New COVID diagnostics, relapse roots in CLL, delving into ferroptosis, and more
Welcome to the September 18, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Advancing COVID-19 diagnostics
Julia Joung, Alim Ladha, MIT McGovern Fellows Omar Abudayyeh and Jonathan Gootenberg, core institute member Feng Zhang, and collaborators have been developing a CRISPR-based diagnostic for COVID-19 that can produce results in 30 minutes to an hour. The test, known as STOPCovid, could in principle be made cheaply enough to enable daily testing. In New England Journal of Medicine, the researchers describe new advances in their protocol and reveal that STOPCovid correctly detected 93 percent of known positive COVID-19 cases in a set of 402 patient samples. Read more in an MIT news story.
Treatment resistance in chronic lymphocytic leukemia
Transplanting blood stem cells from a healthy donor can cure chronic lymphocytic leukemia patients, but some still experience recurrence. Postdoc Pavan Bachireddy, institute member Catherine Wu in the Cancer Program, and colleagues explored the mechanisms behind such post-transplant relapses through genetic, transcriptomic, and epigenetic analysis of cancer cells from 10 patients. They found two distinct patterns among these patients: early relapse, caused by preexisting resistance already present within the patients' cells; and late relapse, driven by rapid changes in surviving cancer cell populations. Learn more in Science Translational Medicine and a tweetorial from Bachireddy.
Signals in a tumor's microenvironment can suppress the body’s own anti-tumor immune response. Using single-cell RNA sequencing, postdoctoral scholars Nandini Acharya and Asaf Madi, core member (on leave) Aviv Regev, institute member Vijay Kuchroo, and institute member Ana Anderson in the Klarman Cell Observatory and colleagues discovered in preclinical models and melanoma patients who did not respond to checkpoint blockade therapy that increased glucocorticoid signaling leads to dysfunctional, “exhausted” CD8+ lymphocytes. Appearing in Immunity, the work suggests that glucocorticoid inhibitors may help patients respond to checkpoint blockade therapy.
Bacteria can regulate immune responses by controlling the length of polysaccharide chains on their surface. However, the impact of chain length on bacterial physiology and antibiotic susceptibility has been unclear. By studying shortened galactan chains (a kind of polysaccharide chain) in mycobacteria, institute member Laura Kiessling of the Infectious Disease and Microbiome Program (IDMP) and collaborators found that cutting chain length by approximately half influences bacterial physiology and several cellular attributes, including cell permeability, morphology, resistance to environmental stress, and antibiotic susceptibility. Learn more in Science Advances.
How do cells become susceptible to ferroptosis, an iron-dependent form of cell death? A team led by postdoctoral researchers Yilong Zou, Whitney Henry, and Emily Ricq, along with associated faculty member Robert Weinberg of the Whitehead Institute and core member Stuart Schreiber of the Chemical Biology and Therapeutics Science Program, used genome-wide CRISPR-Cas9 screening to discover that the oxidative organelles peroxisomes contribute to ferroptosis sensitivity in human cancer cells. Using lipidomic profiling, they found that peroxisomes synthesize ether lipids that act as substrates for lipid peroxidation, which induces ferroptosis. Reporting in Nature, they show that cancer cells with reduced ether lipids can switch to a ferroptosis-resistant state, and that ether lipids drive ferroptosis in other non-cancer cell types.
Grokking the non-coding genome in cancer
To understand the mechanisms behind tumor development, researchers need an accurate picture of what's going on in both the coding and non-coding genome. In a review in Nature Cancer, Xiaoyang Zhang (U. Utah) and institute member Matthew Meyerson of the Cancer Program explore what's known about cancer-related non-coding variants, review methods studying such variants, and discuss the outlook for targeting them therapeutically.
Managing chronic kidney disease with diet
Researchers have not fully explored the mechanistic roles of diet-microbiota interactions in chronic kidney disease (CKD) progression and treatment. Dietary proteins increase hydrogen sulfide (which affects a variety of physiologic functions) and uremic toxin production by gut bacteria. Associate member Wendy Garrett of the IDMP, Lior Lobel, and colleagues found that a diet high in sulfur-containing amino acids altered the activity of a key microbial enzyme, tryptophanase, reducing uremic toxin production and slowing CKD progression in mice. Reporting in Science, the researchers conclude that diet is a crucial aspect in managing CKD.