A Neurosurgeon’s Remarkable Plan to Treat Stroke Victims With Stem Cells

Gary Steinberg defied convention when he began implanting living cells inside the brains of patients who had suffered from a stroke.

The day she had a stroke, Sonia Olea Coontz, a 31-year-old from Long Beach, California, was getting ready to start a new career as a dog trainer. She had just wrapped up a week of training, and she and her boyfriend were taking their own dogs to the park. But something strange kept happening: She’d try to say one thing and end up saying another.

By evening, her boyfriend was worriedly telling her that the right side of her face had gone slack. She wasn’t able to focus on anything except the bedroom walls, and she wondered how they’d gotten to be so white. “It was very surreal,” she recalls.

Coontz spent the next six months mostly asleep. One day she attempted to move an arm, but she couldn’t. Then a leg, but she couldn’t move that, either. She tried to call for her boyfriend but couldn’t say his name. “I am trapped in this body,” she remembers thinking.

That was May 2011. Over the next two years, Coontz made only small improvements. She developed a 20-word spoken vocabulary and could walk for five minutes before needing a wheelchair. She could move her right arm and leg only a few inches, and her right shoulder was in constant pain. So when she learned about a clinical trial of a new treatment at Stanford University School of Medicine, she wasn’t fazed that it would involve drilling through her skull.

At Stanford, a magnetic resonance scan showed damage to the left half of Coontz’s brain, an area that controls language and the right side of the body. Ischemic strokes, like Coontz’s, happen when a clot blocks an artery carrying blood into the brain. (Rarer, but more deadly, hemorrhagic strokes are the result of weakened blood vessels that rupture in the brain.) Of the approximately 800,000 Americans who have strokes each year, the majority make their most significant recoveries within six months. After that, their disabilities are expected to be permanent.

On the day of Coontz’s procedure, Gary Steinberg, the chair of neurosurgery, drilled a nickel-size burr hole into Coontz’s skull and injected stem cells around the affected part of her brain. Then everyone waited. But not for long.

Coontz remembers waking up a few hours later with an excruciating headache. After meds had calmed the pain, someone asked her to move her arm. Instead of moving it inches, she raised it over her head.

“I just started crying,” she recalls. She tried her leg, and discovered she was able to lift and hold it up. “I felt like everything was dead: my arm my leg, my brain,” she says. “And I feel like it just woke up.”    

Coontz is part of a small group of stroke patients who have undergone the experimental stem cell treatment pioneered by Steinberg. Conventional wisdom has long maintained that brain circuits damaged by stroke are dead. But Steinberg was among a small cadre of researchers who believed they might be dormant instead, and that stem cells could nudge them awake. The results of his trial, published in June 2016, indicate that he may well be right.

“This important study is one of the first suggesting that stem cell administration into the brain can promote lasting neurological recovery when given months to years after stroke onset,” says Seth Finklestein, a Harvard neurologist and stroke specialist at Massachusetts General Hospital. “What’s interesting is that the cells themselves survived for only a short period of time after implantation, indicating that they released growth factors or otherwise permanently changed neural circuitry in the post-stroke brain.”

Steinberg, a native of New York City, spent his early career frustrated by the dearth of stroke therapies. He recalls doing a neurology rotation in the 1970s, working with a woman who was paralyzed on one side and couldn’t speak. “We pinpointed exactly where in the brain her stroke was,” Steinberg says. But when Steinberg asked how to treat her, the attending neurologist replied, “Unfortunately, there’s no treatment.” For Steinberg, “no treatment” was not good enough.

After earning his MD/PhD from Stanford in 1980, Steinberg rose to become the chair of the school’s neurosurgery department. In 1992, he co-founded the Stanford Stroke Center with two colleagues.

