People can move this bionic leg just by thinking about it

When someone loses part of a leg, a prosthetic can make it easier to get around. But most prosthetics are static, cumbersome, and hard to move. A new neural interface connects a bionic limb to nerve endings in the thigh, allowing the limb to be controlled by the brain. The new device, which is described today in Nature Medicine, could help people with lower-leg amputations feel as if their prosthesis is part of them.

“When you ask a patient ‘What is your body?’ They don’t include the prosthesis,” says MIT biophysicist Hugh Herr, one of the lead authors on the study. The work is personal for him: he lost both his lower legs in a climbing accident when he was 17. He says linking the brain to the prosthesis can make it feel more like part of someone’s anatomy, which can have a positive emotional impact. 

Getting the neural interface hooked up to a prosthetic takes two steps. First, patients undergo surgery. Following a lower leg amputation, portions of shin and calf muscle still remain. The operation connects shin muscle, which contracts to make the ankle flex upward, to calf muscle, which counteracts this movement. The prosthetic can also be fitted at this point. Reattaching the remnants of these muscles can enable the prosthetic to move more dynamically. It can also reduce phantom limb pain, and patients are less likely to trip and fall. 

“The surgery stands on its own,” says Amy Pietrafitta, a para-athlete who received it in 2018. “I feel like I have my leg back.” But natural movements are still limited when the prosthetic isn’t connected to the nervous system. 

In step two, surface electrodes measure nerve activity from the brain to the calf and shin muscles, indicating an intention to move the lower leg. A small computer in the bionic leg decodes those nerve signals and moves the leg accordingly, allowing the patient to move the limb more naturally. 

“If you have intact biological limbs, you can walk up and down steps, for example, and not even think about it. It’s involuntary,” says Herr. “That’s the case with our patients, but their limb is made of titanium and silicone.” 

The authors compared the mobility of seven patients using a neural interface with that of patients who had not received the surgery. Patients using the neural interface could walk 41% faster and climb sloped surfaces and steps. They could also dodge obstacles more nimbly and had better balance. And they described feeling that the prosthetic was truly a part of their body rather than just a tool that they used to get around. 

“It’s a very forward-thinking approach,” says Hamid Charkhkar, a biomedical engineer at Case Western Reserve University, who was not involved in the study. “Our limbs are not like shoes. They’re not worn over our bodies. They are integrally attached to our bodies via bones, muscles, and nerves.” 

There are limitations. The surgery can be done during amputation or several years later, but it won’t work equally well for every patient. If it’s done later, for example, some people’s upper thigh muscles could have atrophied too severely for them to receive the full benefits. 

The surgery connecting the shin and calf muscles has become the standard of care at Brigham and Women’s Hospital in Boston. But the surface electrodes that give patients full neural control of their limbs are a few years away from being clinically implemented. Plus, the neural interfaces have only been used in laboratory settings, and it will be important to know how they hold up in the real world. 

Herr and his team at MIT hope to provide users with even greater control over their prosthetic limbs. In the future, their efforts will likely involve replacing the surface electrodes with magnetic spheres, which can more accurately track muscle dynamics. 

“The goal that we have is to really reconstruct bodies, to rebuild bodies,” says Herr. And to fully achieve that ambition, he says, “neural integration and embodiment is our long-term goal.” 

Is this the end of animal testing?

In a clean room in his lab, Sean Moore peers through a microscope at a bit of intestine, its dark squiggles and rounded structures standing out against a light gray background. This sample is not part of an actual intestine; rather, it’s human intestinal cells on a tiny plastic rectangle, one of 24 so-called “organs on chips” his lab bought three years ago.

Moore, a pediatric gastroenterologist at the University of Virginia School of Medicine, hopes the chips will offer answers to a particularly thorny research problem. He studies rotavirus, a common infection that causes severe diarrhea, vomiting, dehydration, and even death in young children. In the US and other rich nations, up to 98% of the children who are vaccinated against rotavirus develop lifelong immunity. But in low-income countries, only about a third of vaccinated children become immune. Moore wants to know why.

His lab uses mice for some protocols, but animal studies are notoriously bad at identifying human treatments. Around 95% of the drugs developed through animal research fail in people. Researchers have documented this translation gap since at least 1962. “All these pharmaceutical companies know the animal models stink,” says Don Ingber, founder of the Wyss Institute for Biologically Inspired Engineering at Harvard and a leading advocate for organs on chips. “The FDA knows they stink.” 

But until recently there was no other option. Research questions like Moore’s can’t ethically or practically be addressed with a randomized, double-blinded study in humans. Now these organs on chips, also known as microphysiological systems, may offer a truly viable alternative. They look remarkably prosaic: flexible polymer rectangles about the size of a thumb drive. In reality they’re triumphs of bioengineering, intricate constructions furrowed with tiny channels that are lined with living human tissues. These tissues expand and contract with the flow of fluid and air, mimicking key organ functions like breathing, blood flow, and peristalsis, the muscular contractions of the digestive system.

More than 60 companies now produce organs on chips commercially, focusing on five major organs: liver, kidney, lung, intestines, and brain. They’re already being used to understand diseases, discover and test new drugs, and explore personalized approaches to treatment.

As they continue to be refined, they could solve one of the biggest problems in medicine today. “You need to do three things when you’re making a drug,” says Lorna Ewart, a pharmacologist and chief scientific officer of Emulate, a biotech company based in Boston. “You need to show it’s safe. You need to show it works. You need to be able to make it.” 

All new compounds have to pass through a preclinical phase, where they’re tested for safety and effectiveness before moving to clinical trials in humans. Until recently, those tests had to run in at least two animal species—usually rats and dogs—before the drugs were tried on people. 

But in December 2022, President Biden signed the FDA Modernization Act, which amended the original FDA Act of 1938. With a few small word changes, the act opened the door for non-animal-based testing in preclinical trials. Anything that makes it faster and easier for pharmaceutical companies to identify safe and effective drugs means better, potentially cheaper treatments for all of us. 

Moore, for one, is banking on it, hoping the chips help him and his colleagues shed light on the rotavirus vaccine responses that confound them. “If you could figure out the answer,” he says, “you could save a lot of kids’ lives.”

