An Extended Interview with the Editors of Bioelectricity Initiated by the French Science Magazine,Epsiloon

Could You Tell Me How You Came up with the Idea of Starting Your Work on Bioelectricity?

MD. It was pure curiosity! I was convinced of the power of electricity in the body as a teenager when I had electric shocks several times while building a radio transmitter. Through my tertiary education and training, initially in physics and biophysics, I ended up as a professor of neurobiology, all at Imperial College London, in 1995. Then, I fancied a change, and that curiosity led me to ask: (i) Do cancer cells generate electrical signals (a very naive question in hindsight), and (ii) do these signals differ between cancer cells that are aggressive (capable of invading their surroundings and ultimately metastasizing) and nonaggressive/noninvading (“benign”) cancer cells? The rest is history, and I ended up with a second professorship (in cancer biology) in 2005.

ML. I have always been interested in intelligence and, in particular, the fact that we are all collective inteligences—we’re made of parts, and we can pursue goals and have memories that none of our parts have. What makes each of us more than a pile of neurons? Electrical networks in the brain. And where do we come from? Embryonic development: but how does a pile of cells become an “embryo,” with all the cells cooperating to build one specific structure and solve problems along the way (such as, if it gets split in half, each half rebuilds what’s needed and becomes two twins)? What allows cells in the body to work together to solve anatomical problems? In 1986, I discovered Becker’s book “The Body Electric,” which showed me that there is a long history of research into bioelectricity in embryogenesis and regeneration, which can be used to weave cognitive neuroscience, philosophy of mind, evolutionary biology, and developmental biophysics into a theory of how we can read and re-write the mind of the body.

RM. During my postdoctoral work, as an engineer by training, I noticed that almost everyone working in bioelectronics was focused on capturing the electrical language of excitable cells only, i.e., neurons and muscle cells firing rapid action potentials, while treating the rest of the body as electrically silent. Yet, I encountered numerous studies on the broader biological roles of bioelectricity and came to appreciate that every living cell, not just neurons, relies on subtle electric fields and ion flows to sense its surroundings, make decisions, and coordinate with its neighbors. So, I began to wonder: what if we could translate similar technologies to a much broader area of inquiry, especially cancer, where cell-to-cell communication is so critical to how cancer grows and spreads? That question became the seed of my past European project, which developed in the current work of the research group I am building.

AR. My bioelectricity story started in 1984, when I undertook my first research placement to identify a potential PhD supervisor in my first year at Purdue University. I worked with Joseph Vanable Jr., using a vibrating electrode system to measure the electric wound currents associated with limb stumps in amphibians. I found it immensely fascinating that something as apparently simple as an electric current could contribute so much to an event as important as limb regeneration. What amazed me most, though, was that I hadn’t heard about it before (hadn’t been taught about it as part of my undergraduate teaching). So, I wanted to know more, but ultimately, I chose to work under the supervision of Ken Robinson studying the role of electric fields in amphibian wound healing and nerve cell axon guidance. Then I moved to the University of Aberdeen in 1990 to begin a postdoctoral appointment jointly with Colin McCaig and Neil Gow to study how nerve and fungal growth were influenced by electrical cues, and I’ve been there ever since, all the while continuing my interest in bioelectricity.

Were You Surprised by the Results?

MD. Yes! Whilst I was not surprised that the cancer cells turned out to be electrically active, I thought this would have a lot to do with calcium since Ca²⁺ does “everything” in the body, from the most fundamental (e.g., gene expression) to whole-cell behaviors (e.g., motility). Instead, the research led to a sodium channel, strictly a “voltage-gated sodium channel” (VGSC). This brought up the concept of excitability of cancer cells, and we formulated the “CELEX Model” (CELEX = Cellular Excitability), according to which it is the electrical excited state of cancer cells that makes them aggressive. Such aggressiveness leads to invasion of tissues surrounding the primary tumor, ultimately leading to metastasis, the main cause of death from cancer.

ML. Yes! I am always pleasantly surprised at how many of the tools and concepts of neuroscience can be applied outside of the brain to understand cell behavior in embryogenesis, regeneration, and cancer. This field also provides numerous surprises in outcomes because the bioelectric interface to the collective intelligence of cells is very powerful. Surprising facts include that bioelectric signals can be used to flip or duplicate the left-right asymmetry of the whole body, to make complete eyes appear in new locations all over the organism, to create two-headed flatworms that continue to develop two heads forever into the future despite their normal genome, to repair birth defects despite the presence of powerful teratogenic mutations, etc.

