Research Roundup: January 29, 2021

Ribosome engineering, expansion sequencing, aneuploidy analysis, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the January 29, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Recipe for engineering ribosomes

Natalie Kolber, Broad Fellow Ahmed Badran, and colleagues have developed a high-throughput method for building ribosomes that uses parts from different microbes, and measures and optimizes the ribosomes’ ability to catalyze protein production. The team showed the successful insertion of more than 30 different ribosomes into E. coli. Because antibiotics typically target ribosomes in various bacteria, the new method could be a way to rapidly test new antibiotics that target only the ribosomes of specific human pathogens, and provides new tools for synthetic biology. Read more in Nature Communications and a Broad story.

Expanding and sequencing cells to learn how they work

To understand which genes control different parts of a cell, researchers would need to sequence RNAs from different spatial compartments. However, current methods don’t have the necessary resolution to identify mRNAs in specific cellular areas. Shahar Alon (MIT), Daniel Goodwin (MIT), Anubhav Sinha (MIT), Asmamaw Wassie (MIT), core institute member Fei Chen, senior associate member George Church, Adam Marblestone (MIT), associate member Edward Boyden, and colleagues have solved this problem with expansion sequencing. This method sequences RNAs directly within cells stretched with an expandable gel matrix, which spreads transcripts apart while maintaining their relative positions. The improved resolution shows scientists how gene expression differs across a single cell, or between different interacting cell types. Read more in Science and an MIT story.

Gut reaction

Associate member Francisco Quintana of the Immunology Program and Brigham and Women’s Hospital (BWH), Liliana Sanmarco (BWH), Michael Wheeler, and others used refined gene- and protein-analysis tools to identify a novel subset of astrocytes in the brain. Expressing the proteins LAMP1 and TRAIL, these astrocytes limit inflammation in the central nervous system by inducing cell death in pro-inflammatory T-cells. They found that microbes in the gut modulate expression of interferon-gamma in natural killer cells, which regulates astrocytes' TRAIL expression. The study shows how the gut can control central nervous system inflammation, and suggests that probiotics could regulate the astrocytes’ anti-inflammatory activity. Read more in Nature and a Brigham and Women’s Hospital news story.

Up in arms

Aneuploidy (the presence of extra or missing chromosome arms) in cancer cells represents an untapped therapeutic opportunity. Yael Cohen-Sharir (Tel Aviv University), associate director of cancer data science James McFarland, Broad director Todd Golub, visiting scientist Uri Ben-David, and others in the Golub lab mapped the aneuploidy landscapes of nearly 1,000 human cancer cell lines and analyzed genetic and chemical perturbation screens to identify vulnerabilities. Aneuploid cells showed increased sensitivity to mitotic checkpoint inhibition, which the cells can overcome at the cost of reduced viability and proliferation. The researchers identified a mitotic kinesin with perturbed activity in aneuploid cancer cells that, when overexpressed, restored the cells’ sensitivity to mitotic checkpoint inhibition. Read more in Nature.

SCAR removal

CRISPR-Cas9 genome engineering has been a boon to cancer biology and immunology studies. However, CRISPR system components can be immunogenic, limiting engineered cells' use in in vivo models. Juan Dubrot, Sarah Kate Lane-Reticker, Kathleen Yates, Robert Manguso, and colleagues in the Cancer Program's Tumor Immunotherapy Discovery Engine team and the Genetic Perturbation Platform profiled the immune responses against CRISPR components, including Cas9, and developed an approach called SCAR that removes CRISPR-related antigens from engineered tumor cells. SCAR prevents immune responses against engineered cells, opening up new opportunities for running high-throughput genetic tumor screens in in vivo models. Learn more in Immunity.

Closer look at immune defense 

One of the major limitations in fully understanding the associations of human leukocyte antigen (HLA) and T cell receptor (TCR) genes with disease physiology is identifying which HLA molecules, peptides, and TCRs form functional protein complexes. Mark Lee and institute member Matthew Meyerson of the Cancer Program have developed a high-throughput screening method to identify specific parts of an antigen, called epitopes, recognized by a T cell receptor of interest to provide immune defense. Their epitope-discovery platform will enable more efficient identification of HLA-epitope-TCR complexes relevant to the cause, control, or treatment of disease. Learn more in Science Immunology.

Single-cell view of synovial sarcoma 

Synovial sarcoma (SyS), a rare but highly aggressive soft tissue cancer, is known to evade immune infiltration through unknown mechanisms. Livnat Jerby-Arnon, Cyril Neftel, Hannah Weisman, institute member Mario Suvà of the Epigenomics Program and the Klarman Cell Observatory, Nicolò Riggi (MGH), Aviv Regev (Genentech), and colleagues used single-cell RNA-sequencing profiling of patient samples, spatial transcriptomics, and functional approaches to define the molecular underpinnings of SyS, highlighting new mechanisms involved in modulating its anti-tumoral immune response. The team was also able to block the malignant cellular state of SyS with a combination of HDAC and CDK4/6 inhibitors, thus suggesting potential therapeutic strategies for SyS management. Learn more in Nature Medicine.

Understanding ELANE-mutant neutropenia

Severe congenital neutropenia (SCN) is a life-threatening disorder most often caused by dominant mutations in the gene ELANE. These mutations interfere with the maturation of neutrophils, a type of white blood cell. To better understand the molecular mechanisms of this disease, a team led by associate member Daniel Bauer and colleagues conducted a pooled CRISPR screen in human hematopoietic stem cells dissecting ELANE mutations. The researchers identified a variety of gene edits that both promote and impede neutrophil cell maturation, and explored potential therapeutic approaches for SCN. Read the full story in Cell Stem Cell.

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