While many teams have worked on organ chips over the last 30 years, the OG in the field is generally acknowledged to be Michael Shuler, a professor emeritus of chemical engineering at Cornell. In the 1980s, Shuler was a math and engineering guy who imagined an “animal on a chip,” a cell culture base seeded with a variety of human cells that could be used for testing drugs. He wanted to position a handful of different organ cells on the same chip, linked to one another, which could mimic the chemical communication between organs and the way drugs move through the body. “This was science fiction,” says Gordana Vunjak-Novakovic, a professor of biomedical engineering at Columbia University whose lab works with cardiac tissue on chips. “There was no body on a chip. There is still no body on a chip. God knows if there will ever be a body on a chip.”

Shuler had hoped to develop a computer model of a multi-organ system, but there were too many unknowns. The living cell culture system he dreamed up was his bid to fill in the blanks. For a while he played with the concept, but the materials simply weren’t good enough to build what he imagined. 

“You can force mice to menstruate, but it’s not really menstruation. You need the human being.”

Linda Griffith, founding professor of biological engineering at MIT and a 2006 recipient of a MacArthur “genius grant”

He wasn’t the only one working on the problem. Linda Griffith, a founding professor of biological engineering at MIT and a 2006 recipient of a MacArthur “genius grant,” designed a crude early version of a liver chip in the late 1990s: a flat silicon chip, just a few hundred micrometers tall, with endothelial cells, oxygen and liquid flowing in and out via pumps, silicone tubing, and a polymer membrane with microscopic holes. She put liver cells from rats on the chip, and those cells organized themselves into three-dimensional tissue. It wasn’t a liver, but it modeled a few of the things a functioning human liver could do. It was a start.

Griffith, who rides a motorcycle for fun and speaks with a soft Southern accent, suffers from endometriosis, an inflammatory condition where cells from the lining of the uterus grow throughout the abdomen. She’s endured decades of nausea, pain, blood loss, and repeated surgeries. She never took medical leaves, instead loading up on Percocet, Advil, and margaritas, keeping a heating pad and couch in her office—a strategy of necessity, as she saw no other choice for a working scientist. Especially a woman. 

And as a scientist, Griffith understood that the chronic diseases affecting women tend to be under-researched, underfunded, and poorly treated. She realized that decades of work with animals hadn’t done a damn thing to make life better for women like her. “We’ve got all this data, but most of that data does not lead to treatments for human diseases,” she says. “You can force mice to menstruate, but it’s not really menstruation. You need the human being.” 

Or, at least, the human cells. Shuler and Griffith, and other scientists in Europe, worked on some of those early chips, but things really kicked off around 2009, when Don Ingber’s lab in Cambridge, Massachusetts, created the first fully functioning organ on a chip. That “lung on a chip” was made from flexible silicone rubber, lined with human lung cells and capillary blood vessel cells that “breathed” like the alveoli—tiny air sacs—in a human lung. A few years later Ingber, an MD-PhD with the tidy good looks of a younger Michael Douglas, founded Emulate, one of the earliest biotech companies making microphysiological systems. Since then he’s become a kind of unofficial ambassador for in vitro technologies in general and organs on chips in particular, giving hundreds of talks, scoring millions in grant money, repping the field with scientists and laypeople. Stephen Colbert once ragged on him after the New York Times quoted him as describing a chip that “walks, talks, and quacks like a human vagina,” a quote Ingber says was taken out of context.

Ingber began his career working on cancer. But he struggled with the required animal research. “I really didn’t want to work with them anymore, because I love animals,” he says. “It was a conscious decision to focus on in vitro models.” He’s not alone; a growing number of young scientists are speaking up about the distress they feel when research protocols cause pain, trauma, injury, and death to lab animals. “I’m a master’s degree student in neuroscience and I think about this constantly. I’ve done such unspeakable, horrible things to mice all in the name of scientific progress, and I feel guilty about this every day,” wrote one anonymous student on Reddit. (Full disclosure: I switched out of a psychology major in college because I didn’t want to cause harm to animals.)

EMULATE

Taking an undergraduate art class led Ingber to an epiphany: mechanical forces are just as important as chemicals and genes in determining the way living creatures work. On a shelf in his office he still displays a model he built in that art class, a simple construction of sticks and fishing line, which helped him realize that cells pull and twist against each other. That realization foreshadowed his current work and helped him design dynamic microfluidic devices that incorporated shear and flow. 

Ingber coauthored a 2022 paper that’s sometimes cited as a watershed in the world of organs on chips. Researchers used Emulate’s liver chips to reevaluate 27 drugs that had previously made it through animal testing and had then gone on to kill 242 people and necessitate more than 60 liver transplants. The liver chips correctly flagged problems with 22 of the 27 drugs, an 87% success rate compared with a 0% success rate for animal testing. It was the first time organs on chips had been directly pitted against animal models, and the results got a lot of attention from the pharmaceutical industry. Dan Tagle, director of the Office of Special Initiatives for the National Center for Advancing Translational Sciences (NCATS), estimates that drug failures cost around $2.6 billion globally each year. The earlier in the process failing compounds can be weeded out, the more room there is for other drugs to succeed.

“The capacity we have to test drugs is more or less fixed in this country,” says Shuler, whose company, Hesperos, also manufactures organs on chips. “There are only so many clinical trials you can do. So if you put a loser into the system, that means something that could have won didn’t get into the system. We want to change the success rate from clinical trials to a much higher number.”

In 2011, the National Institutes of Health established NCATS and started investing in organs on chips and other in vitro technologies. Other government funders, like the Defense Advanced Research Projects Agency and the Food and Drug Administration, have followed suit. For instance, NIH recently funded NASA scientists to send heart tissue on chips into space. Six months in low gravity ages the cardiovascular system 10 years, so this experiment lets researchers study some of the effects of aging without harming animals or humans. 

Scientists have made liver chips, brain chips, heart chips, kidney chips, intestine chips, and even a female reproductive system on a chip (with cells from ovaries, fallopian tubes, and uteruses that release hormones and mimic an actual 28-day menstrual cycle). Each of these chips exhibits some of the specific functions of the organs in question. Cardiac chips, for instance, contain heart cells that beat just like heart muscle, making it possible for researchers to model disorders like cardiomyopathy. 

