What will it take to translate the insights from basic and translational genomics research into a better understanding of disease and new treatments for patients?

Researchers at the Center for Genomic Medicine (CGM) at Massachusetts General Hospital have become pivotal players in the emergence of precision medicine due to their roles as local and international leaders in genomics.

These Mass General researchers have created an environment with access to a rapidly growing pool of genomics data, foundational research programs in basic and translational genetics, and the ability to work with patients from diagnosis to treatment. We caught up with one of the investigators leading such work in the CGM.

“Since its inception over a decade ago, the CGM was envisioned with the premise that our research collectively represents a cycle that begins and ends with the patient,” says Michael Talkowski, PhD, an investigator at the CGM and the Department of Neurology, and a Desmond and Ann Heathwood MGH Research Scholar.

“The research that occurs as we traverse that cycle can teach us about the genetic history of individual patients; predict which changes in their genome may be related to disease; evaluate the function of those variants in experimental systems; and help usexplore treatment options based on this information. This is the one of the few places in the world where all of that can happen in one Center.”

Local Connections

One key advantage for Mass General is its close connection to the Broad Institute, an international leader in genomics since its launch in 2004. The Broad is located just a short distance from Mass General in nearby Cambridge, MA.

Over the past 10+ years, Broad investigators have processed more than two million genetic samples from individuals in more than 50 countries. Many CGM faculty are co-appointed at the Broad and are part of the institute’s leadership team.

“This creates a bridge, both literally and figuratively, between Mass General and one of the largest and most impressive genome centers in the world. The Broad has been a critical catalyst for the success of Mass General researchers in the genomic medicine space,” says Talkowski.

Working with All of Us

Mass General researchers also have close connections with the National Institutes of Health’s All of Us Research Program, which seeks to create a biobank of one million individuals from across the United States. Jordan Smoller, MD, ScD, of the CGM and Department of Psychiatry, is helping to lead recruitment efforts for All of Us New England.

As a testament to the depth of local leadership in the broader genomics community, another team of CGM and Broad investigators are leading one of three national sequencing centers to conduct genomics studies on those samples provided by All of Us participants.

This team is co-led by Heidi Rehm, PhD, of the CGM and Mass General Department of Medicine, and Stacey Gabriel, PhD, of the Broad Institute, as well as Talkowski and fellow CGM and Department of Medicine investigator Daniel MacArthur, PhD.

“Our various teams at Mass General and the Broad Institute, including Daniel, Heidi, Jordan and many, many others are involved in every phase of the precision medicine process—bringing patients in the door, sequencing them, creating computational infrastructures to process and store their genomes, analyzing their data, and returning their results,” Talkowski says.

Gathering Insights from A Global Perspective

CGM researchers are already using other locally developed initiatives to gain new insights into the genetic underpinnings of health and disease.

This includes the Genome Aggregation Database (gnomAD), which was created by a team at the Broad Institute led by MacArthur and is already a leading resource for the human disease research and clinical genetics communities.

gnomAD is a first-of-its kind collection of deidentified and standardized genomic data gathered from large-scale sequencing projects across the world.

The database, which is open to the scientific community, includes nearly 126,000 exome sequences and 16,000 whole-genome sequences contributed by an international consortium of researchers.

“Using these data, and the tools that the MacArthur lab and Mass General researchers in the CGM and Analytic and Translational Genetics Unit (ATGU) have developed, we can explore the population genetics of hundreds of thousands of individuals, catalogue the frequency of these variants across populations, and begin to predict which will be deleterious. This project, and its predecessors, have become foundational resources in virtually all aspects of human genetics,” Talkowski says.

Mark Daly, PhD, Chief of the ATGU, Benjamin Neale, PhD, and Talkowski, were among the Mass General investigators who have contributed data and played key scientific leadership roles in the gnomAD program.

“Now, because of gnomAD, when we process a patient’s genome, we can know whether the variant we find exists in the population and predict its likelihood to be associated with disease due to methods developed in ATGU,” Talkowski says.

“We can then bring it back to labs to study these variants with model systems, such as induced pluripotent stem cells using CRISPR/CAS9, to learn how it alters the function of proteins, and hopefully this will eventually lead to targeted treatments, as has already been shown for various diseases.

“It’s truly remarkable that our teams can accomplish all of this within one Center and affiliated units at Mass General.”

About the Mass General Research Institute
Research at Massachusetts General Hospital is interwoven through more than 30 different departments, centers and institutes. Our research includes fundamental, lab-based science; clinical trials to test new drugs, devices and diagnostic tools; and community and population-based research to improve health outcomes across populations and eliminate disparities in care.
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