Bioelectronics is the field of developing medicines that use
electrical impulses to modulate the body's neural circuits as an
alternative to drug-based interventions. How far away are we from
having these very targeted "electroceuticals"?
Twenty years ago, neurosurgeon and researcher Kevin Tracey was
studying whether an experimental molecule called CNI-1493 could
limit damage to the brain after a stroke. His team was injecting
the molecule into the brains of rats during a stroke to see how
successfully it prevented swelling -- an immune system response --
of the brain.
To Tracey's surprise the drug not only prevented swelling
locally, but it shut down the immune response in the whole body.
The drug was having an impact on the vagus nerve -- a long, thin
nerve that snakes its way from the brain through the abdomen.
Stimulating the vagus nerve seemed to reduce the production of
cytokines -- immune system mediators -- and block inflammation.
"The drug was stimulating the vagus nerve and turning the brake
on the immune system," Tracey, who is president of the Feinstein Institute,
told Wired.co.uk. "Once we understood that, it was a 'eureka'
moment. We realised you didn't need the drugs, you could just
manipulate the nerve itself."
This accidental discovery has led Tracey to focus his research
efforts into the field of bioelectronics. This is, broadly, the
field of developing medicines that use electrical impulses to
modulate the body's neural circuits. Virtually all of the body's
organs and functions are regulated through circuits of neurons
communicating through electrical impulses. The theory is that if
you can accurately map the neural signatures of certain diseases,
you could then stimulate or inhibit the malfunctioning pathways
with tiny electrodes in order to restore health, without having to
flood the system with molecular medicines.
The fruits of Tracey's efforts were encapsulated in 2012, when he travelled to Bosnia to implant a
vagus nerve stimulator into the neck of a human patient with
disabling rheumatoid arthritis. After years of debilitating pain in
his joints, the patient is now in clinical remission. Eight weeks
after the surgery he returned to work, performed manual labour and
drove a delivery truck. The theory was, at least in this case,
A step-change from pacemakers and
Of course, we've been crudely treating diseases using electrical
impulses for many years. In 1933 a heart specialist called Dr
Albert Hyman sought an alternative to injecting drugs directly into
the heart and developed a device called the Hyman Otor.
This consisted of a hollow needle that was used to carry an
insulated wire to the heart area in order to deliver an electrical
shock. This eventually paved the way for modern day defibrillators.
The first implantable pacemaker was placed into a 43-year-old man
suffering from cardiac arrhythmia syndrome in 1958, and the patient
went on to outlive his surgeon, Dr Ake Senning from the Karolinska
Institute in Stockholm.
Similarly, deep-brain stimulation has been found to improve the
quality of life for sufferers of depression and Parkinson's.
However, the electrical devices have been clunky and imprecise,
shocking large areas of neural tissue to stimulate the desired
Research teams across the globe have realised that by targeting
individual nerve fibres or specific brain circuits they may soon be
able to treat a wide range of conditions that have formerly relied
on drug-based interventions. This could include inflammatory
diseases such as rheumatoid arthritis, respiratory diseases such as
asthma and diabetes. In the long run you could also control
neuro-psychiatric disorders like Parkinson's and epilepsy.
It wouldn't be possible to treat infectious diseases, since the
bacteria and viruses that cause them aren't directly connected to
the nervous system, nor would you be able to treat cancer directly
in this way. However, in both cases you could stimulate the
relevant nerves to boost aspects of the immune system.
GlaxoSmithKline is taking a huge punt on these so-called "electroceuticals",
believing that they could present a lucrative opportunity. It is
working to bring together researchers from different disciplines in
academia and industry in a bid to drive progress through open
innovation. It has committed to fully funding up to 40 researchers
in up to 20 external labs to conduct exploratory work mapping
disease-associated neural circuits. Findings will be shared among
researchers in the network and IP rights will be retained by the
inventors. Meanwhile, towards the end of 2013, GSK will hold a
global forum for research leaders to collectively identify a key
hurdle in the bioelectronics field. It will then fund a $1 million
(£660,000) prize for the group that comes up with an innovation to
overcome that hurdle.
"This is quite a bit step-change from pacemakers and
defibrillators," explains Kristoffer Famm, vice president of bioelectronics research and development at GlaxoSmithKline. He
compares it to molecular medicine. "We've known for centuries that
you can take different substances to have an effect on the body,
but only at the end of the last century did we learn that we can
exquisitely fine-tune these molecules and a whole new area of
medicine opened up. We are at a similar juncture with the use of
Electroceutical research is still in its early stages, with the
focus being on mapping the neural networks associated with certain
diseases in their highest possible resolution. Tools such as
optogenetics, which allow for cellular-level control, have improved
researchers' ability to analyse the signals and circuits running
through the nervous system. Meanwhile efforts to control prosthetic
limbs and generate brain-machine interfaces are giving rise to
electrode architectures that can interact with individual neurons,
as seen in systems such a University of Pittsburgh-developed robotic limb called
Hector. Similarly the development of
cochlear and retinal implants is allowing for improvements to
neural signal processing.