Shuler thinks organs on chips will revolutionize the world of research for rare diseases. “It is a very good model when you don’t have enough patients for normal clinical trials and you don’t have a good animal model,” he says. “So it’s a way to get drugs to people that couldn’t be developed in our current pharmaceutical model.” Shuler’s own biotech company used organs on chips to test a potential drug for myasthenia gravis, a rare neurological disorder. In 2022,the FDA approved the drug for clinical trials based on that data—one of six Hesperos drugs that have so far made it to that stage. 

Each chip starts with a physiologically based pharmacokinetic model, known as a PBPK model—a mathematical expression of how a chemical compound behaves in a human body. “We try and build a physical replica of the mathematical model of what really occurs in the body,” explains Shuler. That model guides the way the chip is designed, re-creating the amount of time a fluid or chemical stays in that particular organ—what’s known as the residence time. “As long as you have the same residence time, you should get the same response in terms of chemical conversion,” he says.

Tiny channels on each chip, each between 10 and 100 microns in diameter, help bring fluids and oxygen to the cells. “When you get down to less than one micron, you can’t use normal fluid dynamics,” says Shuler. And fluid dynamics matters, because if the fluid moves through the device too quickly, the cells might die; too slowly, and the cells won’t react normally. 

Chip technology, while sophisticated, has some downsides. One of them is user friendliness. “We need to get rid of all this tubing and pumps and make something that’s as simple as a well plate for culturing cells,” says Vunjak-Novakovic. Her lab and others are working on simplifying the design and function of such chips so they’re easier to operate and are compatible with robots, which do repetitive tasks like pipetting in many labs. 

Cost and sourcing can also be challenging. Emulate’s base model, which looks like a simple rectangular box from the outside,starts at around $100,000 and rises steeply from there. Most human cells come from commercial suppliers that arrange for donations from hospital patients. During the pandemic, when people had fewer elective surgeries, many of those sources dried up. As microphysiological systems become more mainstream, finding reliable sources of human cells will be critical.

“As your confidence in using the chips grows, you might say, Okay, we don’t need two animals anymore— we could go with chip plus one animal.”

Lorna Ewart, Chief Scientific Officer, Emulate

Another challenge is that every company producing organs on chips uses its own proprietary methods and technologies. Ingber compares the landscape to the early days of personal computing, when every company developed its own hardware and software, and none of them meshed well. For instance, the microfluidic systems in Emulate’s intestine chips are fueled by micropumps, while those made by Mimetas, another biotech company, use an electronic rocker and gravity to circulate fluids and air. “This is not an academic lab type of challenge,” emphasizes Ingber. “It’s a commercial challenge. There’s no way you can get the same results anywhere in the world with individual academics making [organs on chips], so you have to have commercialization.”

Namandje Bumpus, the FDA’s chief scientist, agrees. “You can find differences [in outcomes] depending even on what types of reagents you’re using,” she says. Those differences mean research can’t be easily reproduced, which diminishes its validity and usefulness. “It would be great to have some standardization,” she adds.

On the plus side, the chip technology could help researchers address some of the most deeply entrenched health inequities in science. Clinical trials have historically recruited white men, underrepresenting people of color, women (especially pregnant and lactating women), the elderly, and other groups. And treatments derived from those trials all too often fail in members of those underrepresented groups, as in Moore’s rotavirus vaccine mystery. “With organs on a chip, you may be able to create systems by which you are very, very thoughtful—where you spread the net wider than has ever been done before,” says Moore.

FELICE FRANKEL

Another advantage is that chips will eventually reduce the need for animals in the lab even as they lead to better human outcomes. “There are aspects of animal research that make all of us uncomfortable, even people that do it,” acknowledges Moore. “The same values that make us uncomfortable about animal research are also the same values that make us uncomfortable with seeing human beings suffer with diseases that we don’t have cures for yet. So we always sort of balance that desire to reduce suffering in all the forms that we see it.”

Lorna Ewart, who spent 20 years at the pharma giant AstraZeneca before joining Emulate, thinks we’re entering a kind of transition time in research, in which scientists use in vitro technologies like organs on chips alongside traditional cell culture methods and animals. “As your confidence in using the chips grows, you might say, Okay, we don’t need two animals anymore—we could go with chip plus one animal,” she says. 

In the meantime, Sean Moore is excited about incorporating intestine chips more and more deeply into his research. His lab has been funded by the Gates Foundation to do what he laughingly describes as a bake-off between intestine chips made by Emulate and Mimetas. They’re infecting the chips with different strains of rotavirus to try to identify the pros and cons of each company’s design. It’s too early for any substantive results, but Moore says he does have data showing that organ chips are a viable model for studying rotavirus infection. That could ultimately be a real game-changer in his lab and in labs around the world.

“There’s more players in the space right now,” says Moore. “And that competition is going to be a healthy thing.” 

Harriet Brown writes about health, medicine, and science. Her most recent book is Shadow Daughter: A Memoir of Estrangement. She’s a professor of magazine, news, and digital journalism at Syracuse University’s Newhouse School. 

FDA advisors just said no to the use of MDMA as a therapy

On Tuesday, the FDA asked a panel of experts to weigh in on whether the evidence shows that MDMA, also known as ecstasy, is a safe and efficacious treatment for PTSD. The answer was a resounding no. Just two out of 11 panel members agreed that MDMA-assisted therapy is effective. And only one panel member thought the benefits of the therapy outweighed the risks.

The outcome came as a surprise to many, given that trial results have been positive. And it is also a blow for advocates who have been working to bring psychedelic therapy into mainstream medicine for more than two decades. This isn’t the final decision on MDMA. The FDA has until August 11 to make that ruling. But while the agency is under no obligation to follow the recommendations of its advisory committees, it rarely breaks with their decisions.  

Today on The Checkup, let’s unpack the advisory committee’s vote and talk about what it means for the approval of other recreational drugs as therapies.

One of the main stumbling blocks for the committee was the design of the two efficacy studies that have been completed. Trial participants weren’t supposed to know whether they were in the treatment group, but the effects of MDMA make it pretty easy to tell whether you’ve been given a hefty dose, and most correctly guessed which group they had landed in. 

