May 12, 2015
Using Electricity to Treat Arthritis and Cancer?
Electrical Therapy: Background
Medscape: What exactly is bioelectrical medicine?
Dr Tracey: Bioelectronic medicine is the concept of beginning with the drug target in mind rather than the drug or device. You ask, "What are the nerve circuits that can control that target?," and then identify devices or methods to act on those nerves in order to control the therapeutic target.
If you look at the history of implantable devices, most of them are based on the device itself. Only years later, or sometimes never, do we figure out exactly what the molecular mechanism of action is for the device. What we're proposing now is to say, "Okay, let's begin with the target in mind."
Medscape: How did you get involved in bioelectrical research?
Dr Tracey: It was an unexpected result in the lab that prompted this from the beginning. We had developed a new anti-inflammatory molecule, named CNI-1493, and we were studying its effects in the brain. Surprisingly, a small amount of CNI-1493 in the brain completely blocked the release of tumor necrosis factor (TNF)—a proinflammatory cytokine—throughout the body of the animal. This made almost no scientific sense at the time. In the course of unraveling that finding, it became clear that we had come across something that was extremely important—the ability to control the drug target, TNF, by using a mechanism that was based on nerve function. The mechanism proved to be dependent upon CNI-1493 activating the vagus nerve, and signals traveling in this nerve to the body inhibited TNF production by the immune system.
Medscape: Was there prior research suggesting this relationship between the immune and nervous systems?
Dr Tracey: The results were completely unexpected and generated a series of papers in Science andNature.[1-5] What those papers did was reveal very precisely how a neural reflex circuit works to control TNF at a molecular level.
Medscape: In rodent work, you identified neuronal pathways—particularly in the vagus nerve—that innervate organs and influence local immune and inflammatory activity. Can you elaborate on this?
Dr Tracey: We started by mapping the nerve pathways and ended up inside the spleen. When we began to look at the signaling inside the spleen, it was revealed that the nerve signals were converted to chemical signals that required signaling through a T cell. This was another surprise—a nerve traveling into the spleen to control a group of immune cells. Those T cells in turn respond to the nerve signal by making the neurotransmitter acetylcholine, which then inhibits macrophages from producing TNF.
Medscape: So you're saying that neuronal activity can dampen an inflammatory response?
Dr Tracey: Absolutely. Yes.
Treating Inflammation (and Possibly Cancer)
Medscape: What conditions has bioelectrical therapy been tested in? Also, can you describe the device you helped develop?
Dr Tracey: I cofounded a company called SetPoint Medical, which performed the clinical trials. The first trial results were reported at the American College of Rheumatology and were done with a vagus nerve stimulator designed to treat patients with epilepsy. It's implanted in the chest. The lead from the stimulator is carried to the neck and put on the vagus nerve. From there, it works very similarly to what I've been explaining. The signals travel in the vagus nerve to block TNF production. The first trial tested the device in patients with rheumatoid arthritis and showed a significant clinical response.
Medscape: Can you briefly review the efficacy and safety findings that came out of that first trial?
Dr Tracey: The initial patients who were treated had a very significant clinical response. There's a patient I met in Bosnia who went from being unable to walk around or play with his kids to essentially returning to work as a truck driver and playing with his children regularly. He had a dramatic clinical response after having a vagus nerve stimulator implanted. The New York Times reported another patient who was unable to even pick up a pencil prior to receiving an implant. She had not responded to many biologic agents, but now she's essentially in remission. It's fairly clear that the approach can work in patients. It's hard to argue that when someone has failed to respond to five biologic agents that her improvement is due to the placebo effect. There are plans to have these trials replicated and extended.
There are also ongoing trials in inflammatory bowel disease, another disease in which anti-TNF treatment is often used. But I think we're just at the tip of the iceberg. The vagus nerve has 80,000 fibers in it, and the challenge will be to develop strategies where we can just target a few of those fibers. The other opportunity that exists is to extend the idea of using devices to target other nerves and to control other therapeutic endpoints.
Medscape: Bioelectrical therapy also shows promise in cancer, correct?
