We're learning to speak the electrical language of the body - and using it to develop treatments for diseases from arthritis to diabetes

FOR Goran Ostovich*, just driving his delivery van was a daily agony. The painful swelling in his hands, wrists and elbows made it nearly impossible to grip and turn the wheel - never mind loading and unloading the produce his van carried. The drugs that he had taken for years to alleviate his rheumatoid arthritis didn't help much. He had reluctantly abandoned his favourite sport, ping pong. He stopped working. The final cruelty was when he could no longer lift his young children or play with them.

It was then that Ostovich volunteered for a last resort treatment: he had a small computer implanted in his neck that would instruct his immune cells to stand down.

Ostovich's implant is a harbinger of a revolution in the pharmaceutical industry. Researchers are waking up to the idea that the electrical language of nerves might be spoken more widely in the body than anyone thought, playing a pivotal role in coordinating the actions of our organs, glands and cells. It may even be possible to use the nervous system to coax the body into healing itself in ways we never dreamed of.

The pharmaceutical industry is on the case, and a spate of projects is under way around the world to map the exact circuits that allow the nervous system to intervene when things go wrong in the body.

Autoimmune diseases, asthma, diabetes and gastric conditions are just a few of the disorders that appear amenable to electrical intervention. There are even hints it could be used as a radical way of treating cancer. Within a decade or two, electrical implants could replace many common drugs. Welcome to the brave new world of electroceuticals.

The idea that electrical signals can control the immune system will sound bizarre to anyone who has studied biology. After all, electricity is the language of the nervous system, not the immune system. Electrical signals, in the form of action potentials, travel to and from the brain via the numerous nerve pathways throughout the body. For example, to regulate your heartbeat, sensory nerve fibres detect your heart rate and relay that information to the brain, which in turn sends instructions back to the heart telling it to speed up or slow down. A similar circuit controls blood pressure. "It's like setting a thermostat," says Kevin Tracey of the Feinstein Institute for Medical Research in New York. "The nervous system constantly responds to changes and adjusts everything back to the set point." We can manipulate that electrical language when the body's natural thermostat goes wrong, with defibrillators that use electricity to jump-start a stalled heart, or pacemakers that regulate the rate at which it pumps blood.

No such central governor was thought to control the immune system. A decentralised army, including white blood cells and virus-eating macrophages, was thought to roam around in the bloodstream fighting ad hoc battles against bacteria and viruses where they needed to be fought. Damaged tissue might send out a call for reinforcements, but there was no central command.

Tracey challenged that understanding in the late 1990s. He and his colleagues were testing a new anti-inflammatory drug. When they injected it into rats' brains, they noticed it also dampened inflammation in their limbs and peripheral organs. "The amount of drug we were using was vanishingly small so we knew the signal wasn't going through the bloodstream," Tracey says. The only explanation was the nervous system. The idea was too intriguing to ignore. "So we started stimulating different nerves to see if we could reproduce the effect," he says. Sure enough, he found that electrically stimulating the nerve fibres that linked to the spleen - home to immune cells known as T-cells - dampened their activity. It was one of the first hints that the brain might be talking to the immune system after all.

But how? Tracey had discovered that nerve cells speak to immune cells in the spleen using chemicals called neurotransmitters - the same language they use to speak to each other. Nerve stimulation triggered a complex reaction that told the T-cells to stop the production of inflammatory substances, such as tumour necrosis factor (TNF).

In healthy people this nerve circuit ensures that levels of TNF never get too high. However, in autoimmune disorders such as rheumatoid arthritis, the normal brakes fail and TNF production spirals out of control. It accumulates in people's joints, triggering pain, inflammation and the breakdown of tissue.

To stave off these debilitating effects, people with rheumatoid arthritis often turn to drugs called TNF inhibitors. However, because these mop up all the TNF they find, they leave people at increased risk of infection. Worse, they don't always work for rheumatoid arthritis. Ostovich was on several different drugs, but his pain was still debilitating.

But he was fortunate. The clinic he attended had just started recruiting people for a trial of a therapy based on Tracey's findings. Following successful animal studies, Tracey had founded a company called SetPoint Medical to treat arthritis in people. For its pilot trial, SetPoint chose Ostovich's home country, Bosnia and Herzegovina, where few have access to TNF inhibitors. The plan was to implant tiny computers into the necks of 12 people with rheumatoid arthritis to see if electrical stimulation eased their symptoms.