In 2021, MIT Technology Review’s Charlotte Jee interviewed an MDMA trial participant named Nathan McGee. “Almost as soon as I said I didn’t think I’d taken it, it kicked in. I mean, I knew,” he told her. “I remember going to the bathroom and looking in the mirror, and seeing my pupils looking like saucers. I was like, ‘Wow, okay.’”

The Multidisciplinary Association for Psychedelic Studies, better known as MAPS, has been working with the FDA to develop MDMA as a treatment since 2001. When the organization met with the FDA in 2016 to hash out the details of its phase III trials, studies to test whether a treatment works, agency officials suggested that MAPS use an active compound for the control group to help mask whether participants had received the drug. But MAPS pushed back, and the trial forged ahead with a placebo. 

No surprise, then, that about 90% of those assigned to the MDMA group and 75% of those assigned to the placebo group accurately identified which arm of the study they had landed in. And it wasn’t just participants. Therapists treating the participants also likely knew whether those under their supervision had been given the drug. It’s called “functional unblinding,” and the issue came up at the committee meeting again and again. Here’s why it’s a problem: If a participant strongly believes that MDMA will help their PTSD and they know they’ve received MDMA, this expectation bias could amplify the treatment effect. This is especially a problem when the outcome is based on subjective measures like how a person feels rather than, say, laboratory data.

Another sticking point was the therapy component of the treatment. Lykos Therapeutics (the for-profit spinoff of MAPS) asked the FDA to approve MDMA-assisted therapy: that’s MDMA administered in concert with psychotherapy. Therapists oversaw participants during the three MDMA sessions. But participants also received three therapy sessions before getting the drug, and three therapy sessions afterwards to help them process their experience. 

Because the two treatments were administered together, there was no good way to tell how much of the effect was due to MDMA and how much was due to the therapy. What’s more, “the content or approach of these integrated sessions was not standardized in the treatment manuals and was mainly left up to the individual therapist,” said David Millis, a clinical reviewer for the FDA, at the committee meeting. 

Several committee members also raised safety concerns. They worried that MDMA’s effects might make people more suggestible and vulnerable to abuse, and they brought up allegations of ethics violations outlined in a recent report from the Institute for Clinical and Economic Review. 

Because of these issues and others, most committee members felt compelled to vote against MDMA-assisted therapy. “I felt that the large positive effect was denuded by the significant confounders,” said committee member Maryann Amirshahi, a professor of emergency medicine at Georgetown University School of Medicine, after the vote. “Although I do believe that there was a signal, it just needs to be better studied.”

Whether this decision will be a setback for the entire field remains to be seen. “To make it crystal clear: It isn’t MDMA itself that was rejected per se, but the specific, poor data set provided by Lykos Therapeutics; in my opinion, there is still a strong chance that MDMA, with a properly conducted clinical Phase 3 trial program that addresses those concerns of the FDA advisory committee, will get approved.” wrote Christian Angermayer, founder of ATAI Therapeutics, a company that is also working to develop MDMA as a therapy.

If the FDA denies approval of MDMA therapy, Lykos or another company could conduct additional studies and reapply. Many of the committee members said they believed MDMA does hold promise, but that the studies conducted thus far were inadequate to demonstrate the drug’s safety and efficacy. 

Psilocybin is likely to be the next psychedelic therapy considered by the FDA, and in some ways, it might have an easier path to approval. The idea behind MDMA is that it alleviates PTSD by helping facilitate psychotherapy. The therapy is a crucial component of the treatment, which is problematic because the FDA regulates drugs, not psychotherapy. With psilocybin, a therapist is present, but the drug appears to do the heavy lifting. “We are not offering therapy; we are offering psychological support that’s designed for the patient’s safety and well-being,” says Kabir Nath, CEO of Compass Pathways, the company working to bring psilocybin to market. “What we actually find during a six- to eight-hour session is most of it is silent. There’s actually no interaction.”

That could make the approval process more straightforward. “The difficult thing … is that we don’t regulate psychotherapy, and also we don’t really have any say in the design or the implementation of the particular therapy that is going to be used,” said Tiffany  Farchione, director of the FDA’s division of psychiatry, at the committee meeting. “This is something unprecedented, so we certainly want to get as many opinions and as much input as we can.” 

Another thing

Earlier this week, I explored what might happen if MDMA gets FDA approval and how the decision could affect other psychedelic therapies. 

Sally Adee dives deep into the messy history of electric medicine and what the future might hold for research into electric therapies. “Instead of focusing only on the nervous system—the highway that carries electrical messages between the brain and the body—a growing number of researchers are finding clever ways to electrically manipulate cells elsewhere in the body, such as skin and kidney cells, more directly than ever before,” she writes. 

Now read the rest of The Checkup

Read more from MIT Technology Review’s archive

Psychedelics are undeniably having a moment, and the therapy might prove particularly beneficial to women, wrote Taylor Majewski in this feature from 2022.

In a previous issue of The Checkup, Jessica Hamzelou argued that the psychedelic hype bubble might be about to burst.

MDMA does seem to have helped some individuals. Nathan McGee, who took the drug as part of a clinical trial, told Charlotte Jee that he “understands what joy is now.” 

Researchers are working to design virtual-reality programs that recreate the trippy experience of taking psychedelics. Hana Kiros has the story. 

From around the web

In April I wrote about Lisa Pisano, the second person to receive a pig kidney. This week doctors removed the kidney after it failed owing to lack of blood flow.

Bird flu is still very much in the news.

–   Finland is poised to become the first country to start administering bird flu vaccine—albeit to a very limited subset of people, including poultry and mink farmers, vets, and scientists who study the virus  (Stat)

–   What are the most pressing questions about bird flu? They revolve around what’s happening in cows, what’s happening in farm workers, and what’s happening to the virus. (Stat)

– A man in Mexico has died of H5N2, a strain of bird flu that has never before been reported in humans. (CNN)

Biodegradable, squishy sensors injected into the brain hold promise for detecting changes following a head injury or cancer treatment. (Nature)

A synthetic version of a hallucinogenic toad toxin could be a promising treatment for mental-health disorders. (Undark)

The messy quest to replace drugs with electricity

In the early 2010s, electricity seemed poised for a hostile takeover of your doctor’s office. Research into how the nervous system controls the immune response was gaining traction. And that had opened the door to the possibility of hacking into the body’s circuitry and thereby controlling a host of chronic diseases, including rheumatoid arthritis, asthma, and diabetes, as if the immune system were as reprogrammable as a computer.

