Cystic fibrosis is caused by mutations in a single gene. For people born with two mutated copies of that gene, the prognosis is often grim. They can suffer from a variety of ailments, including reduced lung function and digestive problems. Many don’t live into adulthood. Mutations in single genes cause many other diseases such as Tay-Sachs disease or some types of muscular dystrophy; the prognoses for people born with these conditions are similarly bleak.

Some people who have a fateful mutation, however, live healthy lives without any apparent symptoms of illness. These rare individuals are the focus of The Resilience Project, a new initiative that aims to identify people unaffected by their problematic genes and figure out how they have avoided their dismal destinies. The hope is that by studying these people, researchers can find new approaches for treating these genetic diseases. The leaders of the project, Stephen Friend, president of Sage Bionetworks in Seattle, and Eric Schadt, professor of genomics at Icahn School of Medicine at Mount Sinai in New York City, describe it in the May 30 Science.

The new initiative seeks to enroll one million people over the age of 40 to search for such “unexpected heroes,” as project leaders call them. Those who enroll will receive a DNA kit, much like those that companies such as 23andMe use, which they then return with cheek swab samples. Unlike other commercial DNA companies, however, The Resilience Project is looking specifically at 162 genes that can cause what Friend and Schadt refer to as “catastrophic” diseases.

In the vast majority of cases, Schadt says, people will simply get a confirmation that they do not have two copies of any of the mutated alleles that would cause one of the 125 diseases the project is looking for. But they expect that about one in 15,000 people are living healthy lives with mutations that should cause severe illness. That estimate comes from a retrospective analysis of about 600,000 genomes collected by 23andMe and other companies. (In the general populace disease rates vary widely by type of affliction and region, from as many as one in every 2,000 births to one in every million births).

Assuming that figure is correct, Schadt says they expect to find between 50 and 100 people (out of the million they hope to enroll) who have thrived despite having these genetic mutations. Those people would then be invited to undergo further study that will hopefully yield new clues about ways to fight these disorders. “However they were able to naturally resist the disease,” Schadt says, “that would then become the therapeutic angle you would then pursue to prevent the disease.”

Schadt imagines a number of ways that people could avoid these disorders. One is genetic; it’s possible that these resilient people have mutations in other genes that protect them from the effects of the disease-causing mutations. In some cases, a mutation that disables a separate gene can actually have beneficial effects. If that is the case, Schadt says, those other genes would be good targets for pharmaceutical drugs, because it is much easier to knock out a working gene than to make up for a nonworking one. Synthetic molecules can be created to target and disable particular genes.

The “unexpected heroes” may also have been exposed to environmental factors that allowed them to escape their genetic fates. This effect would be much more difficult to tease out, Schadt says, because the environmental cues could involve anything from a person’s diet to exposure to certain toxins. These factors would most likely show up as epigenetic changes, he says, in which the packaging of a person’s DNA is altered.

Daniel MacArthur, a geneticist at Harvard Medical School and Massachusetts General Hospital, wrote in an e-mail that The Resilience Project is “intriguing and extremely ambitious.” He thinks that it will be useful for understanding the genetic basis of these ailments as well as for determining which healthy people in the world actually carry these problematic mutations. But he cautions that “there will be major statistical challenges associated with moving from these ‘heroes’ to fully understanding the genetic basis of disease resistance.”

Schadt, too, recognizes these hurdles. He says he is under “no illusion” that finding the source of resilience will be easy. Nevertheless, he says, this approach nicely complements the typical approach to solving these disorders, which focuses on those people with the genetic mutations who do experience the symptoms. The Resilience Project, Schadt says, is “highly likely to led to novel therapeutic angles.”