Ostovich's computer tapped into his vagus nerve, the electrical superhighway that links the brain to all of the major organs, to intermittently stimulate the nerve fibres that connect to the spleen (see diagram). The researchers hoped that the device would instruct his immune system to stand down and stop attacking his joints.

It worked. The constant pain in Ostovich's joints stopped. Levels of an inflammatory protein called CRP that is usually elevated in people with arthritis fell back to normal. Best of all, this intervention had no serious side effects. Nerve stimulation only removes around 80 per cent of TNF - as opposed to eliminating it the way drugs do. It also suppresses the production of other immune factors that can damage tissue when released in excess. Like Ostovich, seven other volunteers have shown similar improvements (Arthritis and Rheumatism, vol 64, p 1).

With this triumph, Tracey believes that he has identified the first of many neural circuits that control the immune system. Last August, Clifford Woolf of Harvard Medical School announced that he and his colleagues had found a second: nerves in the skin, which were able to suppress infection when stimulated. Similar circuits are cropping up elsewhere too. The carotid body - a cluster of cells that sense glucose levels in the main artery carrying blood to the head - has a connection to the central nervous system that can affect rats' insulin sensitivity and blood pressure (Diabetes, vol 62, p 2905). Implanted electrodes, says Silvia Conde at the New University of Lisbon, where the study was conducted, might manipulate some nerve signals and not others, making it possible to tweak insulin sensitivity without disrupting other vital functions of the carotid body. At any rate, it is becoming clear that these circuits are all plugged into a body-wide electrical grid.

But as Conde's work implies, the immune system isn't the only thing these circuits can manipulate. Electrocore, an electroceutical device manufacturer with headquarters in Basking Ridge, New Jersey, has been working to isolate a different set of fibres within the vagus nerve to treat asthma. "A nerve is like a transatlantic telephone wire," Tracey says. "It has lots of individual cables inside it." The nerve fibres targeted by Electrocore's neck stimulator link to a region of the brain involved in the physiological response to stress and panic. Zapping them triggers the release of noradrenaline, which dampens the activity of neurons that control the airways, prompting them to open, averting the asthma attack. "The message we're sending is: 'everything's fine, you can relax, there's no fight or flight to engage in'," says Electrocore CEO JP Errico. 

It appears to work. In 81 people admitted to emergency departments during an asthma attack who didn't respond to standard drugs within an hour, electrical stimulation with Electrocore's implanted electrode led to a significant improvement in their lung function. Electrocore is now testing a device that activates nerve fibres through the skin.

While vagus nerve stimulation is an attractive strategy, it may not be focused enough, says Brendan Canning of the Johns Hopkins asthma and allergy centre in Baltimore, Maryland. The nerve fibres Electrocore targets are unlikely to combat some of the other troublesome symptoms of asthma, such as coughing and the feeling that you are not getting enough air, he says. Canning has discovered that these symptoms are controlled by a different set of fibres in the vagus nerve. However, stimulating these also triggers "fight or flight" responses such as boosting the heart and breathing rate, which often exacerbate an attack by activating a person's panic response.

Such early measures are relatively blunt instruments. No existing implant is able to isolate individual cables. Instead, SetPoint's implants use a workaround: they are tuned so that the amount of electricity you put in only stimulates a small subset of the cables.

It's an elegant fix, but what if you could also eavesdrop on the electrical signals to detect abnormalities and only speak to the fibres that were misfiring? Such a smart electrode, Canning says, could also "detect changes in nerve activity, provide therapy as needed and then shut off".

This is exactly what global pharmaceutical giant GlaxoSmithKline (GSK) is working on. "The goal is to have rice-sized implants that sit on the peripheral nerves and record the complexity of the electrical language that flows through them, detect when something's out of balance and then fix it," says Kristoffer Famm of GSK. "We believe this treatment could be crucial for a whole host of chronic diseases - things like diabetes, hypertension, arthritis and chronic pain."

Tracey and Woolf's research shows that achieving Famm's goal is possible, although commercialising it will be more difficult. It will require collaboration between scientists who don't usually interact - engineers that design brain-machine interfaces, say, and lung or immunology experts. In December, GSK hosted a forum in New York to identify the key hurdles most likely to stop the field of electroceuticals from progressing, and offered a $1 million bounty to the group that overcomes them.

That reward is only a fraction of what the firm is spending on electroceuticals. GSK has funded six centres to begin teasing apart the neural circuits that underlie specific diseases. Unofficially, 11 more have joined the team.