To do that you’d need a new class of implant: an “electroceutical,” formally introduced in an article in Nature in 2013. “What we are doing is developing devices to replace drugs,” coauthor and neurosurgeon Kevin Tracey told Wired UK. These would become a “mainstay of medical treatment.” No more messy side effects. And no more guessing whether a drug would work differently for you and someone else.

There was money behind this vision: the British pharmaceutical giant GlaxoSmithKline announced a $1 million research prize, a $50 million venture fund, and an ambitious program to fund 40 researchers who would identify neural pathways that could control specific diseases. And the company had an aggressive timeline in mind. As one GlaxoSmithKline executive put it, the goal was to have “the first medicine that speaks the electrical language of our body ready for approval by the end of this decade.” 

In the 10 years or so since, around a billion dollars has accreted around the effort by way of direct and indirect funding. Some implants developed in that electroceutical push have trickled into clinical trials, and two companies affiliated with GlaxoSmithKline and Tracey are ramping up for splashy announcements later this year. We don’t know much yet about how successful the trials now underway have been. But widespread regulatory approval of the sorts of devices envisioned in 2013—devices that could be applied to a broad range of chronic diseases—is not imminent. Electroceuticals are a long way from fomenting a revolution in medical care.

At the same time, a new area of science has begun to cohere around another way of using electricity to intervene in the body. Instead of focusing only on the nervous system—the highway that carries electrical messages between the brain and the body—a growing number of researchers are finding clever ways to electrically manipulate cells elsewhere in the body, such as skin and kidney cells, more directly than ever before. Their work suggests that this approach could match the early promise of electroceuticals, yielding fast-healing bioelectric bandages, novel approaches to treating autoimmune disorders, new ways of repairing nerve damage, and even better treatments for cancer. However, such ventures have not benefited from investment largesse. Investors tend to understand the relationship between biology and electricity only in the context of the nervous system. “These assumptions come from biases and blind spots that were baked in during 100 years of neuroscience,” says Michael Levin, a bioelectricity researcher at Tufts University. 

Electrical implants have already had success in targeting specific problems like epilepsy, sleep apnea, and catastrophic bowel dysfunction. But the broader vision of replacing drugs with nerve-zapping devices, especially ones that alter the immune system, has been slower to materialize. In some cases, perhaps the nervous system is not the best way in. Looking beyond this singular locus of control might open the way for a wider suite of electromedical interventions—especially if the nervous system proves less amenable to hacking than originally advertised. 

How it started

GSK’s ambitious electroceutical venture was a response to an increasingly onerous problem: 90% of drugs fall down during the obstacle race through clinical trials. A new drug that does squeak by can cost $2 billion or $3 billion and take 10 to 15 years to bring to market, a galling return on investment. The flaw is in the delivery system. The way we administer healing chemicals hasn’t had much of a conceptual overhaul since the Renaissance physician Paracelsus: ingest or inject. Both approaches have built-in inefficiencies: it takes a long time for the drugs to build up in your system, and they can disperse widely before arriving in diluted form at their target, which may make them useless where they are needed and toxic elsewhere. Tracey and Kristoffer Famm, a coauthor on the Nature article who was then a VP at GlaxoSmithKline, explained on the publicity circuit that electroceuticals would solve these problems—acting more quickly and working only in the precise spot where the intervention was needed. After 500 years, finally, here was a new idea. 

Well … new-ish. Electrically stimulating the nervous system had racked up promising successes since the mid-20th century. For example, the symptoms of Parkinson’s disease had been treated via deep brain stimulation, and intractable pain via spinal stimulation. However, these interventions could not be undertaken lightly; the implants needed to be placed in the spine or the brain, a daunting prospect to entertain. In other words, this idea would never be a money spinner.

WELLCOME COLLECTION

What got GSK excited was recent evidence that health could be more broadly controlled, and by nerves that were easier to access. By the dawn of the 21st century it had become clear you could tap the nervous system in a way that carried fewer risks and more rewards. That was because of findings suggesting that the peripheral nervous system—essentially, everything but the brain and spine—had much wider influence than previously believed. 

The prevailing wisdom had long been that the peripheral nervous system had only one job: sensory awareness of the outside world. This information is ferried to the brain along many little neural tributaries that emerge from the extremities and organs, most of which converge into a single main avenue at the torso: the vagus nerve. 

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 Institutes 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.

MIKE DENORA VIA WIKIPEDIA

The next problem appeared in short order: how to target the correct nerve. The vagus nerve has roughly 100,000 fibers packed tightly within it, says Kip Ludwig, who was then with the US National Institutes of Health and now co-directs the Wisconsin Institute for Translational Neuroengineering at the University of Wisconsin, Madison. These myriad fibers connect to many different organs, including the larynx and lower airways, and electrical fields are not precise enough to hit a single one without hitting many of its neighbors (as Ludwig puts it, “electric fields [are] really promiscuous”).

This explains why a wholesale zap of the entire bundle had long been associated with unpredictable “on-target effects” and unpleasant “off-target effects,” which is another way of saying it didn’t always work and could carry side effects that ranged from the irritating, like a chronic cough, to the life-altering, including headaches and a shortness of breath that is better described as air hunger. Singling out the fibers that led to the particular organ you were after was hard for another reason, too: the existing  maps of the human peripheral nervous system were old and quite limited. Such a low-resolution road map wouldn’t be sufficient to get a signal from the highway all the way to a destination.

In 2014, to remedy this and generally advance the field of peripheral nerve stimulation, the NIH announced a research initiative known as SPARC—Stimulating Peripheral Activity to Relieve Conditions—with the aim of pouring $248 million into research on new ways to exploit the nervous system’s electrical pathways for medicine. “My job,” says Gene Civillico, who managed the program until 2021, “was to do a program related to electroceuticals that used the NIH policy options that were available to us to try to make something catalytic happen.” The idea was to make neural anatomical maps and sort out the consequences of following various paths. After the organs were mapped, Civillico says, the next step was to figure out which nerve circuit would stimulate them, and settle on an access point—“And the access point should be the vagus nerve, because that’s where the most interest is.” 

