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(Image: Angus Greig)

We鈥檙e learning to speak the electrical language of the body 鈥� and using it to develop treatments for diseases from arthritis to diabetes

FOR Goran Ostovich*, just driving his delivery van was a daily agony. The painful swelling in his hands, wrists and elbows made it nearly impossible to grip and turn the wheel 鈥� never mind loading and unloading the produce his van carried. The drugs that he had taken for years to alleviate his rheumatoid arthritis didn鈥檛 help much. He had reluctantly abandoned his favourite sport, ping pong. He stopped working. The final cruelty was when he could no longer lift his young children or play with them.

It was then that Ostovich volunteered for a last resort treatment: he had a small computer implanted in his neck that would instruct his immune cells to stand down.

Ostovich鈥檚 implant is a harbinger of a revolution in the pharmaceutical industry. Researchers are waking up to the idea that the electrical language of nerves might be spoken more widely in the body than anyone thought, playing a pivotal role in coordinating the actions of our organs, glands and cells. It may even be possible to use the nervous system to coax the body into healing itself in ways we never dreamed of.

The pharmaceutical industry is on the case, and a spate of projects is under way around the world to map the exact circuits that allow the nervous system to intervene when things go wrong in the body. Autoimmune diseases, asthma, diabetes and gastric conditions are just a few of the disorders that appear amenable to electrical intervention. There are even hints it could be used as a radical way of treating cancer. Within a decade or two, electrical implants could replace many common drugs. Welcome to the brave new world of electroceuticals.

The idea that electrical signals can control the immune system will sound bizarre to anyone who has studied biology. After all, electricity is the language of the nervous system, not the immune system. Electrical signals, in the form of action potentials, travel to and from the brain via the numerous nerve pathways throughout the body. For example, to regulate your heartbeat, sensory nerve fibres detect your heart rate and relay that information to the brain, which in turn sends instructions back to the heart telling it to speed up or slow down. A similar circuit controls blood pressure. 鈥淚t鈥檚 like setting a thermostat,鈥� says Kevin Tracey of the Feinstein Institute for Medical Research in New York. 鈥淭he nervous system constantly responds to changes and adjusts everything back to the set point.鈥� We can manipulate that electrical language when the body鈥檚 natural thermostat goes wrong, with defibrillators that use electricity to jump-start a stalled heart, or pacemakers that regulate the rate at which it pumps blood.

No such central governor was thought to control the immune system. A decentralised army, including white blood cells and virus-eating macrophages, was thought to roam around in the bloodstream fighting ad hoc battles against bacteria and viruses where they needed to be fought. Damaged tissue might send out a call for reinforcements, but there was no central command.

Tracey challenged that understanding in the late 1990s. He and his colleagues were testing a new anti-inflammatory drug. When they injected it into rats鈥� brains, they noticed it also dampened inflammation in their limbs and peripheral organs. 鈥淭he amount of drug we were using was vanishingly small so we knew the signal wasn鈥檛 going through the bloodstream,鈥� Tracey says. The only explanation was the nervous system. The idea was too intriguing to ignore. 鈥淪o we started stimulating different nerves to see if we could reproduce the effect,鈥� he says. Sure enough, he found that the spleen 鈥� home to immune cells known as T-cells 鈥� dampened their activity. It was one of the first hints that the brain might be talking to the immune system after all.

But how? Tracey had discovered that nerve cells speak to immune cells in the spleen using chemicals called neurotransmitters 鈥� the same language they use to speak to each other. Nerve stimulation triggered a complex reaction that told the T-cells to stop the production of inflammatory substances, such as tumour necrosis factor (TNF).

In healthy people this nerve circuit ensures that levels of TNF never get too high. However, in autoimmune disorders such as rheumatoid arthritis, the normal brakes fail and TNF production spirals out of control. It accumulates in people鈥檚 joints, triggering pain, inflammation and the breakdown of tissue.

To stave off these debilitating effects, people with rheumatoid arthritis often turn to drugs called TNF inhibitors. However, because these mop up all the TNF they find, they leave people at increased risk of infection. Worse, they don鈥檛 always work for rheumatoid arthritis. Ostovich was on several different drugs, but his pain was still debilitating.

