NIH to jump-start genomic medicine with new program
Genomic data will play increased role in studies at the NIH Clinical Center
By Raymond MacDougall
Associate Director of Communications, Division of Intramural Research
"We're trying to jump-start genomic medicine," Dr. 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 1-2 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 flat land and wanting the third dimension to navigate the landscape of the disease you're studying," Dr. 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.
NIH is renowned for outstanding clinical facilities where scientists study approximately 600 different diseases. These facilities will be made even better with the addition of the CCGO program. Set to launch this summer, it will begin with a review committee's selection of projects that take optimal advantage of NIH Clinical Center phenotyping resources-the imaging, detailed documentation of physiological changes in patients and annotations of medical consequences of diseases. The successful applicants will be awarded from 50-300 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, M.D., chief of NHGRI's Medical Genomics and Metabolic Genetics Branch in the NHGRI intramural research program 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, M.D., Ph.D. "CCGO is a way of laying the groundwork for this pipeline."
Proposed by Drs. 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 I. Gallin, M.D. "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 Dr. 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, a number of pilot projects have provided investigators insight into the opportunities and challenges of clinical genomics. Dr. Biesecker, for example, uses exome sequencing in ClinSeq®, a study that compares an individual's exome and genome data to their 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, are knowledgeable in genetics, but who 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 Director's Challenge Innovation Award Program that is administered by 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 (CLIA), which sets quality standards for laboratory processes that generate results that are 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, sequencing machine time, computational analyses and our years of genomics expertise with exome data," said Jim Mullikin, Ph.D., NISC director and associate investigator in the Cancer Genetics and Comparative Genomics Branch in the NHGRI intramural research program. "We're excited about expanding NIH-wide access to genome sequencing and analysis. It's the way that healthcare is going and NHGRI should continue to be at the forefront of this research."
Dr. Mullikin described the dramatic decline in costs associated with sequencing-from $10,000 per exome five years ago, to $3,000 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 Dr. Biesecker. "Use of exome data is the way to get a toe-hold in this field and develop those capabilities. Then the practice of genomic medicine at the Clinical 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," Dr. Gottesman said. "But there's a lot we need to learn from here to there."
Note: NIH intramural researchers may attend a town hall meeting to learn more about the Clinical Center Genomics Opportunity (CCGO) on Monday, April 28, 2014, from 10 - 11 a.m. at Lipsett Amphitheater, Building 10 (Clinical Center). For details, see: The NIH Yellow Sheet.
NIH intramural investigators who are interested in applying for participation in the CCGO program may contact Dr. Biesecker at email@example.com.