Exploring diseases' sex differences, new uses for old drugs in treating COVID-19, a new perspective on brain tumor cells, and more
Research Roundup: May 15, 2020
Welcome to the May 15, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Combing through old drugs to find new ones for COVID-19
The Broad’s Center for the Development of Therapeutics (CDoT) is making copies of its Drug Repurposing Hub — a collection of nearly 7,000 compounds that are either FDA-approved or proven safe in clinical trials — and sharing them with collaborators in Boston and around the world to help them hunt for existing compounds that might prove effective against COVID-19. Institute scientist Florence Wagner, director of medicinal chemistry in CDoT and the Stanley Center for Psychiatric Research spoke to the Broadminded Blog about how she and her team at CDoT are working with other research groups on both near- and long-term projects.
C4 in sex-biased disease risk
In Nature, a team led by Nolan Kamitaki, institute member Steve McCarroll, and Timothy Vyse (King's College London), including many colleagues from the Stanley Center, explored disease-related variation between men and women in the genes C4A and C4B. The team showed that genetic variants that increased risk for schizophrenia were, at the same time, highly protective against the autoimmune conditions lupus and Sjögren’s syndrome. The effects were particularly pronounced in men — and potentially explain why females develop lupus and Sjögren’s syndrome more often than males, and vice versa for schizophrenia. Read more in a news story from HMS and coverage in STAT.
A gut-brain connection underpinning ALS?
Not everyone who carries the mutation most commonly seen in amyotrophic lateral sclerosis (ALS) — a variant in the gene C9orf72 — goes on to develop symptoms of the disease. After rearing C9orf72-mutant mice in two different facilities, Aaron Burberry, institute member Kevin Eggan in the Stanley Center, and colleagues noticed that mice with a pro-inflammatory gut microbiome developed ALS symptoms; those with anti-inflammatory gut bugs did not. Antibiotics and fecal transplants both reduced inflammation in mutant mice carrying pro-inflammatory microbiomes, suggesting a gut-brain link behind C9orf72's relationship with ALS. Learn more in Nature and a story from the Harvard Department of Stem Cell and Regenerative Biology.
Supreme stature gene
With an analysis of samples from ethnically diverse Peruvians, a population known to have one of the shortest statures in the world, a team led by institute member Soumya Raychaudhuri and postdoctoral scholar Samira Asgari in the Program in Medical and Population Genetics discovered the single largest genetic contributor to height known to date. In Nature, the scientists describe a previously unknown, population-specific variant of the FBN1 gene found only in people of Native American ancestry and strongly associated with lower height. The work highlights the advantage of a diverse, worldwide strategy to understand complex traits like height. Read more in a Harvard Medical School news story.
Tracing lineage history of cells in combination with analyzing single-cell gene expression levels can help answer many questions in biology. Reporting in Cell, associate member Sahand Hormoz of the Cell Circuits Program and colleagues describe a CRISPR array repair lineage tracing (CARLIN) mouse line. This mouse model is engineered to generate inducible, heritable, and transcribed barcodes in individual cells, and works across all embryonic and adult mouse tissues. The researchers have also developed the analysis tools and reference datasets required to interpret the detected barcodes and quantify their statistical significance. The CARLIN system enables researchers to simultaneously study lineage and transcriptomic profiles of single cells and will help uncover many aspects of developmental biology.
Dwell on cells
Cancer stem cells in gliomas have been inconsistently defined due to tumor heterogeneity and assay limitations, creating barriers for the field. In a perspective piece in Cancer Cell, institute member Mario Suvà in the Epigenomics Program and visiting scientist Itay Tirosh in the Regev Lab revisit the glioma stem cell model, considering new findings from single-cell expression profiling studies. They describe various classes of gliomas with different cellular architectures, and propose a set of definitions informed by the single-cell data that better describe the cellular architecture of gliomas. They further suggest a potential therapeutic approach aimed at inducing stem cells to differentiate into an astrocyte-like state.
Activating activin-A in multiple sclerosis
In multiple sclerosis (MS), Th17 cells are known drivers of inflammation and demyelination, but the factors controlling their impact are not well understood. A team led by associate member Francisco Quintana and colleagues from the Biomedical Research Foundation of the Academy of Athens now reports that administering the cytokine activin-A ameliorated disease severity in a mouse model of MS is associated with decreased activation of these Th17 cells. When the researchers investigated the underlying mechanisms, they discovered that activin-A signaling represses pathogenic transcriptional programs in Th17 cells while boosting anti-inflammatory gene modules. Read more about their findings in Proceedings of the National Academy of Sciences.
Developing an RNA-seq toolbox
Single-cell and single-nucleus RNA-Seq, using fresh and frozen tissue samples, is an essential tool for understanding cancer. In Nature Medicine, a team led by Michal Slyper, Caroline Porter, Orr Ashenberg, institute scientist Orit Rozenblatt-Rosen, and core institute member and Klarman Cell Observatory director Aviv Regev provides guidelines for selecting appropriate protocols for profiling tumor tissues, depending on the sample characteristics and scientific questions being pursued. The researchers evaluated and compared a variety of protocols, examining cell and nucleus quality, recovery rate, and cellular composition for each. Their toolbox will help researchers systematically profile additional human tumors, paving the way for charting atlases of human tumors and other tissues in health and disease.
Cancer molecular markers linked to genetic ancestry
Postdoctoral fellow Jian Carrot-Zhang, graduate student Ashton Berger, Cancer Program group leader Andrew Cherniack, associate member Rameen Beroukhim, and their colleagues provide the most comprehensive look to date at the effect of ancestry on the molecular makeup of normal and cancerous tissues. Drawing on data from The Cancer Genome Atlas (TCGA) involving 10,678 patients and 33 cancer types, the investigators found that ancestry was tied to variations in hundreds of genes, but that the most important of these differences were linked to specific tissue types. This suggests that tracking the molecular effects of ancestry — both in normal tissue and in cancer tissue — needs to take a tissue-by-tissue approach. Learn more in Cancer Cell.