RM. I was excited but not surprised; after all, bioelectric activity in cancer cells has been recognized for some time. What remains challenging is demonstrating it reliably and uncovering its patterns: electrical fluctuations in tumors are much tinier than the hundreds of microvolts routinely recorded in neurons with high-throughput technologies, and the same electrode designs and amplification schemes often do not directly translate. Our preliminary measurements do suggest the presence of voltage patterns that track with cell behavior, but we are still in the process of rigorously validating those signals by running controls, testing multiple cell types, and ruling out artifacts before we can claim we have truly mapped the hidden electrical language happening in cancer. This is precisely what pushes us to do better everyday in developing suitable technologies and diving into our results in this exciting field.

AR. The notion that electricity could drive nerve guidance and guide cells toward a wound site was both surprising and amazing to my young scientific self. But the more I learned about the physiology of the underlying systems it increasingly made sense to me that non-excitable cells should also be sensitive to ionic and electrical gradients too. But what needed further exploration, and what is still being deciphered, is the detail of the cellular mechanisms for how cells “read” and interpret spatial electrical gradients. This understanding is critical to devising safer, more effective implantable electrical stimulation devices and pharmacological therapies.

Did You Directly Measure the Importance of These Results in Terms of Therapeutic Applications?

MD. Yes, but this came later. First, we had to convince the medical field, including oncologists, that the VGSC was/is a part of the cancer/metastatic process and not an epiphenomenon. So, we (and others increasingly around the world) spent a lot of time showing (i) that the activity of the VGSC does make a direct contribution to metastasis and (ii) that the VGSC is an integral part of the cancer process by associating with growth factors, hormones, etc. Thus, we were convinced very early on that the VGSC would have therapeutic applications. However, in order to demonstrate that the cancer VGSC is clinically amenable, we had to show that it could be differentiated from other VGSCs in the body, especially the so-called “excitable” cells/tissues (nerves, muscles, etc.). In turn, this led to two further significant discoveries: i)

The cancer VGSC is an embryonic/neonatal splice variant. In the case of breast and colon cancers (and some other cancers), where the VGSC subtype is Nav1.5, there is a significant molecular difference between the embryonic and adult variants, and, consequently, these are pharmacologically distinguishable. Furthermore, we could target the neonatal VGSC using a blocking antibody.

In the event, we now believe that by controlling/inhibiting metastasis (e.g., using ranolazine), we can live with cancer chronically. The alternative of aiming to kill cancer cells (e.g., using cytotoxic drugs such as chemotherapy) can, in the long run, make cancer more aggressive by promoting their drug resistance and stemness (J. Hopkins and MBA Djamgoz, article in preparation).

ML. We have three kinds of therapeutic applications that we measure (but ours are not yet in the clinic for human patients). The first is the repair of birth defects induced by chemical or genetic means. We measure the quality of the shape of the face, heart, gut, and brain; the degree of normal gene expression; and the quality of learning (to see if brain function is restored). The second is induction of regeneration, where we measure the ability of animals that don’t regenerate their limbs to do so when treated with our bioelectrical method. The third is cancer, where we measure the efficacy of our approach to reconnect cells to their normal neighbors and thus induce oncogene-bearing cells to participate in normal development instead of tumorigenesis.

RM. Not yet; we are still in the foundational stage. Having launched my own lab just six months ago, we have poured our efforts into engineering the next generation of bioelectronics that can access cancer cell networks at high throughput. Our short-term aim is to validate those subtle fluctuations across hundreds or even thousands of cells simultaneously, identify communication patterns, and learn how to perturb them in a controlled way, for example, by modulators of specific ion channels. Once these electrical signatures are unraveled and reliably linked to specific cancer events, we can begin to treat them as actionable biomarkers. From there, the plan is to translate those insights into drug-discovery pipelines. It’s a long road from a measuring device to a medicine, but we are proud to be contributing to laying the groundwork in this direction.

Did These Results Mark a Turning Point in Ion Channel Research?

