Somewhere in the world are 13 incredibly lucky people. Although they do not know it, each inherited a mutated gene that causes a fatal or terribly debilitating disease in infancy or childhood - but these people are adults, and healthy.
Their DNA may hold clues to treating others who did not escape the gene's effects.
That is the conclusion of a new paper, published in the journal Nature Biotechnology, in which researchers searched databases containing genetic sequences from nearly 600,000 healthy adults and found these remarkable 13.
"A real tour de force," Dr Randall Bateman, a professor of neurology at Washington University in St Louis who was not involved with the research, said of the paper.
The paper is among the first fruits of a research direction that geneticists have discussed and dreamed about for years, said Dr Eric Green, director of the National Human Genome Research Institute.
Until now, with the accumulation of large databases of people who have had their genomes sequenced, it had not been possible to find people who met such criteria.
But the triumph is not complete.
When the people in the databases provided their DNA for analysis, they signed agreements guaranteeing that they would remain anonymous. So the researchers cannot go any further.
"You can imagine the level of frustration," said the study's lead researcher, Dr Stephen Friend, president of the non-profit Sage Bionetworks and a genomics professor at the Icahn School of Medicine at Mount Sinai in New York.
"It is almost as if you got to take the wrapping off the box but you couldn't open the box."
The finding, though, is a proof of concept, he and others say.
Now, Dr Friend and his colleagues, Dr Eric Schadt and Associate Professor Jason Bobe of Mount Sinai, are beginning the next phase of their project, which they call the Resilience Project. That will involve recruiting at least 100,000 people who will agree to have their genomes sequenced and to be contacted only if they have a mutated gene that should have made them ill or killed them, but did not.
The study was prompted by Dr Friend's frustration. He spent years in academia and biotech companies searching for ways to fix genetic defects that cause disease. Success was rare, because even when researchers knew that a gene-destroying mutation was causing a disease, they rarely found a drug to restore the gene.
"Maybe we should flip it around," he thought. The idea was to create "a compensating mutation" that would, in effect, cancel out the bad one.
"Maybe we could develop new therapies." That led to the idea of searching for healthy people who had been born with compensating mutations, but researchers could not simply put out a call for such individuals.
Healthy people would have no reason to be screened for mutated genes, and would therefore have no idea that they were resilient, noted Dr Daniel MacArthur, a geneticist at the Massachusetts Institute of Technology and the Broad Institute who was not involved with the new study.
So, a little over three years ago, Dr Friend and Dr Schadt began searching international databases for people who were over 30 and healthy but carried mutations that typically cause childhood diseases like Tay-Sachs or muscular dystrophy.
They cobbled together genetic data from 12 large studies, looking for mutations in any of 874 genes that were linked to 584 severe diseases.
They found 15,597 people who might fit their criteria for resilience. But they discarded nearly all, either because they found errors in the data or because the evidence supporting the notion that those mutations inevitably caused a severe childhood disease was shaky.
What remained were 13 people who had verifiable mutations that cause one of eight serious diseases before age 18 in all who inherit them - or so it had been thought.
The eight diseases were cystic fibrosis, Smith-Lemli-Opitz syndrome, familial dysautonomia, epidermolysis bullosa simplex, Pfeiffer syndrome, autoimmune polyendocrinopathy syndrome, acampomelic campomelic dysplasia and atelosteogenesis.
The tiny number of individuals, 13 out of more than half a million, "teaches us something about how big these studies must be", Dr MacArthur said. To truly understand why these people did not get sick, many more resilient individuals are needed, including unrelated resilient people with mutations in the same disease gene.
For that, he said, "even a million samples will not be enough".
"It is a sobering thought, but it is not completely ridiculous," Dr MacArthur added.
Efforts are under way now - like the Precision Medicine Initiative and the Million Veterans Programme in the United States, and the UK Biobank in Britain - that make the idea feasible.
These databases will include millions of people, and the data will be more reliable and of higher quality than what is available now because of improved methodology, Dr Green said. And they will allow participants to agree to be contacted again by researchers.
Yet daunting challenges lie ahead, researchers studying resilience from another angle said.
They are identifying rare individuals in families with a disease-causing mutation. These people have the mutated gene but do not become ill; or if they do, their illness starts more than a decade later than expected.
Dr Bateman and his colleagues at Washington University have identified a man with a mutated gene that nearly always causes Alzheimer's disease. In his family, the age of onset is in the early 50s. But this man is in his mid-60s and does not have the disease.
Dr Thomas Bird, a geneticist at the University of Washington, found a man with a mutated gene that causes another sort of dementia, frontotemporal. The man has no signs of the disease, although he is 67 and the disease in his family typically starts 20 years earlier.
In Britain, Dr Steve P. Jackson, a professor of biology at the University of Cambridge, is studying cells from two middle-aged people who inherited a gene for ataxia telangiectasia, a disorder that results in difficulty with coordination. People with the disease typically need wheelchairs by their teenage years. But these two people have only the mildest of symptoms.
Yet, Dr Bateman says, the next question - why are these people protected? - is fiendishly difficult. He and his colleagues have DNA from multiple members of the family with Alzheimer's disease, as well as the sequence of every one of the 20,000 genes of the man who has not developed the disease.
But, he notes, each person has about 200 unique gene mutations, most of which are inconsequential. If one of those mutations is protective, how would researchers know? And what if, as is likely, protection involves five, 10, 20 mutations elsewhere in the DNA? Or what if it is not genes at all, but something in the environment that is protective?
Dr Friend has some ideas to overcome these obstacles but, for now, the problem looms.
"It's a problem the whole field faces," he said.
"Biology is so complex."
NEW YORK TIMES