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Rise of the machines

Bioelectronic medicine, which combines molecular medicine, bioengineering and neuroscience to develop nerve-stimulating and sensing technologies to regulate biological processes, could have a major impact on the future of medical treatment, a leading authority in the field tells the Medical Independent (MI).

Implantable electronic devices that control the signals that pass along the nerves could successfully treat such diseases as rheumatoid arthritis, inflammatory bowel disease, asthma, hypertension and diabetes, according to Dr Kevin Tracey, Professor of Molecular Medicine and Neurosurgery at Hofstra North Shore School of Medicine in Long island, New York, who is a pioneer in the field.

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Dr Kevin Tracey

In the 1980s, Dr Tracey was part of the team that discovered the critical role of tumour necrosis factor (TNF) in infection and sepsis. His research on TNF led to the discovery that the nervous system plays a key role in regulating the immune response. He showed that injecting a small amount of a drug that inhibits TNF into the brain actually blocked production of TNF throughout the body. He determined this effect was dependent on the vagus nerve, which transmits nerve impulses to and from several organs and the brain.

Armed with that information, he went on to develop an electrical device that stimulates the vagus nerve and prevents production of TNF by a type of immune cell called a macrophage, effectively inhibiting inflammation. The device has shown promising results in improving symptoms in patients with rheumatoid arthritis.

The development of cardiac stents revolutionised the treatment of heart disease, frequently eliminating the need for surgery, and today bioelectronic medicine could have a similar impact, Dr Tracey believes.

Dr Tracey is also President and CEO of the Feinstein Institute for Medical Research in New York. Under his leadership, research focusing on immunology, inflammation, neuroscience and behavioural medicine has played a major role in advancing our understanding of the role of bioelectronic medicine.

“I am a surgeon who is fascinated by inflammation. Along with my laboratory colleagues, I examine molecules that cause inflammation so that we can discover methods for alleviating the pain, swelling and tissue damage that is a consequence of many diseases,” he tells MI.

“Some of this work has already benefited patients. In 1987, I published the results of an experiment that targeted TNF to rescue lab baboons from the consequences of lethal infection — a study that contributed to the discovery of a new class of drugs for inflammatory, autoimmune and other diseases that disrupt the normal functioning of the body’s immunological defences.

This use of nerve-stimulating electronic devices to treat inflammation and reverse disability is laying the foundation for a new discipline called bioelectronic medicine

“As a neurosurgeon, I am also intensely interested in the workings of the brain. A surprising discovery we made in the late 1990s, again involving TNF, merged insights from neuroscience and immunology. We inadvertently discovered that neurological reflexes — predictable responses to certain sensory stimuli—block the production of TNF. This insight culminated in an invention I devised to treat inflammation using small, electrical nerve stimulators implanted in patients. This use of nerve-stimulating electronic devices to treat inflammation and reverse disability is laying the foundation for a new discipline called bioelectronic medicine.”

What is key to these advances is the bringing together of three fields of science that in the past, Dr Tracey says, have not collaborated. “The three fields are molecular biology, neuroscience and biomedical engineering. And bringing those three fields together is revolutionary.”

Dr Tracey says his work is based on the relatively simple concept that nerves, which affect nearly every cell in the body, can be controlled with electrical signals. “Bioelectronic medicine uses a tiny device to stimulate a specific nerve, which then sends a signal to a specific tissue to make and release the natural chemical the body needs to treat the problem at the site of the problem.”

Breakthroughs

In a wide-ranging interview with MI, Dr Tracey describes the breakthrough in the field in 1998 and what led up to it. “Simply put, we used stimulators and electronic devices to replace some drugs and that is what the excitement was about, that was a breakthrough in 1998.

“At the time I began my work on bioelectronics [in the 1980s], you could have searched through textbooks and found that nerves ended in lymph nodes, thymus, spleen and other sites where certain immune cells resided. And it was generally known that immunological diseases were the result of white blood cells floating through the blood vessels, jumping into action to produce inflammation and disease.

“It was dogmatic that the neuroendocrine system could regulate the immune system and that neurotransmitters could alter immune cell functions, but it was unimaginable that neural reflex circuits regulated these systemic inflammatory responses. The immune system was studied as an autonomous, self-regulating system.

“When I first challenged that assumption, based on my own observations as a neurosurgeon and immunology researcher, as well as on the work of scientists who preceded me, many of my colleagues were stunned. But the discoveries were unequivocal: electricity delivered to the vagus nerve regulates the immune system. The nerve signals turn off inflammation, in a manner that can replace anti-inflammatory drugs.

