Jump-Starting Genomic Medicine

New Program at the NIH Clinical Center

BY RAY MACDOUGALL, NHGRI

NIH clinical researchers will be using genomic data in many areas of clinical research in the coming decade, according to Michael Gottesman, NIH’s deputy director for intramural research. To advance this goal, he is backing a new, two-year initiative called the Clinical Center Genomics Opportunity (CCGO).

“We’re trying to jump-start genomic medicine,” Gottesman said. “We first need to build an infrastructure for clinical genomic sequencing that can be used by researchers in their projects at the NIH Clinical Center.”

The CCGO program will underwrite the DNA sequencing and analysis of a total of 1,000 exomes, which are the functionally important one to two percent of an individual’s genome that codes for proteins. Until now, only a few clinical research projects in the NIH intramural program have included exome sequencing. Instead, they have relied on clinically observable—or phenotypic—information and the targeted sequencing of specific candidate genes often suggested by that phenotypic information.

“It’s as if we were missing a whole dimension—like living in Flatland and wanting the third dimension to navigate the landscape of the disease you’re studying,” Gottesman said. He believes a combination of both observable and genomic data will be immensely valuable in understanding human health and improving the prevention, diagnosis, and treatment of disease.

Set to launch this summer, the CCGO program will begin with a review committee’s selection of projects that take optimal advantage of the NIH Clinical Center’s phenotyping resources—the imaging, the detailed documentation of physiological changes in patients, and the annotations of medical consequences of diseases. The successful applicants will be awarded 50 to 300 exome sequences derived from patient samples. The samples will be collected at the NIH Clinical Center and sequenced at the NIH Intramural Sequencing Center, a specialized facility for high-throughput, next-generation sequencing operated by the National Human Genome Research Institute (NHGRI). Investigators who receive exome data through CCGO will receive help handling the data and navigating challenges associated with the interpretation and return of clinical genetic results.

“The initiative will help investigators take advantage of genomic technologies and develop capabilities to work with genomic data from clinical-research patients,” said Leslie Biesecker, chief of NHGRI’s Medical Genomics and Metabolic Genetics Branch and an early adopter of clinical genomics at NIH. “NIH investigators will advance their own research, and CCGO will develop the infrastructure and pipeline within the Clinical Center to begin to manage genomic data in a clinical context.”

“We’re trying to build infrastructure and apply genomic approaches to many different clinical-research challenges,” said NHGRI Scientific Director Daniel Kastner. “CCGO is a way of laying the groundwork for this pipeline.”

Proposed by Biesecker and Kastner, the new program received enthusiastic support from the NIH Deputy Director of Intramural Research and the NIH Clinical Center.

“The NIH Clinical Center is the best place in the world to do detailed characterization of the disease phenotypes and natural histories of rare and unusual disorders,” said NIH Clinical Center Director John Gallin. “This program will harness genomics to help us solve otherwise insoluble problems and get answers in much less time. It’s a great synergy of resources and an important project that will transform our emphasis on disease prevention.”

“There’s no doubt that exomes and genomes can be used to figure out the genetic cause of a lot of different kinds of disorders,” said Biesecker. “We also know that genome data can be used to enhance medical care and we want to figure out how to take best advantage of these data.”

At NIH, several pilot projects have provided investigators insight into the opportunities and challenges of clinical genomics. Biesecker, for example, uses exome sequencing in ClinSeq, a study that compares an individual’s exome and genome data with family health histories. Launched in 2007, the ClinSeq study could be expanded to explore the molecular underpinnings of a wide variety of diseases. Similarly, the NIH Undiagnosed Diseases Program has incorporated exome sequencing into its study of extremely rare conditions.

While intramural researchers across NIH use various genomic technologies, not all who would like to access genomic tools or infrastructure have had the chance to budget for the use of these tools. CCGO will change that. It will be inviting applications from principal investigators—at institutes that participate in the NIH Clinical Center—who are knowledgeable in genetics but do not currently have a major research program in clinical genomics.

The cost of exome sequencing conducted through CCGO will be offset by a combination of funds from the NIH Office of Intramural Research, sequencing discounts from the NIH Intramural Sequencing Center, NHGRI clinical support for incidental findings analysis and counseling, and NIH Clinical Center sample processing and informatics. CCGO will also leverage clinical, scientific, and bioinformatics resources within participating institutes.

For its part, the NIH Intramural Sequencing Center (NISC) will seek certification of its laboratory processes under the federal Clinical Laboratory Improvement Amendments, which set quality standards for laboratory processes that generate results to be returned to patients. In addition, NISC personnel will help intramural researchers prepare data files for submission to the Database of Genotypes and Phenotypes, or dbGaP, which stores and manages access to data from medical studies.

“The contribution from NISC is our laboratories’ talents, [our] sequencing-machine time, [our] computational analyses, and our years of genomics expertise with exome data,” said Jim Mullikin, NISC director and associate investigator in NHGRI’s Cancer Genetics and Comparative Genomics Branch. “We’re excited about expanding NIH-wide access to genome sequencing and analysis. It’s the way that health care is going, and NHGRI should continue to be at the forefront of this research.”

Mullikin described the dramatic decline in costs associated with sequencing—from $10,000 per exome five years ago to $3,000 per exome when NISC began offering exome sequencing three years ago. The current cost is $600, which covers just the cost of the chemical reagents used for DNA sequencing. The other costs for sequencing infrastructure and staff are being donated by the NHGRI. Just a handful of hospital systems in the United States have begun using genome sequencing in clinical care. NIH clinical investigators will be on the vanguard of clinical genomics.

“We want the Clinical Center to be at the forefront of individualized genomic medicine,” said Biesecker. “Use of exome data is the way to get a toehold in this field and develop those capabilities. Then [the practice of genomic medicine at the Clinil Center] can evolve over time so that it becomes both more generalized and more useful for researchers and patients.”

“At some time in the future, I imagine we will be sequencing everybody—maybe full whole-genome sequencing, but there’s a lot we need to learn [between] here [and] there,” Gottesman said. “We expect the CCGO initiative to have a long-term impact on how genomic medicine is practiced.”

For an application and background on the CCGO, including the application deadline and timeline, go to http://www.genome.gov/CCGO/. For more information, contact Leslie Biesecker at lesb@mail.nih.gov.