The family that feels almost no pain
An Italian scientist’s colleagues noticed she seemed impervious to injury, said journalist Matthew Shaer in Smithsonian magazine. Her family’s rare genetic condition could be the key to understanding chronic pain.
Years ago, the scientist Letizia Marsili was skiing with her sister in Trentino, high in the Italian Alps, when she lost her balance on a double black diamond run and crashed shoulder first into the snow. Marsili felt a jolt of pain. Then the pain subsided, so she brushed herself off and headed back to the lifts. By the end of the day, she’d skied another 18 miles.
“Everything was normal,” Marsili told me recently, through an interpreter. “We got back to the lodge, we went to the sauna. I was in such a happy mood.” But over dinner, Marsili noticed that she was having trouble holding her fork and knife—they kept dropping out of her hand. The next day, she got an X-ray. “And the doctor, he said, ‘Well, yes, your shoulder is broken,’” Marsili remembers.
She was shaken, but not surprised. Things like this had been happening as far back as she could remember. Shortly after her sixth birthday, while climbing a pole in a neighbor’s yard in the Tuscan city of Siena, she stuck herself in the side on an errant nail; after stanching the flow of blood, while her friends watched in horror, she pronounced herself fine to keep playing. Later, she twisted her ankle while rock climbing and kept going; she burned her hands with hot oil. In each situation, the experience was the same: She felt a shudder of discomfort that melted away in seconds.
“I just thought of it as part of who I was,” Marsili told me proudly. “I was strong, I was resilient. I bounced back.” And it wasn’t as if she’d known any different: Her mother, Maria Domenica, and her sister, Maria Elena, had been the same way—masses of scar tissue and healed fractures and bruised shins, juggernauting their way through life.
At the University of Siena, where Marsili has worked since 1998 as a professor of marine ecology, her colleagues took to calling her Superwoman. She seemed to be made of steel, impervious to injury. On summer expeditions to the Sea of Cortez, in the Pacific Ocean, she’d spend hours on the deck of research vessels, protected from the boiling heat by only a thin layer of sunblock.
In the late 1990s, Marsili was introduced to a colleague named Anna Maria Aloisi, a physician and the director of the university’s pain clinic. Because Aloisi had access to a new high-tech lab, she volunteered to help Marsili with an experiment to test the impact of contaminants on swordfish and tuna. “A normal collaboration between scientists,” is how Aloisi describes it.
One of their early meetings took place on a cold day. Aloisi remembers a bitter wind blowing across campus. Marsili wore a short-sleeve dress. Her ankles were bare. “What are you doing?” Aloisi asked. “Don’t you feel the temperature?”
Marsili shrugged and shook her head. “It doesn’t bother me,” she said. Aloisi told me, “I thought, OK, this may be some version of pain insensitivity. Not very common. Not super-rare, either.”
Normally, pain is our early warning system. We put down a hot pan handle before we’re severely burned. But people with a pain insensitivity disorder may not always realize they are seriously hurt until it’s too late.
And yet the better Aloisi got to know Marsili, the more curious she became. There was the important fact that Marsili did feel some pain, albeit in small amounts. Her early warning system, as it were, functioned just fine. As a researcher herself, Marsili understood Aloisi’s interest in her, and she told the physician, by now a friend, that she’d be happy to submit to a battery of tests, if Aloisi would be the one running them.
So Aloisi used a syringe to inject capsaicin, the chemical that gives chile peppers their heat, directly into Marsili’s forearm. Marsili reacted the way most of us would: She flinched, she shuddered, she screwed her face up into a tremendous grimace. “Oh, mama mia,” she recalls shouting. “What have you done to me?”
But after about a minute, Marsili’s features rearranged themselves. She slumped back into the chair. “Do you feel anything?” Aloisi asked, examining the syringe, which was still embedded in Marsili’s arm, feeding capsaicin into the skin. “No,” Marsili said.
“The way I’d put it,” Aloisi told me, “is that she was feeling the good pain, the pain that alerts us to danger. Then it disappeared. The bad kind of pain, the chronic pain, the ongoing pain that we take painkillers for—she simply didn’t feel that.”
Pain is one of our oldest evolutionary traits. It connects us to the outside world and modulates our interactions with it. But pain becomes a problem when its causes are mysterious, and when it persists beyond its usefulness in alerting us to danger—which, as anybody can tell you, happens all the time. We get headaches and bad knees; our backs start to hurt. One in five American adults, according to the Centers for Disease Control and Prevention, suffers from chronic pain, or pain unrelated to a recent injury and lasting longer than six months.
Despite colossal amounts of study focused on understanding how pain works, the phenomenon remains enigmatic. Unlike senses such as touch, taste, or smell, there is no single brain region responsible for the experience; there may be half a dozen or more. This has made treatment for pain an often crude exercise, as the widespread prescription of opioids and the related epidemic tragically illustrates.
“You have a situation where the world’s population is aging rapidly, and more people are suffering from pain. And life expectancy is actually going down in the U.S. as a result of opioid abuse,” John Wood, who heads the sensory neurobiology group at University College London’s Wolfson Institute for Biomedical Research, told me this past winter. “So if you could find a solution to chronic pain that’s not addictive, not deadly, well, it would be greatly helpful, wouldn’t it? It would be a breakthrough of tremendous proportions.”
For more than three decades, Wood, a molecular neurobiologist, has devoted himself to understanding how the body processes pain. In the mid-2000s, Wood’s lab at University College partnered with a Cambridge University scientist named Geoff Woods on a pioneering research project centered on a group of related families—all from a clan known as the Qureshi—in rural northern Pakistan. Woods had learned about the families accidentally: On the hunt for potential test subjects for a study on the brain abnormality microcephaly, he heard about a young street performer, a boy who routinely injured himself (walking across burning coals, stabbing himself with knives) for the entertainment of crowds.
Woods knew that the Wolfson Institute, John Wood’s lab, had recently published a paper on an inherited phenotype—essentially a collection of observable characteristics, such as eye color—that appeared to influence pain resistance. Perhaps, Woods theorized, the boy in Pakistan possessed the same phenotype. When Woods found the boy’s family, they told him that the boy had died from injuries sustained during a stunt leap from a rooftop. But several family members allowed Woods to collect blood samples, which researchers in England scanned for genetic irregularities.
Sure enough, the Pakistani subjects all possessed the same abnormality Wood’s lab had documented: a subtle mutation in a gene regulating pain-sensing neurons that disabled a key component known as Nav1.7. In 2006, with Woods as lead author, the scientists published their findings in the journal Nature.
Two years after the publication of the Nature paper, John Wood flew from London to Italy to attend a pain conference sponsored by the University of Siena. There he met Anna Maria Aloisi. “I remember Anna Maria telling me, ‘We’ve got this scientist here—she walks around in the winter in short dresses!’” Wood says. “And the whole story, it just got better and better as she went.”
Not only did Letizia Marsili possess an exceptionally high tolerance for pain, Aloisi explained, but so did much of her family. Letizia’s mother, her sister, her sister’s daughter, and her sons, Ludovico and Bernardo, all shared the same reaction to pain.
Wood asked if anyone at Siena had done any genetic mapping of the Marsilis. When Aloisi said nobody had, Wood requested new blood samples from as many family members as were willing to give them. Back in London, he summoned a young scientist named James Cox to his office. Cox, a self-described “gene hunter,” had played a crucial role in the research into Nav1.7 as a Cambridge postdoc. Now he was at University College on a fellowship. Wood’s instructions to him were simple: Find the cause of the Marsilis’ pain resistance.
Cox needed more than five years and several tries to isolate the gene responsible for the Marsili family’s pain tolerance. In 2014, after sequencing the Marsilis for a third time with the latest technology, Cox found a mutation in a gene known as ZFHX2, which affects neurons that play a role in transmitting pain signals to the brain. It seemed like it might hold the key to the Marsilis’ condition.
After more tests showed promise, the next step was to reproduce the mutation in a living creature. In early 2015, a batch of mice engineered to lack ZFHX2 arrived at the lab, where they were put through a series of pain threshold tests. The researchers used two different methods, which would serve as a proxy for pain under Britain’s animal-testing regulations: One applied gradually increasing pressure to the mice’s tails; the other test involved miniature hot plates. “It’s like if you put your hand on a radiator,” Cox told me, “how long does it take for you to move?”
The mice missing the ZFHX2 gene had remarkable reactions: They showed higher pain thresholds for applied pressure to their tails, but some were extra sensitive, rather than less sensitive, to heat—the opposite of what the scientists expected. Still, the experiment seemed to show that ZFHX2 played an important role in regulating pain, even if they hadn’t yet figured out how. “So we went at it again,” Cox recalled. This time they ordered mice with copies of the precise ZFHX2 mutation observed in the Marsilis’ genetic code.
Several months later, the second batch of mice were put through the same tests as the first. This time, the animals’ reaction to the hot plates was consistent—they were significantly less sensitive to heat. They seemed to tolerate it in the same way the Marsilis did.
In late 2017, Cox published his findings in the journal Brain, noting that the mutation to the ZFHX2 gene, now known as Marsili syndrome, was extremely rare or even unique. As far as he could tell, only the members of one small family in Tuscany possessed it.
The broad significance of the scientists’ analysis is that it showed that ZFHX2 was crucially involved in pain perception in a way nobody had previously understood. Unlike more frequently documented cases of pain insensitivity, for instance, the Marsili family’s mutation didn’t prevent the development of pain-sensing neurons; those were still there in typical numbers. Yet it was also different from the Pakistani family’s mutation, a genetic anomaly that disabled a single function in pain-sensing neurons. Rather, ZFHX2 appeared to regulate how other genes operated, including several genes already linked to pain processing and active throughout the nervous system—a sort of “master regulator,” in the words of Alexander Chesler, a neurobiologist specializing in the sensory nervous system at the National Institutes of Health, in Bethesda, Md.
“What’s so exciting is that this is a completely different class of pain insensitivity,” Chesler says. “It tells you that this particular pathway is important in humans. And that’s what gets people in the industry excited. It suggests that there are changes that could be made to somebody to make them insensitive to chronic pain.”
On a visit to Siena I dropped in on Letizia’s son, Bernardo, in the small grocery store he’s opened inside Siena’s cobbled old town, filled with specialty cheeses and wines and dozens of slabs of cured meat.
Bernardo, 22, does not yet have children of his own, but he told me he’d be pleased if they inherited his family syndrome. “You know, my friends sometimes tease me, joke with me,” he said. “And yeah, I have to be a little more careful than other people. But it’s also something that’s special, what we have. It’s something that could change the world.” He smiled. “And something I’d want to share.”
Adapted from a story that originally appeared in Smithsonian magazine. Used with permission. ■