Research Roundup: November 6, 2020

Welcome to the November 6, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Turn on the heat

Brown fat cells help generate body heat using triglycerides stored in lipid droplets as energy, but it’s unclear whether those lipids are required. Lead author Chandramohan Chitraju (Harvard), Alexander Fischer (Harvard), and associate members Robert Farese and Tobias Walther of the Metabolism Program and of Harvard Medical School and Harvard School of Public Health generated mice lacking triglycerides in brown adipose tissue by deleting enzymes that synthesize the lipids. Described in Cell Reports, the work showed that brown fat tissue is functional without triglycerides and that the triglyceride-lacking mice were able to maintain body temperature in the cold. The brown fat cells in these mice instead used circulating glucose and fatty acids and stored glycogen to fuel thermogenesis.

Pancreatic cancer dependency screen

Pancreatic ductal adenocarcinoma relies on altered metabolic pathways that help the cancer cells survive in a nutrient-poor microenvironment. Associate member Andrew Aguirre of Dana-Farber Institute and the Cancer Program, along with Douglas Biancur and Alec Kimmelman (NYU Medical Center), used CRISPR/Cas9 screening to map the metabolic dependencies of pancreatic cancer in vitro and in vivo. While vulnerabilities of cells in vitro and in vivo were largely similar, the screen revealed targetable metabolic liabilities and important limitations of cell culture model systems. The work demonstrates that genetic screening can help define in vivo dependencies that could have therapeutic potential. Read more in Cell Metabolism (paywall).

Where the parasites are

Plasmodium vivax is the predominant human malarial parasite in the Americas, but little has been done to use genomics to map the parasite's local and regional transmission patterns in endemic regions. Writing in PLOS Neglected Tropical Diseases, Angela Early and associate member Daniel Neafsey of the Infectious Disease and Microbiome Program (IDMP) and Genomic Center for Infectious Diseases, together with Marcelo Ferreira (University of São Paulo) and collaborators, report a study of more than P. vivax isolates from malarial hotspots in Brazil and Peru using whole genome sequencing. They noted a number of highly related but distinct P. vivax lineages circulating in the region and pinpointed high-priority parasite populations for targeted malaria control efforts.

Genetic clues for Crohn’s disease 

A missense variant A391T in the SLC39A8 gene is a risk allele for multiple conditions, including cardiovascular disease, schizophrenia, Parkinson’s disease, and Crohn’s disease (a form of inflammatory bowel disease, or IBD). Toru Nakata, senior group leader Daniel Graham, core institute member and IDMP co-director Ramnik Xavier, and colleagues generated a SLC39A8 A391T mouse model to study how it impacts such a variety of tissues. The mice exhibited severe manganese deficiency in the colon associated with impaired intestinal barrier function, thus sensitizing the mice to intestinal inflammation. The findings, reported in PNAS, suggest a tissue-specific mechanism by which this allele increases susceptibility to IBD and potentially other diseases.

Single-cell view of Ebola’s lethal maneuvers 

The first ever study to sequence single cells infected with a BSL-4 level pathogen has revealed new details of how the Ebola virus alters the host’s immune response for its own benefit during infection. Aaron Lin, Dylan Kotliar, and colleagues adapted a portable, low-cost single cell RNA sequencing approach called Seq-Well for use in a BSL-4 lab at the National Institutes of Health, and identified both antiviral defense genes that the virus suppresses and pro-viral genes the virus activates. During infection, conventional monocytes were replaced by ones with impaired class II antigen presentation, and interferon production decreased. Read more in Cell and a Broad story.

To learn more about research conducted at the Broad, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.