This Man’s Insensitivity to Pain Is Helping Those Who Can’t Escape It
Steven Pete has broken 70 bones—and never felt a thing. Now scientists hope his genetic condition will help people with the opposite issue: constant agony.
On a scale of one to ten, how would you rate your pain? Would you say it aches or stabs? Does it burn, or does it pinch?
Steven Pete has no idea how you feel. Sitting in a café in Longview, Washington, he tells me he cannot fathom aches or pinches, much less the searing scourge of peripheral neuropathy that keeps millions of people awake at night or hooked on pills. He was born with a rare neurological condition called congenital insensitivity to pain, and for 37 years, no matter the wound, he has hovered at or near a one on the pain scale. Because he never learned to avoid injury, which is the one thing pain is really good for, he gets hurt a lot. When I ask how many bones he has broken, he lets out a quick laugh.
“I haven’t actually done the count yet,” he says. “But probably somewhere around 70 or 80.”
A few years ago, Steven noticed that the movement in his left arm and shoulder felt off. His back felt funny too. He got an MRI. The doctor looked at the results and stared at his patient in disbelief. “You’ve got three fractured vertebrae.” It turned out that Steven had broken his back eight months earlier while inner-tubing down a snowy hill.
Throughout his body today, Steven feels “a weird radiating sensation,” as he describes it, an overall discomfort but not quite pain as you and I know it. He and others born with his condition have been compared to superheroes; he even owns a framed sketch of a character in full body armor, with the words “Painless Pete.” But Steven knows better. If he could feel pain, he says, he would probably be constrained to a bed.
“I worry about him all the time,” his wife, Jessica Pete, says with a sigh—about him working with his power tools and cooking over a grill. “If he has a heart attack, he won’t be able to feel it. He’ll rub his arm sometimes, and I freak out: ‘Are you OK?’” She looks over at him, and he chuckles. “He thinks it’s funny,” she says. “I don’t think it’s funny.”
Pam Costa, who lives about 100 miles away, in Tacoma, Washington, is on the other end of the pain scale. The 52-year-old was born with a rare neurological condition called erythromelalgia, otherwise known as “man on fire” syndrome, in which inflamed blood vessels throughout her body are constant sources of pain. Pam wears loose-fitting clothes because fabric feels like a blowtorch against her skin. She sleeps with chilled pillows because the slightest heat makes her limbs feel as if they’re crackling. (These are the pain symptoms you should never ignore.)
Pam takes 50 milligrams of morphine twice a day. A college psychology instructor and the mother of a teenage daughter, she agonizes over her morphine dependency. But if she goes without her medication, her pain becomes unbearable.
A year ago, she went to Las Vegas for a work conference and the plane home got stuck on the tarmac with a mechanical issue. There was no air conditioning, and the temperature started to rise. With her skin throbbing, Pam persuaded a flight attendant to let her off. “I was so afraid I was going to pass out or throw up or get to where I was immobilized.”
Pam and Steven have never met, and their daily negotiations with the world could not be more different. Yet, thanks in part to studies the two have participated in, scientists have uncovered an unprecedented genetic link that binds their mirror-image conditions together. Scores of pharmaceutical researchers are now deep into clinical trials on a new type of drug that would mimic Steven’s condition as a way to treat Pam and millions of other chronic-pain patients—without the sometimes severe side effects of existing painkillers such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. Here are the signs of a pain pill addiction.
If you burn yourself on a stove, it hurts. More specifically, the nerve cells in your hand sense the heat and send signals to the brain that tell you to stop doing what you are doing and get help. Fortunately, most kinds of acute, or temporary, pain can be treated: Opioids can dull the sting from an incision; anti-inflammatories can mask the discomfort of a sprain.
Chronic pain, on the other hand, never turns off. It can be inflammatory (brought on by diseases such as arthritis) or neuropathic (affecting the nerves, as in some cases of shingles, diabetes, and chemotherapy treatments). Some chronic pain can never be traced to a coherent cause.
That kind of undiagnosable pain creates its own issues. When Pam was a child, she was sometimes accused of having behavioral problems. In school, she’d sneak off to water fountains to wipe down her limbs with cold water. She would dawdle in the deep gutters near her home, the cool, mucky water providing momentary pain relief. One physician said her symptoms were psychosomatic. Then, in 1977, when Pam was 11, a letter from the Mayo Clinic arrived. A cousin had been referred to the medical center after complaining of constant pain. The doctors there discovered that 29 members of Pam’s extended family appeared to have erythromelalgia. After learning more about Pam’s symptoms, a Mayo researcher told her parents that their daughter had apparently inherited the same problem.
Pam was determined not to pass on her man on fire syndrome. “I had my tubes tied right after my 18th birthday,” she says, a hint of grief filling her voice. “Always, since I was a little girl, I wanted to be a mother more than anything in the world.” When she got married, she and her husband adopted a daughter.
Stephen Waxman was a medical student in the early 1970s when he became fascinated by pain—how people feel it, how the body transmits it, and how, as a future neurologist, he could learn to control it. Later in his career, when his father was in the final stages of agonizing diabetic neuropathy, he became obsessed with helping patients who could find no relief from their pain. “We simply had to do better,” he says. Learn ways to manage chronic pain without medication.
Today, Dr. Waxman, 72, is the director of the Center for Neuroscience and Regeneration Research at the Yale University School of Medicine. For much of his career, he has been interested in sodium channels—portals that allow charged particles to flow in and out of nerve cells. In particular, he believed that one of those channels, Nav1.7, played a powerful role in how we experience pain.