“We were working on animals that had a stroke in their brain and discovered that when we blocked the TNF in the brain by putting a drug in the brain, that the TNF was also blocked in the spleen. And this didn’t make any sense whatsoever until we realised that the brain was sending a specific signal to the spleen through the vagus nerve. And when we followed that (what took 15 years was dissecting the nature of that signal in the vagus nerve) and realised what the nature of the signal in the vagus nerve was, then it became possible to think about using that signal as the treatment.”

Promising results

Dr Tracey explains that what this means in laboratory studies and clinical trials is that a nerve stimulator, “a sort of pacemaker-type device for the vagus nerve, can replace the need for powerful and expensive drugs”. The devices, based on the original discoveries in his lab in 1998 are now showing promising results, particularly for patients with rheumatoid arthritis, in clinical trials in Europe, Dr Tracey confirms, citing trials in The Netherlands, Bosnia and Croatia. Trials have not yet started in the United States.

“In 2011 in Mostar, Bosnia and Herzegovina, I met the first rheumatoid arthritis patient treated with a vagus nerve stimulator — a more sophisticated version of the simple hand-held device that I had used in my lab. A middle-aged father of young children, he told me that his hands, feet and knees hurt so much that he spent days at a time lying on the couch, unable to work, play with his children or enjoy life. He participated in a clinical trial led by Dr Paul-Peter Tak, a leading rheumatologist at the Academic Medical Centre at the University of Amsterdam and GlaxoSmithKline.

 ‘So the idea in bioelectronic medicine is actually to understand the molecular basis of the device — how it actually works’

“Neurosurgeons implanted a vagus nerve stimulator just underneath his collarbone. Within days he was improving and within weeks he was nearly pain-free. Now, nearly four years after surgery, he remains in remission, free of medications.”

His case was presented at the November 2012 meeting of the American College of Rheumatology in Washington, by Dr Tak and his colleague Dr Frieda Koopman of the Academic Medical Centre, along with a representative of SetPoint Medical, a company Dr Tracey originally co-founded, with investment from the pharmaceutical industry to develop nerve stimulation to regulate the inflammatory reflex.

“Of the eight patients with long-standing, disabling, rheumatoid arthritis, he and five others benefited significantly after surgical implantation of a vagus nerve stimulator,” Dr Tracey reports.

Studies are also underway to see if similar devices can potentially help to treat other diseases, Dr Tracey tells MI. He is optimistic about how the trials are proceeding so far and predicts some devices could be approved in a few more years. “The first studies were done in rheumatoid arthritis and additional studies are occurring as we speak for inflammatory bowel disease. Clinical trials and repeats can take a number of years and then you have the regulatory approval steps but I’m hoping they’ll be approved for use in a few more years in Europe and a few years after that in the US [after clinical trials].”

Potential

How did Dr Tracey become interested in the field of bioelectronics? “There was no such field before 1998. The discovery catapulted this field into existence. In the past, medical devices were made based on an empirical observation of one kind or another but we didn’t understand how most medical devices actually work. So the idea in bioelectronic medicine is actually to understand the molecular basis of the device — how it actually works.”

These devices could be targeted at most conditions in the body, he suggests. “Almost every cell in the body is connected to the nervous system in one way or another and so if you understand those connections, you can ask the question ‘how can I use a nerve connection to the device to act like a drug?’ That really becomes the key question. I’ll be happy when these devices are available for patients with a wide range of diseases, from diabetes, to cancer, to Alzheimer’s disease. I think these are achievable goals in the future.”

Some critics are sceptical, however, saying bioelectronics may be too risky. But Dr Tracey is not deterred by such views and sees scepticism as a natural part of scientific discovery. “I think it’s fair to be sceptical of things that are new. If there weren’t sceptics, then it wouldn’t really be new. So I would react by saying that scepticism is an important part of science and medicine. What this field requires is time and research and additional knowledge to prove what we know and what we don’t know.

‘What matters most to me is that by implanting one device for one disease, it should be possible to eliminate suffering and pain in individual patients’

“What we know today is that there is at least one way to use an electronic device to replace drugs and we know that you can do this in a laboratory, we know that we can do this in people, we know how it works and why it works and when it works and where it works. So that is an accepted fact and it’s very, very difficult to argue with.”

He also believes the principle might ultimately be applied to treating some cancers. “I believe it can be applied to other conditions because the biology is telling us you can do it and sceptics will say, ‘well I won’t believe it until you do it’ and I say, ‘well then we have to wait’.

