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News / 03.21.22

Research Roundup: March 21, 2022

Susanna M. Hamilton
Credit : Susanna M. Hamilton
By Broad Communications

A new form of cell death, a better approach to sequencing, a cellular map of white fat, and more

Welcome to the March 21, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

How copper kills

Copper is an essential element of life, but too much is toxic. Cancer Program research scientist Peter Tsvetkov, institute director Todd Golub, and colleagues have discovered how copper kills cells, and that it is a new form of cell death distinct from apoptosis and ferroptosis — a process they call cuproptosis. They found that copper binds to specialized proteins, causing them to form toxic clumps, and also interferes with other essential proteins, leading to cell death. The researchers also identified key genes involved in the process and which cells are particularly vulnerable to copper-induced death. The findings could inform the development of new cancer treatments. Read more in Science and a Broad story.

Detecting disease with MAESTRO

Cancer cells in the body “shed” DNA fragments into the bloodstream, with telltale mutations indicating they came from the diseased tissue. Gregory Gydush, Erica Nguyen, Michael Makrigiorgos (Dana-Farber Cancer Institute), institute director Todd Golub, Gerstner Center for Cancer Diagnostics associate director Viktor Adalsteinsson, and colleagues have developed a new method to accurately detect these fragments, picking up thousands of rare DNA mutations in a blood sample with minimal sequencing. The approach, called MAESTRO, could one day allow doctors to detect residual cancer in patients who have undergone treatment, flagging disease recurrence earlier than current methods can. Read more in Nature Biomedical Engineering and a Broad news story.

Putting white fat on the map

White adipose tissue, aka white fat, is a dynamic tissue active in many biological and metabolic processes. Margo Emont, institute member Evan Rosen of the Metabolism Program, and colleagues have released the first-ever single-cell atlas of white fat in humans and in mice. The atlas reveals the composition of white fat at unprecedented detail, highlighting a variety of adipocyte subtypes, including new ones associated with conditions like type 2 diabetes; pointing out differences between adipose tissues from different sites in the body (subcutaneous versus visceral); and providing an initial view into key cellular interactions. Learn more in Nature and a news story from Beth Israel Deaconess Medical Center.

Tracking pathogens’ wily moves

To track changes in bacterial antibiotic resistance mutations, a team led by Hattie Chung, Roy Kishony (Technion), and associate member Gregory Priebe of Boston Children’s Hospital and the Infectious Disease and Microbiome Program (IDMP) developed a genomic surveillance tool, called resistance-targeted deep amplicon sequencing (RETRA-Seq). They combined RETRA-Seq with whole-genome sequencing to track changes in rare, low-frequency resistance mutations over time in seven mechanically ventilated patients with acute respiratory Pseudomonas aeruginosa infections. The frequency of resistance mutations increased or decreased rapidly within patients as antibiotics were switched. The approach could help patients get more effective and better-timed treatment for infections. Read more in Nature Communications and a story from Boston Children’s Hospital.

Machine learning trips out

Psychedelic experiences are often studied in controlled laboratory settings with small numbers of participants. In Science Advances, Galen Ballentine (SUNY Downstate), Sam Freesun Friedman from the Data Sciences Platform, and Danilo Bzdok (McGill) use machine learning to analyze more than 6,000 testimonials of experiences with 27 psychoactive drugs. By grouping the words used in the testimonials with each drug's receptor binding affinities, the team was able to connect subjective experiences, like mysticism and hallucination, with 40 neurotransmitter receptors. They then used transcriptomics to map those receptors throughout the whole brain in 3D, linking states of consciousness with specific brain regions. Learn more in a press release from McGill University and coverage in MIT Technology Review.

A flexible approach to base editor screens

Like CRISPR screens, base editor screens can help reveal cellular pathways and targets for drug and biomarker development. In Nature Communications, Audrey Griffith, Annabel Sangree, institute scientist John Doench, and colleagues in the Genetic Perturbation Platform describe the use of Cas9 variants with more flexible PAM binding sites to increase C>T and A>G base editor screen coverage. They identify known and new loss-of-function mutations in BRCA1 and venetoclax resistance mutations in BCL2. The low upfront costs and ease of use of pooled base editing libraries, they argue, suggest that such screens could help validate new compound targets and flag potential resistance mechanisms long before seeing what arises in patients. Learn more in a tweetorial by Doench.

Regulating the regulators

Dendritic cells play an important role in regulating the immune system. To better understand their molecular circuitry, a team led by Ruihan Tang and institute member Vijay Kuchroo in the Klarman Cell Observatory turned to mouse models of cancer and an autoimmune disorder called experimental autoimmune encephalomyelitis (EAE). Knocking out a protein called Bat3 in the mice’s dendritic cells ultimately suppressed their T cells and reduced inflammation, mitigating EAE symptoms but promoting tumor growth, and suggesting that the modified dendritic cells induced T cells to become more tolerant. The results provide insight into how dendritic cells themselves are regulated, and could inform the development of therapeutic strategies that rely on controlling the immune system. Read more in Science Immunology.

A matter of timing and context 

Histone deacetylases (HDACs) are enzymes that regulate gene activity and play a central role in human diseases. Therefore, they are often considered as attractive drug targets for therapeutics research. To better understand the molecular basis of the unexpected isoform- and complex-selectivity of certain small molecule HDAC inhibitors, Connor Payne (Massachusetts General Hospital) and IDMP associate member Ralph Mazitschek developed orthogonal TR-FRET assay strategies that allowed them to systematically dissect the compounds' time- and context dependencies. Their study, published in Cell Chemical Biology, provides a mechanistic understanding of how dynamic cellular processes that regulate HDAC-complex dynamics can drive HDAC inhibitors' activity.

The hunt for biomarkers for heart disease target

Inhibiting the secreted protease ADAMTS7 is a proposed therapeutic strategy for coronary artery disease. To identify ADAMTS7's extracellular substrates and their cleavage sites, research scientists Bryan MacDonald of the Cardiovascular Disease Initiative (CVDi) and Hasmik Keshishian of the Proteomics Platform, institute scientist and Proteomics Platform senior director Steven Carr, institute member and CVDi and Precision Cardiology Lab director Patrick Ellinor, and colleagues used TAILS, a method for identifying protease-generated neo-N termini. They found hundreds of potentially disease-related substrates and cleavage sites to explore, which could aid in the development of activity-based biomarkers for ADAMTS7. Read more in Molecular and Cellular Proteomics.

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