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Translational Genomics is Not a Spectator Sport: A Call to Action

Despite political and popular rhetoric, changes in our health care system will occur because of pressures to control costs, promote prevention, and increase efficacy. As part of these pressures, there is increasing desire to leverage the power of genomic technologies to discover novel disease susceptibility genes and drug targets, and to tailor therapies that account for a person’s genetic predisposition and disease etiology. Fortunately, the United States has the research infrastructure to realize this translational genomics goal in both a timely and cost-effective manner. The question is whether the scientific and political leadership has the will to follow through. To maintain preeminence in this area and to keep the fruits of the human genome project in the public domain, what is needed in the United States is a national effort to coordinate existing large populationbased studies and large-scale sequencing and analysis centers so as to form a “synthetic cohort” that spans cradle to grave (Box 1), whose participants are fully sequenced and whose wealth of longitudinal data, including high-quality data on clinical outcomes and response to treatment, are made rapidly available to the scientific community. It represents an avenue of enormous potential and is the only such avenue whereby progress beyond the incremental can be made in short order. President Obama should adopt and promote this initiative with the same vigor and imagination that President Kennedy promoted manned spaceflight to the moon. The individual components of this undertaking are wellestablished and could form the backbone of this undertaking. Studies such as the National Heart Lung and Blood Institute’s Atherosclerosis Risk in Communities Study and the National Cancer Institute’s Multiethnic Cohort Study of Diet and Cancer have tens of thousands of wellphenotyped participants who have been followed longitudinally for decades to monitor disease risk. The National Children’s Study offers the opportunity to learn more about the role of genetic alterations in early growth and development, possibly leading to better diagnostics and treatment for such conditions as common birth defects and autism. In the area of health outcomes for cancer patients, much will be the benefit of improved treatment and reduced side effects as the result of knowing the sequence of a patient’s genome, of their primary tumors, and any metastases, as is being done in the Cancer Genome Atlas. As a result of innovation and investment stemming from the Human Genome Project and continuing today, the United States has the capacity to sequence the genomes of enormous numbers of individuals. One can now get the protein coding part of their genome (i.e., exome) sequenced for less than it costs to get a routine MRI. The pace of advance is accelerating and the once fictitious $1,000 genome is clearly in reach. Equally important are the commensurate developments in computing and analytic infrastructure. Previous investments in medical technology provide the ability to measure, characterize, and quantify the spectrum of health and disease as never before. The CHARGE consortium is an example of innovative management and cooperative data analysis among large population studies yielding unprecedented gene discoveries. The introduction of “cloud computing” holds great promise on the horizon once cost and data security issues are more fully addressed. A key component of any resource-building initiative is making the data readily available to the scientific community. Fortunately, study investigators and participants along with their local Institutional Review Boards have carefully worked through many of the issues and such sharing is now routine, and data portals such as dbGAP have built the capacity and knowledge base to fill the needs of a very large number of clients. Further innovation is needed so that available DNA sequence and extensive phenotype data may be used to facilitate biomedical research while protecting the privacy of study participants. The US economy and employment statistics are depressed, and there are increasing references to the great depression of the 1930s. During that difficult time, science worked diligently and effectively to improve the quality of life of individuals and helped the country crawl back to economic health. The 1930s saw the invention and proliferation of modern plastics and the introduction of antibiotics into routine health care. Science needs to do the same thing today. Specifically, this is the time to use genomic sciences to create jobs, help control health care costs, and better prevent and treat disease. There has been considerable anxious ink spread on the topic of the lean state of PHARMA’s pipeline and the fact that many blockbuster drugs are nearing the end of patent protection. Having a large population study of well-phenotyped individuals with complete DNA sequence data will provide a database of naturally occurring loss-of-function mutations associated with reduced disease risk. These genes’ products form obvious drug targets because “nature’s experiment” documents that their inhibition leads to a reduction in disease risk without obvious adverse effects (Box 2). There are many notable examples of advances in clinical practice as a result of genomics research; an exhaustive list is not possible and not necessary. An example that may portend the future is KRAS and EGFR mutations in adenocarcinomas of the lung and response to kinase-inhibitor therapy. A proposal such as this one will draw criticism that is welcome and will make the final study more productive and appealing. For example, a synthetic cohort assembled from existing large population studies may not be fully representative of the entire general US population. Although this is true, a concerted effort must be made to be as inclusive as possible and plug gaps in the