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News / 02.14.20

Research Roundup: February 14, 2020

Len Rubenstein
Credit : Len Rubenstein
By Broad Communications

Beating a path to better base editors, patient participation fuels rare cancer discoveries, keeping an eye on mumps, and more.

Welcome to the February 14, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Building better base editors

Core institute member David Liu and his team have shown in two papers in Nature Biotechnology how they’ve improved the precision and genome-targeting ability of base editors. In one paper, Jordan Doman, Aditya Raguram, and collaborators designed new cytosine base editors that reduced a type of off-target editing, called Cas9-independent editing, by 10- to 100-fold. In the other paper, Shannon Miller, Tina Wang, and colleagues evolved a new generation of CRISPR-Cas9 proteins capable of targeting a much larger fraction of the genome, including a mutation that causes sickle cell anemia. Learn more in a story on the Broad website. 

New discoveries from the Angiosarcoma Project

Hundreds of patients across the U.S. and Canada have enabled a new study on angiosarcoma, a rare, aggressive cancer of blood vessel walls. Corrie Painter in the Cancer Program, associate member Nikhil Wagle of the Broad and Dana-Farber Cancer Institute, and others with Count Me In analyzed nearly 50 tumors from patients, found dozens of mutated genes, and revealed potential therapeutic options. Appearing in Nature Medicine, the work showed how engaging patients directly can yield unexpected findings about an incredibly rare disease that urgently needs new treatment options. Read more about the scientific discoveries and a patient who’s had a unique and inspiring journey living with angiosarcoma.

Monitoring mumps outbreaks

Analyzing viral genomes from an outbreak can show how a virus is evolving and being transmitted — data that can help public health officials slow and stop disease spread. In 2016 and 2017, a surge of mumps cases at Boston-area universities prompted Shirlee Wohl, Hayden Metsky, Stephen Schaffner, Bronwyn MacInnis, institute member Pardis Sabeti, and colleagues to track the virus using genomic data, collaborating with the Massachusetts Department of Public Health and local university health services. The teams shared their findings in real-time during the outbreaks, and now report their conclusions in PLOS Biology. Read more in a Broad news story and coverage in Reuters.

Screening cells without the single cell cloning

Peter DeWeirdt, Annabel Sangree, Ruth Hanna, institute scientist John Doench, and colleagues in the Genetic Perturbation Platform have come up with a method that creates isogenic pairs of cell lines while avoiding single cell cloning — saving time and labor. The team screened these pairs with genome-wide CRISPR-Cas9 libraries to generate genetic interaction maps. Using their method, published in Nature Communications, the scientists identified previously known and new gene interactions with the anti-apoptotic genes BCL2L1 and MCL1, and the DNA damage repair gene PARP1.

How to build a blood vessel

Blood vessel growth, or angiogenesis, supports a variety of important (e.g., wound repair) and harmful (e.g., cancer progression) processes in the body. Little is known, however, about the gene expression programs that vessel-building endothelial cells (ECs) use during angiogenesis. To learn more, associate member Timothy Hla at Boston Children's Hospital and colleagues profiled the transcriptomes and chromatin states of ECs from the mouse retina. Their findings, reported in Developmental Cell, reveal a network of receptors and signals that establish a gradient of JunB transcription factor expression along growing vessels, as well as insights into the molecular mechanisms that drive angiogenesis and ECs' organ-specific adaptations, such as blood-retinal barrier formation.

Written in the stars

To explore how astrocyte heterogeneity contributes to the development of multiple sclerosis (MS), Metabolomics Program associate member Francisco Quintana, Michael Wheeler at Brigham and Women’s Hospital, and others conducted single-cell RNA sequencing in astrocytes from mice with experimental autoimmune encephalomyelitis, a preclinical model of MS. Reporting in Nature, they found a population of astrocytes with reduced NRF2-driven gene expression and increased MAFG and MAT2ɑ signaling, which may contribute to MS pathogenesis. The findings suggest that epigenetic modifiers could be therapeutic targets to suppress dysfunctional astrocytes in MS.

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