“We don’t know if it will work in cancer yet in people, but in laboratory experiments there is evidence that nerves can control the growth or the spread of some kinds of cancer in mice. It’s a research question; it’s not a clinical product yet. But the research evidence in mice is that there are very important signals in nerves that can control the cancer in mice.

“In diabetes, there is evidence that nerve signals can control the insulin effects and the glucose effects. So that would be very important in looking at the possibility of using nerve signals to regulate glucose levels or nerve signals to regulate insulin levels. The treatment of diabetes is far from perfect with insulin and any advance on that front could end up being important.”

So is Dr Tracey suggesting that ultimately, medicines will not be needed to fight disease and that all we have to do is to control the nerve reaction with an electrical device? “No,” he emphasises, “I think we’re always going to have drugs. I don’t think drugs will disappear from the planet; I don’t think anybody thinks that. There will be some diseases that will continue to be treated with drugs and some diseases that will be treated by implanting nerve stimulators, pacemaker-like devices, and I think there will be other diseases that will be treated by both — drugs and devices.”

He addresses head-on the question of whether bioelectronic medicine presents a threat to the drugs industry. “I believe that bioelectronic devices will replace some drugs and supplement others. Antibiotics and other anti-infection agents, however, are here to stay. But I expect that drug companies will continue to increase their investments in bioelectronic medicine.”

The methods of manufacturing and implanting such devices will also become more sophisticated over time, he says. “Today, the devices are implanted very much like a pacemaker. In the future, these devices are going to get smaller and smaller and they’ll be implanted through very small incisions and perhaps even through needles, almost like they’re being injected. They will be injected to wherever they need to go. Right now the trials are being done by surgeons who implant devices that target the vagus nerve in the neck.”

These devices could also have a positive impact economically for patients, Dr Tracey suggests, but that would depend on the particular drugs being used. “Depending on the drug, it’s possible these [devices] will have economic advantages. For instance, some drugs that target TNF cost $30,000 (€27,200) a year. Some of these devices could be implanted potentially at much less than that, for $30,000 or $40,000, but that would last for the life of the patient. They get recharged by a battery charger that a patient can wear like a collar; that’s one form. It’s possible to put in a device that would last the lifetime of the patient from a single use.”

With no side-effects? “Well, everything has side-effects but we think it’s possible to make nerve-modulating devices that would have minimal side-effects or potentially no side-effects.”

From Dr Tracey’s ‘eureka moment’ in 1998, has he ever had doubts about the progress of bioelectronics medicine? “Most of the experiments that you do in a lab have to be done many, many times before you understand how they work or what they mean…

“Having great ideas is important and working hard is important but this simple idea of using an electrode to treat inflammation goes back to the 1990s so we’ve been working on this continuously for 17 years. So persistence and focus are absolutely critical to discovery research in medicine.”

Does bioelectronic medicine thus have the potential for a major impact in the future? ”Yes, I am very optimistic about it. The data in the laboratory is overwhelming. The first [device] to emerge from the clinical trials will probably be to treat rheumatoid arthritis, then inflammatory bowel disease. Diabetes and Alzheimer’s are all areas of active research but you’re looking at five-to-seven years down the road. The short-term diseases are probably rheumatoid arthritis and inflammatory bowel disease. It’s too early to say what types of cancer could be treated this way.”

Challenges

And what kinds of challenges lie ahead? “The biggest challenge now is going to be learning more about the best way to do this in patients. That’s the biggest next step now — doing more clinical studies to really perfect what we’re doing. Right now, the devices are not microscopic, they are a device that you hold in your hand but they’re going to get smaller and smaller in the foreseeable future. The steps that have to happen are that we have to continue to map additional mechanisms and pathways to understand how to make new devices and then we have to understand how to make the devices smaller and smaller so that they’re still effective.”

Then there is the security question. Could such devices in patients be hacked, for example? This issue was dramatically highlighted by former US Vice-President Dick Cheney in 2013, when he revealed in a CBS interview that his cardiologist turned off the wireless function of his implanted defibrillator in case a terrorist hacked into it and tried to kill him by sending a fatal shock to his heart.

