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Louis Langman was ahead of his time. Working in the 1920s in New York City, he offered patients on his ward at the Bellevue Gynaecological Service an unusual diagnostic for cancer: two electrodes, one placed into the vaginal canal and another onto the pubis. These allowed him to measure the electrical voltage gradient between the cervix and the ventral abdominal wall. If Langman detected a marked change in this gradient, he offered the woman a laparotomy to check if his suspicions were justified.

The technique was surprisingly effective. Out of the 102 cases in which fluctuations revealed a significant shift in the voltage gradient, 95 were confirmed to have malignancies (Langman and Burr, 1947). The exact locations of the cancer varied, but they were often identified before the woman had experienced obvious symptoms.

Langman and his co-author, the Yale anatomist Harold Saxton Burr, were among a small clique of scientists investigating the electrical properties of human tissue. They believed that all living things – from mice to men to plants – are moulded and controlled by electrical fields that can be measured and mapped with standard voltmeters.

Just as electrical signals underpin the communications networks of the world, we are discovering that they do the same in our bodies.

If this seems unlikely to you, it’s probably because you assume electricity and the human body don’t mix. But just as electrical signals underpin the communications networks of the world, we are discovering that they do the same in our bodies: bioelectricity is how our cells communicate with each other. It is hard to overstate how wholly and utterly your every movement, perception and thought – and mine – are controlled by electricity.

Thanks to more sensitive instruments, better techniques to measure our innate electricity at the cellular level and a consequent deeper understanding of those cellular processes, we can now do a lot more to interpret, interrupt or redirect those communication signals. The applications are myriad, but especially promising and immediate for fixing the body when it goes wrong, whether because of trauma, birth defects, or cancer. The kinds of fixes enabled by bioelectric interventions are downright shocking.

The Tipping Point - Spark for life

A shocking oversight

Bioelectricity is not the kind of electricity that turns on your lights when you flick the switch. That kind of electricity is based on electrons: negatively charged particles flowing in a current. The human body – including the brain – runs on a very different version: the movements of mostly positively charged ions of elements like potassium, sodium and calcium. This is how all signals travel within and between the brain and every organ and agent of perception, motion and cognition in all living things. It’s fundamental to our ability to think and talk and walk. And it turns out, it also plays a big part in how our cells tell each other the systems in which they reside are healthy - or not.

This has not always been obvious. Langman and Burr were correct but their findings were poorly understood until 1949 when Alan Hodgkin and Andrew Huxley discovered how ions help electrical signals hop across nerve cell membranes. That breakthrough, for which they later won a Nobel prize, should have sparked an explosion of research, including looking for ionic communication beyond the nervous system.

But no sooner had Hodgkin and Huxley discovered this mechanism than it was eclipsed by another breakthrough: in 1953, James Watson and Francis Crick announced that they had discovered the double helix structure of DNA. The entire discipline of biology rapidly reorganised itself around genes. Bioelectricity was relegated to a niche concern within neuroscience.

It didn’t help that there was no way of studying ion flows in many other types of cells in the body without killing them, thereby extinguishing the very processes being studied. That is, until 1976, when Erwin Neher and Bert Sakmann developed a tool to do just that – enabling scientists to watch individual ions drifting into and out of neurons. They used their “patch clamp” technique to discover the channels that allow ions to permeate cell membranes.

Under the skin

The hunt for bioelectrical communication was on, and genetics went from being bioelectricity’s nemesis to its best friend. Scientists could now clone cells with and without particular ion channels and see what happened. That led quickly to the re-discovery of bioelectric signalling in many kinds of cells beyond the nervous system.

One of the earliest was skin cells, which generate an electric field when injured. You can feel this so-called injury current yourself: bite your cheek hard and then put your tongue on it. You’ll feel a tingle. That’s you sensing the voltage. The wound current calls out to the surrounding tissue, attracting helpers like healing agents, macrophages to mop up the mess, and collagen-weaving repair cells called fibroblasts.

