Pooled testing in schools, a low-cost COVID diagnostic device, modeling how the human germline mutates, and more
Research Roundup: August 13, 2021
Welcome to the August 13, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Profiles of proliferating persisters
A rare population of cancer cells called cycling persister cells resist drug treatment and maintain the ability to grow and proliferate. Scientists think these cells may contribute to cancer recurrence. Now, postdoctoral researcher Yaara Oren, Joan Brugge (Harvard Medical School), core institute member (on leave) Aviv Regev of the Cell Circuits and Complex Tissues Program, and colleagues have developed a labeling system called Watermelon to track such cells, learn more about their metabolic and RNA profiles, identify new pathways for intervention, and potentially shed light on why some therapeutics that seem promising in the lab fail in the clinic. The results, published in Nature, could help researchers design therapies to delay or ultimately prevent recurrence. Read more in a Broad news story.
Pooled testing passes the feasibility test
Back in February, Broad’s Clinical Research Sequencing Platform (CRSP) began processing pooled COVID-19 tests from students and staff of K-12 schools across Massachusetts. In a recent Journal of Clinical Microbiology paper, Nira Pollock (Boston Children's Hospital), institute scientist Niall Lennon of the Genomics Platform, and colleagues looked back at data from the first three months of testing, during which time CRSP processed nearly 40,000 pools from more than 730 schools. The team concluded that pooled testing with a combination of PCR and rapid antigen testing is achievable at scale. Learn more about how pooled testing works in a Broad news story and video.
Low-cost point-of-care device detects SARS-CoV-2 in saliva
Postdoctoral scholars Helena de Puig and Xiao Tan and institute member Jim Collins in the Infectious Disease and Microbiome Program, and colleagues have developed the CRISPR-based SHERLOCK diagnostic technology into a tabletop device that can detect SARS-CoV-2 in saliva samples and be used at the point of care. The low-cost platform, called minimally instrumented SHERLOCK, extracts, purifies, and concentrates viral RNA, and also amplifies, detects, and provides a fluorescent visual readout within an hour. The system, which includes a smartphone app, has demonstrated accuracy similar to PCR tests, and can be reconfigured for other viruses and variants of concern. Learn more in Science Advances, MIT News, and from the Wyss Institute.
Machine learning predicts potent chaperone peptide
Drugs called antisense phosphorodiamidate morpholino oligomers (PMOs) are remarkably effective for treating Duchenne muscular dystrophy, and work best when combined with molecular chaperones called cell-penetrating peptides (CPPs). By combining experimental chemistry with machine learning, Carly Schissel (MIT), Somesh Mohapatra (MIT), Rafael Gómez-Bombarelli (MIT), associate member Bradley Pentelute of the Chemical Biology and Therapeutics Science Program, and colleagues were able to sift through a massive number of CPP sequences and predict non-toxic, highly-active combinations of CPPs dubbed miniproteins that enhance PMO delivery into muscle cells. Learn more in Nature Chemistry and an MIT News story.
Taking new aim at malaria
A team including Robert Summers, Charisse Flerida Pasaje (MIT), Joao Pisco (University of Dundee), associate member Jacquin Niles of MIT, Beatriz Baragaña (University of Dundee), and Amanda Lukens in the Infectious Disease and Microbiome Program has identified a potential new drug target within the Plasmodium falciparum parasite that causes malaria. The researchers found that two promising compounds from a previous screening effort block the parasite’s acetyl-CoA synthetase enzyme, a target they confirmed through genetic and chemical validation. Appearing in Cell Chemical Biology, their study suggests that these or similar compounds could be new starting points for future malaria drugs. Read more in MIT News.
On gut microbes, urban life, and immunity
Gut microbes can impact the immune system by releasing metabolites and ligands, but the molecular mechanisms by which these effects occur are unclear. To study microbes in a range of populations, Martin Stražar, Mihai Netea, Quirijn de Mast, core institute member Ramnik Xavier of the Infectious Disease and Microbiome Program, and colleagues analyzed stool metagenomes, plasma metabolites, and immune response biomarkers from Tanzanians in rural and urban communities, as well as from a Dutch control group. The team found that microbial composition varied along an urbanization gradient, and that microbes mediated histidine and arginine metabolism, which were associated with immune responses. The results could help researchers design population-specific therapeutic strategies for inflammatory diseases. Read more in Nature Communications.
A model for human germline mutations
Human germline mutations drive both genetic variation and disease, but it’s unclear how they occur. In Science, Vladimir Seplyarskiy, associate member Shamil Sunyaev, and colleagues in the Program in Medical and Population Genetics modeled the mutational processes underlying germline mutations based on the mutation frequency at different regions of the genome. By leveraging the large genetic sequencing database TOPMed, they found nine potential mutational mechanisms that could explain the variation in mutation frequency between loci. They provided biological interpretations for seven of the nine processes, including DNA damage, errors during replication, and a mutagenic process specific to oocytes. This research could help design therapies that prevent harmful, heritable mutations.
Improving epigenetic editing
Artificial transcription factors (aTFs) can be programmed to bind specific regulatory regions of DNA to affect gene expression. However, while genes can be robustly upregulated by targeting aTFs to promoters, activating genes by binding to enhancers has been a challenge. In Nature Methods, a team supervised by Broad associate member Keith Joung shows that gene activation can be achieved more efficiently and reliably by directing aTFs concurrently to both promoters and enhancers. The researchers demonstrate this approach in a variety of contexts, broadening the potential applications of the epigenetic editing toolbox for research and therapeutics. Read more in a tweetorial from Joung.