The harnessing of electrical stimulation to treat human disease dates back to the 19th century and the work of Guillaume Duchenne, who is considered the pioneer of electrophysiology.
Duchenne used electrodes to map the neuromuscular pathways that governed muscle movements, and also made preliminary attempts to treat paralysis, predicting in the 1860s that - one day - electrical impulses may be used to help patients suffering from disease such as muscular dystrophy.
His work was not widely appreciated at the time, however, and the use of electricity as treatment quickly became subverted by dubious practitioners interested more in selling quasi-medical gizmos than treating patients effectively.
It was not until the 20th century that electrotherapy started to re-emerge as a serious treatment modality, and since then the concept has been applied (albeit fairly crudely) to pain relief, wound healing and - latterly - neuropsychiatric conditions such as depression, epilepsy and Parkinson's through the use of electronic implants.
The pharmaceutical industry - with its focus on chemical and biological treatments - has been largely absent from the picture, but that looks set to change over the coming years as companies increasingly evolve from simple pill-pushers to organisations offering a multi-disciplinary approach to the provision of healthcare.
Significant big pharma interest
Among big pharma companies, GlaxoSmithKline has been the most vocal in its support for the approach, proffering a $1m R&D prize for 'bioelectronics' research earlier this year and following that up with funding to support up to 20 research projects in the field and a $50m venture capital fund to support companies with bioelectronic medicines and technologies.
Given that practically all of the body's organs and functions are regulated through neural circuits communicating via electrical impulses, it should theoretically be possible to interpret the electrical language of diseases. By extension, it could be possible to stimulate or inhibit the malfunctioning pathways with tiny electrodes in order to correct the defect.
This micro-manipulation of the nervous system - targeting impulses (action potentials) to specific cells within neural circuits - could conceivably be exploited to manipulate a broad range of bodily functions, such as controlling appetite or blood pressure or stimulating the release of insulin in response to rising blood sugar, according to Kristoffer Famm, the head of GSK's bioelectronics research programme.
“We believe that it is now possible to create medicines that control action potentials in individual neurons and in functional groups of them,” Famm wrote in an April commentary for Nature, in which he likened the research to the target identification and validation steps that underpin molecular drug discovery.
The applications of this approach are intuitive for central nervous system (CNS) diseases, but could be even more widespread in light of research which suggests stimulation of certain nerve fibres can boost the immune response. Harnessing that potential could bring cancer and potentially even infectious diseases into the electroceutical spectrum.
Accessing and interpreting the signals even in the CNS is challenging, however, and researchers are starting to explore the use of probes to monitor neural activity deep in the brain and even nanoscale devices that could cross the blood brain barrier and - potentially - send signals outside the body.
The emerging field of optogenetics, combining optical and genetic techniques to monitor and control the activity of individual neurons in living tissue in real time, is in its infancy but could become a critical tool in this endeavour.
GSK's R&D chief Moncef Slaoui predicted recently that every major pharma company would have a bioelectronics programme within the next twenty years, tapping into advances in bioelectronics research in academia that is already happening at a breakneck pace.
For example, researchers at Brown University in the US are starting to work with implanted electrodes that allow paralysed patients to direct a robotic arm using their thoughts, while a team led by Kevin Tracey of the Feinstein Institute - using a vagal nerve implant developed by US firm SetPoint Medical - relieved the inflammation and pain associated with rheumatoid arthritis in a patient last year.
While GSK is embarking on the first steps down a blue-sky route to exquisitely tailored electroceuticals that will probably remain elusive for many years, GSK-backed SetPoint Medical and other companies are developing electronic devices that could add to the bioelectronic armamentarium in the near-term.
Another such is ElectroCore Medical, which is rolling out a non-implanted device called GammaCore that stimulates the vagal nerve as a means of treating cluster headache and migraine in Canada, Germany, the UK and other parts of Europe. The non-invasive device is also being developed for other indications such as epilepsy, asthma, irritable bowel syndrome and even Alzheimer's disease.
ElectroCore has a somewhat different vision from GSK. Chief executive JP Errico has suggested that it will be harder to isolate the nerve bundles sending efferent signals involved in specific diseases from the peripheral nervous system to the brain, and blocking them will likely involve an invasive procedure. The company's strategy of blocking the afferent signal from being released in the brain will have a broader impact.
“We think you'll gain the same benefit - and potentially collateral benefit as well - from targeting the afferent signal,” he says.
A criticism of the broad-based approach espoused by ElectroCore and others is that stimulation of the vagal nerve is inherently imprecise, involving thousands of individual nerve fibres which communicate with many internal organs, which could lead to side effects.
To date however there does not seem to be much evidence for that in the thousands of patients that have been treated with implants for epilepsy and other conditions, although some patients experience mild problems such as difficulty swallowing and hoarseness.
“There is a 20-year history of implantable vagal nerve stimulators in more than 100,000 people, with 250 to 300 impulses a day, which back up the safety of the approach,” says Errico.
While taking a different stance from GSK on the specifics of bioelectronics, Errico shares the view that the field will become a significant part of every major pharmaceutical company's R&D programme over the coming years, in part out of necessity as the dynamics of the traditional drug discovery approach change.
“I think it will take a lot less than 20 years,” he said.
Open source bioelectronics research
For GSK, the next stage in the bioelectronics project is the hosting of a conference in New York later this year to discuss the key challenges and objectives in the field and set the terms of its $1m prize for a project that overcomes a key obstacle to the development of the technology, according to the company.
GSK says it wants to serve as a catalyst in the field and encourage an open source-type approach to bioelectronics research, helping to bring together researchers in fields as diverse as biology, nanotechnology, materials science, micro-power generation and IT. “Clearly, open innovation and flexibility in dealing with intellectual property will be important,” says Famm.
The last word goes to Duchenne's student and neurological pioneer Jean-Martin Charcot, who memorably described the symptoms of disease as “nothing but a cry from suffering organs.”
Perhaps gaining a deep understanding of this 'language' of disease - taking into account both the electrical and the molecular miscommunications that disrupt the body's proper functioning - will usher in a new era in medicine.