The street performer was only 10 years old. He put knives through his arms and walked on hot embers. By 14 he was dead. Someone dared him to jump from a roof. He did it, knowing it wouldn’t hurt.
The case of the Pakistani boy with a rare genetic disorder was described in 2006. He could feel warmth and cold and the texture of objects. But he never felt pain.
Now scientists have paired the discovery with the gene-editing tool CRISPR, in what they say is a step toward a gene therapy that could block severe pain caused by diabetes, cancer, or car accidents without the addictive effects of opioids.
The new approach to pain eradication, which mimics the rare DNA mutation the Pakistani boy had, was demonstrated in mice in the laboratory of Prashant Mali at the University of California, San Diego. The research was led by Ana Moreno, who is now the CEO of a startup, Navega Therapeutics, which plans to develop a CRISPR treatment for pain.
The research, in which CRISPR was used to temporarily block a key molecule in pain-transmitting neurons in the spinal cord of mice, was described in a preprint paper published in July. The company didn’t want to comment before the report is formally published, but the idea is to inject the cerebral spinal fluid with viral particles carrying a modified version of CRISPR designed to interrupt pain signals.
The first tests of CRISPR gene therapies on humans began only recently. This year CRISPR Therapeutics started treating patients with sickle-cell anemia, and another company, Editas Medicine, plans to try to reverse an inherited blinding disease. Both those programs involve altering DNA sequences in a person’s genome so that needed genes are turned on.
A pain treatment would extend CRISPR therapies into far more common conditions—about 20% of Americans have chronic pain, according to the Centers for Disease Control and Prevention. The project also highlights how, by mining genetic oddities, scientists can identify the causes of certain unusual people’s physical superpowers and use gene editing to grant them to others.
Finding the pain gene
A scramble for a new generation of pain treatments began when scientists zeroed in on a gene called SCN9A, which makes a molecule present in nerves (called Nav1.7) that is a key player in transmitting pain to the brain.
Evidence for the gene’s central role came from people with strange inherited syndromes. Some mutations in the gene cause people to feel more pain. The Pakistani boy, meanwhile, was a member of a family with a mutation that disabled SCN9A entirely.
The clear effect of the genetic differences—more pain on the one hand, no pain if the mutation inactivated the gene—drew intense interest from drug companies. The gene has been called a perfect example of how valuable drug “targets” can be discovered by studying people with rare traits.
So far, efforts to mimic the pain-free effect with conventional drugs have not met with clear success. One company, Genentech, says it is still searching for “highly targeted” drugs to block Nav1.7 and recently described how that can be done with toxins from scorpions and tarantulas.
Researchers have tried using gene therapy to dampen the activity of Nav1.7 before. It was attempted in 2005 using another gene-modulating technique, and at least two companies, Voyager Therapeutics and Coda Biotherapeutics, are exploring potential treatments.
The new report, however, is the first to use CRISPR to treat pain in mice. “The animal data suggest you would still feel a burning kettle, but the pain might be much diminished,” says John Wood of University College London. He calls the use of CRISPR to treat “a major advance.”
There are some downsides to fooling with pain. People with the no-pain DNA mutation have a limited sense of smell and, without pain, they don’t know when they are injured. A number of members of the Pakistani family were limping from broken limbs. Others had lost parts of their tongues—they’d bitten them off.
There are still plenty of unanswered questions about whether CRISPR will be a useful pain fix, including how long the effect will last and how it would affect preexisting pain, something the researchers didn’t look at. Gene therapy is also high-tech and very expensive—one recently approved treatment costs $2.1 million.
“It’s going to be a massive gamble for the investors to take it forward at the moment,” Wood says. “It’s exciting, and I am sure it will happen … but it’s problematic at the moment.”
New pain control tactics are likely to draw interest from the military, which is looking at technologies that would let soldiers keep moving, keep shooting, and keep communicating for days after an injury, according to the abstract of an upcoming talk by Peter Murray, of the US Army Medical Research & Development Command. Murray writes that the question is: “Can we create an analgesic that can treat severe, post-traumatic pain that doesn’t interfere with cognition or motor control?”
In 2017 Vladimir Putin told students at a youth festival in Sochi that genetic engineering could create soldiers who feel no pain or fear, which could be “scarier than a nuclear bomb.”
In addition to the no-pain mutation, there’s a genetic variant that could let an air traffic controller—or a soldier—get by on four or five hours of sleep per day. As gene-therapy techniques advance and become less expensive, it might be feasible to routinely enhance people with similar genetic changes.