Stimulation of the nervous system could replace drugs for inflammatory and autoimmune conditions
Theuse of nerve-stimulating electronic devices to treat inflammation and reversedisability is laying the foundation for a new discipline called bioelectronicmedicine. It is being tested in clinical studies of patients with rheumatoid arthritis and other diseases. It is based on a deceptively simple concept of harnessing the body’s natural reflexes to develop an array of effective, safe and economical alternatives to many pills and injectable drugs. By precisely targeting the biological processes underlying disease, this nerve-stimulating technology should help avoid the troublesome side effects of many drugs.
Heat, touch, pressure, light and the presence of specific molecules generate an electrical signal in nerve cells called sensory neurons. This electrical information is transmitted to “interneurons,” another type of nerve cell in the central nervous system that passes the incoming impulse along to motor neurons, which complete the third and final stage in the simple reflex circuit. The subsequent firing of the motor neuron sends electrical signals back to the body’s muscles and organs, triggering behaviors ranging from the withdrawal of a finger from a hot plate to the dilation of an airway during a three-mile run.
Simple reflex circuits harmonize the activity of individual organs, so that you do not have to consciously plan the minute organs, so that you do not have to consciously plan the minute actions that keep your body functioning efficiently. When you leap from a chair and run up the stairs to answer the ring of a telephone, you do not have to think about coordinating your respiration, heart rate and blood pressure. Reflexes take care of all the essentials, matching organ function to the body’s needs, whether resting comfortably or running at full speed.
Charles Scott Sherrington (1857–1952), the Nobel Prize–winning British physiologist, proposed that simple reflexes made up of neural circuits are the basic building blocks of the nervous system. The combined output of millions of nerve signals that control reflexes directs the functioning of the body’s organs. But Sherrington did not address one lingering question: How do the electrical signals that course through motor neurons actually control organ function? The answer is relatively simple. In effect, they produce “drugs.” Neurons transmit information along nerve fibers, or axons, the long, wirelike extensions that terminate in the organ being regulated. At the very end of the axon lies the “synapse,” a word coined by Sherrington. The motor neuron’s axon on one side of the synapse does not physically touch the nerve or organ cells on the opposite side of the narrow gap called the synaptic cleft. Instead the arrival of the electrical signals at the end of the axon stimulates release of neurotransmitters that diffuse across the synaptic cleft and bind to receptors, docking sites on the target nerve or organ cells. Chemical neurotransmitter molecules latch on to receptors at the other side of this cleft to alter the behavior of the targeted cells, changing their function. It turns out that many drugs work in a similar manner.
The pharmaceutical industry invests billions of dollars to design, synthesize and develop new chemicals as experimental drugs that, like neurotransmitters, are nothing more than molecules that interact with receptors. Many blockbuster drugs selectively bind to specific receptors that modify metabolic activity and turn on genes in selected cells. But drugs can have dangerous side effects. Once swallowed or injected, pharmaceuticals travel throughout the body, where they may produce undesired consequences when interacting with cells that are not their intended targets.
Using a device to send signals down a nerve to stimulate production of druglike neurotransmitters offers a distinct advantage. The body’s self-made drugs deliver chemicals to specific tissues in precise, nontoxic amounts at just the right time, diminishing the occurrence of side effects.
By the late 1990s a new class of pharmaceutical called monoclonal antibodies were being used to treat patients with rheumatoid arthritis, inflammatory bowel disease and other disorders. Monoclonal antibodies, which Dr. Tracey and his colleagues helped to pioneer, can alleviate the pain, swelling, tissue destruction, and other symptoms of inflammation caused by the overproduction of TNF and other molecules. For many patients, it offers their only chance for a normal life. But success has come with soaring costs. Drug bills range from $15,000 to $30,000 annually for a single patient, even though anti-TNF is ineffective in up to 50 percent of patients. Perhaps most worrisome to patients and their caregivers, these drugs can cause dangerous, even lethal, side effects.
Initially Dr. Tracey’s team reasoned that perhaps CNI-1493 activated the brain’s pituitary gland at the base of the brain to stimulate production of hormones, including steroids—or glucocorticoids—that in turn inhibited TNF production in distant organs. Alas, after surgically removing the pituitary gland in rats and repeating the experiments, we found that CNI-1493 injected into the brain still inhibited TNF. This result meant that the pituitary gland did not convey the signal that turned off TNF production in the body. Searching for another explanation, they began to consider the improbable possibility that motor neurons exiting the brain carried electrical signals to inhibit TNF in the rest of the body.
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