In the years that followed, two treatments emerged for acute stroke patients. Tissue plasminogen activator, or tPA, was approved by the FDA in 1996. Delivered by catheter into the arm, it could dissolve clots, but it needed to be administered within a few hours of the stroke and caused hemorrhaging in up to 6 percent of patients. Mechanical thrombectomy emerged about a decade later: By inserting a catheter into an artery in the groin and snaking it into the brain, doctors could break up a clot with a fluid jet or a tiny suction cup. But that treatment could only be delivered within six hours of a stroke and couldn’t be used in every case. After the window closed, doctors could offer nothing but physical therapy.

When Steinberg started looking into stem cell therapy for stroke patients, in the early 2000s, the idea was still unorthodox. Stem cells start off unspecialized, but as they divide, they can grow into particular cell types. That makes them compelling to researchers who want to create, for example, new insulin-producing cells for diabetics. But stem cells also help our bodies repair themselves, even in adulthood. “And that’s the power that Steinberg is trying to harness,” says Dileep Yavagal, a professor of clinical neurology and neurosurgery at the University of Miami.

Steinberg began testing this in a small trial that ran between 2011 and 2013. Eighteen volunteers at Stanford and the University of Pittsburgh Medical Center agreed to have the cells—derived from donor bone marrow and cultured by the Bay Area company SanBio—injected into their brains.

Sitting in his office, Steinberg boots up footage of a woman in her 70s wearing a NASA sweatshirt and struggling to wiggle her fingers. “She’s been paralyzed for two years. All she can do with her hand, her arm, is move her thumb,” says Steinberg. “And here she is—this is one day later,” he continues. Onscreen, the woman now touches her fingers to her nose. “Paralyzed for two years!” Steinberg repeats jubilantly.

His staff calls this woman and Coontz their “miracle patients.” The others improved more slowly. For example, a year after their surgery, half of the people who participated in a follow-up exam gained 10 or more points on a 100-point assessment of motor function. Ten points is a meaningful improvement, says Steinberg: “That signifies that it changes the patient’s life.” His team hadn’t expected this. “It changes the whole notion—our whole dogma—of what happens after a stroke,” he says.

But how did the stem cells jump-start those dormant circuits? “If we understood exactly what happened,” he says wryly, “we’d really have something.” Here’s what didn’t happen: The stem cells didn’t turn into new neurons. In fact, they died off within a month.

Steinberg thinks the circuits in question were somehow being inhibited. He’s not exactly sure why, but he thinks chronic inflammation could be one reason. He has a clue: After the procedure, 13 of his patients had temporary lesions in their brains. Steinberg thinks these indicated a helpful immune response. In fact, the size of the lesions after one week was the most significant predictor of how much a patient would recover.

For all 18 patients, Steinberg also thinks the cells secreted dozens, perhaps hundreds, of proteins. Acting in concert, these proteins influenced the neurons’ environment. “Somehow,” Steinberg reflects, “it’s saying, ‘You can act like you used to act.’”

Some of the participants had adverse reactions to the surgery, but not to the cells themselves. (A small European study published later also indicated that stem cells are safe for stroke sufferers.) And Steinberg says his patients’ recovery “was still sustained on all scales at two years.”

He’s now collaborating with Yavagal on a randomized controlled study that will include 156 stroke patients. Key questions await future researchers: How many cells should doctors use? What’s the best way to administer them? And are the cells doing all the work, or is the needle itself contributing? Could the death of the cells be playing a role?

Steinberg thinks stem cell therapy might help alleviate Parkinson’s, Lou Gehrig’s disease, maybe even Alzheimer’s. His lab is also testing its effects on traumatic brain and spinal cord injuries. Even though these conditions spring from different origins, he thinks they might all involve dormant circuits that can be reactivated. “Whether you do it with stem cells, whether you do it with optogenetics, whether you do it with an electrode, that’s going to be the future for treating neurologic diseases.”

