, and cancer:
One thing they showed was a meta-analysis of the resting potential and various kinds of cells:
The pattern is obvious: highly active, proliferating cells (cancer, stem, embryonic) are depolarized, while mature, quiescent, terminally-differentiated cells are hyperpolarized. In several of my reviews and talks on bioelectricity and cancer I used this updated version of this slide:
and then we updated this information further with a bigger meta-analysis like this:
The good thing about that voltage axis slide was that people got it immediately – when I showed it in talks, everyone understood the point. But eventually I had to stop using it. What I noticed was that the audience focused on it, and really connected with this idea that the resting potential of a given cell determined its behavior. That’s true, but it overshadows the more important picture: bioelectric control of cancer and developmental phenotypes is not a single-cell phenomenon. Yes, a single cell’s voltage can control its differentiation, proliferation, and other cell behaviors. But, the focus on the unicellular Vmem distracts from the bigger point: bioelectricity really shines when we appreciate how voltage information is processed in large cell networks. It controls top-down information at the level of organs, not just individual cells, and is processed non-locally across the entire body. What’s really important about bioelectricity is not that it’s one more piece of physics that needs to be added to single-cell models, but that it is a kind of cognitive glue and sets the computational boundary of the collective intelligence of cells; full story, as we glimpse it for now, is here: