When Letizia Marsili was six years old, she loved to climb anything in sight, from tree branches to light poles. One day while climbing a pole, she pierced her chest with a nail jutting out of the wood. Instead of screaming in pain, she simply pulled her flesh off the nail, and covered the bloody hole with her shirt. It wasn’t until her mother noticed the wound days later while giving her a bath that anyone realized she’d been hurt.
Marsili, now 52, says this was one of many times when she had an accident—like a bicycle fall or an ankle sprain—and didn’t react with pain. “I thought it was my character that was strong,” she says.
Actually, Marsili carries a mutation in one of her genes that leads to congenital hypoalgesia, or human pain insensitivity disorder. It’s a rare genetic condition that causes people to be unable to feel pain, and are often insensitive to other stimuli like heat or intense pressure. One of Marsili's colleagues, a pain researcher, first suspected Marsili might be insensitive to pain in 2000. Because the disorder is genetic, they found that five of Marsili’s family members have it too—her mother Mary, 78; her sister Maria Elena, 50; her children Ludovico and Bernardo, 24 and 21; and her niece Virginia, 17.
Together, the Marsilis provide a unique opportunity for scientists to uncover the genes that allow us to feel pain. In a new study published in Brain last week, a group of scientists announced they have found the specific mutation in the ZFHX2 gene in the Marsili family and, with it, a potential drug target for alternative pain treatments.
Painlessness usually runs in families, in people who are otherwise completely normal intellectually and mentally. They're able to feel touch, even very light touch, and pressure. They can feel the difference between hot and cold and, neurologically, they’re normal as well. But when it comes to pain, they just don’t feel it. Some cases are more severe than others, depending on which genetic mutation they carry. James Cox, a molecular biologist at University College London and lead author on the new study, says one family he worked with in the past also didn’t have a sense of smell.
The Marisili family can smell, and they do still have some pain sensing, it’s just dulled. Marsili says they aren’t bothered by spicy food, and since they’re very tolerant to heat, often aren’t as bundled in winter clothes when it’s cold. Marsili’s other family members have also had injuries they didn’t know about. Cox says that Marsili’s mother once fell and broke her ankle, and when they went to the doctor afterwards, her scans showed she had broken her ankle before. She had no idea. The same happened with Marsili’s son: doctors noticed calcification on his elbow, meaning he had broken it without realizing.
To find the gene that causes their pain insensitivity, Cox used exome sequencing—a type of genetic sequencing where you analyze only the genes that make something: either a protein or noncoding RNA. By analyzing everyone in the family who has the condition, and comparing them to healthy controls from the general population, he found two mutated genes that the painless Marsilis had in common. It’s a painstaking process: he first took their blood samples back in 2010, and it took three tries to nail down the mutation. After finding the gene, he and his collaborator, sensory neurobiologist John Wood, used mice to show that the gene they found was involved in pain processing.
There have been only a few of genes discovered that lead a person to pain insensitivity, says Geoff Woods, a medical geneticist at the University of Cambridge, who also studies painless families but wasn't involved with this paper. “That’s a little bit odd, because if you look at blindness, or deafness, people who are born blind or deaf, there’s a couple hundred of genes that will cause either of those," he says. "But in pain, it’s odd that there’s only a handful.”
The goal in finding these genes is to hopefully understand how the body feels pain, and to be able to disrupt the process in those who have chronic pain. One in four people in the US have pain that lasts longer than 24 hours, and for those with chronic pain who've become resistant to drugs like opioids, we don’t have any meaningful alternatives to offer.
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The gene Cox and his team found makes a very large protein that doesn’t have one specific function, but affects other genes’ functions, and how much they're expressed—it's like a pain regulator. While it makes their findings more complicated, Woods says it’s also exciting. “In some ways it reveals a pathway," he says. "If you’re thinking of treatment of chronic pain, you can either find some way of blocking this gene itself, or, some of its downstream targets. Although it’s a terribly rare family, and it appears a very, very rare mutation, the message that’s much more important is that it’s giving you a whole lot of new targets when you’re thinking about pain control.”
Woods has previously published studies on two genes that he’s found from painless families, that were involved in how pain neurons work and develop. “In one way they’re different [than Cox's gene], in another they’re very much the same,” he says. “You form your pain neurons, but they’re unable to function properly. And so the idea of pain treatment obviously would be: could you reverse the effect of those genes so to not destroy your pain neurons, because being completely painless would be dangerous, but to actually make your pain neurons quiescent.” In other words, rather than finding the off-switch for pain, Woods is hoping this work will find the dimmer switch, and make pain neurons less sensitive when they turn on.
But genetic findings don’t always translate perfectly to treatment. One of Woods’s most promising gene findings didn’t have much effect when it was knocked out in a mouse model. “So that was a real shock to the system because we thought it would be a wonderful protein and gene to block,” he says. “It should be a beautiful analgesic, and yet it isn’t.”
A drug based on another gene, identified decades ago in painless families, is now being tested in clinical trials and Woods says those trials are very promising. There were only a few families in the world with that specific mutation, he says. “But despite that rarity, it still shows us a pain pathway, which if you block it, you block pain and you shouldn’t get any other side effects,” he says. “So it’s very much two steps. It’s the clinical discovery, and the initial proof that the gene is important for pain. And then: a whole different kind of discovery about the molecules to block that specific interaction.”
Still, it’s important to remember that the goal of this work isn’t to recreate the painlessness these families feel—just to discover the pathways that allow us to turn down pain in those who can’t seem to turn it off. We shouldn’t be envious of a lack of pain, because it’s protective, Cox says.
Marsili’s family didn’t encounter any severe problems as children, but little kids who can’t feel pain often do: they bite off their fingertips or cause damage to their lips, mouths, and other body parts. “As toddlers do, they explore the world with their mouth and their teeth,” Woods says. “And some will get burns because they just sit on a radiator or put their hand on a hot plate.” Woods says one 12-year-old boy he treated loved to pick fights at school. “That’s a behavior that you only do if you don’t feel pain.”
Woods says it’s unfortunately common for people to get seriously hurt, and sometimes die, from lack of pain. “That’s a general finding, in any cause of congenital painlessness,” he says. “There are, generally males, who will die prematurely. That’s because they take excess risks. There’s no pain restraining their behavior, and we have a number of tragic stories where males, in particular, have done just crazy things because there was no reason for them not to do them. Even if they had a bad fall or an injury, it just wasn’t painful.”
Ironically, if you don’t feel pain, it’s more important to be restrained, Woods says. Marsili says that now that her family knows about their condition, they try to pay attention to anything they feel, however slight, as an indication that they might be hurt. “A positive thing is that we are almost always good, the negative is that we must listen to our body very well to avoid underestimating the pain,” she says.
Marsili, a researcher herself at Siena University in marine ecotoxicology, says she’s happy to offer her family as “guinea pigs” to help them understand their own condition and help others along the way. “People should know that...you can only take advantages and leave the disadvantages on the way," she says.
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