When I was in grad school, back in the last century, it was well known that some people possessed disease-causing genes but were nevertheless not sick. The profs dealt with this puzzling fact via a certain amount of hand waving. They spoke of “incomplete penetrance.”
Nobody knew then (or knows now) exactly why some people were able to resist their bad genes. The assumption, reasonable enough, was that other genes were somehow interfering with the bad gene and preventing it from carrying out its badness. Or, perhaps, some environmental something was shutting down the bad gene’s destined activity.
Finally, that idea is going to be investigated. With your help, if you’re older than 40. The staggeringly ambitious Resilience Project is recruiting a million over-40s to donate a bit of saliva, which contains cells with their complete genomes. The plan is to sequence those million genomes in order to find fewer than 100 people who are, well, resilient. Who have the bad genes but not the disease.
Those resilient few will then undergo further testing in hopes of identifying just what it is that is keeping them healthy when they should be sick–or even dead. The Resilience Project folks–Stephen Friend, president of Sage Bionetworks in Seattle, and Eric Schadt, professor of genomics at Icahn School of Medicine at Mount Sinai in New York City–described their plans in an open-access article in the May 30 Science. You can also find a video describing the Resilience Project here. It’s a TED talk Stephen Friend gave in March.
“We see this as a pilot to learn how best to look for those carrying protective alleles. We feel that such protective factors could eventually provide a very valuable approach to designing new therapies and preventions for these diseases,” Friend told me in an email.
The point is better therapies and maybe even prevention
Friend and Schadt say that treatments for genetic disease have so far been something of a disappointment. The point of the Resilience Project is to learn things that will lead to better therapies for these diseases, or maybe even prevention. For example, identifying genes that block the action of disease genes could provide clues for new drugs that could do the same thing.
Friend and Schadt are starting their search with a list of 125 Mendelian diseases, diseases caused by a particular mutant gene. Some of the 125 disorders can be due to more than one gene, so the search will involve 164 genes all told. These genes have a total of 685 known variants–mutant versions of the gene–that nearly always cause serious, and sometimes fatal, disorders.
The list of 125 includes both dominant disorders (where just one mutant gene causes the disease) and recessive disorders (where both genes in a pair are mutated.) These are all rare diseases, some very rare. Pfeiffer syndrome, which affects bone growth and especially skull growth by causing premature fusion of skull bones, one of the dominant disorders, occurs only once in 100,000 births. Cystic fibrosis, one of the recessives, is much more common, especially among those of European descent. But even so, it occurs in only about 1 in 3,500 U.S. births.
The fact that these disorders are so uncommon is the reason why the researchers will be studying a million genomes. They will need that many people in order to find the small number of the healthy who have specific mutant genes that should have made them very sick or killed them. The researchers are expecting to find fewer than 100 of those resilient people.
Most of the diseases on the list are metabolic disorders, but many are developmental disorders or disorders of the nervous system. All the diseases manifest themselves before the age of 18, so by studying only those over 40, the researchers can be sure that any people they find with mutant genes for these diseases have not been affected by them. They are resilient.
Crowdsourcing for resistance to common diseases?
What about research on resistance to common ailments like heart disease or cancer? It is enormously difficult, at this stage, to study factors that help some people resist common diseases even though they possess genes that should have predisposed them. Researchers know that there are such resilient people, but the genetic factors in these disorders are very complex and have not yet been completely figured out.
I wrote about exactly this problem in relation to breast cancer here at GLP not long ago. In addition to the famous breast cancer genes like BRCA1 and BRCA2, dozens of other genes affecting breast cancer risk are known, and as many as a hundred could still be undiscovered.
But there is hope. Some people with even high-risk breast cancer genes don’t get breast cancer, so clearly there are resistance factors awaiting discovery. Friend and Schadt point out that genes protecting people against cardiovascular disease and diabetes have already been found. “We hope that the approaches we are using will soon become standard procedures and that future studies will not be restricted to childhood Mendelian diseases,” Friend told me in an email.
Sequencing a million genomes sounds formidable. Until recently such a gigantic project would have been unthinkable. But technology now makes it possible to analyze hundreds of genomes simultaneously. Friend and Schadt estimate the cost at only tens of dollars per genome and say it can be done in less than a year.
“Technologies to investigate environmental factors, probe epigenetic phenomena, profile microbes, differentiate and manipulate induced pluripotent stem cells, and directly edit genomes are now advanced enough to decipher the extremely complex mechanisms of buffering human genetic variations,” they said in the Science article.
Logistical and ethical issues surrounding genetic screening will be reduced, they say, by the fact that the project will be looking for comparatively few genes for specific rare diseases. This is in contrast to reporting genetic risks for many disorders as some direct-to-consumer genetic testing companies have been attempting.
Still, it occurred to me that a million genomes could be an immensely valuable future resource for all kinds of studies, even though nearly all of them are going to be irrelevant for the Resilience Project itself. When I asked Friend what they planned to do with those million samples, he told me they were figuring out ways for volunteers to opt in or out to having their samples saved for posterity–and future research.
You can find out more about this pioneering genetic crowdsourcing project, including how to donate your saliva, at the Resilience Project site.
Tabitha M. Powledge is a long-time science journalist and a contributing columnist for the Genetic Literacy Project. She writes On Science Blogs for the PLOS Blogs Network. New posts on Fridays. Follow me on Twitter @tamfecit