Six years after her stroke, Coontz now speaks freely, although her now-husband sometimes has to help her find words. Her shoulder pain is gone. She goes to the gym, washes dishes with both hands and takes her infant son on walks in the stroller. For Coontz, motherhood is one of the greatest joys of post-stroke life. During her pregnancy, she worked out five times a week so she would be able to hold and bathe and deliver the baby. After so many medical procedures she couldn’t control, this time, she felt, “I am awake, I can see, I know how I want this to be.”

Her son is now 1 year old. “My husband picks him up and holds him way over his head, and obviously I can’t do that,” she says. “But I will. I don’t know when, but I will. I guarantee it.”

This article originally appeared on smithsonianmag.com and was written by Kara Platoni

Hacking the Nervous System - Learning to Control One Nerve

Shaping your health by learning to control the one nerve that connects your vital organs

When Maria Vrind, a former gymnast from Volendam in the Netherlands, found that the only way she could put her socks on in the morning was to lie on her back with her feet in the air, she had to accept that things had reached a crisis point. “I had become so stiff I couldn’t stand up,” she says. “It was a great shock because I’m such an active person.”

It was 1993. Vrind was in her late 40s and working two jobs, athletics coach and a carer for disabled people, but her condition now began taking over her life. “I had to stop my jobs and look for another one as I became increasingly disabled myself.” By the time she was diagnosed, seven years later, she was in severe pain and couldn’t walk any more. Her knees, ankles, wrists, elbows and shoulder joints were hot and inflamed. It was rheumatoid arthritis, a common but incurable autoimmune disorder in which the body attacks its own cells, in this case the lining of the joints, producing chronic inflammation and bone deformity.

Inflamed joints

Waiting rooms outside rheumatoid arthritis clinics used to be full of people in wheelchairs. That doesn’t happen as much now because of a new wave of drugs called biopharmaceuticals – such as highly targeted, genetically engineered proteins – which can really help. Not everyone feels better, however: even in countries with the best healthcare, at least 50 per cent of patients continue to suffer symptoms.

Like many patients, Vrind was given several different medications, including painkillers, a cancer drug called methotrexate to dampen her entire immune system, and biopharmaceuticals to block the production of specific inflammatory proteins. The drugs did their job well enough – at least, they did until one day in 2011, when they stopped working.

I was on holiday with my family and my arthritis suddenly became terrible and I couldn’t walk – my daughter-in-law had to wash me.

Vrind was rushed to hospital, where she was hooked up to an intravenous drip and given another cancer drug, one that targeted her white blood cells. “It helped,” she admits, but she was nervous about relying on such a drug long-term.

Luckily, she would not have to. As she was resigning herself to a life of disability and monthly chemotherapy, a new treatment was being developed that would profoundly challenge our understanding of how the brain and body interact to control the immune system. It would open up a whole new approach to treating rheumatoid arthritis and other autoimmune diseases, using the nervous system to modify inflammation. It would even lead to research into how we might use our minds to stave off disease.

And, like many good ideas, it came from an unexpected source.

The nerve hunter

Kevin Tracey, a neurosurgeon based in New York, is a man haunted by personal events – a man with a mission. “My mother died from a brain tumour when I was five years old. It was very sudden and unexpected,” he says. “And I learned from that experience that the brain – nerves – are responsible for health.” This drove his decision to become a brain surgeon. Then, during his hospital training, he was looking after a patient with serious burns who suddenly suffered severe inflammation. “She was an 11-month-old baby girl called Janice who died in my arms.”

Dr Kevin Tracey

These traumatic moments made him a neurosurgeon who thinks a lot about inflammation. He believes it was this perspective that enabled him to interpret the results of an accidental experiment in a new way.

In the late 1990s, Tracey was experimenting with a rat’s brain. “We’d injected an anti-inflammatory drug into the brain because we were studying the beneficial effect of blocking inflammation during a stroke,” he recalls. “We were surprised to find that when the drug was present in the brain, it also blocked inflammation in the spleen and in other organs in the rest of the body. Yet the amount of drug we’d injected was far too small to have got into the bloodstream and travelled to the rest of the body.”

