Mapping the gut's nervous system, tracing blood's genetic circuitry, connecting variants and expression, and more
Research Roundup: September 11, 2020
Welcome to the September 11, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Fresh findings from GTEx
For 10 years, the Genotype-Tissue Expression (GTEx) Consortium, led at Broad by Kristin Ardlie in the Program in Medical and Population Genetics (MPG) and François Aguet in the Cancer Program, has been working to map the relationships between genetic variants (termed quantitative trait loci, or QTLs) and gene expression in tissues throughout the body. In a set of 15 papers in Science and other journals, GTEx scientists released their most comprehensive catalog to date of QTLs and the genes they impact. Read a Broad news story and a news piece in Science to learn about the work of GTEx, how cell type influences QTLs' impact, and how the effects of multiple QTLs come together to tune any given gene's expression.
A web of connections
The enteric nervous system (ENS), an extensive array of neurons in the gastrointestinal system, coordinates nearly all activities involved in digestion, gut motility, and response to noxious stimuli. In Cell, a team led by Eugene Drokhlyansky, Christopher Smillie, Nicholas Van Wittenberghe, institute scientist and Klarman Cell Observatory scientific director Orit Rozenblatt-Rosen, core institute member Ramnik Xavier of the Infectious Disease and Microbiome Program (IDMP), and Aviv Regev describes a single-cell map of the ENS in humans and mice. The findings suggest that the ENS plays an important role in allergic, inflammatory, and motility disorders of the gut, as well as diseases affecting the brain. Studying related neuro-immune interactions is also the next phase of the Food Allergy Science Initiative. Read more in a Broad news story.
Blood circuit schematic
Blood development, or hematopoiesis, is a complex, highly regulated process. In a study published in Cell, a large international collaboration lead at Broad by Erik Bao, Caleb Lareau (now at Stanford), and MPG associate member Vijay Sankaran traced the genetic circuitry behind hematopoiesis, mapping more than 7,000 regions of the genome that control 29 blood cell traits. The study also reveals how these genetic variants in aggregate can influence a person's likelihood of developing a blood disease together with rare variants. Learn more in a news story.
A mobile app teaches students about pandemic response
Andrés Colubri, Molly Kemball, institute member Pardis Sabeti of the Infectious Disease and Microbiome Program, and their collaborators developed Operation Outbreak, a Bluetooth-based simulation app intended to teach high school and college students about pandemic response. The app is designed to simulate outbreaks and record data about real human behavior that can help inform epidemiological models in the future. The authors are also developing a free, open-source curriculum, including a textbook and series of educational videos. Learn more in Cell and this press release.
Checking in on checkpoint inhibitors
Immune checkpoint blockade, a revolutionary form of cancer treatment, doesn’t work for all patients. A team led by Ivy Chen of Massachusetts General Hospital and Harvard Medical School (HMS); associate member Meromit Singer in the Cell Circuits Program and of HMS and Dana-Farber Cancer Institute; institute member Arlene Sharpe in the Immunology Program and of HMS; and associate member Rakesh Jain in the Cancer Program and of Mass General and HMS introduced an approach to studying the tumor microenvironment before or shortly after treatment, using bilateral tumor implantation in a mouse cancer model coupled with anti-PD-1 therapy. The approach identified biomarkers for response or resistance at early time points, with gene signatures segregating by survival and patient response. The approach could help guide the use of combination therapy to boost the efficacy of immune checkpoint blockade therapy. Read more in PNAS.
Antibiotic combinations that nab persistent bugs
Bacterial persisters have repressed metabolism and resist most antibiotics. In many cases, antibiotics that are effective against persisters are also toxic to human cells. Graduate student Erica Zheng, postdoctoral scholar Jonathan Stokes, and institute member James Collins of the IDMP studied the metabolic dependencies of various classes of bactericidal antibiotics and designed combinations that can sterilize both metabolically active and persister cells, while minimizing the antibiotic concentrations required. These combinations could lead to better treatments for chronic and recurrent infections. Read more in Cell Chemical Biology.