But this current was tricky to measure until just a few years ago – the fragile, ultrasensitive devices that were capable of identifying the ions flowing in and out of cells couldn’t be disturbed and wouldn’t work on a dry environment like skin. But in 2012 Richard Nuccitelli created a non-invasive device that could deal with skin, allowing human injury currents to be closely monitored. He discovered that it peaks at injury, wanes as the wound heals and returns to undetectable when healing is complete. But interestingly, he also found that people whose injury current was weak healed more slowly than people whose injury current was ‘louder’. More interesting still: wound current strength declines with age, emitting a signal that is only half as strong over-65s as in under-25s.

Could amping up the skin’s natural electric field decrease healing times, or even allow healing of wounds that are extremely resistant to healing at all?

This has led to a surge of interest in using our body’s natural electricity to accelerate or improve wound healing. Ann Rajnicek at the University of Aberdeen has found that if she used channel blocking drugs to inhibit sodium ions, and thereby interrupt the electrical signals sent by the wound current in rats, their wounds took longer to heal. Could the opposite be true? Could amping up the skin’s natural electric field decrease healing times, or even allow healing of wounds that are extremely resistant to healing at all?

Recent trials indicate that the answer is yes. Perhaps the most harrowing kinds of wounds are severe bed sores, which can take months to years to heal (if they heal at all) and attack tissue, muscle and bone deep beneath the skin. Two recent meta-analyses concluded that amplifying the natural wound current with electrical stimulation prevented them all from getting worse, and even healed some of the worst ones completely. Electrical stimulation almost doubles their healing rate (Girgis and Duarte, 2018, Koel and Hoghton, 2014). Similarly intriguing results have been obtained for non-healing diabetic wounds - the kind that lead to the amputation of limbs, which usually leads within a few years to death.

Nor is the effect limited to skin; a growing body of evidence over the past few decades suggests that the same kind of electrical stimulation can accelerate healing in bone fractures - which may be relevant for treating or even preventing osteoporosis. There is even growing evidence the same cellular electric mechanisms could be harnessed to fix spinal injuries.

So why isn’t electrical stimulation used by every surgeon on every wound? A recent study found that the idea of electricity being relevant in biology is still too novel and counterintuitive for wide acceptance. And even when clinicians have heard of it, they don’t know how to use it: No existing guidelines specify either the current type (direct? alternating?) or the parameters (how long should it be applied? How strong should it be?). Even the tools are not standardised. Little wonder that in the absence of clear recommendations, therapists prefer to resort to antibiotics rather than take responsibility for this intimidating set of options.

So why isn’t electrical stimulation used by every surgeon on every wound?

In addition, in many of the clinical trials, researchers complain that the kit, with its electrodes and power sources, is too cumbersome, limits natural movement and gets in the way of patient compliance. But this may not be a problem for much longer. Many labs and private companies are now working on bioelectric wound dressings - polyester or other substrates impregnated with silver and other biologically active agents that are activated by the ‘wound fluid’ and amplify the natural wound current. Future versions may carry a more powerful charge.

Late last year, a joint US-Chinese team from the University of Wisconsin and Huazhong University developed a wearable nanogenerator that could be slipped into the bandage design to generate the augmenting electric field from everyday movements of the wearer. Rats that wore this bandage took on average three days to heal; those that didn’t took twelve (Long, 2018).

It may even be possible to enhance the wound current without electrical stimulation: this is important for injuries where you don’t necessary want to apply electricity or a bandage, like eye injuries. Min Zhao at the University of California, Davis, showed that rips in the cornea heal more quickly when certain ion channels are manipulated with simple eye drops to increase the size of wound currents - bioelectricity without the electricity (Reid and Zhao, 2011).

Ill communication

If physicians’ hearts and minds can be won over, wound healing is probably the most immediate clinical application of bioelectrical research. But what we can expect to see over the next ten years is greater clarity about how individual cells use electrical communication to co-operate in the service of the body as a whole.

