At the Institute of Human Genetics in Aachen, Germany, Dr Ingo Kurth is preparing for a rather unusual appointment. She’s collecting blood samples from Stefan Betz, a 21-year-old university student who suffers from a genetic disorder so rare that only a few hundred people worldwide are estimated to have it. Betz has congenital insensitivity to pain, or CIP. It means he can place his hand in boiling water or undergo an operation without anaesthetic, and yet feel no discomfort whatsoever. In every other way, his sensory perceptions are normal. He sweats when a room is too hot, and shudders at the biting chill of a cold wind. But like almost all who suffer from CIP, Betz finds his condition a curse rather than a blessing. “People assume that feeling no pain is this incredible thing and it almost makes you superhuman,” Betz says. “For people with CIP it’s the exact opposite. We would love to know what pain means and what it feels like to be in pain. Without it, your life is full of challenges.” As a young child, Betz’s parents initially believed he was mildly mentally retarded. “We couldn’t understand why he was so clumsy,” his father Dominic remembers. “He was constantly bumping into things and getting all these bruises and cuts.” Neither his parents or siblings have the condition, but the diagnosis of CIP eventually came when aged five, he bit off the tip of his tongue, without any apparent pain response. Shortly afterwards he fractured the right metatarsal in his foot, after jumping down a flight of stairs. From an evolutionary perspective, one of the reasons scientists believe CIP is so rare is because so few individuals with the disorder reach adulthood. “We fear pain, but in developmental terms from being a child to being a young adult, pain is incredibly important to the process of learning how to modulate your physical activity without doing damage to your bodies, and in determining how much risk you take,” Kurth explains. Without the body’s natural warning mechanism, many with CIP exhibit self-destructive behaviour as children or young adults. Kurth tells the story of a young Pakistani boy who came to the attention of scientists through his reputation in his community as a street performer who walked on hot coals, and stuck knives in his arms without displaying any signs of pain. He later died in his early teens, after jumping from the roof of a house. “Of the CIP patients I’ve worked with in the UK, so many of the males have killed themselves by their late 20s by doing ridiculously dangerous things, not restrained by pain,” says Geoff Woods, who researches pain at the Cambridge Institute for Medical Research. “Or they have such damaged joints that they are wheelchair-bound and end up committing suicide because they have no quality of life.” Betz has been to hospital more times than he can remember. He has a slight limp in his left leg, due to an infection, known as osteomyelitis, following a tibial bone fracture sustained skateboarding. “You learn that you have to pretend you have pain to prevent yourself from being reckless,” he says. “Which isn’t easy when you don’t know what it is. I now to try to be vigilant otherwise one day my body will just give out.” But the very mechanisms which cause Betz’s disorder, could one day soon improve the lives of millions globally. CIP was first reported in 1932 by a New York physician called George Dearborn who described the case of a 54-year-old ticket salesman who claimed not to recall any pain despite a range of experiences such as being impaled by a lathing hatchet as a child, and subsequently running home. Over the next 70 years, scientists took little notice of this obscure condition which occasionally popped up in the case notes of medical journals around the world. But with the advance of social media making it easier than ever to find groups of people with CIP, scientists began to realise that studying this rare disorder may provide new understanding of pain itself, and how to switch it off for the many afflicted by chronic pain conditions. The underlying incentive is financial. Pain is a global industry on an almost staggering scale. The world’s population consumes around 14 billion doses of pain-relief medication daily, with estimates suggesting that one in 10 adults are diagnosed with chronic pain each year, lasting for an average of seven years at a time. The reason we feel pain is due to the actions of proteins which live on the surface of our pain neurons, cells which stretch from the skin all the way to the spinal cord. There are six types of pain neuron in total, and when activated by stimuli as varied as high temperatures to the acid in a lemon, they send a signal to the spinal cord where it reaches the central nervous system and is perceived as pain. The brain can shut down this pain signalling network itself if it chooses, through natural chemicals called endorphins