Two years later, as SPARC began to distribute its funds, companies moved forward with plans for the first generation of implants. GSK teamed up with Verily (formerly Google Life Sciences) on a $715 million research initiative they called Galvani Bioelectronics, with Famm at its helm as president. SetPoint, which had relocated to Valencia, California, moved to an expanded location, a campus that had once housed a secret Lockheed R&D facility.

How it’s going

Ten years after electroceuticals entered (and then quickly departed) the lexicon, the SPARC program has yielded important information about the electrical particulars of the  peripheral nervous system. Its maps have illuminated nodes that are both surgically attractive and medically relevant. It has funded a global constellation of academic researchers. But its insights will be useful for the next generation of implants, not those in trials today.

Today’s implants, from SetPoint and Galvani, will be in the news later this year. Though SetPoint estimates that an extended study of its phase III clinical trial will conclude in 2027, the primary outcomes will be released this summer, says Ankit Shah, a marketing VP at SetPoint. And while Galvani’s trial will conclude in 2029, Famm says, the company is “coming to an exciting point” and will publish patient data later in 2024.

The results could be interpreted as a referendum on the two companies’ different approaches. Both devices treat rheumatoid arthritis, and both target the immune system via the peripheral nervous system, but that’s where the similarities end. SetPoint’s device uses a clamshell design that cuffs around the vagus nerve at the neck. It stimulates for just one minute, once per day. SetPoint representatives say they have never seen the sorts of side effects that have resulted from using such stimulators to treat epilepsy. But if anyone did experience those described by other researchers—even vomiting and headaches—they might be tolerable if they only lasted a minute. 

But why not avoid the vagus nerve entirely? Galvani is using a more precise implant that targets the “end organ” of the spleen. If the vagus nerve can be considered the main highway of the peripheral nervous system, an end organ is essentially a particular organ’s “driveway.” Galvani’s target is the point where the splenic nerve (having split off from a system connected to the vagus highway) meets the spleen.  

To zero in on such a specific target, the company has sacrificed ease of access. Its implant, which is about the size of a house key, is laparoscopically injected into the body through the belly button. Famm says if this approach works for rheumatoid arthritis, then it will likely translate for all autoimmune disorders. Highlighting this clinical trial in 2022, he told Nature Reviews: “This is what makes the next 10 years exciting.”

GALVANI VIA BUSINESSWIRE

Perhaps more so for researchers than for patients, however. Even as Galvani and SetPoint prepare talking points, other SPARC-funded groups are still pondering the sorts of research questions suggesting that the best technological interface with the immune system is still up for debate. At the moment, electroceuticals are in the spotlight, but they have a long way to go, says Vaughan Macefield, a neurophysiologist at Monash University in Australia, whose work is funded by a more recent $21 million SPARC grant: “It’s an elegant idea, [but] there are conflicting views.”

Macefield doesn’t think zapping the entire bundle is a good idea. Many researchers are working on ways to get more selective about which particular fibers of the vagus nerve they stimulate. Some are designing novel electrodes that will penetrate specific fibers rather than clamping around all of them. Others are trying to hit the vagus at deeper points in the abdomen. Indeed, some aren’t sure either electricity or an implant is a necessary ingredient of the “electroceutical.” Instead, they are pivoting from electrical stimulation to ultrasound.

The sheer range of these approaches makes it pretty clear that the electroceutical’s final form is still an open research question. Macefield says we still don’t know the nitty-gritty of how vagus nerve stimulation works.

However, Tracey thinks the variety of approaches being developed doesn’t contravene the merits of the basic idea. How tech companies will make this work in the clinic, he says, is a separate business and IP question: “Can you do it with focused ultrasound? Can you do it with a device implanted with abdominal surgery? Can you do it with a device implanted in the neck? Can you do it with a device implanted in the brain, even? All of these strategies are enabled by the idea of the inflammatory reflex.” Until clinical trial data is in, he says, there’s no point arguing about the best way to manipulate the mechanism—and if one approach fails to work, that is not a referendum on the validity of the inflammatory reflex.

After stepping down from SetPoint’s board to resume a purely consulting role in 2011, Tracey focused on his lab work at the Feinstein Institutes, which he directs, to deepen understanding of this pathway. The research there is wide-ranging. Several researchers under his remit are exploring a type of noninvasive, indirect manipulation called transcutaneous auricular vagus nerve stimulation, which stimulates the skin of the ear with a wearable device. Tracey says it’s a “malapropism” to call this approach vagus nerve stimulation. “It’s just an ear buzzer,” he says. It may stimulate a sensory branch of the vagus nerve, which may engage the inflammatory reflex. “But nobody knows,” he says. Nonetheless, several clinical trials are underway.

SETPOINT MEDICAL

“These things take time,” Tracey says. “It is extremely difficult to invent and develop a completely revolutionary new thing in medicine. In the history of medicine, anything that was truly new and revolutionary takes between 20 and 40 years from the time it’s invented to the time it’s widely adopted.” 

“As the discoverer of this pathway,” he says, “what I want to see is multiple therapies, helping millions of people.” This vision will hinge on bigger trials conducted over many more years. These tend to be about as hard for devices as they are for drugs. Many results that look compelling in early trials disappoint in later rounds—just as for drugs. It will be possible, says Ludwig, “for them to pass a short-duration FDA trial yet still really not be a major improvement over the drug solutions.” Even after FDA approval, should it come, yet more studies will be needed to determine whether the implants are subject to the same issues that plague drugs, including habituation. 

This vision of electroceuticals seems to have placed about a billion eggs into the single basket of the peripheral nervous system. In some ways, this makes sense. After all, the received wisdom has it that these nervous signals are the only way to exert electrical control of the other cells in the body. Those other trillions—the skin cells, the immune cells, the stem cells—are beyond the reach of direct electrical intervention. 

Except in the past 20 years it’s become abundantly clear that they are not.

Other cells speak electricity 

At the end of the 19th century, the German physiologist Max Verworn watched as a single-celled marine creature was drawn across the surface of his slide as if captured by a tractor beam. It had been, in a way: under the influence of an electric field, it squidged over to the cathode (the pole that attracts positive charge). Many other types of cells could be coaxed to obey the directional wiles of an electric field, a phenomenon known as galvanotaxis.