And while GSK may have the biggest budget, it is by no means the only company betting big on this technology. Beyond Electrocore, the field includes medical device giant Medtronic, which is working on electrical interference for stubborn gastrointestinal problems. "We're learning to speak the electrical language of the body," says Famm. GSK expects to treat a range of common disorders with electrical implants.

However, even that may be just the tip of the iceberg. Electroceuticals may also offer new avenues to treat cancer.

The reason nerve cells can transmit electrical signals is because the inside of the cell is negatively charged relative to the outside, known as its resting potential. When a nerve cell fires, there is a sudden influx of positive ions into the cell through channels in its membrane. These ion channels open and close much more quickly in nerve cells, but other cells speak this electrical language too. "All cells maintain a resting potential. They use it signal to their neighbours," says Michael Levin of Tufts University in Medford, Massachusetts.

Each kind of cell has its own resting potential, and Levin has discovered that these differences play a key role in determining which embryonic cells turn into what part of the body during development. In frog embryos, for example, setting the voltage of what are normally destined to become gut cells to the normal range of eye cells triggered the growth of complete eyes in the embryo's gut. "A lot of this can be done using drugs that are already in human use," he says.

Levin has taken it even further. By soaking the stump of a frog's amputated leg in a cocktail of drugs that trigger the flow of sodium ions into cells, his lab has managed to coax adult frogs to grow new legs - something which is not normally possible.

Intrigued, he wondered whether he could reverse this logic to inhibit unwanted cells. Last year, he successfully used ion channel drugs to stop the growth of tumours in tadpoles primed to develop cancer.

Levin's work is early, and electroceuticals won't cure every disease - but we should expect to see a lot more stories like Ostovich's. Eight weeks after getting his implant, he returned to work. When Tracey heard the success story, he says, "I said, 'I have to meet this guy'".

Tracey speaks no Bosnian and Ostovich speaks no English, so the meeting required a translator. But conversation was hardly necessary to see that the treatment had changed Ostovich's life. "The expression on his face was unbridled joy, gratitude and relief," Tracey says. "It made all the years of basic bench research worthwhile." Ostovich told Tracey that the device had worked so well he had been able to take up ping pong again. And he felt so great after playing ping pong that he decided to try tennis. Indeed, this may have revealed a potential downside of the device: in his pain-free enthusiasm, he overdid it and ended up with a tennis-related knee injury. His doctors were forced to caution the man who, just two months earlier was unable to play with his children, to take it easy.

*name has been changed to protect confidentiality

 By Leonard David, Space.com's Space Insider Columnist   |   February 19, 2014 06:38am ET

Is it time to push the "up" button on the space elevator?

A space elevator consisting of an Earth-anchored tether that extends 62,000 miles (100,000 kilometers) into space could eventually provide routine, safe, inexpensive and quiet access to orbit, some researchers say.

A new assessment of the concept has been pulled together titled "Space Elevators: An Assessment of the Technological Feasibility and the Way Forward." The study was conducted by a diverse collection of experts from around the world under the auspices of the International Academy of Astronautics (IAA). [Quiz: Sci-Fi vs. Real Technology]

The study's final judgment is twofold: A space elevator appears possible, with the understanding that risks must be mitigated through technological progress...and a space elevator infrastructure could indeed be built via a major international effort.

The tether serving as a space elevator would be used to economically place payloads and eventually people into space using electric vehicles called climbers that drive up and down the tether at train-like speeds. The rotation of the Earth would keep the tether taut and capable of supporting the climbers.

Rooted in history

The notion of a beanstalk-like space elevator is rooted in history.

Many point to the ahead-of-its-time "thought experiment" published in 1895 by Russian space pioneer Konstantin Tsiolkovsky. He suggested creation of a free-standing tower reaching from the surface of Earth to the height of geostationary orbit (GEO; 22,236 miles, or 35,786 km).

Over the last century or so, writers, scientists, engineers and others have helped finesse the practicality of the space elevator. And the new study marks a major development in the evolution of the idea, says IAA president Gopalan Madhavan Nair. [10 Sci-Fi Predictions That Came True]

"No doubt all the space agencies of the world will welcome such a definitive study that investigates new ways of transportation with major changes associated with inexpensive routine access to GEO and beyond," Nair writes in the new study's preface.

"There is no doubt that the Academy, due to this study, will contribute to advancing international consensus and awareness on the need to search and develop new ways of transportation in conducting space exploration while preserving our universe in the same way we are now trying to preserve our planet Earth," Nair adds.

