“Perhaps they are carrying special mutations—helpful, not harmful ones—that are protecting them from the diseases that medical textbooks would say they are almost guaranteed to get,” Friend says. These insights, in turn, could pave the way for the development of new drugs that mimic the effect of the protective mutation to prevent a disease or lessen its severity in those who are at high risk of developing it.
“It’s really an untapped research opportunity,” says Dr. Tom Insel, director of the National Institute of Mental Health. Most genetic studies, he notes, focus on mutations that increase disease susceptibility, not on genetic or environmental factors that buffer the effects of those mutations to keep people healthy.
“Knowing how some people dodge the slings and arrows of disease that they were at extremely high risk of getting, whether through bad luck or pedigree, I suspect will tell us more about treating disease than studying those who already have it,” Insel said.
Dr. Eric Schadt, director of the Icahn Institute, professor of genomic science at Mount Sinai’s School of Medicine and co-principal Investigator of the Resilience Project, says evidence of such buffering exists across species, including humans, and is well-documented throughout the medical literature universe. Rare mutations in one gene block HIV infection, for example, while mutations in another dramatically lower cholesterol levels and make a person virtually immune to heart disease.
There are others, too. Schadt points to two patients who have come through Mt. Sinai: a woman in her mid-50’s with a mutation in the CFTR gene—the gene understood to cause 100 percent of all cases of cystic fibrosis—who has never had more than mild respiratory issues. And a 45-year-old man who learned during an unrelated medical procedure, that he had Louis–Bar syndrome—a rare neurological disorder caused by a gene mutation—though he had never exhibited any symptoms of the usually fatal disease.
“Both carry the code for an inherited childhood disease but do not bear the symptoms of the disease,” he said. “This Resilience Project hopes to uncover others like them who, everyday, unbeknownst to them, are walking around, buffering against illnesses they were all but guaranteed to get.”
He estimates that one person in about every 25,000 people has a gene that places them at exceptionally high risk for a disease they were somehow able to avoid, but to date there have not been large-scale, systematic efforts to profile large numbers of individuals to identify those who were successfully protected.
Until recently, he says, profiling more than two to three genes per patient posed considerable challenges in both time and cost. But recent technological advances, which have dramatically slashed the time and cost of gene sequencing technologies, and the arrival of supercomputers, which make sense of mega-datasets at dizzying speed, have made it possible to screen each DNA sample for “tens of dollars” in a “matter of hours.”