Because of the complexity of the brain, the lowest-hanging fruit
in the electroceuticals space will be those interventions that
target the peripheral nervous system -- outside of the spinal cord
and the brain -- as we have seen with the vagus-nerve-targeting
Dangling mice from their tails to prevent
Multiple sclerosis is another disease that could benefit from
bioelectronic interventions instead of steroids and other
disease-modifying drugs. In 2012 a remarkable
piece of research from Osaka University's Yasunobu Arima and
colleagues came to light.
They were studying the mouse model of multiple sclerosis, which is induced by
introducing to the blood stream a type of white blood cell -- a
T-cell -- that has been primed to attack the animal's own nerves.
They noticed that in the early stages of the disease, the
neuron-damaging T-cells cross the blood-brain barrier at a very
specific location: the area of the spinal cord right by the fifth
lumbar vertebrae. At this point they detected that the blood
vessels were producing high levels of a chemokine
-- a signalling protein released by cells -- called CCL20. It
was acting as a beacon for T-cells, showing them where to cross
into the central nervous system. The team theorised that this might
have something to do with the fact that the fifth vertebrae lie
close to a collection of nerves that carry impulses from the leg
muscles and other parts of the body to the spinal cord, and on to
the brain. They decided to test whether interfering with the neural
signals could have an impact on this process in the development of
the disease. Remarkably, they found that by simply suspending the
animal from its tail they could prevent the mouse MS from entering
into the spinal cord.
The researchers aren't entirely sure how the activity in the
muscle (limited by having the mice dangling from their tails)
influences the endothelial cells that express CCL20. However,
the study does suggest that a particular neural circuit could
control a critical step in the progression of this and
other autoimmune diseases. This, in turn, suggests that it
could be possible to inhibit a specific neural impulse in order to
prevent the onset of such diseases. "For immunologists this is
groundbreaking," says Tracey.
"The immune system is an innervated organ. It is not
controversial to say that it participates in mediating in the
pathogenesis of most of the major diseases needing therapy. So it's
incredibly important to do the mapping now," urges Tracey.
The anatomical aspect of the mapping of neurons is relatively
easy, but it's also important to map how electrical signals travel
along them and what immune responses they provoke. This sort of
research is done by stimulating a subset of nerve fibres with a
certain amount of electricity and seeing which ones fire. Nerves
can be categorised based on how much electricity you need to put
into them to make them fire. "But we have some distance to go
before we can get recordings from individual nerve fibres in
parallel," explains Famm. "We can record from one, but monitoring a
thousand in parallel is harder."
Tracey's biomedical research lab is primarily focused on
understanding how the nervous system senses the specific components
of the immune system. "The nervous system reacts differently to
glucose and steroids, it reacts differently to light and sound, so
why wouldn't it react differently to IL-1 and TNF [cell-signalling
molecules associated with the body's immune response]?"
"We know that IL-1 causes a
fever and that if you cut the vagus nerve, fever doesn't occur.
But how does the vagus nerve tell the brain to have a fever? What
does the signal look like and can we manipulate it?"
This is explored using electrodes and highly purified IL-1 and
TNF. Researchers examine the neurons before and after exposure to
these substances to see how they respond.
Tracey refers to the immune system and the nervous system as the
two memory systems of the body. "They co-evolved," he says. As a
consequence, he believes that there will be plenty of other neural
circuits or "reflexes" that modulate the body's immune response.
He's particularly interested in the "adaptive" immune response --
this is the long-term immunity that gets built up by the body as
opposed to the short-term defence mechanism.
While this is a daunting task, Tracey is optimistic: "I remember
when people thought it would be impossible to map the human genome
as well -- with enough time and resources, it's doable."
Unlocking the central nervous system
While the peripheral nervous system and its relationship with the
immune system keeps Tracey busy, the brain remains the focus of
many researchers' attention and there have been some large-scale
investments made in mapping it. In the US, the Brain Activity Map
was awarded $100m (£66m) in research funding and the Human Brain Project
(formerly known as the Blue Brain Project) was awarded a billion
Euros over ten years. These projects have been made possible thanks
to advancements in supercomputers and big data processing. But it's
no mean feat.
