Important & fascinating article from 12/13/06 NY Times. Researchers Find Gene Tied to Perception of Pain By NICHOLAS WADE Geneticists following up the case of a 10-year old Pakistani boy who could walk on coals without discomfort have discovered a gene that is central to the perception of pain. A mutation in the gene knocks out all perception of injury, raising hopes of developing novel drugs that would abolish pain by blocking the gene’s function. The boy lived in Lahore, Pakistan, and was well known to the city’s medical authorities because he would come to the clinic asking to be patched up after his street theater. In these exhibitions, he would pass knives through his arms and walk on burning coals without feeling pain. A research team led by C. Geoffrey Woods, a physician at the Cambridge Institute for Medical Research in Cambridge, England, reports in the journal Nature that team members have identified a genetic defect in some of the boy’s relatives who are also unable to feel pain. The defect inactivates a gene that is critical to the body’s perception of pain. The gene is obviously an attractive new target for drug developers seeking to eliminate pain. Dr. Allan Basbaum, an expert on pain at the University of California, San Francisco, said the finding was “a very exciting story” and provided strong proof of principle that inhibition of the gene “can result in powerful pain control with minimal side effects.” But if drugs can be developed, it would be important to avoid eliminating pain altogether, he said, because of its protective effects. Dr. Woods, who has patients among the Pakistani emigrant community in Britain, said in an interview today that he was told of the boy during one of his periodic visits to Pakistan. He decided to examine him on a later visit but learned that the boy had died after jumping off the roof of a house to impress his friends. Dr. Woods then looked to see if there were any other pain-free individuals in the Qureshi clan to which the boy belonged. The clans, now Muslim, are historical remnants of the Hindu caste system, and the people in a clan are often closely related. After much effort, he and colleagues in Pakistan and Britain eventually found three Qureshi families among whom six members reported that they had never experienced pain in any part of their body. “None knew what pain felt like, although the older individuals realized what actions should elicit pain,” the researchers write. Children who don’t feel pain soon realize they are regarded as peculiar and learn to simulate it when it would be expected, such as after tackles on the football field, Dr. Woods said. After six years of work, Dr. Woods found that the affected members of all three families had a defect in a gene known as sodium channel N9A, or SCN9A. The gene is one of a family of 11 human genes whose protein products govern the initiation of signals that nerves send through the body. The protein products of the genes open channels that let sodium ions rush across a nerve cell’s membrane, setting off a nervous signal. The SCN9A gene is active both in nerves that mediate pain and in those of the sympathetic nervous system, which controls vital bodily functions like heart rate. But for reasons that are not yet understood, the affected members of the Pakistani families had no symptoms of a disordered sympathetic nervous system, such as irregular heart rate, and seemed entirely normal apart from the occasional self-inflicted damage caused by their inability to feel pain. Several had inadvertently bitten off the tips of their tongue in infancy. Dr. Woods’ discovery “is an important part of a fascinating story,” said Dr. Stephen G. Waxman, a neurologist at Yale University who studies erythromelalgia, a disease in which patients feel an intense burning sensation after exposure to mild warmth. This disease is also caused by mutations in the SCN9A gene, but ones that enhance the gene’s activity instead of blocking it. Drug developers might find the gene particularly interesting because the defective form in the Pakistani patients seems to have no side-effects, even in the sympathetic nervous system where they would be expected, Dr. Waxman said. “But having a target doesn’t guarantee that drugs can be developed,” he said. Dr. Woods said he believed the Qureshi boy in Lahore whose exploits stimulated his research would have had a defective SCN9A gene. The boy’s mother had one defective copy of the gene, as presumably did his father, a first cousin of the mother, who died of a heart attack before he could be examined. Two copies of the defective gene must be inherited, one from each parent, for a person to lack the sensation of pain. Because many genes and nerves are involved in mediating pain, it is surprising that a mutation in a single gene could inactivate the whole system. The reason, Dr. Woods said, is probably that a common mechanism is involved in all feelings of pain. The first step in pain is not universal. Nerve fibers have different proteins embedded in their endings, each of which is sensitive to a different kind of injury, whether from changes in temperature, pressure or acidity, or some other cause. These sensor proteins act by letting a few sodium ions flow into the nerve, though not enough to set off a pain signal that travels to the brain. The proteins made by the SCN9A gene amplify the initial activity by letting a much larger number of sodium ions flow in, initiating an electrical signal that is interpreted as painful when it reaches the brain. Presumably because all pain fibers depend on the SCN9A gene’s protein for amplification, all signals of pain are muted at their source when the gene is inactive, Dr. Woods said.