Dr Tracey: Yes, there are some very interesting data from a number of laboratories that nerves producing nerve-derived signals can control the ability of some tumors to grow and of some tumors to metastasize. Considering what we know about angiogenesis and factors regulating metastatic potential, we can begin to think in terms of how those drug targets might be influenced by neurotransmitter-based signals. This is not something in the distant future; this is a testable hypothesis now. It's being tested as we speak.
The key to future bioelectronic medicines will be based on the molecular mechanisms that regulate the therapeutic target. For example, let's say that you wanted to go after cyclo-oxygenase as the target of aspirin or celecoxib (Celebrex®). The question becomes: "In which tissue do you want to control cyclo-oxygenase?" Let's say that you want to control it in the heart or the liver: The approach will be to map the nerve circuits to the liver that control cyclo-oxygenase. In this way, you may actually be able to develop a device that wouldn’t have the side effects of celecoxib, for instance, because the device could target the cyclo-oxygenase in the liver without affecting the heart.
Medscape: So rather than focusing on a specific disease, you would focus on the localized molecular target itself?
Dr Tracey: Yes. It's like flipping through pharmacopeia and saying that this drug hits this target—then you ask yourself, "What nerves can we stimulate to hit this target?"
Advantages and Drawbacks
Medscape: What are the advantages and disadvantages of bioelectrical approaches compared with those of pharmacotherapies?
Dr Tracey: It is possible that bioelectrical therapy can avoid many drug side effects attributable to either off-target activities or from clearance mechanisms producing toxic metabolites. None of this would be expected to happen with localized nerve stimulation that focuses specific release of neurotransmitters in a select tissue for a brief period of time.
Medscape: Do you then see bioelectrical therapy as replacing certain drug therapies?
Dr Tracey: I think that some drugs can potentially be replaced. On the other hand, I don't think that devices are going to replace all drugs. I think that they're going to supplement some drugs, replace some drugs, and that some drugs are here to stay.
Medscape: Could bioelectrical implants also be used to monitor inflammatory disease activity?
Dr Tracey: Yes. The father of reflex biology, Charles Sherrington, pointed out that reflexes originate with sensory input. There is no reflex response without a change in the environment that is sensed by sensory nerves. Within the sensory nerves resides the information required to activate the outgoing neurosignals. So, if the key to these outgoing signals is held by the incoming sensory signals, then there's a tremendous opportunity for mapping the incoming signals in response to changes in the inflammatory or metabolic environment. My colleagues and I are actively pursuing this now.
Medscape: How widely are bioelectrical approaches being studied? Are there other groups pursuing similar research avenues?
Dr Tracey: There is a tremendous ecosystem of research out there now. The National Institutes of Health has launched a major initiative in support of this, on the order of $248 million. The Defense Advanced Research Projects Agency has announced a major initiative as well. And GlaxoSmithKline, one of the world's largest drug companies, has launched an initiative upwards of $50 million. SetPoint Medical, the company I cofounded, has also actively engaged in clinical trials. Here at the Feinstein Institute at the North Shore-LIJ Health System, we are in the process of significantly expanding our investment in this area. We are looking now to add an additional 10 laboratories or more into a new center for bioelectronic medicine.
iPads and Administration
Medscape: Who will actually implant bioelectrical devices?
Dr Tracey: I think at the outset, devices will be implanted surgically—whether by neurosurgeons or other specialists will depend on the indication. Downstream in the not so distant future, as these devices get smaller and more adaptable, I think they'll be implanted percutaneously by any number of specialists, including cardiologists and interventional radiologists. Maybe someday even general practitioners could be involved in deploying devices using patches or transdermal application.
Medscape: And how are the devices controlled?
Dr Tracey: These devices will communicate to the doctor through hand-held iPads and smartphones. The "prescription"—the degree of nerve stimulation or inhibition—will be delivered from the doctor's iPad right to the patient's device.
Medscape: Do you have final thoughts on the potential of bioelectrical technology in medicine?
Dr Tracey: We are not talking about the distant future. It's happening already, and there is clear evidence that it works through mechanisms that we understand and can modulate. I believe that the adoption of these devices and of this approach will be driven by clinical successes, patient satisfaction, and the interest that doctors have in providing therapies to their patients that are less toxic, safer, and more effective.