Elevator operator

While it's always tricky to predict the future study lead editor Peter Swan told Space.com that space elevators are more than just a science-fiction fantasy. "The results of our study are encouraging," he said.

Swan's view is fortified by the late science fact/fiction soothsayer, Arthur C. Clarke, who stated in 2003: "The space elevator will be built ten years after they stop laughing...and they have stopped laughing!"

Swan is chief engineer at SouthWest Analytic Network, Inc. in Paradise Valley, Ariz., and is focused on developing and teaching innovative approaches to "new space" development. He's also head elevator operator of the International Space Elevator Consortium (ISEC), which has organizational members in the United States, Europe and Japan and individual members from around the world.

ISEC's goal is nothing short of getting a lengthy space elevator built.

"The question is when, of course," Swan said. "But the point is that the technologies are progressing in a positive manner, such that we who work in it believe that there will be space elevators."

Pacing technologies

Swan said the giggle factor regarding space elevators is "down significantly" given work carried out over the last decade by a global network of individuals and groups. "Still, there are many, many issues and I certainly would not want to say that it's not a challenging project."

The IAA appraisal delves into a number of issues, such as: Why build a space elevator? Can it be done? How would all the elements fit together to create a system of systems? And what are the technical feasibilities of each major space elevator element?

Two technologies are pacing the development of the space elevator, Swan said.

Producing an ultra-strong space tether and other space elevator components, Swan said, has been advanced by the invention of carbon nanotubes (CNTs) that are 1,000 times better in strength-to-weight ratio than steel. The good news, he said, is that CNTs are being developed with billions of dollars by nanotechnology, electronics, optics, and materials specialists.

Similarly, lightweight solar cells "are coming along nicely," Swan said. "That's an industry that the space elevator people are watching, too. We're not going to drive it, but we can certainly watch it and appreciate the advances."

Money, motivation and desire

Regarding who would erect a space elevator, Swan said the study dives into details. A primarily commercial effort with some government support is possible, as is a public-private enterprise, or an entirely governmental project.

"All three are viable. Any one of them could work. It's a matter of money, motivation and the desire to do it," Swan said, though the study centers on commercial development of the space elevator. "It's conceivable all three could be going on at the same time."

The study team was encouraged by the future, though Swan and others acknowledge there are many questions left to be studied. Indeed, another evaluation of the space elevator idea 10 years hence would be worthwhile, Swan said.

Are there any technical, political or policy "showstoppers" that could prevent the space elevator from becoming a reality?

"You're asking the wrong guy," Swan responded. "I am an optimist. I have always had the attitude that good people, motivated by good rationale working hard will make it work. My guess is that space elevators are going to work, whether it's by 2035, 2060 or even 2100."

Swan said the rationale is moving beyond the "rocket equation," which involves tossing away 94 percent of a rocket's mass sitting on the launch pad.

"And it still costs a lot of stinking money to get up there," he said.

The space elevator opens everything up, Swan said. It's a soft ride, a week to GEO. There are no restrictions on the size or shape of payloads.

"People will laugh and ask why did we ever do space rockets...it's a dumb idea," Swan said. "Space elevators are the answer if we can make them work. Why would you do anything else?"

Leonard David has been reporting on the space industry for more than five decades. He is former director of research for the National Commission on Space and is co-author of Buzz Aldrin's new book "Mission to Mars - My Vision for Space Exploration" published by National Geographic. Follow us @Spacedotcom,Facebook or Google+. Originally published on Space.com.

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By Kevin Bullis on February 17, 2014 

http://www.technologyreview.com/news/524781/a-battery-with-liquid-electrodes-can-be-recharged-or-refilled/?utm_campaign=newsletters&utm_source=newsletter-weekly-energy&utm_medium=email&utm_content=20140217  

ARPA-E is funding several projects that use liquid battery electrodes to cut costs and increase energy density. 

A new kind of battery stores energy in what researchers are calling "rechargeable fuel"-electrodes in liquid form. The result can be either recharged like a conventional battery or replaced by pumping in new fuel like gasoline.

The materials could theoretically allow an electric car to travel 500 miles on a charge, five times farther than most electric vehicles can now, say the researchers developing the technology, who are based at Argonne National Laboratory and the Illinois Institute of Technology. Replacing them at a fueling station would take just a few minutes. In contrast, even the fastest charging stations for conventional batteries take an hour to provide a full charge.