After months puzzling over this, he finally hit upon the idea that the brain might be using the nervous system – specifically the vagus nerve – to tell the spleen to switch off inflammation everywhere.

It was an extraordinary idea – if Tracey was right, inflammation in body tissues was being directly regulated by the brain. Communication between the immune system’s specialist cells in our organs and bloodstream and the electrical connections of the nervous system had been considered impossible. Now Tracey was apparently discovering that the two systems were intricately linked.

The first critical test of this exciting hypothesis was to cut the vagus nerve. When Tracey and his team did, injecting the anti-inflammatory drug into the brain no longer had an effect on the rest of the body. The second test was to stimulate the nerve without any drug in the system. “Because the vagus nerve, like all nerves, communicates information through electrical signals, it meant that we should be able to replicate the experiment by putting a nerve stimulator on the vagus nerve in the brainstem to block inflammation in the spleen,” he explains. “That’s what we did and that was the breakthrough experiment.”

The vagus nerve

The wandering nerve

The vagus nerve starts in the brainstem, just behind the ears. It travels down each side of the neck, across the chest and down through the abdomen. ‘Vagus’ is Latin for ‘wandering’ and indeed this bundle of nerve fibres roves through the body, networking the brain with the stomach and digestive tract, the lungs, heart, spleen, intestines, liver and kidneys, not to mention a range of other nerves that are involved in speech, eye contact, facial expressions and even your ability to tune in to other people’s voices. It is made of thousands and thousands of fibres and 80 per cent of them are sensory, meaning that the vagus nerve reports back to your brain what is going on in your organs.

Operating far below the level of our conscious minds, the vagus nerve is vital for keeping our bodies healthy. It is an essential part of the parasympathetic nervous system, which is responsible for calming organs after the stressed ‘fight-or-flight’ adrenaline response to danger. Not all vagus nerves are the same, however: some people have stronger vagus activity, which means their bodies can relax faster after a stress.

The strength of your vagus response is known as your vagal tone and it can be determined by using an electrocardiogram to measure heart rate. Every time you breathe in, your heart beats faster in order to speed the flow of oxygenated blood around your body. Breathe out and your heart rate slows. This variability is one of many things regulated by the vagus nerve, which is active when you breathe out but suppressed when you breathe in, so the bigger your difference in heart rate when breathing in and out, the higher your vagal tone.

Breathing and the vagus nerve

Research shows that a high vagal tone makes your body better at regulating blood glucose levels, reducing the likelihood of diabetes, stroke and cardiovascular disease. Low vagal tone, however, has been associated with chronic inflammation. As part of the immune system, inflammation has a useful role helping the body to heal after an injury, for example, but it can damage organs and blood vessels if it persists when it is not needed. One of the vagus nerve’s jobs is to reset the immune system and switch off production of proteins that fuel inflammation. Low vagal tone means this regulation is less effective and inflammation can become excessive, such as in Maria Vrind’s rheumatoid arthritis or in toxic shock syndrome, which Kevin Tracey believes killed little Janice.

Having found evidence of a role for the vagus in a range of chronic inflammatory diseases, including rheumatoid arthritis, Tracey and his colleagues wanted to see if it could become a possible route for treatment. The vagus nerve works as a two-way messenger, passing electrochemical signals between the organs and the brain. In chronic inflammatory disease, Tracey figured, messages from the brain telling the spleen to switch off production of a particular inflammatory protein, tumour necrosis factor (TNF), weren’t being sent. Perhaps the signals could be boosted?

He spent the next decade meticulously mapping all the neural pathways involved in regulating TNF, from the brainstem to the mitochondria inside all our cells. Eventually, with a robust understanding of how the vagus nerve controlled inflammation, Tracey was ready to test whether it was possible to intervene in human disease.