MD. Yes, in many different respects, in depth and breadth. First, it confirmed how broad and fundamental the roles of ion channels are in the human body’s physiology and disease states. Second, by necessitating a deeper understanding of the membrane potential, we were compelled to introduce complementary techniques such as multielectrode arrays and imaging using voltage-sensitive dyes. These revealed that cancer cells have fluctuating membrane potentials coupled to the generation of regenerative action potentials/spikes, which are likely to sub-serve cell-cell interactions within the tumor microenvironment. Third, revealing the molecular nature of the cancer VGSC highlighted the clinical potential of nontoxic drugs acting on ion channels against cancer. These include drugs repurposed from other medical areas such as neurology and cardiology. Fourth, we have strengthened our grip on the understanding and exploitation of the post-genomic era. Fifth, even more broadly, we now appreciate the impact of bioelectricity in living things, beyond classically ‘excitable’ cells, from single-cell organisms to plants and complex primates.

ML. Yes, by (i) showing that the currency of cooperation and computation in growth and form is not just biochemistry but also the remarkable biophysics of electricity; (ii) by showing how the brain evolved all of its amazing cognitive tricks—from ancient bioelectrical mechanisms that implemented decision-making in anatomical space; and (iii) by revealing new biomedical applications that can come from rewriting the electrical pattern memories in tissue and not genomic editing (showing how ion channels can be an interface to the software of life, beyond the genetic hardware).

RM. I believe we are standing at the threshold of a real paradigm shift. Until now, ion channel research in cancer has largely relied on studying individual cells in isolation or examining bulk tissue responses, which inevitably masks the subtle collective behaviors that emerge when cells talk to one another electrically. The focus of high-throughput technologies has been entirely devolved to studying neuronal and cardiac cell behavior. By creating tools that can interrogate single cancer cells across entire cell networks simultaneously, we have the potential to open a door to experiments that were never conducted before. That level of throughput and resolution could compress years off the drug‐discovery timeline. Equally, if not more, important, it gives us the power to ask and answer deep biological questions about how cancer utilizes electrical signaling to coordinate growth, invasion, and metastasis.

What Is Your Opinion on This Recent Work Published in Nature: “Intrinsic Electrical Activity Drives Small-Cell Lung Cancer Progression” (https://www.nature.com/articles/s41586-024-08575-7)

MD. It is excellent (and music to my ears)! So, they have shown that small-cell lung cancer (strictly the neuroendocrine/NE subgroup) cells are electrically excitable/excited, and the higher the state of excitation, the more aggressive the cancer will be. Of course, I have been saying these things for 20 years—our CELEX hypothesis (see also below). This immediately raises the possibility of electrodiagnosis of cancer, and I have, in the past, introduced the term “electro-oncogram” (analogous to ECG, EEG, etc.). The article goes deeper and links the heightened activity to metabolism based on oxidative phosphorylation rather than the classical Warburg effect (aerobic glycolysis). The article also highlights, again, the cleverness of cancer by showing (i) that the NE cells are metabolically supported by the non-NE cells and (ii) that the cancer as a whole exploits its exogenous nerve input. Altogether these mechanisms promote the metastatic process.

ML. Yes, fascinating article integrating bioelectricity with metabolic control in cancer. I am very happy to see the field expanding and people applying state of the art cell biology to understand how bioelectricity works together with other aspects of cellular function.

RM. The study delivers a truly groundbreaking demonstration that neuroendocrine cells in small-cell lung cancer fire action potentials, and that this excitability drives cancer progression via metabolic coupling. Patch-clamp and calcium imaging are the most reliable technologies to investigate new biophysical phenomena. Even more exciting, those results underscore the transformative potential of scaling these insights with high-throughput technologies to access network-level phenomena.

AR. This is a very intriguing article! It is exciting to see refined understanding of how biochemical, bioenergetic, and bioelectrical phenomena intertwine in ways that can be exploited for innovative targeted therapies, in this case small-cell lung cancer subtypes.

What News Do You Have Regarding Your Research?

