The decade-long quest to hack the body’s immune system with electricity

Starting in the 1990s, research by Linda Watkins, a neuroscientist leading a team at the University of Colorado, Boulder, suggested that this main superhighway of the peripheral nervous system was not a one-way street after all. Instead it seemed to carry message traffic in both directions, not just into the brain but from the brain back into all those organs. Furthermore, it appeared that this comms link allows the brain to exert some control over the immune system—for example, stoking a fever in response to an infection.

And unlike the brain or spinal cord, the vagus nerve is comparatively easy to access: its path to and from the brain stem runs close to the surface of the neck, along a big cable on either side. You could just pop an electrode on it—typically on the left branch—and get zapping.

Meddling with the flow of traffic up the vagus nerve in this way had successfully treated issues in the brain, specifically epilepsy and treatment-resistant depression (and electrical implants for those applications were approved by the FDA around the turn of the millennium). But the insights from Watkins’s team put the down direction in play. 

It was Kevin Tracey who joined all these dots, after which it did not take long for him to become the public face of research on vagus nerve stimulation. During the 2000s, he showed that electrically stimulating the nerve calmed inflammation in animals. This “inflammatory reflex,” as he came to call it, implied that the vagus nerve could act as a switch capable of turning off a wide range of diseases, essentially hacking the immune system. In 2007, while based at what is now called the Feinstein Institute for Medical Research, in New York, he spun his insights off into a Boston startup called SetPoint Medical. Its aim was to develop devices to flip this switch and bring relief, starting with inflammatory bowel disease and rheumatoid arthritis

By 2012, a coordinated relationship had developed between GSK, Tracey, and US government agencies. Tracey says that Famm and others contacted him “to help them on that Nature article.” A year later the electroceuticals road map was ready to be presented to the public.

The story the researchers told about the future was elegant and simple. It was illustrated by a tale Tracey recounted frequently on the publicity circuit, of a first-in-human case study SetPoint had coordinated at the University of Amsterdam’s Academic Medical Center. That team had implanted a vagus nerve stimulator in a man suffering from rheumatoid arthritis. The stimulation triggered his spleen to release a chemical called acetylcholine. This in turn told the cells in the spleen to switch off production of inflammatory molecules called cytokines. For this man, the approach worked well enough to let him resume his job, play with his kids, and even take up his old hobbies. In fact, his overenthusiastic resumption of his former activities resulted in a sports injury, as Tracey delighted in recounting for reporters and conferences.

Such case studies opened the money spigot. The combination of a wider range of disease targets and less risky surgical targets was an investor’s love language. Where deep brain stimulation and other invasive implants had been limited to rare, obscure, and catastrophic problems, this new interface with the body promised many more customers: the chronic diseases now on the table are much more prevalent, including not only rheumatoid arthritis but diabetes, asthma, irritable bowel syndrome, lupus, and many other autoimmune disorders. GSK launched an investment arm it dubbed Action Potential Venture Capital Limited, with $50 million in the coffers to invest in the technologies and companies that would turn the futuristic vision of electroceuticals into reality. Its inaugural investment was a $5 million stake in SetPoint. 

If you were superstitious, what happened next might have looked like an omen. The word “electroceutical” already belonged to someone else—a company called Ivivi Technologies had trademarked it in 2008. “I am fairly certain we sent them a letter soon after they started that campaign, to alert them of our trademark,” says Sean Hagberg, a cofounder and then chief science officer at the company. Today neither GSK nor SetPoint can officially call its tech “electroceuticals,” and both refer to the implants they are developing as “bioelectronic medicine.” However, this umbrella term encompasses a wide range of other interventions, some quite well established, including brain implants, spine implants, hypoglossal nerve stimulation for sleep apnea (which targets a motor nerve running through the vagus), and other peripheral-nervous-system implants, including those for people with severe gastric disorders.

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