One nerve connects
your vital organs, sensing and shaping your health. If we learn to
control it, the future of medicine will be electric.
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.
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.
(Photo: © Job Boot)
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.”
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.”
(Photo: © Job Boot)
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.
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.
(Photo: © Job Boot)
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.”
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.”
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.”
(Photo: © Job Boot)
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.
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.”
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 anesthesia 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!”
This
story first appeared on Mosaic and is republished here under a Creative Commons license.