Pacemaker implant

Stimulating trial

In the summer of 2011, Maria Vrind saw a newspaper advertisement calling for people with severe rheumatoid arthritis to volunteer for a clinical trial. Taking part would involve being fitted with an electrical implant directly connected to the vagus nerve. “I called them immediately,” she says.

I didn’t want to be on anticancer drugs my whole life; it’s bad for your organs and not good long-term.

Tracey had designed the trial with his collaborator, Paul-Peter Tak, professor of rheumatology at the University of Amsterdam. Tak had long been searching for an alternative to strong drugs that suppress the immune system to treat rheumatoid arthritis. “The body’s immune response only becomes a problem when it attacks your own body rather than alien cells, or when it is chronic,” he reasoned. “So the question becomes: how can we enhance the body’s switch-off mechanism? How can we drive resolution?”

When Tracey called him to suggest stimulating the vagus nerve might be the answer by switching off production of TNF, Tak quickly saw the potential and was enthusiastic to see if it would work. Vagal nerve stimulation had already been approved in humans for epilepsy, so getting approval for an arthritis trial would be relatively straightforward. A more serious potential hurdle was whether people used to taking drugs for their condition would be willing to undergo an operation to implant a device inside their body:

There was a big question mark about whether patients would accept a neuroelectric device like a pacemaker,” Tak says.

He needn’t have worried. More than a thousand people expressed interest in the procedure, far more than were needed for the trial. In November 2011, Vrind was the first of 20 Dutch patients to be operated on.

They put the pacemaker on the left-hand side of my chest, with wires that go up and attach to the vagus nerve in my throat,” she says. “I waited two weeks while the area healed, and then the doctors switched it on and adjusted the settings for me.”

Pacemaker x-ray

She was given a magnet to swipe across her throat six times a day, activating the implant and stimulating her vagus nerve for 30 seconds at a time. The hope was that this would reduce the inflammatory response in her spleen. As Vrind and the other trial participants were sent home, it became a waiting game for Tracey, Tak and the team to see if the theory, lab studies and animal trials would bear fruit in real patients. “We hoped that for some, there would be an easing of their symptoms – perhaps their joints would become a little less painful,” Tak says.

At first, Vrind was a bit too eager for a miracle cure. She immediately stopped taking her pills, but her symptoms came back so badly that she was bedridden and in terrible pain. She went back on the drugs and they were gradually reduced over a week instead.

And then the extraordinary happened: Vrind experienced a recovery more remarkable than she or the scientists had dared hope for.

“Within a few weeks, I was in a great condition,” she says. “I could walk again and cycle, I started ice-skating again and got back to my gymnastics. I feel so much better.” She is still taking methotrexate, which she will need at a low dose for the rest of her life, but at 68, semi-retired Vrind now plays and teaches seniors’ volleyball a couple of hours a week, cycles for at least an hour every day, does gymnastics, and plays with her eight grandchildren.

Other patients on the trial had similar transformative experiences. The results are still being prepared for publication but Tak says more than half of the patients showed significant improvement and around one-third are in remission – in effect cured of their rheumatoid arthritis. Sixteen of the 20 patients on the trial not only felt better, but measures of inflammation in their blood also went down. Some are now entirely drug-free. Even those who have not experienced clinically significant improvements with the implant insist it helps them; nobody wants it removed.

We have shown very clear trends with stimulation of three minutes a day,” Tak says. “When we discontinued stimulation, you could see disease came back again and levels of TNF in the blood went up. We restarted stimulation, and it normalised again.”

Nerve stimulation

Tak suspects that patients will continue to need vagal nerve stimulation for life. But unlike the drugs, which work by preventing production of immune cells and proteins such as TNF, vagal nerve stimulation seems to restore the body’s natural balance. It reduces the over-production of TNF that causes chronic inflammation but does not affect healthy immune function, so the body can respond normally to infection.