Limited driving range and long recharging times are two of the biggest challenges for electric cars. Liquid battery electrodes could allow longer range by increasing the amount of energy battery packs can store, and because fewer non-energy-storing components would be needed, it could also make them cheaper.

Batteries that use liquid electrodes could also be safer than conventional ones, says Ping Liu, a program manager at the Advanced Research Projects Agency for Energy, which is funding the work. Positive and negative electrode materials would be stored in separate tanks, rather than inside the same battery cell as in conventional batteries. This could prevent the short circuits and overheating that can cause lithium-ion batteries to catch fire. 

Rechargeable fuels are at an early stage, but ARPA-E has deemed them promising, announcing funding for four groups that are developing the technology. In addition to the Illinois project, it is backing projects at GE, the National Renewable Energy Laboratory, and 24M, an MIT spinoff.

The Illinois researchers have so far demonstrated a small "half-cell" battery that uses one fluid electrode and one solid one. For their $3.4 million ARPA-E-funded project, which started last month, they plan to build a prototype that uses liquids for both the positive and negative electrodes. This battery should store one kilowatt-hour of energy, enough for a few miles of driving.

In conventional electric-car batteries, as much as 75 percent of the material inside a battery pack consists of components that don't store energy-cell packaging, sensors, electrical connections, cooling systems, and so on. With fluid energy storage, at least in theory, much of that material can be eliminated, decreasing the size and cost of battery packs. 

The key is separating the energy-storing materials from the structures used to extract that energy and create electrical current. In a conventional battery, every layer of electrode material is paired with a sheet of foil and a plastic membrane that allow electrons and ions to flow, creating electrical current. If you want to store more energy, you need to add more layers of foil and plastic, too.

In the new battery, the fluid electrodes would be stored in tanks and pumped through a relatively small device to interact and generate electricity. Increasing energy storage would just be a matter of making the storage tanks bigger; the device where electricity is generated could stay the same size. The larger the tanks, the less of the total volume the energy-generating device would take up.

Fluid electrodes have been around for a while-for example, as part of devices called flow batteries-but they typically store energy in a dilute solution that requires too much volume to be used in a car. Some batteries have molten electrodes that are better suited for stationary applications (see "Ambri's Better Battery"). Each of the ARPA-E projects aims to find ways to increase the energy density of the liquids by an order of magnitude. The MIT spinoff 24M is a pioneer in this area, having shown that it's possible to suspend high concentrations of conventional, energy-dense electrode powders in a liquid and extract energy from them (see "A Car Battery at Half the Price"). The main challenge is achieving high enough electrical conductivity for a practical battery.

The Illinois researchers have a similar approach. They emphasize the use of nanoscale powders that can be suspended in very high concentrations and still flow easily, thanks to the peculiar properties of particles at such a small scale. They've also developed a new way of extracting electrical current from the particles, and they hope this will allow them to increase conductivity. The details are secret until they finish filing patents. 

Liquid electrode batteries do have some potential drawbacks. Nanoparticles can degrade quickly, and the researchers have only begun to design the entire system. They need to design a way to pump the materials efficiently and manufacture the battery cheaply. And recharging cars by refilling the tanks with new material would require installing new infrastructure, which can be expensive.

Meanwhile, conventional batteries continue to get cheaper, and improved technology is making them faster to recharge (see "How Tesla Is Driving Electric Car Innovation" and "Forget Battery Swapping: Tesla Aims to Charge Electric Cars in Five Minutes"). 

 www.NobelPrize.org  February 2014

Exploring the Future of Energy   Audiences across the globe joined Nobel Laureates, world-leading experts and business leaders in a discussion about the future of energy during the 2013 Nobel Week Dialogue. Watch Physics Laureate David Gross' introduction Three Nobel anniversaries - the case for basic science.   Watch the lecture Morning Plenary Session 2 - Nobel Week Dialogue 2013

Sources of Energy   "Why does the Sun shine?" One of Physics Laureate Hans Bethe's contributions was to reveal how the Sun behaves and to describe the role nuclear reactions play in producing the energy of the Sun and the stars. More about Hans Bethe's Nobel Prize

Nuclear Energy   One way nuclear energy can originate is from the splitting of uranium atoms in a process called fission. It is a powerful source for energy, but it can also be misused. IAEA, awarded the 2005 Nobel Peace Prize, works to ensure that nuclear energy is not misused for military purposes.  Watch a documentary about IAEA's work

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