Research Roundup: May 1, 2020

Welcome to the May 1, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Introducing CARMEN

A research team led by postdoctoral associates Cheri Ackerman and Cameron Myhrvold, graduate students Catherine Freije and Gowtham Thakku, core institute member Paul Blainey, and institute member Pardis Sabeti unveiled a new technology in Nature that combines the SHERLOCK CRISPR-based diagnostic with the miniaturization of microfluidics for a flexible, sensitive diagnostic platform. The platform, called CARMEN (Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids), uses new microfluidics chips that can run thousands of tests simultaneously for same-day results, and could someday be harnessed for broad public-health efforts. Learn more in a Broad news release and coverage in GenomeWeb, Axios, and The Holland Sentinel.

Prostate, regenerate

Androgen deprivation, used to treat prostate cancer, shrinks the prostate substantially, due to loss of luminal cells. Androgen reintroduction induces rapid regeneration. A team led by Wouter Karthaus and Charles Sawyers of Sloan Kettering, postdoctoral associate Matan Hofree, and core institute member Aviv Regev used single-cell RNA sequencing to follow prostate remodeling and regeneration in response to androgen in a mouse model. Under castration, luminal cells adopted stem-like expression patterns, and regeneration was driven by nearly all persisting luminal cells of this organ, not just a rare stem-cell population. Similar cell populations were found in human prostate tissue. Read more in Science.

Written in the stars

For a deeper look at the role of non-neuronal cells in Alzheimer’s disease (AD), a team including visiting scientist Naomi Habib of the Hebrew University of Jerusalem, senior molecular biologist Cristin McCabe, core institute member Regev, and visiting scientist Michal Schwartz of the Weizmann Institute used single-nucleus RNA sequencing to uncover a population of disease-associated astrocytes in a mouse model of AD. The cells appeared early in disease and became more abundant as the disease progressed. Described in Nature Neuroscience, the effort also found similar astrocytes in aged wild-type mice and aging human brains. The work supports a central role for disease-associated astrocytes in AD pathogenesis.

Family history isn't everything

Standard clinical care doesn't include testing for rare genetic variants for conditions like heart disease. Aniruddh Patel, Wallace Wang, associate member Amit Khera (all in the Cardiovascular Disease Initiative), and colleagues screened data from nearly 50,000 UK Biobank participants for variants linked to familial hypercholesterolemia, breast and ovarian cancers, and Lynch syndrome (which predisposes to colorectal and uterine cancers). They found that about one percent of the cohort carried a high-risk variant for at least one condition, but only 40 percent of those carriers had a family history of that condition. This, they write in JAMA Network Open, supports consideration of broader testing. Learn more in a Massachusetts General Hospital press release.

Reading the T (cell) leaves

Conditions like monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) often precede multiple myeloma (MM). Not everyone with these conditions develops full-blown MM, making it hard to know when doctors should intervene. A team led by Oksana Zavidij, Nicholas Haradhvala, institute member Gad Getz, and associate member Irene Ghobiral in the Cancer Program used single-cell RNA sequencing to profile the bone marrow's immune microenvironment in MGUS and SMM patients. They found changes in T and NK cell abundance and monocyte function that may help reveal why some patients progress, and which could be used to stratify patients for treatment. Learn more in Nature Cancer and a Dana-Farber press release.

Rheumatoid arthritis research takes it up a NOTCH

In rheumatoid arthritis, the synovial tissue found in joints becomes inflamed and invasive, ultimately destroying the joint. A subset of fibroblasts, cells that provide structural support in these tissues, undergo a major expansion in rheumatoid arthritis. However, the molecular mechanisms associated with the expansion process is unknown. Using single-cell RNA sequencing and synovial tissue organoid models, institute member Soumya Raychaudhuri of the Program in Medical and Population Genetics and colleagues found the critical role of NOTCH3 signaling in the regulation of the disease. Reporting in Nature, the authors confirm that upregulation of the gene NOTCH3 in synovial fibroblasts is a possible mechanism for inflammatory arthritis.

Shedding light on SOUL

Optogenetics is a biological technique that is used to manipulate neuronal activity. However, a significant disadvantage of the method is the requirement to surgically implant devices such as optical fibers. To overcome such challenges, institute member Guoping Feng of the Stanley Center for Psychiatric Research, Xin Gong, and their collaborators asked if it is possible to turn on and off neurons inside the brain by shining light from outside the head. In Neuron, they report SOUL, a newly developed light-responsive molecule, which is so sensitive to light that it can activate neurons inside the brain of mice and macaques with external illumination. This discovery may further help in the development of minimally invasive optogenetic tools for the treatment of neurological disorders.

Therapeutic clues for neurodegenerative diseases

Many neurodegenerative diseases are caused by mutations in genes that are involved in lipid metabolism. Using wobbler mice, a model for neurodegenerative disease, Metabolism Program associate members Robert Farese and Tobias Walther, and colleagues investigated whether modulating sphingolipid metabolism affects cell dysfunction. The team found that treating the mice with the sphingolipid synthesis inhibitor myriocin reduced their toxic effects, improved wellness scores in the mice, and ultimately extended the animals’ lifespan. The findings, published in the Proceedings of the National Academy of Sciences, could help in the development of therapies for a range of neurodegenerative diseases. Read more in an HSPH press release. 

Better data sharing, better privacy

Sharing biomedical data across different repositories while maintaining data privacy is often challenging. Schmidt fellow Hyunghoon Cho, associate member Bonnie Berger, and colleagues have developed query-answering systems with formal privacy guarantees, using recent advances in differential privacy (DP). They show that their DP-based system improves accuracy over existing approaches for each query type. They also provide case studies on how their DP mechanisms could be used to enable data sharing with privacy, following real-world workflows in published studies for cohort discovery and variant lookup. Learn more in Cell Systems. 

To learn more about research conducted at the Broad, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.