Thirty years ago, Stephen Friend was a pediatric oncologist at Children’s Hospital of Philadelphia. A father and son walked into his office, each missing his right eye as a result of retinoblastoma, a rare eye cancer. “The father knew that he had passed on that fate to his son—that moment changed my life,” says Friend.

It propelled him to co-lead a team looking into the genetic roots of eye cancers, which led to the discovery of the first tumor suppressor gene in 1987. That approach—treating disease through a better knowledge of underlying genetic causes—has taken Friend in an ambitious new direction.

With Eric Schadt at the Icahn School of Medicine at Mount Sinai, Friend co-leads the Resilience Project. This is an effort to find and study people who are resilient—those who have a high genetic risk of developing serious rare diseases, but who nevertheless have stayed healthy. As a first step, the project will collect a million DNA samples from volunteers around the world, the largest genetic study to date. The goal of the Resilience Project is to sift out a “genetic decoder ring” from resilient subjects to find clues to help prevent disease in others.

Q: You study the healthy instead of the sick. Doesn’t that invert the traditional approach?
A: There are historical precedents. Clinicians in San Francisco found a particular protein, CCR5, that was defective in those who had high levels of the HIV virus but never got AIDS. Researchers at Children’s Hospital in Boston studied children with sickle cell disease who weren’t expected to live into adulthood but reached their forties. The patients carried a genetic element that protected them. What no one has done is take on the theme as broadly as we have.

Q: How does the Resilience Project work?
A: We’re focusing on 125 childhood diseases, known as Mendelian diseases, each of which is caused by a single gene. These are severe diseases, such as cystic fibrosis, in which you’re likely to suffer the full illness if you have the mutated gene. We’re looking for people who’ve inherited the mutation and have reached adulthood without developing the disease. They probably don’t know who they are.

Q: Then how do you intend to find them?
A: It’s like finding a needle in a haystack. These diseases have a very low frequency—cystic fibrosis, for example, occurs in only about one of 3,500 births. And instead of looking for that sick person, we’re looking for the 0.1% to 1.0% who have the risk factor but don’t get the disease. Based on past numbers, we know how small these numbers are. If we enroll a million volunteers, we expect to find 50 to 100 people to study for protective genes or other factors. Volunteers can sign up on our website, We’ll send out a cotton swab that you scrape inside your cheek, a sample containing enough cells to allow your DNA to be analyzed.

Q: How will the project analyze why these people remained healthy?
A: Some of the disorders we’re studying can stem from more than one gene, so the search will involve 164 genes in total. Each sample will be scanned for 685 gene mutations—each at different points on the genome—where disease-causing mutations are known to occur. For those who do carry the mutations, we’ll ask whether they’re willing to be examined further to collect more information about the genetic and environmental factors that may have offered protection. During the past five years, there have been awesome new tools developed in network and systems biology that allow us to think that maybe we can decipher why those at high risk never got sick.

Q: Why are you doing it this way rather than using more traditional methods?
A: We need a new approach. After spending decades developing therapeutic approaches that start with disease causes, I can say it’s really hard to create therapies to fix a broken part in the system of the human body. Instead of developing therapies to modify symptoms or consequences of inherited diseases, it’s time to search for resilience factors that would shift the focus to preventing or changing the course of a disease. My hope is that this will become a common way of doing science and developing treatments. And we have the technology available now, tools that we didn’t have in the past, to make it all possible.