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Welcome to the May 22, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Ó³»­´«Ã½ and their collaborators.

Cas9 doesn’t need a guide to cut DNA 

Oana Enache, Veronica Rendo (DFCI), Cancer Program associate member Rameen Beroukhim, core member and Cancer Program director Todd Golub, Uri Ben-David (now at Tel Aviv University) and their colleagues show in that Cas9 can cut DNA even without any guide RNA. Moreover, Cas9, when introduced into cell lines, ultimately favored the growth of cells with mutations in the p53 gene — the same mutations found in many cancers. The team found that when they introduced Cas9 into 165 cell lines, a high fraction had activation of the p53 pathway. In a smaller subset of these cell lines, the researchers found mutations that inactivated p53. The authors suggest that researchers can modify their genome editing pipeline to avoid or mitigate these off-target effects. Read more in a Q&A with Uri on the Ó³»­´«Ã½ site.

EKG points to genetic markers for arrhythmias 

Cardiovascular Disease Initiative (CVDi) associate member Steven Lubitz at MGH and his colleagues conducted a GWAS in search of genetic markers for arrhythmias. They looked at abnormalities in the PR interval, a measurement on the electrocardiogram (EKG) that reflects atrioventricular conduction and is associated with a number of common electrical disorders such as atrial fibrillation and bradyarrhythmias. By studying a cohort of 293,051 people, the researchers found 202 genomic locations underlying cardiac conduction — 141 of which had not been previously identified. The loci collectively explain about 62 percent of heritability of this trait. Read more in and in a Ó³»­´«Ã½ story.

No stretch of the imagination

Fusing tissue with hydrogel creates a hybrid that enables the fine-structural and molecular phenotyping of intact biological systems, but the hybrids face issues with permeability and stability. A team led by Taeyun Ku (MIT) and associate member Kwanghun Chung of the Regev lab and MIT has created a technology known as entangled link-augmented stretchable tissue-hydrogel (ELAST), which elasticizes tissues into hydrogels that offer structural stability while enabling fast transport of molecular probes. Described in , the method allows tissue to be stretched or compressed without mechanical damage, and may enhance the study of tissues from animal models and clinical human samples. 

Therapeutic insights for Fragile X syndrome

Fragile X syndrome (FXS) is a heritable cause of autism and intellectual disability. The enzyme GSK3, which has two isoforms GSK3α and GSK3β, is known to be implicated in many diseases including neurological diseases. Previous research has shown that selective inhibitors of GSK3 may have the potential to treat FXS in mouse models but also cause toxicities. Director of medicinal chemistry in the Stanley Center for Psychiatric Research and the Center for the Development of Therapeutics (CDoT) Florence Wagner and collaborators report in  that major toxicity can be avoided by selective pharmacological inhibition of GSK3α. The authors also report that inhibition of GSK3α was sufficient to correct a range of disease phenotypes in a mouse model of FXS, whereas inhibition of GSK3β was ineffective.

How EBV evades the immune system

Once the Epstein-Barr virus (EBV) infects someone, it persists in the body for the rest of that person's life, and is associated with 200,000 human cancers annually. For the virus to evade the immune system in lifelong infection, many of its genes must be silenced. A team led by Rui Guo and associate member Ben Gewurz at Brigham and Women's, including colleagues from the Genetic Perturbation Platform, conducted CRISPR-Cas9 knockout screening of EBV in Burkitt’s lymphoma cells to identify the cellular factors involved in this gene silencing. Their results point toward potential therapeutic targets to manipulate the virus. Read the full story in .

Nothing left to lose

In cancer cells, many genes lose one of their two parental alleles through a phenomenon called loss of heterozygosity (LOH). In , Caitlin Nichols, Brenton Paolella, Beroukhim, and colleagues report that essential genes (e.g., ones that generate energy or eliminate waste), which aren't generally considered cancer vulnerabilities, could be turned into powerful therapeutic targets by exploiting LOH. Methods that interfere with essential gene alleles that remain after LOH, they write, can play havoc with cancer cells while leaving normal cells alone. Learn more in a story from Dana-Farber. 

Researchers study single cells to ask why children generally fare better against COVID-19 

In a #WhyIScience Q&A, Klarman Cell Observatory institute member Alex Shalek and associate member Jose Ordovas-Montanes at Boston Children's Hospital talk about a new study on COVID-19 disease in children, which is being done in collaboration with clinicians at Boston Children’s Hospital and scientists at the Ó³»­´«Ã½ as part of the Human Cell Atlas initiative. They also talk about how their approach to research, and the field of single-cell genomics, have changed in the age of COVID.

To learn more about research conducted at the Ó³»­´«Ã½, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.