Researchers have spent decades studying the genes of people who have genetic diseases in hopes of developing better treatments. Sometimes, they’ve had success. More often, new therapies have been slow to emerge.
An ambitious new study, called The Resilience Project, takes the exact opposite approach: By sifting through the genes of healthy people, scientists hope to discover fresh approaches to treating rare inherited diseases.
“When we find a [genetic] defect, very few times does that give a direct path towards developing a therapy or intervention,” says Stephen Friend, president of Sage Bionetworks, the biomedical research non-profit leading the project. “What if we flipped what we were trying to do? Maybe those who are sick are the wrong people to be studying.”
The Resilience Project essentially aims to uncover a few needles in a massive evolutionary haystack--people who have gene mutations that put them at an extremely high likelihood of getting rare and serious childhood diseases, but have lived to adulthood without even knowing it or developing serious symptoms. The goal will be to first discover these "unexpected heroes" who have the mutations directly linked to about 100 rare single-gene disorders, such as cystic fibrosis and Gaucher’s disease, and then try to figure out why they've been protected.
Finding these candidates will be a massive undertaking, even in a time of growing genetic testing. The project's leaders, at Sage Bionetworks and New York's Icahn School of Medicine at Mount Sinai, only expect that about 1 in 15,000 healthy adults tested will have the rare mutations that are helpful to the project. That means to find even several dozen candidates, they are aiming to screen up to 1 million adults over the age of 40 in the next several years.
The entire idea is only now becoming possible, as the cost of screening the genetic code drops. The researchers will use a chip technology developed at Mount Sinai, and are aiming for an initial total cost of under $100 per sample with the idea that costs will decrease as more people sign up. "It's a relatively low-cost to entry compared to what we're used to hearing around genetic testing costs," says Elissa Levin, assistant professor in the Mount Sinai Department of Genetics and Genomic Science and co-investigator on the project.
That there are people who have unknowingly lived their life with a genetic free pass isn’t without precedent.
A small percentage of people who contract the HIV virus, for example, never develop AIDS because of a protective mutation that is now the subject of much study by the medical community. And an early proof-of-concept for the Resilience Project uncovered tantalizing evidence that protective mutations do exist for inherited diseases: Looking at thousands genomes already sequenced for other purposes, for example, researchers found one individual who inherited the mutations from both a mother and father that cause cystic fibrosis, but who didn't appear to have the disease.
Mike Bamshad, a University of Washington geneticist who isn't involved in the project, says the work could advance what is known about how genetic variation influences some diseases, but there will be challenges, such as fully understanding whether individuals have symptoms or mild manifestations of these diseases as well as recruiting hundreds of thousands of volunteers in the first place. “Here, scale is a necessity," he says.
For recruitment, the project leaders will rely on crowdsourcing, crowdfunding, and partnerships. Anyone can now go to the website and sign-up to receive a kit for submitting a cheek swab of DNA in the mail. Disease communities, including friends and families of patients, are likely to be early contributors. To reach a wider diversity of people around the world, the researchers aim to collaborate with governments and businesses. Friend says they are in discussions with some large tech companies, with the idea that the test could be a new kind of do-gooding benefit they offer their employees (see if your DNA can help cure diseases!).
“We need to be ready for a hundred thousand people to say, 'Hey, I want to be tested,'” says Friend. They’ve partnered with the genetics testing company 23andMe, the Beijing Genomics Institute, and other organizations to distribute kits and test samples. Most people will simply find out the obvious; they are not a “hero,” at least for the specific diseases being tested. But for a few individuals, positive results will be conveyed carefully, and there will ideally be follow-up full genome testing and interviews.
In the long-term, Levin sees potential for similar work to look for resilience genes and environmental factors that offer protection in relation to more complex adulthood diseases, such as breast cancer, Alzheimer’s, or Parkinson's. The National Institutes of Environmental Health is an advisor to the team.
"We know that pretty much all diseases are a combination of genetic and non-genetic factors, especially when we get into the broad range of adulthood diseases," says Levin. "This could have the potential to break it down and really start to assess how can we be more predictive about it."
[Image: Abstract via Shutterstock]