Cancer has been called a wound that does not heal. There are many similarities: for example, new blood vessels form both as wounds heal and as cells turn malignant; and there are changes to electrical signals in both cases. The difference is that in cancer, the signals never stop. And as Langman and Burr suspected in the 1920s, cancers can be detected by their disruption of widely distributed bioelectrical properties of the body – disruptions detectable at locations far away from the tumour itself. Burr showed that if you implant a tumour into an animal, its body’s electrical signalling would almost immediately go haywire.

Cancer is beginning to be viewed increasingly as a failure of communication; a mis-regulation of the field of information that orchestrates individual cells’ activities towards functioning as part of a normal living system. Individual cells “forget” they are part of a larger whole and treat the rest of the body as an environment whose resources can be exploited to feed themselves.

Cancer is beginning to be viewed increasingly as a failure of communication.

This is a big departure from the mainstream view, which for decades held that what turns a healthy cell into a cancer cell is simply the accumulation of genetic damage. Mutations, the story went, lead to unlimited proliferation. But what if there was more to this story? Michael Levin at Tufts University was among the earliest to wonder if a cell’s inability to communicate normally with the body’s patterning networks was also relevant to the behaviour of cancer.

There’s growing evidence that’s the case. The electric fields generated by ions pumping across skin or organ tissue send cues to cells to start migration, which is also crucial in cancer spreading around the body. Mustafa Djamgoz at Imperial College London has investigated the role of a particular kind of sodium channel in breast and prostate cancer. These proliferate in cancerous cells, making them more electrically active than the body’s normal control mechanisms can manage. Such cells then invade other tissues, and metastasize (Djamgoz, 2014).

It’s not just metastasis that bioelectrical signals are implicated in. Frankie Rawson at the University of Nottingham has discovered that a different kind of biologically-generated current is important in cancer by enabling energy reprogramming – another key aspect of cancer.

Could cancer be reversed by controlling the bioelectric conversations among cells? In 2013, Levin’s group showed that they could prevent or reverse some tumours in tadpoles by using drugs to target their bioelectric signalling (Chernet and Levin, 2013). The same drugs could turn cancer on and off at a distance, by treating the environment, not the cells themselves. In 2016 they restored normal bioelectric signalling in frog tadpoles with tumours. These had grown, spread and formed their own blood supply, until Levin added new, light-activated ion channels with gene therapy. That caused the cells to stop uncontrollably dividing - in fact, they reverted to a healthy state after the tumours had already formed. The cells inside them simply stopped being cancer cells.

This approach would be problematic in humans, since gene therapy remains experimental, but Levin is working to repeat his results with drugs approved for other ailments (Tuszynski and Levin, 2017).

Getting into reverse

Fixing a broken bioelectrical communication system could have still more dramatic results. Levin aimed to reverse catastrophic deformities in tadpoles that had been subjected to the equivalent of heavy smoking or alcohol consumption during human gestation – both of which cause embryonic defects by interfering with bioelectrical signals sent by developing foetal cells. After a single two-day bath in a widely available ion channel drug, the tadpoles rearranged themselves and grew as normal (Levin, M., Vaibhav P., et al, 2018) The implication is that disorders like foetal alcohol syndrome and other birth defects could eventually be reversible in humans.

The broader implication still is that within the next decade, we could learn enough about bioelectricity to change how cell networks communicate and make decisions about how they grow and develop. New computational modelling tools will be a major factor here. Researchers including Levin are now using these to tell them exactly which channels need to be tweaked to produce desired changes in larger electrical circuits (and thus physical changes).

Ultimately, wound healing looks rather like the kind of regeneration for which salamanders are famous – and indeed, Levin has demonstrated in several experiments that limbs and tails can be regenerated by bioelectric tweaking, even in species like frogs that are not naturally predisposed to it. This raises the prospect of future treatments that involve simply removing an affected body part and re-growing it.