MD. First, overall, we are delighted that our findings have stood the test of time! More recently: (i) we updated the CELEX Model (mentioned above). (ii). There are also realistic possibilities of –“electrotherapy”—both (a) direct and (b) indirect. The direct mode is already in the clinic approved as tumor-treating field (TTFs), recently approved by the FDA for lung cancer. In the indirect mode, ion channels generating the electrical activity are a target, and this benefits from available neuroactive drugs. We have proposed that the persistent current of the cancer VGSC (the basis of the electrical excitation) is such a target, and its blocker, ranolazine, is a potential anti-metastatic drug. The evidence now extends to humans. Ranolazine is already used clinically against angina with a mechanism exactly the same as in cancer (hypoxia driven, etc.). In essence, we have repurposed it. (iii). We are now beginning to study cancer as a system,’ initially in association with other ion channels (K+ channels), adhesion molecules (integrins), and pH regulation (NHE1). I have always seen the VGSC as the lead violinist in the metastatic “orchestra.” Now, we are beginning to bring in the other players as well and thus appreciate the music more fully! Our recent paper also includes patient survival analysis (not mentioned in the Nature article)!

Altogether, it is wonderful to see the field of “cancer neuroscience” blossom!

ML. We are working on several new things, including the following. First, with a company called Morphoceuticals, we are building an atlas of bioelectric states in adult mammals, which will for the first time allow us to know the correct voltage patterns to which organs need to be driven in order to repair or heal. We are also working on moving our limb regeneration technology from amphibian models to mammals. And, with a company called Astonishing Labs, we are working on the bioelectrics of cancer, using AI to decode the bioelectric communication between cells that enables them to be an organ-building collective instead of having a unicellular metastatic lifestyle.

RM. Since starting my position 6 months ago, I have been busy assembling a multidisciplinary team of biologists, computer scientists, and engineers. We are kicking off right now with our first projects in breast cancer using classical patch-clamp recordings to capture ionic currents in single cells while simultaneously developing custom microsystems that can deliver precise electromechanical stimulation. These platforms will let us probe how electrical and mechanical cues cooperate in cancer progression.

How Do You See Bioelectricity in Biotechnology and Bioengineering?

MD. Bioelectricity is a core component of many applications in both these field. There are just too many examples to cover. On the “biotechnology” side, for example, by linking bioelectric signals to cellular/molecular mechanisms of disease states, we can use bioelectricity to monitor the state of the disease, including response to therapy. The possibility of developing an electro-oncogram was mentioned earlier. In bioengineering, many clinical devices use organs’ intrinsic electrical activity as the basis of their (patho)physiological state. This approach is now being galvanized using bioelectrically active materials (e.g., graphene) and wearables, including implantable devices.

ML. We have recently shown the bioengineering of two new synthetic life forms: Xenobots (made from frog cells) and Anthrobots (made from adult human cells). In both cases, we do not use DNA editing or materials scaffolds but rather study the plasticity of life in its ability to form entirely new kinds of beings with the same parts. We are next going to use the bioelectric interface to attempt to reprogram the form and behavior of these proto-organisms to enable useful living machines for applications in the environment (with a company called Fauna Systems) and in-the-body repair (with Astonishing Labs). I think that because bioelectric networks implement the decision-making machinery for regulating anatomical outcomes, bioengineering and the field of synthetic morphology will benefit greatly from including bioelectric signaling as a target for intervention to produce novel outcomes.

RM. Bioelectricity is a truly fascinating frontier from a technological standpoint, particularly in probing and manipulating cellular behavior in diseases like cancer. While we know that cancer cells exhibit altered electrical properties compared to healthy cells, many knowledge gaps remain. For example, the precise electrical signatures of various cells and how these drive or reflect crucial behaviors such as metastatic ability are still largely unmapped. This lack of a cohesive paradigm limits our ability to fully utilize bioelectricity as a biomarker in precision medicine. The great news is that technology can help access the language of cells and build this missing map. The dual opportunity of advancing knowledge while driving medical innovation is why I have chosen to focus my newborn research group at the University of Southampton precisely at this intersection.

AR. Biotechnology and bioengineering are key disciplines in the bioelectricity sphere, which is truly interdisciplinary. They drive emerging research techniques (e.g., ways to reveal real time electrical events at an intracellular scale) and new modes of electrical stimulation at tissue level. For example, implantable materials based on bipolar electrochemistry that generate small-scale electric fields spontaneously. On a tissue level, arrays of such materials generate spontaneous electric fields without an external power source. At the cell scale, bipolar nanoscale particles delivered to the cytoplasm can manipulate cell function. These technologies may transform the way targeted electrotherapies are delivered.