Dr Tracey notes concerns about hacking already exist with regard to other devices. “Security is a very, very important concern and will require new ways of thinking about encryption. It’s extremely important. Right now there are already millions of people walking around with devices that could theoretically be hacked — this isn’t creating a new problem; this is an existing problem. It’s a problem that already exists with people’s cell phones and millions of people who have implanted devices for other reasons. So as more and more people have more and more kinds of devices implanted, the issue is going to continue to come up until there is a solution. This is going to call more attention to it and increase the need for solutions to prevent hacking.”

Looking to the future of medical treatment, Dr Tracey is optimistic that bioelectronic medicine is here to stay. “It’s a way to think about taking everything we’ve learned about the molecular basis of medicine and go after it through the nervous system. And I look forward to the day when a lot of patients can be treated this way.

“With collaborators together under a very big tent of research, financial support and development, I believe that it’s only a matter of time before bioelectronic medicine fulfils its promise.

“It’s likely that this will produce a bigger, broader impact than cardiac stents,” Dr Tracey suggests. “When it does, the number of therapies using electricity will rival the number using biological agents. But what matters most to me is that by implanting one device for one disease, it should be possible to eliminate suffering and pain in individual patients.”

Bioelectronics in Ireland

Galway-based biomedical engineer Prof Gearóid Ó Laighin is “very involved” in the area of bioelectronics, through his research in electronic techniques for application in medicine.

He is Professor of Electronic Engineering at NUI Galway and Principal Investigator in the bioelectronics cluster in the National Centre for Biomedical Engineering Science (NCBES) at NUIG. He was founding Director of the Biomedical Electronics Laboratory at the University of Limerick.

The NCBES brings together engineers like Prof Ó Laighin, scientists and clinicians. Their research involves collaborative projects focused on cardiovascular, musculoskeletal, rehabilitation, and neural bioelectronics research. Research clusters work in the areas of biomechanics, biomaterials and tissue engineering, and bioelectronics.

“The kinds of things I’m involved in are neuromuscular electrical stimulation for use for a variety of medical applications. What you’re doing is, you’re artificially activating a neural response and that can give rise to muscular contraction or a sensory response,” Prof Ó Laighin explains in an interview with the Medical Independent.

“A major application of electrical stimulation in stroke rehab is called ‘drop-foot correction’. If you can apply electrical stimulation at the right point in the walking cycle, you can lift up the foot when it’s needed and drop it when it’s not needed to be lifted. The first use of the drop-foot stimulator was back in 1961. That was the first application of functional electrical stimulation. It now has the title of neuromuscular electrical stimulation, or NMES. You’re stimulating not the muscle, but the nerve structure because it’s easier to activate a nerve than a muscle.”

Using NMES, he says, much work has been done in the area of venous insufficiency. “Let’s say if a person is immobilised or they’re sedentary, the blood is pooling and that gives rise to all sorts of venous disease problems. You also have the so-called ‘economy-class syndrome’ when you’re flying and there’s the risk of deep-vein thrombosis. So we can apply electrical stimulation to the calf muscle to contract it cyclically and that can assist venous return.

“If a person is hospitalised for a long period of time and they are lying in bed, there would be a risk of pooling but by applying electrical stimulation, you are helping with that venous return and reducing the risk of deep-vein thrombosis.”

Prof Ó Laighin and his colleagues have now developed a muscle stimulator device that has been independently certified for safety and a significant amount of testing of that device has been carried out on patients. “At the moment it’s a research device, so for that to become a product on the market would require the involvement of a company that would bring it through the full regulatory process as a medical device.

“This device could be used in the home as well as in hospitals. It could be used in the home if you were concerned about varicose vein formation. One application would be that you would apply electrical stimulation in the evening to reduce your overall exposure to venous pressure during the day.”

Brainwave: The Neural Tourniquet

In June, the Feinstein Institute for Medical Research announced a partnership with Battelle, a non-profit scientific research and development organisation, to bring the ‘Neural Tourniquet’ from the lab to reality.

The Neural Tourniquet aims to staunch blood loss through electronic nerve stimulation. If successful it will be the first major breakthrough for the treatment and control of bleeding since the invention of the surgical tourniquet in the middle of the 19th Century.

Studies conducted during the past decade by the Feinstein Institute demonstrate that a nerve stimulation device can significantly reduce bleeding. Electrical stimulation of neural pathways to the spleen, for as little as 60 seconds, prepares the body for clotting in the event of a wound. The primed coagulation system is able to clot 50 per cent more rapidly and reduce the volume of blood loss by 50 per cent.

The Neural Tourniquet has anticipated applications in planned surgeries, emergency medicine and on the battlefield, and is slated to enter the market in the next three-to-five years.

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