PerspectiveTranslational Genomics

Clues from the resilient

Science  30 May 2014:
Vol. 344, Issue 6187, pp. 970-972
DOI: 10.1126/science.1255648

The genetics approach to uncovering the causes of disease has focused mainly on finding the underlying primary mutations, with diseased individuals playing the leading role in this discovery. But as health care begins to focus more on preventive therapies, an emphasis on understanding how individuals remain healthy—“resilient” to disease—may provide insights into disease pathogenesis and new treatments. This view underlies “The Resilience Project” (, an effort to search broadly for these apparently healthy people (see the photo). There are, indeed, individuals whose genetics indicate exceptionally high risk of disease, yet they never show any signs of the disorder. What are the genetic and environmental factors that buffer disease for them? How can such information be gathered and harnessed most efficiently and effectively?

Talk the talk.

“The Resilience Project” is described in a Technology, Entertainment, Design (TED) conference. See


For 127 catastrophic Mendelian diseases (those caused by a single gene such as cystic fibrosis and ataxia-telangiectasia), there are presently 164 genes harboring 685 known recurrent variants that are highly penetrant and causal for deleterious traits, most typically manifesting in individuals before the age of 18 (1). More generally, thousands of variants spanning many hundreds of genes have now been associated with common diseases ranging from inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, and cancer, to Alzheimer's disease, schizophrenia, and asthma (2). Yet, despite this wealth of discoveries, few gene variants have translated directly into diagnostic predictors of disease risk and severity or into therapeutic interventions. For common diseases, the observed small effect sizes of individual gene variants limit diagnostic potential, and given that most variants identified have an unclear function, how to target the corresponding gene for therapeutic intervention is typically unclear. For rarer Mendelian disorders, although genetics directly implicate a specific gene in a disease, a majority of such cases relate to loss-of-function mutations. Designing small molecules to fix the corresponding broken protein has proven difficult. Compounds are effective in some cases, such as potentiators of mutant (loss-of-function) forms of the cystic fibrosis transmembrane conductance regulator in patients (3). However, substantial challenges remain in delivering functional versions of the aberrant proteins to specific cell types at the right time to treat or prevent disease.

The prominent role of second-site mutations and environmental factors that enable resistance to (or buffer against) disease traits has been well established in a multitude of model organisms from yeast to mice (47). Screening for second-site mutations in “resilient” individuals that prevent disease-causing alleles from manifesting their effects could identify targets to which drugs would be designed to disrupt their function, as opposed to targeting the disease-causing gene directly. Genetic studies examining seemingly healthy people have revealed, for example, rare mutations in chemokine (C-C motif) receptor type 5 (the co-receptor for human immunodeficiency virus) that block HIV infection (8), and secondary mutations in fetal globin genes that modify the severity of sickle cell disease by buffering primary mutations in β-globin genes (9). Even among common diseases, examples of protective alleles are growing, such as mutations in the gene encoding the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) (10) and the gene encoding zinc transporter 8 (ZNT8) (11). These are striking examples of mutations that confer strong protective effects against cardiovascular disease and diabetes, respectively. Importantly, studies highlighting cases in which disease-causing mutations fail to result in disease (12) and rare individuals carrying disease modifiers are identified in extended families segregating disease (13) raises the question: Could more general worldwide searches across all childhood diseases be undertaken to find evidence for resilience factors, be they genetic or environmental?

The search.

A scheme to identify new treatments for disease is shown that begins with screening large populations of seemingly healthy people for disease-associated variations in their genomes. Once validated, multiple dimensions of data on a resilient individual would be combined with existing knowledge and clinical genetic expertise to generate an in-depth characterization that could point to new ways to suppress a disease trait.

A search of individuals older than 40 years of age for highly penetrant alleles in genes that cause catastrophic disease in children (with severe phenotypes that typically manifest before 18 years of age) is consistent with classical genetic study designs in which individuals with extreme phenotypes are analyzed because they are more likely to be homogeneous, and the extreme phenotypes are more likely explained by a smaller number of loci or environmental factors with big effect sizes. The identification of resilient individuals is thus much less ambiguous. This is opposed to identifying mutations that may have a relatively high carrier frequency in the population but far lower penetrance. The trade-off for this clarity is the need to sample many individuals, which requires systematic screening across general populations and diverse regions of the globe.

Given the ability to sequence hundreds of samples simultaneously, it is now within reach to screen a million individuals for relatively low cost (tens of dollars per individual) and in a short period of time (less than a year). The challenge will be to decipher which of the hundreds of candidate second site mutations or environmental factors may be responsible for the buffering against disease. The power to resolve the buffering effect statistically will be very low as the number of candidates expected to be identified will be relatively small. However, recent studies successfully combined biochemical, molecular, and genetic pathway and network analysis tools to identify individuals with rare genomic variants that suppress a disease phenotype. For example, one recent study sequenced the genomes of a small number of positive responders to a drug administered in a clinical trial; by combining multiple types of data, the study identified the basis for the responders' sensitivity to the drug (14). Such tools have further validated these “positive outliers” and have led to personalized treatments. 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.

The scale required in a resilience study can only be supported by the sharing of data and ideas among collaborators that operate in a large network spanning a large scope of disciplines and knowledge. Critical to such a network are clinical genetics experts who could rapidly filter through candidate resilient individuals to validate their genetic status, rule out what may be common explanations such as mosaicism, and ultimately identify factors that enable resistance. The Online Metabolic and Molecular Bases of Inherited Disease reference offers a potential model of clinical experts who study individual genes responsible for rare disorders and can assess the clinical and primary gene defects. A version of this model that covers a broad range of diseases could facilitate the kinds of connections required to elucidate the complexity of resilience to a given disease.

Obtaining informed consent from 1 million individuals in such a study could not be done in a traditional way, but would need to be done electronically. What would be their motivation? Low risk and potentially high reward. Enabling participants to assess whether they can serve as an “unexpected hero” to others who are afflicted with catastrophic disease could be personally inspiring. There is also low risk in that this strategy minimizes the likelihood of conveying future risk of disease to participants. Collecting and processing patient samples in a highly automated way would be necessary, but direct to consumer genomic companies and lab testing companies have demonstrated that efficient, large-scale sample acquisition and processing can be done routinely. Given that the study would only report individuals with resistance to disease, not generalized risks of disorders across spectrums of disease, both the regulatory and ethical requirements would be reduced.

A resilience project (see the figure) approach helps shift thinking on treating disease. Rather than developing therapies that modify symptoms or the consequences of inherited diseases, a systematic search for resilience factors will change the focus in ways that prevent or modify the course of diseases. This should initially be easier for single-gene Mendelian childhood diseases, but emerging network approaches that define clusters of genes that drive a disease (such as diabetes, cancer, and Alzheimer's disease) could eventually be amenable to this strategy.

The resilience approach (see the figure) can well complement emerging efforts to follow well individuals longitudinally (15) and to identify and characterize human “knockouts” (people lacking specific genes) (16, 17) by more rapidly targeting (in a large number of individuals and at relatively low cost) a specific set of genes that harbor what are thought to be completely penetrant mutations that cause catastrophic disease, to find people who should have gotten sick, but did not. Achieving the greatest degree of success across all of these types of efforts will require collating and making publicly accessible the data collected in each study. The focus on genetic and environmental factors that offer protection against disease as opposed to putting you at risk for disease may also help engage a public that is more participatory in sharing their insights and data to help others.

References and Notes

  1. Acknowledgments: S.H. F. is a principal investigator of The Resilience Project (


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