produced in situations of high stress or adrenaline. The world of painkillers is dominated by opiates such as morphine, heroin and tramadol, which work in a similar way to endorphins, including the addictive ‘high’. The consequences have been devastating. In the US, 91 people die every day from opioid overdoses, to the tune of more than half-a-million since the year 2000. Alternatives such as aspirin aren’t effective with severe pain and can cause severe gastrointestinal side-effects over a long period of time. But while the need for breakthroughs in pain research has been desperate, little has been achieved. Until recently, that is. In the early 2000s, a small Canadian biotech company called Xenon Pharmaceuticals heard about a family from Newfoundland where several members of the family were affected by CIP. “The boys in the family had often broken their legs and one even stood on a nail without any apparent sense of pain,” says Simon Pimstone, president and CEO of Xenon. The company began scouring the globe for similar cases, to try and sequence their DNA. The resulting study found a common mutation in a gene called SCNP9A, which regulates a pathway in the body called the Nav1.7 sodium channel. The mutation knocked out this channel, and with it, the ability to feel pain. It was the breakthrough the pharmaceutical industry had been waiting for. “Drugs which inhibit the Nav1.7 channel could be a new way of treating chronic syndromes such as inflammatory pain, neuropathic pain, lower back pain and osteoarthritis,” says Robin Sherrington, senior vice-president of business and corporate development at Xenon, who was heavily involved in the initial study. “And because all sensory functions remain normal in CIP patients apart from the lack of pain, it offers the prospect of minimal side effects.” Over the past decade, Nav1.7 has sparked a “pain race” across the biotech industry between pharmaceutical giants including Merck, Amgen, Lilly, Vertex and Biogen, all vying to become the first to bring an entirely new class of painkiller to market. But developing sodium channel blockers which act specifically on the peripheral nervous system, isn’t entirely straightforward, and while the promise is there, it may take another five years to fully know whether inhibiting Nav1.7 is really the key to modulating pain signalling in humans. Xenon themselves are banking that it is. They currently have three products in clinical trials in partnership with Teva and Genentech, one in phase two trials for shingles pain, and two more in the first phase of safety studies. “Nav1.7 is a difficult and challenging drug target as it’s one of nine sodium channels which are all very similar,” Sherrington says. “And these channels are active in the brain, the heart, the nervous system. So you have to design something which only hits that one particular channel and only works on the tissues you want it to work in. It requires a lot of caution.” In the meantime, new pathways behind pain continue to emerge from studying CIP. One of the most exciting is a gene called PRDM12 which appears to work as a master switch, turning on and off a series of genes relating to pain neurons. “It could be that in chronic pain states, your PRDM12 isn’t working properly and it’s overactive,” Woods says. “If we could rewire that, you could potentially switch the pain neurons back to a normal acquiescent state. The other interesting thing about PRDM12 is that it’s only expressed in pain neurons, so if you had a drug which modulated it you might have an analgesic with very few side effects as it wouldn’t affect any other cells in the body.” But while the world of painkiller research is benefiting from the uniqueness of those with this extraordinary disorder, for CIP sufferers themselves, the prospect of a future life with pain and all its advantages remains slim. Pimstone points out that by taking part in studies, these individuals are seen by medical professionals, and in many cases for the first time, begin to receive specialist advice. “Without their contributions we wouldn’t be able to move the field forward in the way we can, so we’re enormously grateful,” he says. “And being part of the medical system benefits them as strategies can be implemented within these families so that kids with this disorder do less harm to themselves growing up. Through these studies, a diagnostic could also become available which can detect CIP early on.” Gene therapy is not yet at a stage where scientists could contemplate restoring a missing channel and perhaps giving back pain to someone who’s never had it, and for such a small percentage of individuals the financial motives of finding a way simply aren’t there. But Betz says he lives in hope. “I want to contribute and be able to help the world understand more about pain. Perhaps one day they could use the understanding we gave them, to help us too.” Source
