Evaluating drug safety, opening up ovarian cancer, biomarker for prion disease, and more
By Broad Communications
June 26, 2020
Credit: Erik Jacobs
Welcome to the June 26, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A secret to low blood cholesterol
Doug Kenny, Damian Plichta, institute member Emily Balskus, core institute member Ramnik Xavier of the Infectious Disease and Microbiome Program, and their colleagues have found gut bacteria that can metabolize enough cholesterol to potentially affect people’s cardiac health. The researchers sequenced nearly six million microbial genes from the microbiomes of 3,097 people, and looked for bacterial genes that resembled those encoding enzymes that perform similar functions to cholesterol metabolism and that were present only in people who excreted a cholesterol breakdown product called coprostanol. They homed in on a gene they named Intestinal Sterol Metabolism A (ismA) that could metabolize cholesterol. People with the ismA gene had lower blood cholesterol levels than those without any copies of the ismA genes in their microbiomes. Read more in Cell Host & Microbe and a Broad news story.
Finding the BEst base editor
In Cell, Mandana Arbab, Max Shen, core institute member and Merkin Institute of Transformative Technologies director David Liu, and colleagues describe a new tool to identify which base editors are most likely to achieve desired genetic edits. By analyzing experimental data on the single-letter edits made by 11 of the most popular base editors at more than 38,000 target DNA sites, the researchers created a machine learning model that accurately predicts which changes each of the base editors will make — and also revealed insights that led to base editors with new capabilities. The tool, called BE-Hive, is available as a web app. Learn more in a Harvard news story.
Opening up ovarian cancer
Patients with ovarian cancer may develop a condition called ascites, an accumulation of abdominal fluid associated with treatment resistance. To better understand this disease landscape, a team led by Benjamin Izar, Itay Tirosh, Elizabeth Stover, institute scientist Orit Rozenblatt-Rosen, associated scientist Asaf Rotem, and core institute member and Klarman Cell Observatory director Aviv Regev used single-cell RNA sequencing to profile roughly 11,000 cells in abdominal fluid collected from ovarian cancer patients. The researchers uncovered significant inter-patient variability in the makeup and function of ascites cells, along with shared expression of inflammatory programs. The team also found that an inhibitor targeting the JAK/STAT pathway displayed antitumor activity. Learn more in Nature Medicine.
Evaluating drug safety
One treatment avenue for osteoporosis is medication that inhibits the action of the protein sclerostin. However, there is some evidence that sclerostin inhibitors may also increase risk of serious cardiovascular events. In Science Translational Medicine, a team including Chia-Yen Chen, institute member Ben Neale in the Stanley Center for Psychiatric Research, visiting scientist Cecilia Lindgren (University of Oxford), and colleagues reports data examining this risk from clinical trials and naturally occurring genetic variation in humans. The researchers found that sclerostin inhibition is likely to elevate cardiovascular risk, warranting a rigorous evaluation of the safety of these drugs. Learn more in a news release from University of Oxford and coverage in GenomeWeb.
The genetic swaps that underlie clonal hematopoiesis
Associate member Po-Ru Loh, Giulio Genovese, and institute member Steve McCarroll in the Stanley Center for Psychiatric Research have uncovered a key genetic mechanism that helps drive clonal hematopoiesis (CH), a common condition in which some mutant blood stem cells give rise to clones that outgrow normal blood cells, increasing the risk of blood cancer and cardiovascular disease. The team showed that clones often swap certain inherited genetic variants on one chromosome arm for those on its counterpart chromosome arm, effectively duplicating one parent’s genetic contribution and erasing the other’s. The researchers found 52 inherited genetic variants in seven genes that led to clones that had swapped inherited variants in consistent ways, boosting their growth. The findings highlight an important interplay between inherited genetic variation and somatic mutations. Read more in Nature and a Broad news story.
Normal biomarker profiles in people at risk for genetic prion disease
In neurodegenerative disorders including Alzheimer's and Huntington's, markers of neuronal damage in blood and spinal fluid begin to change decades before disease onset, suggesting that a disease process is underway long before the first symptom appears. Stanley Center’s Sonia Vallabh, Eric Minikel, and Steven Arnold (Mass General) recruited people at risk for genetic prion disease to contribute blood and spinal fluid to assess biomarkers in that disorder. They found that biomarkers are generally normal, even in people with high-risk mutations, suggesting that a disease process is probably not underway decades in advance, and pointing to an opportunity to intercept disease before it begins. Prion protein in spinal fluid was stable in these individuals and could serve as a readout of a drug's effect in a trial. Read more in BMC Medicine.
The earlier, the better
There is currently no way to screen for small, localized kidney tumors, which can often be cured if found early. A team including Pier Vitale Nuzzo (DFCI), Jacob Berchuck, Keegan Korthauer (University of British Columbia), Sandor Spisak (DFCI), Daniel De Carvalho (University of Toronto), associate membersToni Choueiri, and Matthew Freedman validated the novel liquid biopsy method, cfMeDIP-seq. Described in Nature Medicine and a Dana-Farber press release, the method was used to accurately classify patients across all stages of renal cell carcinoma (RCC) using blood plasma and to identify patients with RCC using urine cell-free DNA.
A fresh look at fresh tumor cells
A patient’s own tumor cells may hold the best clues to identifying the most effective treatments. A team led by Patrick Bhola and associate member Anthony Letai of the Cancer Program improved upon their dynamic BH3 profiling (HT-DBP) method for screening candidate drugs on freshly isolated tumor cells, applying it to screen hundreds of drugs in breast cancer cells from mice. The method determines how closely a drug causes tumor cells to die through apoptosis, and the team scaled it up by miniaturizing and automating the DBP technology. Read more in Science Signaling and Genetic Engineering & Biotechnology News.
Creating a molecular map of exercise
In the largest exercise research program of its kind, researchers are poised to collect and turn data from nearly 2,600 volunteers into comprehensive maps of the molecular changes in the body due to exercise. The NIH-funded Molecular Transducers of Physical Activity Consortium (MoTrPAC) aims to increase our understanding by measuring molecular changes in healthy adults and children before, during, and after exercise. MoTrPAC researchers detail their approach in Cell. Institute scientists Steve Carr and Clary Clish are co-PIs, along with Robert Gerszten (BIDMC) and Chris Newgard (Duke); Hasmik Keshishian and Pierre Jean-Beltran from the Proteomics Platform and Courtney Dennis and Julian Avila-Pacheco from the Metabolomics Platform are also key members of the consortium.