Neurologist and engineer Brian Litt -- who heads up the
"translational neuroengineering" Litt Lab at the
University of Pennsylvania -- knows this all too well. His
speciality is epilepsy, and he does a lot of work placing
electrodes in patients' brains to figure out where seizures come
from. He acknowledges that early successes in using brain
stimulation for movement disorders use "pretty crude tech" with
"multi-millimetre to centimetre scale electrodes", which get placed
into a particular region that can then be inhibited or
"But it turns out that the networks involved are much more
complex, with multiple cell types with different functions existing
in the same place," Litt told Wired.co.uk. "Rather than smacking
the rock with a stick like Moses you want to talk to it."
Ed Boyden -- an engineer turned neuroscientist at MIT Media
Lab, whose work Wired UK covered in November 2012 -- agrees, explaining
that the mapping of the brain must be done at the anatomical,
connectivity and activity levels. "The brain contains a hundred
thousand neurons, connected by a billion synapses in every
cubic millimetre, and those neurons operate electrically at the
millisecond timescale -- that is a huge challenge, from an
understanding or engineering standpoint!"
That's not to say that the crude, stick-smacking approach
doesn't work for some people's brain disorders, but scientists
don't currently have the mapping resolution to understand
complicated seizure disorders with clinical-scale devices.
Litt is conducting experiments with very high resolution
recording. "Instead of 60 electrodes [implanted in the brain], we
might have 10,000. Instead of a centimetre array, we might have one
of maybe 50 microns. We try to put together an image of how these
different groups of cells are working. The question is what
technologies are best developed to do this and how do you get the
He sees his biggest challenges as sampling error and
invasiveness: "How can I map a statistically-accurate
representation of a network without sticking a million needles into
At this stage it's not clear on what level one needs to map the
brain on. He offers up the analogy of trying to record the chatter
of people on the streets of Manhattan. He likens an implanted EEG recording -- one existing way of measuring
seizures in epileptic brains -- to holding a microphone and
suspending it from a helicopter; it allows you to get a sense of
whether the volume is up or down in the streets below and whether
people are applauding or yelling, "but is it a riot or a birthday
party? Or a presidential speech? You have no idea".
He goes onto say that you could interview individuals on the
street [equivalent to having an electrode connected to each
neuron], but would have to sample enough people to really
understand what was going on. In the middle is putting a probe on
each street corner and hearing the buzz in the localised crowd.
"That's what we are aiming for now," says Litt. Getting that higher
resolution requires smaller devices with more electrodes into deeper parts of the brain.
However, it's problematic sampling enough brain in enough places
without being too invasive and violating brain tissue. "I have to
bore a hole in your head through the bone and put a probe in
there," Litt adds.
The team is exploring nanodevices that could get across the
blood-brain barrier to get over the invasiveness hurdle, but it
will still need to employ novel ways to communicate with the tiny
devices, as the size of the individual cell is too small to make an
antenna big enough to get the signal outside of the body. One
possible solution could be using optogenetic constructs that allow
you to make neurons fire on demand and make them give off some sort
of radiation you can detect, but Litt's putting his money on "high
resolution recording and big data".
From multidisciplinary to "transdisciplinary"
As a consequence, it's no surprise that the entire field
of bioelectronics is underpinned by collaboration between
engineers, computer scientists and biologists.
With these sorts of collaborations, the radially different
development cycles of electronics and pharmaceuticals become
"In the drug world there is a very well established regulatory
and clinical trial mechanism to determine the use of a drug,"
explains Tracey. "But what we are doing is developing devices to
replace drugs. This means that they need to be developed as if they
In the future this could mean that by the time you have jumped
through all of the regulatory hurdles with a new device, you'd be
able to develop a much better one. Although Tracey says that this
would be a "hoped-for problem of the future".
Other hurdles that will need to be overcome include working out
ways to power these devices inside the body through energy
harvesting and how to make them last long enough to make surgical
"It's all of these pieces -- neuroscience, disease biology and
circuit design -- coming together that keep me up at night," says
Famm. "How can we get neural interfaces to really access all of
this information that is flowing through our system? I am confident
we have the computing power, but we are faced with a fascinating
engineering challenge to access and read this information."
Boyden adds: "There are many engineering fields that have never
been applied to the brain; there might be a lot of low hanging
fruit out there, if engineering fields and biological fields can
merge into novel collaborations."
Stewart Smith, a lecturer in bioelectronics at Edinburgh
University's School of Engineering, believes that the key challenge
is one of translation. "Often you are using the same words to mean
different things. When we talk about a substrate it's a different
thing to what a chemist refers to as a substrate, and it can be
quite tricky to disentangle."
"We need more people who can speak both languages," enthuses
Litt. "That's my crusade."
Tracey goes even further and shuns the word "interdisciplinary"
in favour "transdisciplinary", arguing that when collaborations are
successful there "won't be any in-between, only together".
He warns: "Neither engineers nor biologists can succeed without
the other. Technology will create the future in this space and
unless biologists embrace what the engineers bring to the table,
opportunities will be missed."