Research Roundup: February 26, 2021

Keeping tabs on COVID-19 mutations, evolving enzymes for disease treatment, advancing a drug for a rare kidney disease, and more.

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the February 26, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

COVID mutation tracker

Computational associate Albert Chen, postdoctoral fellow Alina Chan, Ben Deverman, director of vector engineering, and colleagues have developed COVID CG, an online tool that allows users to survey the global genetic landscape of the SARS-CoV-2 virus. It pulls together all of the virus’s genome sequences from the GISAID database and lets users detect emerging genetic mutations and viral variants, monitor their prevalence in specific parts of the world and how this changes over time, and identify which variants scientists should test their vaccines and therapeutics against. The team is adding more advanced features and improving the tool’s ability to handle the rapidly growing amount of data. Read more in eLife and a Broad story.

Lab-evolved protein-cutting enzymes eye new targets

Scientists have long sought to use proteases (enzymes that cut specific proteins) as disease treatments, but lacked the technology to adapt them to target proteins of their choosing. Travis Blum, Min Dong (HMS), core institute member and Merkin Institute for Transformative Technologies in Healthcare director David Liu, and colleagues have used a system called PACE, which can rapidly evolve proteins in the lab, to generate botulinum toxin (BoNT) proteases that cut researchers' desired targets and ignore their normal ones. The reprogrammed proteases are highly specific for their new targets (increases between 218- and 11 million-fold) and retain BoNT's special ability to self-deliver into cells. Learn more in Science and a news story from Harvard.

Optimizing designs for pooled testing

In Science Translational Medicine, a team led by Broad Fellow Brian Cleary, James Hay (HSPH), core institute member Aviv Regev (now at Genentech), and associate member Michael Mina presents methods for efficient pooled testing to detect SARS-CoV-2 in the context of substantial resource constraints. Pooled testing is a faster and less expensive diagnostic approach compared to individual testing, but there are tradeoffs in sensitivity, efficiency, and logistics to consider. To find optimal testing protocols, the researchers modeled various scenarios and incorporated data on viral load and an epidemic's progression to maximize the number of infections identified given constrained resources. Read more from the Harvard T.H. Chan School of Public Health.

Early metabolic changes drive squamous cell carcinoma

Many cancer cells promote growth by switching their metabolism from aerobic respiration to glycolysis, a phenomenon known as the Warburg effect. In Nature Metabolism, Jee-Eun Choi (MGH), associate member Raul Mostoslavsky, institute member and Cell Circuits Program co-director Nir Hacohen, and colleagues discovered that this switch is a key driver of squamous cell carcinoma, an aggressive form of head and neck cancer. They also found that these metabolic changes happen early in cancer progression. Using single-cell RNA sequencing, they found that only a subset of tumor promoting cells — cells which give rise to a tumor — were adapted for glycolytic respiration, defining metabolism as another key feature of tumor heterogeneity.

Retracing cells’ pasts to understand blood cancer

Myeloproliferative neoplasms (MPN), a type of chronic blood cancer, arise due to mutations in the JAK2 gene. By sequencing hematopoietic stem cells from newly-diagnosed MPN patients, Debra Van Egeren (HMS), Javier Escabi (HMS), Maximilian Nguyen (HMS), associate member Ann Mullally, Isidro Cortes-Ciriano (EMBL-EBI), associate member Sahand Hormoz, and colleagues deciphered the time interval between appearance of JAK2-V617F, the most common mutation in MPN, and the development of overt cancer. Surprisingly, they found that the mutation occurred decades prior to diagnosis (sometimes in childhood) in patients who presented with MPN in adulthood. Read more in Cell Stem Cell.

Following words and genes across East Asia

A lack of ancient and modern DNA data has stymied efforts to study the deep population history of East Asia. In Nature, an international team led by Chuanchao Wang (Xiamen University and former Broad/HMS postdoc), Johannes Krause (Max Planck Institute for the Science of Human History), Ron Pinhasi (University of Vienna), and associate member David Reich describe their analysis of linguistic data and of genotypes from 166 ancient and 383 modern-day people from the region. They find evidence of four waves of expansion in the area over the last 5,000 years: from Mongolia and the Amur River Basin, the Yellow River Basin, the Yangtze River Valley, and the central Eurasian Steppe.

Brain flame

The brain’s immune response to a traumatic event, such as a stroke, is difficult to study. A team including Michael Askenase (Yale), Brittany Goods, associate member Christopher Love in the Cancer Program and of MIT, institute member Alex Shalek of the Klarman Cell Observatory, and Lauren Sansing (Yale) collected cerebral hemorrhage blood from recovering stroke patients for cellular analysis. Using low-input sequencing technologies to analyze the sparse cells, they observed pathways and genes driving initial inflammation and its resolution, including an unexpected role for cellular metabolism. Described in Science Immunology, the work showed that macrophages with activated glycolysis genes support a successful stroke response. Read more in a Ragon Institute news story.

Scaling synthesis of a potential kidney disease drug candidate 

BRD4780, in Broad’s Drug Repurposing Hub, was identified by institute member Anna Greka’s lab as a small-molecule compound capable of clearing mutant, misfolded version of the protein Mucin 1, associated with MUC1 kidney disease (MKD) in both cell line and mouse model studies. BRD4780 was able to exert similar effects in other toxic proteinopathies with misfolded protein accumulation. Research scientist and group leader Brian Chamberlain of the Center for the Development of Therapeutics (CDoT), institute scientist and CDoT’s director of medicinal chemistry Florence Wagner, and colleagues have developed an approach to synthesize the individual enantiomers of BRD4780 on a multigram scale. Their work, published in the Journal of Organic Chemistry, will enable further study of the pharmacology of BRD4780 and related compounds as the team works to identify a treatment for MKD.

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