FOR a long time, conventional medical wisdom held that there was no connection between the nervous and immune systems, but that was turned on its head in the late 1990s by Kevin Tracey, a professor of molecular medicine and neurosurgery at the Feinstein Institutes for Medical Research in Manhasset, New York.
In a TED Talk, he describes how it began with the death of a little girl called Janice, who was well on her way to recovery from burn wounds when she suddenly died from unexplainable sepsis.
“I realised that basic science lacked a fundamental understanding of why septic shock occurs," he says. “So I decided to go to the lab and study that. And what we found changed how the world thinks about how the body responds to infection.
“We found that it was not bacteria that caused shock but rather the immune system that produces a molecule called tumour necrosis factor, or TNF."
In small doses, TNF is beneficial to the body. Over a certain level, it creates dangerous inflammation which underlies conditions ranging from heart disease to Parkinson’s.
Tracey and his colleagues developed anti-TNF antibodies, and he says they were astonished when they gave these antibodies to a baboon in septic shock and watched how it recovered. Less than 10 years later, anti-TNF was approved for clinical use by the Food and Drug Administration (FDA) in the US.
But, says Tracey, he still found himself thinking about Janice, and he still wanted to understand how the body controlled the production of TNF — why, in some cases, it overproduces it to cause dangerous inflammation.
The first breakthrough
At the time, he was working with patients with diseases of the brain and spinal cord, and one of the first things any physician does in such cases is to test reflexes — tap knees with a rubber hammer or stroke corneas with cotton gauze.
“Reflexes are critical to maintaining healthy organ function, and when the brain swells and bends the brainstem, and cuts off those brainstem reflexes, patients can die from uncontrollable hypertension, apnoea or cardiac arrest."
At that point, nobody had connected the dots between reflexes and TNF … then something strange happened in Tracey's lab. They were studying rats with strokes and treating them with an experimental drug intended to block TNF in the brain, which it did. But surprisingly, they found it also blocked TNF in the heart, gut, liver and spleen.
“It was baffling," says Tracey. “It made no sense because there were no known connections between the brain and the immune system."
The next breakthrough
Tracey and his colleagues started searching for a neural connection that could explain how the brain controlled TNF (inflammatory) response in the body.
And that led them to the vagus nerve.
“The vagus nerve is one of the most important nerves of the body. It's like a transatlantic undersea cable that carries tens of thousands of individual wires to all the organs of the body. It wanders through the body and brings these nerves to the organs. These nerve endings control the activity of cells in the organs that keep them functioning healthily. We realised from a long series of experiments that the vagus nerve was carrying the ‘off switch’; that the vagus nerve was controlling TNF. And when we electrically stimulated the vagus nerve in rats, it turned off TNF in the body."
One could well ask, why electricity? Everything we do, from walking to dreaming, is controlled by tiny impulses travelling through our nervous system. The hub of electrical activity is in the brain; from there, nerves branch out to all corners of the body.
Tracey and his team had found a way to tap into the body's way of communicating through electrical impulses to switch off inflammation without using drugs.
Now, the task was replicating in human patients what they had seen in lab experiments.
Tracey devised an idea (he sketched the prototype on a paper napkin over lunch with colleagues) to put a small stimulator on the vagus nerve in the patient's neck and use it to send an electric signal that turns off TNF. What made it particularly exciting was that there was now a possibility that inflammation could be treated without drugs and their related side effects.
“My colleagues and I spent many years mapping in exquisite molecular detail the mechanisms to explain how signals travelling in the vagus nerve would control TNF. We found that inside the spleen, those electrical signals are turned into chemical signals, activating a white blood cell called the T cell. It responds by making acetylcholine, which turns off TNF — which causes inflammation."
Tracey recruited one of the world's leading rheumatologists, Paul Peter Tak, to do a clinical trial of vagus nerve stimulation in patients with rheumatoid arthritis. In 2016, they published the results of this study of 18 patients.
Patients entered the trial with high levels of TNF, suffering severe disability, severe joint pain, swelling and inability to move. With vagus nerve stimulators implanted, TNF levels started to fall within days. Within six weeks, they were nearly normal.
“[The patients'] pain went away, the swelling in their joints improved and their mobility returned," Tracey says. “One patient talked about how she couldn't grasp a pencil some mornings before the trial. She couldn't dress herself without assistance. She couldn't take long walks, something that she enjoyed. But after the trial, she's off her medication. Her pain is gone. She's taking long walks. And she's riding her bicycle 20-mile round trips to the Dutch coast on weekends."
Vagus nerve stimulation
Vagus nerve stimulation (VNS) is a hot topic across various disciplines, and several clinical trials and studies have looked at different therapeutic applications and possibilities.
Even TikTok and the internet are full of advice on stimulating your vagus nerve — from loud gargling with water and loud singing to activate the vocal cords, to foot massage and plunging your face into ice water.
Back in the serious world of medicine and science, there are now different well-researched methods and devices for performing vagus nerve stimulation. The FDA has approved a device to treat drug-resistant epilepsy and depression by sending impulses to those parts of the brain that regulate seizures and mood .
Another FDA-approved vagus nerve stimulation device treats patients recovering from strokes. It helps to create new brain pathways during exercise and can help people regain bodily functions.
In this paper, VNS is outlined as an effective therapy for treating migraines, cluster headaches and obesity.
And there is interesting new data from Tracey's labs on research into auto-immune diseases. VNS now seems like a promising treatment for Crohn's disease, a debilitating condition caused by inflammation of the gastrointestinal tract.
Preclinical studies and clinical trials have also suggested a potential benefit in treating certain inflammatory bowel diseases, bipolar disorder, obesity and Alzheimer's. Even alcoholism.
As more applications are found for this non-invasive way of controlling inflammation in the body, for electricity replacing pills or complementing drugs, a radical new frontier of bioelectric medicine opens up.
In a recent article, NewScientist says unravelling the secrets of the vagus nerve will “revolutionise medicine", and mapping the nerve's complex structure of more than 160,000 fibres could usher in a new era of precision treatments.
“There are billions of neurons in the body that interact with almost every cell in the body and at each of those nerve endings," says Tracey.
“Molecular signals control molecular mechanisms that can be defined and mapped and potentially put under control. Many of these mechanisms are also involved in important diseases like cancer, Alzheimer's disease, diabetes, hypertension and shock."
“It's a big idea."
♦ VWB ♦
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