I’m really glad I got into the trial,” says Vrind. “It’s been more than three years now since the implant and my symptoms haven’t returned. At first I felt a pain in my head and throat when I used it, but within a couple of days, it stopped. Now I don’t feel anything except a tightness in my throat and my voice trembles while it’s working.

“I have occasional stiffness or a little pain in my knee sometimes but it’s gone in a couple of hours. I don’t have any side-effects from the implant, like I had with the drugs, and the effect is not wearing off, like it did with the drugs.”

Raising the tone

Having an electrical device surgically implanted into your neck for the rest of your life is a serious procedure. But the technique has proved so successful – and so appealing to patients – that other researchers are now looking into using vagal nerve stimulation for a range of other chronic debilitating conditions, including inflammatory bowel disease, asthma, diabetes, chronic fatigue syndrome and obesity.

But what about people who just have low vagal tone, whose physical and mental health could benefit from giving it a boost? Low vagal tone is associated with a range of health risks, whereas people with high vagal tone are not just healthier, they’re also socially and psychologically stronger – better able to concentrate and remember things, happier and less likely to be depressed, more empathetic and more likely to have close friendships.

Twin studies show that to a certain extent, vagal tone is genetically predetermined – some people are born luckier than others. But low vagal tone is more prevalent in those with certain lifestyles – people who do little exercise, for example. This led psychologists at the University of North Carolina at Chapel Hill to wonder if the relationship between vagal tone and wellbeing could be harnessed without the need for implants.

In 2010, Barbara Fredrickson and Bethany Kok recruited around 70 university staff members for an experiment. Each volunteer was asked to record the strength of emotions they felt every day. Vagal tone was measured at the beginning of the experiment and at the end, nine weeks later. As part of the experiment, half of the participants were taught a meditation technique to promote feelings of goodwill towards themselves and others.

Meditating to promote feelings of goodwill

Those who meditated showed a significant rise in vagal tone, which was associated with reported increases in positive emotions. “That was the first experimental evidence that if you increased positive emotions and that led to increased social closeness, then vagal tone changed,” Kok says.

Now at the Max Planck Institute in Germany, Kok is conducting a much larger trial to see if the results they found can be replicated. If so, vagal tone could one day be used as a diagnostic tool. In a way, it already is. “Hospitals already track heart-rate variability – vagal tone – in patients that have had a heart attack,” she says, “because it is known that having low variability is a risk factor.”

The implications of being able to simply and cheaply improve vagal tone, and so relieve major public health burdens such as cardiovascular conditions and diabetes, are enormous. It has the potential to completely change how we view disease. If visiting your GP involved a check on your vagal tone as easily as we test blood pressure, for example, you could be prescribed therapies to improve it. But this is still a long way off: “We don’t even know yet what a healthy vagal tone looks like,” cautions Kok. “We’re just looking at ranges, we don’t have precise measurements like we do for blood pressure.”

Meditation for health

What seems more likely in the shorter term is that devices will be implanted for many diseases that today are treated by drugs:

As the technology improves and these devices get smaller and more precise,” says Kevin Tracey, “I envisage a time where devices to control neural circuits for bioelectronic medicine will be injected – they will be placed either under local anaesthesia or under mild sedation.”

However the technology develops, our understanding of how the body manages disease has changed for ever. “It’s become increasingly clear that we can’t see organ systems in isolation, like we did in the past,” says Paul-Peter Tak. “We just looked at the immune system and therefore we have medicines that target the immune system.

“But it’s very clear that the human is one entity: mind and body are one. It sounds logical but it’s not how we looked at it before. We didn’t have the science to agree with what may seem intuitive. Now we have new data and new insights.”

And Maria Vrind, who despite severe rheumatoid arthritis can now cycle pain-free around Volendam, has a new lease of life: “It’s not a miracle – they told me how it works through electrical impulses – but it feels magical. I don’t want them to remove it ever. I have my life back!”