A Massachusetts General Hospital (MGH)-based research team is one of seven nationwide receiving contracts under the DARPA Safe Genes program, which is designed to improve the safety of gene drives – techniques that can insure a beneficial gene variant spreads through a population of organisms much more rapidly than through normal inheritance. The group led by J. Keith Joung, MD, PhD, associate chief for Research in the MGH Department of Pathology, will also work towards developing better ways to detect and prevent off-target mutations induced by CRISPR-Cas9 gene-editing nucleases.
CRISPR-Cas9 technology utilizes elements found in bacterial immune systems, including DNA-cutting nucleases that enable it to induce breaks at specific gene sites and to insert new genetic material at desired locations in the human genome. In 2013, Joung's team at MGH was the first to report that the nucleases could also have unwanted, off-target effects in human cell lines, raising an important issue to be evaluated prior to therapeutic applications. Since then, his team has developed a way of detecting unwanted CRISPR-Cas9-induced DNA breaks in engineered cells and created a "high-fidelity" nuclease that induced no unwanted mutations that could be detected by that method.
"Although we've made a lot of progress over the past three or four years, we still want to have even more sensitive and robust ways of finding these off-target effects," Joung says. "That is important not only for developing safe therapeutics but also for gene drives developed to propagate a genetic change through a population of, for example, mosquitos. And development of better assays should, in turn, help us engineer even more precise forms of CRISPR-Cas9 nucleases."
Joung's Safe Genes team is receiving more than $10 million for the project and includes investigators at Imperial College (London), North Carolina State University, Boston University and Polo GGB, a non-profit research organization based in Italy. Their focus will be developing even more sensitive methods of measuring and controlling on-target gene-editing activity and detecting and limiting off-target activity. They also hope to develop better means of controlling gene drives, including more precise ways of regulating the expression and activity of CRISPR-Cas9 and other gene drive elements. Efforts at the MGH will be spearheaded by Vikram Pattanayak, MD, PhD, also of MGH Pathology and an instructor in Pathology at Harvard Medical School.
A professor of Pathology at Harvard Medical School and the Desmond and Ann Heathwood MGH Research Scholar, Joung says, "We're delighted that DARPA sees the need for and is willing to fund this type of research, which is a good fit with our continuing interest in pursuing these important questions. Our primary focus is improving the safety of these tools, and our findings should lead to safer therapeutics and gene drives, as well as better research reagents."
The other six Safe Genes teams are led by Amit Choudhary, PhD, the Broad Institute and Brigham and Women's Hospital; George Church, PhD, Harvard Medical School; Kevin Esvelt, PhD, Massachusetts Institute of Technology; John Godwin, PhD, North Carolina State University; Jennifer Doudna, PhD, University of California, Berkeley; and Omar Akbari, PhD, University of California, Riverside.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."