In his theory, a stimulus triggers the Nav1.7 channel to allow sodium ions to pass through, which then enables messages of stinging, soreness, or scalding to register in the brain. When the trigger subsides, Nav1.7 closes. In those with certain mutations in their Nav1.7 channels, sensations that typically wouldn’t register with the brain are instead translated into extreme pain.
In 2004, Dr. Waxman’s team was searching for subjects with some form of inherited pain so they could determine exactly how the Nav1.7 channel worked to either cause or dampen painful sensations. That same year, scientists in a Beijing lab published the results of their study of a Chinese family afflicted with man on fire, in which they linked the disorder to mutations in a single sodium channel gene, SCN9A. When Dr. Waxman spotted the article, he directed his team to find families with erythromelalgia. Pam Costa’s was the first.
Dr. Waxman’s team gathered DNA from 17 of Pam’s cousins, aunts, and uncles who suffered from erythromelalgia and sequenced their genes to find the mutations. Then the team introduced the mutations into DNA that encoded normal sodium channels and tracked how these channels
responded to stimuli.
The results proved Dr. Waxman’s theory correct, not only demonstrating that SCN9A mutations made Nav1.7 channels more likely to open (meaning harmless stimuli often triggered feelings of pain) but also showing that when those channels opened, they did so for longer, amplifying the feeling of discomfort. “We now had a fully convincing link from Nav1.7 to pain.”
If his team could somehow regulate or even turn off the Nav1.7 channel, they could regulate or turn off how we experience certain kinds of pain.
At around six months old, Steven Pete chewed off part of his tongue. As he got older, he would bang his head against walls. His parents made him wear a helmet and wrapped his arms and legs in long socks.
His younger brother, Chris, had many of the same symptoms. A day rarely passed when one of them didn’t bleed or bruise. The boys were eventually diagnosed with congenital insensitivity to pain. Some years later, a doctor told Chris that a lifetime of injuries had caused so much damage he would likely end up in a wheelchair before he was 30. It was too much for Chris to bear. He hanged himself, nine years ago. He was only 26. “It felt like losing … my life,” Steven says.
In the meantime, outside Vancouver, British Columbia, a small company was inching toward a breakthrough in understanding the brothers’ condition. The company, which is now called Xenon Pharmaceuticals, studied rare single-gene disorders in an effort to create drugs to treat more common ailments with similar symptoms. In 2001, it heard about a family in Newfoundland in which four members could not feel pain. Suspecting their illness was genetic, Xenon started hunting for more subjects.
Following news reports and word of mouth, the researchers tracked down and studied 12 families with insensitivity to pain. (The Petes were not among them.) Xenon found one common trait: mutations in a single gene, SCN9A, and the sodium channel it encodes, Nav1.7.
“This single channel, when it is nonfunctioning in a human being, renders them unable to understand or feel any form of pain,” Robin Sherrington, PhD, then senior director of biological sciences at Xenon, says. If Xenon could develop a drug that mimicked this condition—“to inhibit the Nav1.7 channel to partially replicate that absence of pain,” he explains—it could use it to relieve chronic pain without any of the side effects of opioids and other painkillers.
It is rare for a single gene to have such a black-or-white effect on a single sensation. Sherrington’s and Dr. Waxman’s teams learned of each other’s discoveries only through published reports and journal articles. They were as surprised as anyone that people like Pam Costa and Steven Pete had anything in common. “I was overwhelmed when we saw both sides of the genetic coin,” Dr. Waxman remembers. “SCN9A really is a master gene for pain.”
Technicians at Xenon eventually found a compound that plugs up Nav1.7 without major side effects. Unfortunately, when it was tested on 330 patients who suffered from nerve pain, the results were disappointing. After four weeks, their pain levels did not improve significantly.
At Yale, Dr. Waxman and his researchers helped Pfizer test five erythromelalgia patients with a different Nav1.7 blocker. Scientists triggered the subjects’ pain with heating blankets. Three of the patients described a decrease in pain after taking the drug. (Here are the secrets pain doctors aren’t telling you.)
There are other, less conventional approaches under way too. At Amgen, a pharmaceutical company in Thousand Oaks, California, scientists discovered that the toxin of a Chilean tarantula can target Nav1.7. They’ve since engineered a synthetic version that’s more potent than the original.
There are still obstacles to finding a treatment, such as creating compounds that will allow some pain to register without cutting it off altogether. But many now see a way forward. “I hope,” says Steven, “that one day, parents will be able to make a choice for their children who don’t feel pain, to activate that sodium channel so that their children can live a normal life.”
No progress would have been made without people like Pam and Steven, who have taken part in studies for years.
Pam still remembers meeting Dr. Waxman at Yale in 2011, six years after his team first reached out to her family to study their genes. On a computer, he pulled up an image of the neatly folded amino acids that form a normal person’s sodium channel. Then he pulled up another image: The amino acids zigzagged almost off the screen. “This is you,” he said.
Her entire life, Pam could only tell others how she felt—she could never show them. Seeing the medical proof of her pain, she says, “was the most validating experience in my entire life.”
On the other hand, the work to target the Nav1.7 channel won’t help Steven or others with congenital insensitivity to pain—there’s no point blocking a portal that’s permanently closed. The condition remains one with a known cause but no cure, passed down from one generation to the next.
When his daughter was born in 2008, Steven asked the doctor in the delivery room, “Does she feel pain?”
“They pricked her,” his wife remembers. “And she cried.” It felt something like relief.