A sweeping look at the DNA of more than half-a-million people has uncovered a surprise: A few individuals carry a genetic glitch that should make them very sick, yet they are instead seemingly healthy. Studying such disease-resistant people could point to new treatments for rare conditions like Duchenne muscular dystrophy. But the researchers behind the new survey caution that without direct access to the individuals in the database they used, they have not been able to confirm their results through further testing.

The study is a first step in the Resilience Project, an effort led by Stephen Friend, president of Sage Bionetworks in Seattle, Washington, and genomics researcher Eric Schadt of the Icahn School of Medicine at Mount Sinai in New York City. They want to find healthy individuals who have genetic mutations that usually cause serious disease in those who carry them, such as those for the lung disorder cystic fibrosis. If a person who has such a mutation is well, he or she may carry a mutation in a different gene that compensates for, or buffers, the harmful gene’s effect. That protective gene could point to a new therapy for the disease.

To test their idea, Friend, Schadt, Mount Sinai genomics expert Rong Chen, and co-workers gathered genetic data from more than 589,000 generally healthy adults who had donated their DNA for research. The bulk of them—400,000 people whose genomes had been scanned for genetic markers—came from 23andMe, the company that offers genetic testing by mail. Other samples came from 11 academic research studies around the world. The team then combed through these DNA data for mutations in 874 genes known to cause severe disease starting in childhood.

At first, it seemed that nearly 16,000 individuals potentially carried the mutations. But the list got much shorter when researchers removed people with low-quality genetic data or those who had mutations that had not clearly been shown to cause serious illness early in life. The final yield was just 13 people with mutations that normally result in eight severe childhood disorders, the team reports today in Nature Biotechnology. The diseases include cystic fibrosis, an autoimmune disease, a severe skin disorder, and others that normally lead to skeletal deformities and mental retardation.

But the list comes with caveats. For one, the researchers were unable to confirm that the mutations were not simply genotyping errors for eight of the 13 individuals. Second, the researchers could not contact any of the 13 people for further testing that would verify they were indeed healthy, despite having the disease mutation. That’s because when the people donated their DNA, they did so with the understanding that they would not be contacted again. “It’s almost as if you got to take the wrapping off the box and you couldn't open the box up,” Friend says.

Given these limitations, some researchers are underwhelmed by the study. One expert finds it odd that the researchers found three individuals with two copies of the same extremely rare cystic fibrosis mutation. The chances of that are so miniscule that it suggests alternative explanations, says medical geneticist Garry Cutting of Johns Hopkins University in Baltimore, Maryland, who has found mutations that reduce the severity of cystic fibrosis through a different approach. Still, Cutting loves the idea of the Resilience Project. “The concept is very exciting.”

The study is “important as a proof-of-principle,” adds human geneticist Daniel MacArthur of the Broad Institute in Cambridge, Massachusetts, who himself is on the hunt for rare genes that protect against disease and wrote a commentary accompanying the new paper. The paper is “sobering,” he adds, because it shows that pinning down actual resilience genes will require “incredibly large sample sizes,” or DNA from tens of millions of people who have agreed to be contacted for research.

Similar studies are planned or underway, including the United Kingdom’s 100,000 Genomes Project and the U.S. Precision Medicine Initiative’s 1 million person cohort study. And Friend and Schadt are planning a full-scale Resilience Project that will invite brand-new volunteers who agree to be recontacted to participate through a website.