Scientists looking to cure disease typically study the sick—but what if there were a better way? “Maybe we are looking at the wrong people,” said Stephen Friend of Sage Bionetworks in Seattle. “Perhaps we should look at those who should have gotten sick, but did not.” Friend’s Resilience Project, described in a Perspective in the May 30 Science, studies people who are healthy despite carrying mutations that should have made them ill as children. Those lucky folks are likely to tote other mutations that saved them from childhood genetic disease, reason Friend and co-author Eric Schadt of the Icahn School of Medicine at Mount Sinai in New York City, who co-leads the project.
"This is a great project. The idea of looking at protective rather than risk factors is attractive because it has direct potential to result in preventative therapies," Rosa Rademakers of the Mayo Clinic in Jacksonville, Florida, wrote in an email to Alzforum (see full comment below). Of course, people who dodged a genetic bullet are hard to find because they show no obvious symptoms. The researchers will examine DNA samples for 674 known mutations that cause disease. Friend estimates the project will have to screen 35,000 to 50,000 people aged 40 or older to find just one “unwitting escapee,” and he plans to screen one million to find several such individuals. Organizations that already have DNA banks, such as the commercial sequencer 23andMe in Mountain View, California, have agreed to share their data, and the Resilience Project has surged halfway toward its million-sequence goal without spending a dollar, Friend said. The scientists have already discovered tens of potential escapees, Friend reported in a TED talk in March.
Finding these folks will be the easy part. Essentially, all the scientists have to do is search those sequences for known pathogenic mutations. Understanding why they did not cause disease will be harder. Friend invites collaborators to join this phase of the project, so the work can generate new drug targets.
The project has “strong potential for finding new therapies,” agreed Alison Goate of Washington University in St. Louis, who is not involved in the project. Both scientists noted that a similar approach could work for neurodegenerative diseases of aging. To that end, Friend is interested in collaborations to explore the DNA from older donors in the Resilience Project.
In conjunction with Genentech of South San Francisco, California, Goate has already begun a similar project. It identifies people who are homozygotes for the Alzheimer’s risk allele ApoE4, or who are heterozygous for ApoE3/E4 but remain cognitively normal into their 80s. “Something, probably in their genes, protects them [from cognitive decline],” she said. Goate’s team has sequenced the genome of a few hundred such individuals and will screen more.
Starting this summer, the Resilience Project will collect samples, via cheek swab, from the public. Might you be a rare survivor? Detailed information and donation kits are available here.—Amber Dance.
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