But he was fortunate. The clinic he attended had just started recruiting people for a trial of a therapy based on Tracey鈥檚 findings. Following successful animal studies, Tracey had founded a company called SetPoint Medical to treat arthritis in people. For its pilot trial, SetPoint chose Ostovich鈥檚 home country, Bosnia and Herzegovina, where few have access to TNF inhibitors. The plan was to implant tiny computers into the necks of 12 people with rheumatoid arthritis to see if electrical stimulation eased their symptoms.

Ostovich鈥檚 computer tapped into his vagus nerve, the electrical superhighway that links the brain to all of the major organs, to intermittently stimulate the nerve fibres that connect to the spleen (see diagram). The researchers hoped that the device would instruct his immune system to stand down and stop attacking his joints.

It worked. The constant pain in Ostovich鈥檚 joints stopped. Levels of an inflammatory protein called CRP that is usually elevated in people with arthritis fell back to normal. Best of all, this intervention had no serious side effects. Nerve stimulation only removes around 80 per cent of TNF 鈥� as opposed to eliminating it the way drugs do. It also suppresses the production of other immune factors that can damage tissue when released in excess. Like Ostovich, seven other volunteers have shown similar improvements (Arthritis and Rheumatism, vol 64, p 1).

With this triumph, Tracey believes that he has identified the first of many neural circuits that control the immune system. Last August, Clifford Woolf of Harvard Medical School announced that he and his colleagues had found a second: , which were able to suppress infection when stimulated. Similar circuits are cropping up elsewhere too. The carotid body 鈥� a cluster of cells that sense glucose levels in the main artery carrying blood to the head 鈥� has a connection to the central nervous system that can affect rats鈥� insulin sensitivity and blood pressure (Diabetes, vol 62, p 2905). Implanted electrodes, says Silvia Conde at the New University of Lisbon, where the study was conducted, might manipulate some nerve signals and not others, making it possible to tweak insulin sensitivity without disrupting other vital functions of the carotid body. At any rate, it is becoming clear that these circuits are all plugged into a body-wide electrical grid.

The voltage cure

But as Conde鈥檚 work implies, the immune system isn鈥檛 the only thing these circuits can manipulate. Electrocore, an electroceutical device manufacturer with headquarters in Basking Ridge, New Jersey, has been working to isolate a different set of fibres within the vagus nerve to treat asthma. 鈥淎 nerve is like a transatlantic telephone wire,鈥� Tracey says. 鈥淚t has lots of individual cables inside it.鈥� The nerve fibres targeted by Electrocore鈥檚 neck stimulator link to a region of the brain involved in the physiological response to stress and panic. Zapping them triggers the release of noradrenaline, which dampens the activity of neurons that control the airways, prompting them to open, averting the asthma attack. 鈥淭he message we鈥檙e sending is: 鈥榚verything鈥檚 fine, you can relax, there鈥檚 no fight or flight to engage in鈥�,鈥� says Electrocore CEO JP Errico.

It appears to work. In 81 people admitted to emergency departments during an asthma attack who didn鈥檛 respond to standard drugs within an hour, electrical stimulation with Electrocore鈥檚 implanted electrode led to . Electrocore is now testing a device that activates nerve fibres through the skin.

While vagus nerve stimulation is an attractive strategy, it may not be focused enough, says Brendan Canning of the Johns Hopkins asthma and allergy centre in Baltimore, Maryland. The nerve fibres Electrocore targets are unlikely to combat some of the other troublesome symptoms of asthma, such as coughing and the feeling that you are not getting enough air, he says. Canning has discovered that these symptoms are controlled by a different set of fibres in the vagus nerve. However, stimulating these also triggers 鈥渇ight or flight鈥� responses such as boosting the heart and breathing rate, which often exacerbate an attack by activating a person鈥檚 panic response.

Such early measures are relatively blunt instruments. No existing implant is able to isolate individual cables. Instead, SetPoint鈥檚 implants use a workaround: they are tuned so that the amount of electricity you put in only stimulates a small subset of the cables.

It鈥檚 an elegant fix, but what if you could also eavesdrop on the electrical signals to detect abnormalities and only speak to the fibres that were misfiring? Such a smart electrode, Canning says, could also 鈥渄etect changes in nerve activity, provide therapy as needed and then shut off鈥�.