But this was too weird for biology, and charlatans already occupied too much of the space in the Venn diagram where electricity met medicine. (The association was formalized in 1910 in the Flexner Report, commissioned to improve the dismal state of American medical schools, which sent electrical medicine into exile along with the likes of homeopathy.) Everyone politely forgot about galvanotaxis until the 1970s and ’80s, when the peculiar behavior resurfaced. Yeast, fungi, bacteria, you name it—they all liked a cathode. “We were pulling every kind of cell along on petri dishes with an electric field,” says Ann Rajnicek of the University of Aberdeen in Scotland, who was among the first group of researchers who tried to discover the mechanism when scientific interest reawakened.

Galvanotaxis would have raised few eyebrows if the behavior had been confined to neurons. Those cells have evolved receptors that sense electric fields; they are a fundamental aspect of the mechanism the nervous system uses to send its information. Indeed, the reason neurons are so amenable to electrical manipulation in the first place is that electric implants hijack a relatively predictable mechanism. Zap a nerve or a muscle and you are forcing it to “speak” a language in which it is already fluent. 

Non-excitable cells such as those found in skin and bone don’t share these receptors, but it keeps getting more obvious that they somehow still sense and respond to electric fields. 

Why? We keep finding more reasons. Galvanotaxis, for example, is increasingly understood to play a crucial role in wound healing. In every species studied, injury to the skin produces an instant, internally generated electric field, and there’s overwhelming evidence that it guides patch-up cells to the center of the wound to start the rebuilding process. But galvanotaxis is not the only way these cells are led by electricity. During development, immature cells seem to sense the electric properties of their neighbors, which plays a role in their future identity—whether they become neurons, skin cells, fat cells, or bone cells. 

PUBLIC DOMAIN

Intriguing as this all was, no one had much luck turning such insights into medicine. Even attempts to go after the lowest-hanging fruit—by exploiting galvanotaxis for novel bandages—were for many years at best hit or miss. “When we’ve come upon wounds that are intractable, resistant, and will not heal, and we apply an electric field, only 50% or so of the cases actually show any effect,” says Anthony Guiseppi-Elie, a senior fellow with the American International Institute for Medical Sciences, Engineering, and Innovation. 

However, in the past few years, researchers have found ways to make electrical stimulation outside the nervous system less of a coin toss.

That’s down to steady progress in our understanding of how exactly non-neural cells pick up on electric fields, which has helped calm anxieties around the mysticism and the Frankenstein associations that have attended biological responses to electricity.  

The first big win came in 2006, with the identification of specific genes in skin cells that get turned on and off by electric fields. When skin is injured, the body’s native electric field orients cells toward the center of the wound, and the physiologist Min Zhao and his colleagues found important signaling pathways that are turned on by this field and mobilized to move cells toward this natural cathode. He also found associated receptors, and other scientists added to the catalogue of changes to genes and gene regulatory networks that get switched on and off under an electric field.

What has become clear since then is that there is no simple mechanism waiting at the end of the rainbow. “There isn’t one single master protein, as far as anybody knows, that regulates responses [to an electric field],” says Daniel Cohen, a bioengineer at Princeton University. “Every cell type has a different cocktail of stuff sticking out of it.”

But recent years have brought good news, in both experimental and applied science. First, the experimental platforms to investigate gene expression are in the middle of a transformation. One advance was unveiled last year by Sara Abasi, Guiseppi-Elie, and their colleagues at Texas A&M and the Houston Methodist Research Institute: their carefully designed research platform kept track of pertinent cellular gene expression profiles and how they change under electric fields—specifically, ones tuned to closely mimic what you find in biology. They found evidence for the activation of two proteins involved in tissue growth along with increased expression of a protein called CD-144, a specific version of what’s known as a cadherin. Cadherins are important physical structures that enable cells to stick to each other, acting like little handshakes between cells. They are crucial to the cells’ ability to act en masse instead of individually. 

The other big improvement is in tools that can reveal just how cells work together in the presence of electric fields. 

A different kind of electroceutical

A major limit on past experiments was that they tended to test the effects of electrical fields either on single cells or on whole animals. Neither is quite the right scale to offer useful insights, explains Cohen: measuring these dynamics in animals is  too “messy,” but in single cells, the dynamics are too artificial  to tell you much about how cells behave collectively as they heal a wound. That behavior emerges only at relevant scales, like bird flocks, schools of fish, or road traffic. “The math is identical to describe these types of collective dynamics,” he says.

In 2020, Cohen and his team came up with a solution: an experimental setup that strikes the balance between single cell (tells you next to nothing) and animal (tells you too many things at once). The device, called SCHEEPDOG, can reveal what is going on at the tissue level, which is the relevant scale for investigating wound healing. 

It uses two sets of electrodes—a bit the way you might twiddle the dials on an Etch A Sketch—placed in a closed bioreactor, which better approximates how electric fields operate in biology. With this setup, Cohen and his colleagues can precisely tune the electrical environment of tens of thousands of cells at a time to influence their behavior. 

Their subsequent “healing-on-a-chip” platform yielded an interesting discovery: skin cells’ response to an electric field depends on their maturity. The less mature, the easier they were to control.

The culprit? Those cadherins that Abasi and Guiseppi-Elie had also observed changing under electric fields. In mature cells, these little handshakes had become so strong that a competing electric field, instead of gently guiding the cells, caused them to rip apart. The immature skin cells followed the electric field’s directions without complaint.

After they found a way to dial down the cadherins with an antibody drug, all the cells synchronized. For Cohen, the lesson was that it’s more important to look at the system, and the collective dynamics that govern a behavior like wound healing, than at what is happening in any single cell. “This is really important because many clinical attempts at using electrical stimulation to accelerate wound healing have failed,” says Guiseppi-Elie, and it had never become clear why some worked and others some didn’t. 

Cohen’s team is now working to translate these findings into next-generation bioelectric plasters. They are far from alone, and the payoff is more than skin deep. A lot of work is going on, some of it open and some behind closed doors with patents being closely guarded, says Cohen.

