Marathon microbes, a plant gene probe, catching cancer passengers, and more.
By Broad Communications
Credit: Kelly Davidson
Welcome to the June 28, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Microbes may give marathoners a boost
A gut microbe isolated from marathon runners significantly increases endurance in mice. Jacob Luber, senior associate member George Church, Julian Avila-Pacheco, institute scientist and Metabolomics Program senior director Clary Clish, and colleagues noticed a greater amount of Veillonella in stool samples taken from Boston Marathon participants and other elite athletes after exercise. They inoculated mice with the strain Veillonella atypica and demonstrated that the microbes increased mouse treadmill endurance times about 13 percent by using lactate produced by exercise to create a short-chain fatty acid called propionate, which can act as an energy source and anti-inflammatory. Read the full study in Nature Medicine, and check out coverage from The New York Times, NPR, and STAT.
Analyzing checkpoint inhibitor resistance
A study in this week’s Cancer Immunology Research recounted the case of a colorectal cancer patient whose tumor was resistant to immune checkpoint blockers despite having high microsatellite instability, a feature that typically predicts response to immunotherapy. Coming together from the Broad Cancer Program and the Klarman Cell Observatory, Carino Gurjao, David Liu, Matan Hofree, institute scientist Orit Rozenblatt-Rosen, associate member Eliezer Van Allen, Steven Corsello, core institute member Aviv Regev, and associate member Marios Giannakis, together with colleagues at Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute, profiled a pre-treatment biopsy, finding that the tumor's cells displayed very little antigen and that its microenvironment was dominated by natural killer cells and M2 macrophages. The results have implications for novel immunotherapies in colorectal cancer.
A scaled-up look at chromatin accessibility
In Nature Biotechnology, a team led by Caleb Lareau, Fabiana Duarte, associate member Jason Buenrostro, and colleagues presents an improved platform for studying the epigenome in single cells. The technology combines microfluidics and novel software to scale up single-cell ATAC-seq (Assay for Transposase-Accessible Chromatin), which identifies parts of the genome that are open and accessible to regulatory proteins. In their report, the team used the new platform to profile 510,123 cells from the adult mouse brain and human bone marrow, demonstrating the scalability and flexibility of the new droplet-based platform. Read more in a press release from Harvard University.
Open to interpretation
In the American Journal of Human Genetics, institute member Heidi Rehm of the Program in Medical and Population Genetics, Kalotina Machini at BWH, and colleagues describe results of their MedSeq Project, aimed at improving interpretation of genomic sequencing results through a robust workflow. They identified clinically significant findings by analyzing over 5,000 genes spanning monogenic disease risk, carrier status, pharmacogenomics findings, rare blood antigens, and complex-trait risk analysis in 100 people, with or without cardiomyopathy. Monogenic disease risk and carrier status were reported in 21 percent and 94 percent of participants, respectively, and an explanation for disease was found in 48 percent of individuals with cardiomyopathy. In addition, re-analysis within two years uncovered new or updated results for 22 percent of patients.
An enzyme with a taste for hairpins
By analyzing cancer genomes at the “mesoscale” — between the small scale of trinucleotides and the large scale of multi-megabase chromatin domains — a team led by the Cancer Program's Michael Lawrence, associate member Lee Zou at Massachusetts General Hospital, and Remi Buisson (now at UC Irvine) combined computational and experimental biology to study DNA damage in cancer. They found that the APOBEC3A enzyme preferentially mutates hairpin structures in single-stranded DNA, giving rise to “passenger hotspot mutations” in genes unconnected to cancer. The work shows that some recurrently mutated sites may reflect an enzyme’s substrate preference rather than an effect on tumor fitness, and that not all mutational hotspots represent driver mutations. Read more in Science or in this MGH press release.
SHERLOCK on the farm
Omar Abudayyeh, Jonathan Gootenberg, Max Kellner, and core institute member Feng Zhang have tailored the portable, paper strip-based SHERLOCK detection platform for use in plants. In The CRISPR Journal, the team showed that SHERLOCK could readily identify insecticide resistance strains with minimal sample processing, and detect multiple soybean genes at the same time.
A new DNA-encoded library
DNA-encoded libraries, in which small molecules are labeled by unique DNA sequences, have transformed screening experiments and the study of protein biology. However, the size and structural diversity of these collections is limited by chemistry that is DNA-compatible. Christopher Gerry, Mathias Wawer, institute scientist Paul Clemons, and core institute member Stuart Schreiber (all in the Chemical Biology and Therapeutics Science Program) have now developed a new synthesis pathway that can create more diverse compounds in DNA-encoded libraries. The team describes the design, synthesis, structural analysis, and test screening of a new library, called DOS-DEL-1, that includes 107,616 unique compounds with traditionally under-represented chemical features. Learn more in Journal of the American Chemical Society.