This is exactly what global pharmaceutical giant GlaxoSmithKline (GSK) is working on. 鈥淭he goal is to have rice-sized implants that sit on the peripheral nerves and record the complexity of the electrical language that flows through them, detect when something鈥檚 out of balance and then fix it,鈥� says Kristoffer Famm of GSK. 鈥淲e believe this treatment could be crucial for a whole host of chronic diseases 鈥� things like diabetes, hypertension, arthritis and chronic pain.鈥�

鈥淩ice-grain sized implants will sit on the nerve, detect when something is wrong and then fix it鈥�

Tracey and Woolf鈥檚 research shows that achieving Famm鈥檚 goal is possible, although commercialising it will be more difficult. It will require collaboration between scientists who don鈥檛 usually interact 鈥� engineers that design brain-machine interfaces, say, and lung or immunology experts. In December, GSK hosted a forum in New York to identify the key hurdles most likely to stop the field of electroceuticals from progressing, and offered a $1 million bounty to the group that overcomes them.

That reward is only a fraction of what the firm is spending on electroceuticals. GSK has funded six centres to begin teasing apart the neural circuits that underlie specific diseases. Unofficially, 11 more have joined the team.

And while GSK may have the biggest budget, it is by no means the only company betting big on this technology. Beyond Electrocore, the field includes medical device giant Medtronic, which is working on electrical interference for stubborn gastrointestinal problems. 鈥淲e鈥檙e learning to speak the electrical language of the body,鈥� says Famm. GSK expects to treat a range of common disorders with electrical implants.

However, even that may be just the tip of the iceberg. Electroceuticals may also offer new avenues to treat cancer.

The reason nerve cells can transmit electrical signals is because the inside of the cell is negatively charged relative to the outside, known as its resting potential. When a nerve cell fires, there is a sudden influx of positive ions into the cell through channels in its membrane. These ion channels open and close much more quickly in nerve cells, but other cells speak this electrical language too. 鈥淎ll cells maintain a resting potential. They use it signal to their neighbours,鈥� says Michael Levin of Tufts University in Medford, Massachusetts.

Each kind of cell has its own resting potential, and Levin has discovered that these differences play a key role in determining which embryonic cells turn into what part of the body during development. In frog embryos, for example, setting the voltage of what are normally destined to become gut cells to the normal range of eye cells triggered the growth of complete eyes in the embryo鈥檚 gut. 鈥淎 lot of this can be done using drugs that are already in human use,鈥� he says.

Levin has taken it even further. By soaking the stump of a frog鈥檚 amputated leg in a cocktail of drugs that trigger the flow of sodium ions into cells, his lab has managed to coax adult frogs to grow new legs 鈥� something which is not normally possible.

鈥淏y manipulating electrical signals in cells, they regrew the frog鈥檚 amputated leg鈥�

Intrigued, he wondered whether he could reverse this logic to inhibit unwanted cells. Last year, he successfully used ion channel drugs to stop the growth of tumours in tadpoles primed to develop cancer.

Levin鈥檚 work is early, and electroceuticals won鈥檛 cure every disease 鈥� but we should expect to see a lot more stories like Ostovich鈥檚. Eight weeks after getting his implant, he returned to work. When Tracey heard the success story, he says, 鈥淚 said, 鈥業 have to meet this guy'鈥�.

Tracey speaks no Bosnian and Ostovich speaks no English, so the meeting required a translator. But conversation was hardly necessary to see that the treatment had changed Ostovich鈥檚 life. 鈥淭he expression on his face was unbridled joy, gratitude and relief,鈥� Tracey says. 鈥淚t made all the years of basic bench research worthwhile.鈥� Ostovich told Tracey that the device had worked so well he had been able to take up ping pong again. And he felt so great after playing ping pong that he decided to try tennis. Indeed, this may have revealed a potential downside of the device: in his pain-free enthusiasm, he overdid it and ended up with a tennis-related knee injury. His doctors were forced to caution the man who, just two months earlier was unable to play with his children, to take it easy.

*name has been changed to protect confidentiality

See more of electroceuticals past and present in our gallery: 鈥� Electrical healing from Frankenstein to birth pangs鈥�

This article appeared in print under the headline 鈥淭he healing spark鈥