At Stanford, the University of Arizona, and Northwestern, researchers are creating smart electric bandages that can be implanted under the skin. They can also monitor the state of the wound in real time, increasing the stimulation if healing is too slow. More challenging, says Rajnicek, are ways to interface with less accessible areas of the body. However, here too new tools are revealing intriguing creative solutions. 

Electric fields don’t have to directly change cells’ gene expression to be useful. There is another way their application can be turned to medical benefit. Electric fields evoke reactive oxygen species (ROS) in biological cells. Normally, these charged molecules are a by-product of a cell’s everyday metabolic activities. If you induce them purposefully using an external DC current, however, they can be hijacked to do your bidding. 

Starting in 2020, the Swiss bioengineer Martin Fussenegger and an international team of collaborators began to publish investigations into this mechanism to power gene expression. He and his team engineered human kidney cells to be hypersensitive to the induced ROSs in quantities that normal cells couldn’t sense. But when these were generated by DC electrodes, the kidney cells could sense the minute quantities just fine. 

Using this instrument, in 2023 they were able to create a tiny, wearable insulin factory. The designer kidney cells were created with a synthetic promoter—an engineered sequence of DNA that can drive expression of a target gene—that reacted to those faint induced ROSs by activating a cascade of genetic changes that opened a tap for insulin production on demand.

Then they packaged this electrogenetic contraption into a wearable device that worked for a month in a living mouse, which had been engineered to be diabetic (Fussenegger says that “others have shown that implanted designer cells can generally be active for over a year”). The designer cells in the wearable are kept alive by algae gelatine but are fed by the mouse’s own vascular system, permitting the exchange of nutrients and protein. The cells can’t get out, but the insulin they secrete can, seeping straight into the mouse’s bloodstream. Ten seconds a day of electrical stimulation delivered via needles connected to three AAA batteries was enough to make the implant perform like a pancreas, returning the mouse’s blood sugar to nondiabetic levels. Given how easy it would be to generalize the mechanism, Fussenegger says, there’s no reason insulin should be the only drug such a device can generate. He is quick to stress that this wearable device is very much in the proof-of-concept stage, but others outside the team are excited about its potential. It could provide a more direct electrical alternative to the solution electroceuticals promised for diabetes. 

Escaping neurochauvinism

Before the concerted push around branding electroceuticals, efforts to tap the peripheral nervous system were fragmented and did not share much data. Today, thanks to SPARC, which is winding down, data-sharing resources have been centralized. And money, both direct and indirect, for the electroceuticals project has been lavish. Therapies—especially vagus nerve stimulation—have been the subject of “a steady increase in funding and interest,” says Imran Eba, a partner at GSK’s bioelectronics investment arm Action Potential Venture Capital. Eba estimates that the initial GSK seed of $50 million at Action Potential has grown to about $200 million in assets under management. 

Whether you call it bioelectronic medicine or electroceuticals, some researchers would like to see the definition take on a broader remit. “It’s been an extremely neurocentric approach,” says Daniel Cohen. 

Neurostimulation has not yet shown success against cancer. Other forms of electrical stimulation, however, have proved surprisingly effective. In one study on glioblastoma, tumor-treating fields offered an electrical version of chemotherapy: an electric field blasts a brain tumor, preferentially killing only cells whose electrical identity marks them as dividing (which cancer cells do, pathologically—but neurons, being fully differentiated, do not). A study recently published in The Lancet Oncology suggests that these fields could also work in lung cancer to boost existing drugs and extend survival. 

All of this points to more sophisticated interventions than a zap to a nerve. “The complex things that we need to do in medicine will be about communicating with the collective decision-making and problem-solving of the cells,” says Michael Levin. He has been working to repurpose already-approved drugs so they can be used to target the electrical communication between cells. In a funny twist, he has taken to calling these drugs electroceuticals, which has ruffled some feathers. But he would certainly find support from researchers like Cohen. “I would describe electroceuticals much more broadly as anything that manipulates cellular electrophysiology,” Cohen says.

Even interventions with the nervous system could be helped by expanding our understanding of the ways nerve cells react to electricity beyond action potentials. Kim Gokoffski, a professor of clinical ophthalmology at the University of Southern California, is working with galvanotaxis as a possible means of repairing damage to the optic nerve. In prior experiments that involve regrowing axons—the cables that carry messages out of neurons—these new nerve fibers tend to miss the target they’re meant to rejoin. Existing approaches “are all pushing the gas pedal,” she says, “but no one is controlling the steering wheel.” So her group uses electric fields to guide the regenerating axons into position. In rodent trials, this has worked well enough to partially restore sight.

And yet, Cohen says, “there’s massive social stigma around this that is significantly hampering the entire field.” That stigma has dramatically shaped research direction and funding. For Gokoffski, it has led to difficulties with publishing. She also recounts hearing a senior NIH official refer to her lab’s work on reconnecting optic nerves as “New Age–y.” It was a nasty surprise: “New Age–y has a very bad connotation.” 

However, there are signs of more support for work outside the neurocentric model of bioelectric medicine. The US Defense Department funds projects in electrical wound healing (including Gokoffski’s). Action Potential’s original remit—confined to targeting peripheral nerves with electrical stimulation—has expanded. “We have a broader approach now, where energy (in any form, be it electric, electromagnetic, or acoustic) can be directed to regulate neuronal or other cellular activities in the body,” Eba wrote in an email. Three of the companies now in their portfolio focus on areas outside neurostimulation. “While we don’t have any investments targeting wound healing or regenerative medicine specifically, there is no explicit exclusion here for us,” he says.

This suggests that the “social stigma” Cohen described around electrical medicine outside the nervous system is slowly beginning to abate. But if such projects are to really flourish, the field needs to be supported, not just tolerated—perhaps with its own road map and dedicated NIH program. Whether or not bioelectric medicine ends up following anything like the original electroceuticals road map, SPARC ensured a flourishing research community, one that is in hot pursuit of promising alternatives. 

The use of electricity outside the nervous system needs a SPARC program of its own. But if history is any guide, first it needs a catchy name. It can’t be “electroceuticals.” And the researchers should definitely check the trademark listings before rolling it out.

Sally Adee is a science and technology writer and the author of We Are Electric: Inside the 200-Year Hunt for Our Body’s Bioelectric Code, and What the Future Holds.

This article has been updated to correct the name of the Feinstein Institutes for Medical Research.