Research Roundup: April 17, 2020

How brain tumors escape therapy, antibiotic resistance on the move, guidance for CRISPR guides, and more

Erik Jacobs
Credit: Erik Jacobs

Welcome to the April 17, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Travelers’ gut check

International travelers may pick up drug-resistant bacteria in the gut while abroad, contributing to the global spread of these organisms. A team including computational scientist Colin Worby, institute scientist Ashlee Earl, and affiliate member Regina LaRocque in the Infectious Disease and Microbiome Program (IDMP) collected stool samples from 412 U.S. travelers before and after venturing abroad, mostly to India, South Africa, and Peru. Reporting in New England Journal of Medicine, the scientists identified 22 travelers who acquired bacteria resistant to antibiotics of “last resort,” including two carbapenemase-producing carbapenem-resistant Enterobacterales and 20 mcr-mediated colistin-resistant Enterobacterales. Their analysis demonstrates how travel contributes to the spread of bacteria with antibiotic resistance, including their diverse mobilizable resistance genes.

Blight in shining armor

Single genetic mutations that alter the protective capsules of drug-resistant Klebsiella pneumoniae bacteria arise often and make the microbes more pathogenic, according to new work led by institute member and IDMP co-director Deborah Hung and postdoctoral scholar Christoph Ernst. In Nature Medicine, they report that some mutations strengthen the bacterium’s protective capsule and allow it to spread easily to other organs, while others disrupt the capsule and help the microbe to hide out and thrive within the patient’s cells. Read more in a Broad news story to learn why these drug-resistant bacteria may be more dangerous than previously known.

Mutation-heavy brain tumors resist immunotherapies

Brain tumors called gliomas are sometimes "hypermutated," suggesting that they should be vulnerable to immunotherapies (which usually work well against heavily-mutated cancers). Mehdi Touat, Yvonne Li, and associate members Rameen Beroukhim and Mimi Bandopadhayay and affiliate member Keith Ligon in the Broad Cancer Program; and Franck Bielle (Sorbonne University) and others, studied the mutation patterns and clinical outcomes of more than 10,000 gliomas. They report in Nature that hypermutated gliomas tend to shrug off immunotherapy, and that treatment with the drug temozolomide can actually increase gliomas' mutational load. Learn more in a Dana-Farber press release.

Cas13 spots signs of danger in organ transplant patient samples

Organ transplant patients have to take immunosuppressive drugs to reduce the risk of organ rejection, but that makes them susceptible to infection. Institute member James Collins and his colleagues have designed a rapid and inexpensive assay that uses CRISPR-Cas13 to detect the presence of BK polyomavirus DNA and cytomegalovirus DNA from patient-derived blood and urine samples. The team could also detect high levels of CXCL9 messenger RNA (a marker of graft rejection) in urine samples from patients experiencing acute kidney transplant rejection. The assay could be developed for point-of-care use to monitor patients post-transplantation. Learn more in Nature Biomedical Engineering.

The best tool for the job

Numerous software tools and analytical methods have been developed for the design and analysis of CRISPR–Cas experiments, enabling rapid and flexible manipulation of genomes. In Nature Biotechnology, Ruth Hanna and institute scientist John Doench in the Genetic Perturbation Platform discuss software tools that enable the design and selection of guide RNAs, focused analysis of the results of CRISPR editing and knockout experiments, and large-scale analysis of data from pooled genetic screens. Their guide aims to empower both new and experienced users of CRISPR-Cas technologies to select and critically evaluate available and emerging tools for different experimental approaches.

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