Resilience Project to Uncover Why Some Mutation Carriers Stay Well

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.

Comments

  1. 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. It is the extreme version of looking at patients at the ends of the spectrum, but in this case the individuals did not even develop disease.

    There are no doubt challenges to this approach. They will likely only identify very few individuals with mutations in a particular gene, and it will be challenging to determine what it is that protects them. Genetic, epigenetic, and/or environmental factors may all play a role. If they are lucky, and the same factor protects a subset of patients with a particular mutation, it should work.

    There is definitely a possibility of using a similar approach to study dementia-related genes. Carriers of the C9ORF72 repeat expansions have been reported in about 1 to 2 per 1,000 healthy older individuals. Although these individuals may still develop symptoms at a later age, it is worth studying them and comparing them with those who develop disease in their 30s. Our work on the TMEM106B gene also showed that mutations in progranulin (GRN), initially thought to be nearly fully penetrant, can in fact occur in healthy individuals protected by the TMEM106B gene. I strongly believe that secondary mutations and environmental factors play an important role in the disease presentation of C9ORF72 and GRN mutation carriers, and we and others are collecting large series of individuals with these mutations in an attempt to identify such genetic modifying factors.

    In the future I could see similar initiatives being launched for other disease including dementia. The collection of large series of healthy ApoE4 homozygous carriers is particularly attractive and may be even more feasible than the resilience project as the frequency of e4 carriers in the general population is much higher.

    View all comments by Rosa Rademakers

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References

External Citations

  1. Resilience Project
  2. TED talk
  3. here

Further Reading

Papers

  1. Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell. 2013 Apr 25;153(3):707-20. PubMed.
  2. Chen Y, Zhu J, Lum PY, Yang X, Pinto S, Macneil DJ, Zhang C, Lamb J, Edwards S, Sieberts SK, Leonardson A, Castellini LW, Wang S, Champy MF, Zhang B, Emilsson V, Doss S, Ghazalpour A, Horvath S, Drake TA, Lusis AJ, Schadt EE. Variations in DNA elucidate molecular networks that cause disease. Nature. 2008 Mar 27;452(7186):429-35. PubMed.

Primary Papers

  1. Friend SH, Schadt EE. Translational genomics. Clues from the resilient. Science. 2014 May 30;344(6187):970-2. PubMed.

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