Clearly, there are a great many hurdles to clear before we start putting cancer into reverse, lopping off limbs or cutting out vital organs and growing new ones. Human trials will be hard to conduct, and a cell is a fiendishly complicated environment with many variables to keep track of: experiments in manipulating the bioelectric field have revealed that there are still many gaps to be plugged.

In the next decade, we can make rapid progress if we can get our heads around the idea that our bodies are at least as electrical as they are chemical or mechanical.

Nonetheless, we keep discovering more about how involved and connected our cellular communication networks are, in and across all cells. Last year, Djamgoz found that suppressing his particular sodium channels with a drug could stop metastasis in rats with prostate cancer (Djamgoz, 2018) He has already filed a patent to repurpose voltage-gated sodium channel blockers as anti-metastatic drugs.

What has only become clear in the past decade is the possibility of tapping into the communication, amplifying it and interrupting it. In the next decade, we can make rapid progress if we can get our heads around the idea that our bodies are at least as electrical as they are chemical or mechanical. In part, that’s about going beyond simply understanding what effects the bioelectrical signals have, to understanding what they actually mean. Computational models that suggest which ion channel tweaks correspond with which physical changes will only get more precise as computing becomes more powerful. And researchers are beginning to bridge the gaps between disciplines – biophysics, engineering or molecular biology – that have long frustrated progress in this area.

The dream, within ten or twenty years, is to use these insights to profile the electrical properties of biological tissues in the same way we have profiled its genetic basis – that is, to complete the human ‘electrome’ and then use it crack the human bioelectric code. After almost a century of neglect and stagnation, the science of bioelectricity has finally reached a tipping point: we are ready to crack the bioelectric code now.

Sally Adee is a science and technology writer and editor. From 2010 to 2017 she was features and news editor at New Scientist, where she commissioned and wrote articles on where the human mind and body intersects with the machines we create.

References

Chernet B. and Levin, M (2013) Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer. J Clin Exp Oncol S1

Djamgoz, M.B.A., et al. (2018) Anti-metastatic effect of ranolazine in an in vivo rat model of prostate cancer, and expression of voltage-gated sodium channel protein in human prostate. ‘Prostate Cancer and Prostatic Diseases’

Fraser S.P., Djamgoz M.B.A., et al. (2014) Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation. Philosophical Transactions of the Royal Society B Vol. 369: 20130105.

Girgis, B., and Duarte, J.A. (2018) High Voltage Monophasic Pulsed Current (HVMPC) for stage II-IV pressure ulcer healing. A systematic review and meta-analysis. ‘Journal of Tissue Viability.’ Vol. 27, No. 4, pp.274-284

Koel, G., and Houghton, P.E. (2014) Electrostimulation: Current Status, Strength of Evidence Guidelines, and Meta-Analysis. ‘Advances in Wound Care.’ Vol. 3, No. 2, pp.118-126

Langman, L., and Burr, H.S. (1947) Electrometric Studies in Women With Malignancy of Cervix Uteri. ‘Science.’ Vol. 105, No. 2721, pp.209-210

Long, Y. et al (2018) Effective Wound Healing Enabled by Discrete Alternative Electric Fields from Wearable Nanogenerators. ‘ACS Nano.’ Vol. 12, No. 12, pp.12533-12540

Levin, M., Vaibhav P., et al (2018). HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns. 'Nature Communications' Vol. 9, No. 998 [no page number]

Reid, B, Zhao, M., et al. (2011) Modulating Endogenous Electric Currents in Human Corneal Wounds—A Novel Approach of Bioelectric Stimulation Without Electrodes. ‘Cornea.’ Vol. 30, No. 3, p.338–343

Tuszynski, J., Tilli, T.M., and Levin, M. (2017) Ion Channel and Neurotransmitter Modulators as Electroceutical Approaches to the Control of Cancer. ‘Current Pharmaceutical Design.’ Vol. 23, No. 32, pp.4827-4841.