Better data for the bedside: Broad sequencing gets closer to the clinic

The Broad Institute aims to transform biomedicine using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease. This goal cannot be accomplished purely in the laboratory, but must include efforts to bridge findings to the clinic.

In 2013, the Broad launched the institute’s Clinical Research Sequencing Platform (CRSP) to provide high-quality, validated genetic sequencing for clinical researchers in academic, medical, biotechnology, and pharmaceutical organizations, and to bolster the utility of genomic information in medicine. CRSP was developed and is operated by the Genomics Platform under the leadership of Stacey Gabriel, the platform’s director, and Niall Lennon, who directs the platform’s clinical development. Since its launch CRSP has created clinically validated versions of exome sequencing and analysis using Broad-developed methods like hybrid capture, the Genome Analysis Toolkit (GATK), and MuTect. These methods have already been applied to numerous clinical research projects involving more than 1,000 individual samples.

The platform is now expanding its clinical diagnostic expertise by bringing on institute member Heidi Rehm, Ph.D., FACMG, as clinical director. Rehm will continue to serve as the director of the Laboratory for Molecular Medicine (LMM), the CLIA-certified molecular diagnostic laboratory she founded in 2001 at Partners Healthcare Personalized Medicine, and she will build on this experience to lead CRSP on a part-time basis along with assistant director Ozge Ceyhan-Birsoy, Ph.D., a recent graduate of Rehm's Clinical Molecular Genetics training program at Harvard Medical School. Together with Genomics Platform leadership, they will help guide the development of CRSP services so that they best serve the end users: clinicians and clinical researchers. “The Genomics Platform is thrilled to have Heidi and Ozge join us to help us refine our offerings and outline a strategic vision for the platform’s coming years” said Gabriel.

Incoming clinical director, Heidi Rehm
Photo courtesy of Brigham and Women’s Hospital

CRSP is accredited by the College of American Pathologists (CAP), licensed by the State of Massachusetts, and registered with the Centers for Medicare and Medicaid Services to provide testing under the Clinical Laboratory Improvement Amendments (CLIA) regulations. These certifications ensure that the data generated in the platform is “validated” and can be used by physicians to make clinical decisions about diagnosis and treatment of patients or incorporated into clinical trials.

Services offered by CRSP currently include sequencing of the whole exome (all the protein-coding parts of the genome) for germline DNA (typically used to identify mutations underlying Mendelian, or single gene, diseases) and somatic DNA (primarily tumor and normal tissue samples from cancer patients). These validated exomes are produced on the Illumina sequencing platform, using a method that members of the Broad Genomics Platform co-designed with Illumina. Scientists in the Genomics Platform have used Illumina exome sequencing extensively for research applications, but with recent CLIA validation of the process, it can now be used by CRSP in a clinical context.

CRSP currently supports several clinical research projects, including: BabySeq, an NHGRI-funded initiative to explore the return of genomic data to newborns led by Broad associate member Robert Green and Alan Beggs; sequencing of brain cancer samples for the Accelerating Brain Cancer Cure (ABC2) research project; a Dana-Farber Cancer Institute endeavor to facilitate trials of personalized vaccines for cancer patients; and CanSeq, an effort to use whole-exome sequencing to guide the care of cancer patients, co-led by Levi Garraway, institute member of the Broad. The CRSP team also recently completed targeted sequencing on more than 1,000 samples for a large clinical trial in partnership with a biotechnology company.

The platform welcomes its new clinical director Heidi Rehm to help forge even closer connections to the clinic. In particular, one new avenue will be a close collaboration with the LMM. Scientists in CRSP have already begun collaborating more closely with the LMM’s clinical geneticists and scientists to help refine the content of exomes produced at the Broad so that they are the highest value to users of the data, for example, prioritizing disease-relevant regions of the genome in sequencing data.

“The Broad offers innovation and expertise in sequencing and information technology, and the LMM is great at curating and interpreting content in a clinical context,” said Rehm. “The two together are a perfect marriage, but we’ll need to work more closely to get a truly integrated approach and develop compatible solutions. By having people who are using these products on the Broad’s clinical development team, we can ensure that the technology we develop is actually what’s needed by the clinical labs.”

Rehm explained that she plans for the partnership with LMM to serve as a template for developing closer ties with other clinical partners in the Boston and Cambridge area. To start, she is teaming up LMM members with CRSP scientists on task groups to define new services and products that the joint activity would support.

One challenge in this endeavor is that the Broad offers what is known as a “technical exome” — a data file that contains either the raw sequence data or a list of genetic variants that deviate from the human reference genome. It doesn’t tell the physician what the results mean or what is clinically actionable. The end user of the data may be a geneticist or molecular pathologist who needs some assistance in interpreting the data, perhaps annotation on what is known about individual variants and their association with human disease or biology. Rehm would like to see more flexibility with how groups are able to interact with CRSP, so they can use it with customized levels of support that best fit their needs ranging from raw data files to fully annotated exomes.

In CRSP’s coming years, Rehm hopes to see more overlap in the platform’s clinical and research activities. In her own experience leading the LMM for twelve years, she saw it grow from serving as a purely clinical lab that provided tests for use in the clinic, to one that supported research studies with its clinical services and even made its own discoveries through original research.

“There is an increased blurring of the lines between research and clinical services as medicine recognizes the need to support a continuous learning system,” said Rehm. “Allowing Broad CRSP to play a larger role in diagnostic services by supporting physicians and clinical researchers in a more integrated fashion will advance research and medicine.”

With CRSP’s growing capabilities, new collaborative efforts with clinical researchers, and closer partnerships with diagnostic labs, the platform is positioned to help realize the promise of clinical sequencing, by bringing high-quality, expertly curated sequencing data to the bedside.