Cancer and Cellular Voltage: the amazing slide I never show anymore

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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:

22 responses to “Cancer and Cellular Voltage: the amazing slide I never show anymore”

  1. Dr. Pierre Debs Avatar
    Dr. Pierre Debs

    After over 26 years in biology, this topic is for me, the most fascinating.

  2. Bob Averill Avatar

    I wonder if this shows how bioelectricity provides our “purpose” (goal) at any certain point in our lives: when young, it’s time to create and become something; once established, it’s time to help our communities. But this truly makes it seem like it’s bioelectric subjective experience turtles all the way down…

  3. Dr. S Sengupta Avatar
    Dr. S Sengupta

    Amazing Diagrammatic Representation/FlowChart.

    1. Mike Levin Avatar
      Mike Levin

      Yes! But don’t get caught in it 🙂 it’s even more amazing at the above-cell level. The language of the pattern memories of cell collectives, which drive morphogenesis, are way more interesting and rich than the 1D axis of resting potential. We’re just beginning to glimpse it (and trying to decode it).

      1. Alen Puaca Avatar

        I am looking forward to seeing those “pattern memories of cell collectives” and understand their shapes, outcomes, and dynamics. I am working on a (corporate) organizational framework and software that leans into more frequent and transparent information sharing between basic building blocks – humans. Curious how morphogenesis of human teams would compare to the ones of human organs.

      2. David Hughes Avatar
        David Hughes

        Extremely interesting, while not an expert in the domain there are interesting correlations with electromagnetic wavefunctions and language/mathematics, especially in terms of entropy analysis and inductive reasoning. Appears a comparison can be made with how differential transformations are utilized in natural language processing for example. Different layers of the model at rest holding the potential to perform functions from both higher and lower layers of data abstraction and from different dimentional domains which are activated or remain in a rest state untill the system requires that correlative activation. Need to dive further into the data sets but I find the frequency/amplitude correlations interesting in terms of system potential, polarity and communication/signaling through different scalar domains.

  4. Geraldo Medeiros Junior Avatar
    Geraldo Medeiros Junior

    This information is extremely valuable!!! I truly believe that the difference in tensoactive response between healthy and cancerous cells can impact bioelectric communication. Everything suggests that in healthy cells, electrical signaling is finely regulated to coordinate cellular processes, while cancer cells often lose this sensitivity, disrupting communication (bioelectric noise). The depolarization in cancer cells indicates a loss of control in response to electrical tension, altering signaling pathways. The altered tensoactive response can disrupt communication in cellular networks, contributing to uncontrolled growth and tissue invasion. This can also affect the ability of cancer cells to move and spread to other tissues (metastasis). Understanding these mechanisms is crucial for developing targeted therapeutic strategies to regulate bioelectricity in cancers. Thank you Dr. Michael Levin!

  5. Turil Cronburg Avatar

    When you talk about “top down” organizing of cellular activity, I’m wondering what sort of governance regulation this might be. Does the control message just follow the DNA programming directly? Or does it result from a sort of majority rules (democratic) “vote” by the cells? Or does it come about from a more meritocratic approach of adapting to new information from any cell that happens upon some change in its environment/state?

    Or maybe it changes between two or three of these, even?

    1. Mike Levin Avatar
      Mike Levin

      The cells can’t vote on options because the options exist in a different problem space than the cells are aware of. Collective decision-making is a field that studies this issue – how do the properties of the sub-agents result in the behavioral profile of the collective Self. There are papers on this from others, and I’ve just submitted a review of it from the developmental biology perspective. But still many questions remain.

  6. Larisa Broad Avatar
    Larisa Broad

    I would like to ask a question.
    Have you tried using pulses of light and sound waves to see if there are frequencies that create bio electronic differences?
    That is what I had initially thought you were referring to when you described bioelectricity.

    1. Mike Levin Avatar
      Mike Levin

      We’ve played around with it a bit, but right now there is no theory that would tell us which light/acoustic stimulation to use for specific bioelectric outcomes, so it would be mostly just guessing. It’s possible that at some point someone will work out a predictive theory of what stimuli would have the desired effect on the resting potential.

  7. Alex Versa Avatar
    Alex Versa

    This is extremely interesting! And I’m wondering what do you think about how the bioelectric networks and cognitive glue connected to the idea expressed in this paper –
    For instance, they draw connection between cell membranes gap junctions and biological/organic plasmoid phenomena. That it can, according to their experimental work, store and transfer information between such structures. They wrote: “…the membrane of the cell must contain, in order to ensure its viability, channels able to maintain a local gradient of different ion species. This could be possible if at the ends of the channels “micro”-DLs* (*a spherical self-consistent electrical double layer (DL)) are situated with qualities remembering their recent history. This means that the micro-DL preserves its initial ability to sustain and control an anomalous transport of matter and energy through the channel, by the described dynamics. It has obtained this ability during its creation under prebiotic Earth conditions. In this way the living state of a cell can be related to a mechanism able to explain the presence of periodic current patterns observed in the channels of its membrane. This mechanism can tentatively explain also the manner by which the pumping process is sustained in the channels of the cell
    membrane. As mentioned, the CSCCs (*a complex space charge configuration), created in plasma by self-organization, also reveal
    other interesting phenomena such as self-multiplication by division and exchange of information [19]. This latter behavior is realized by the emission of electromagnetic energy with an appropriate frequency by a CSCC during its steady (viable) state and its resonant absorption by another CSCC.” This sounds like it is directly related to bioelectric systems in our body?

  8. Naudi Avatar

    Do you think that a fascial block inhibiting electrical flow in a particular area could be related to cancer in certain regions? For example, if a person’s thoracic spine (T10-T12) and lumbar spine (L1-L2) both had blocks that affected the nerve supply to the kidneys, is it possible that this could be connected to the development of cancer?

  9. Mike Levin Avatar
    Mike Levin

    I don’t know of data on that specifically, but there have been some great papers recently on neuronal signaling and cancer, so I think it’s not impossible that there would be a connection.

  10. james berryhill Avatar
    james berryhill

    Thanks for this, Bioelectricity is a fascinating field and so much future potential. I wonder what is the role of the immune system in regulating/modulating bioelectric networks?

    1. Mike Levin Avatar
      Mike Levin

      Good question. Not known yet, but in the opposite direction – role of bioelectricity in modulating immune system – we know a bit:

  11. Felix Avatar

    Good points.
    It agrees with the “tissue organization field theory” (TOFT) of cancer:

    Bioelectricity + TOFT need to be combined.
    Would be so great to see a joint paper on this topic: Levin, M, & Sonnenschein, C. …

  12. Matěj Nekoranec Avatar

    Thanks for sharing this. It’s great.

    I’m curious about the link between bioelectric fields and their impact on cell bioenergetics. How does this might connect to the Warburg effect and the associated metabolic alteration in cancerous cells?

    1. Mike Levin Avatar
      Mike Levin

      Excellent question; we don’t know yet.

      1. Matěj Nekoranec Avatar

        I did a little research and stumbled across this review that somehow could connect these two. At least the idea that loss of OxPhos pathway could lead to decoherence is interesting:

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