Base editing takes on sickle cell disease, why TB progresses, how to build a clinical COVID test, and more
Research Roundup: June 4, 2021
Welcome to the June 4, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A potential therapeutic approach for sickle cell disease
Sickle cell disease (SCD) is the most common deadly genetic disorder, leading to chronic pain, organ failure, and early death in patients. In Nature, a team led by Gregory Newby, core institute member and Merkin Institute of Transformative Technologies director David Liu, and collaborators at St. Jude Children’s Research Hospital describes a base editing approach that efficiently corrects the mutation underlying SCD in patient blood stem cells and in mice. This treatment rescued the disease symptoms in animal models, enabling the long-lasting production of healthy blood cells. Read more in a Broad news story and coverage from Endpoints and Forbes.
Peptides suggest potential targets for future COVID-19 vaccines
The key to next-generation COVID-19 vaccines may lie in previously unexplored regions of the SARS-CoV-2 genome. A team of researchers including Shira Weingarten-Gabbay, Susan Klaeger, Sisi Sarkizova, institute member Nir Hacohen of the Cell Circuits Program, institute scientist Steven Carr of the Proteomics Platform, Jennifer Abelin, institute member Pardis Sabeti of the Infectious Disease and Microbiome Program (IDMP), and others used mass spectrometry and T cell assays to study peptides presented on the surface of SARS-CoV-2-infected cells. The team identified a surprising fraction of peptides from non-canonical open reading frames that more potently trigger T cells than other studied peptides. Vaccines that target these peptides could potentially provide longer-lasting protection against the virus, and particularly new variants. Read more in Cell and a Broad news story.
Testing TB T cells
Less than 15 percent of those infected with the tuberculosis pathogen go on to develop disease. With partners at Socios en Salud (a part of Partners in Health based in Peru), Aparna Nathan, institute member Soumya Raychaudhuri in the Program in Medical and Population Genetics, and others investigated disease progression by analyzing memory T cells from 259 people with tuberculosis. The scientists integrated single-cell RNA and surface protein data from more than a half-million memory T cells, revealing 31 cell states and a key T cell type that may play a role in progression to active TB. Read more in Nature Immunology and Brigham Clinical and Research News.
What proteins tell us about fitness
Maximal oxygen uptake (VO2max) is a direct measure of cardiorespiratory fitness. However, the molecular factors that affect differences in VO2max between individuals or changes in response to exercise training (ΔVO2max), are largely unknown. Jeremy Robbins (Beth Israel Deaconess Medical Center), senior associate member Robert Gerszten of the Metabolomics Platform, and colleagues in the Proteomics Platform and elsewhere measured ~5,000 plasma proteins in 650 sedentary adults before and after a 20-week endurance exercise program. They identified 147 proteins indicative of baseline VO2max and 102 proteins indicative of ΔVO2max. The study reported in Nature Metabolism highlights the value of protein biomarkers in understanding exercise responsiveness in humans. Read more in a BIDMC news release.
A PANOPLY of tools for cancer discovery
Several recent publications have shown that by taking a proteogenomic view — one that integrates genomic, transcriptomic, proteomic, and post-translational modification data — scientists can gain deeper insights into a cancer's biology and potential vulnerabilities. Integrating disparate -omic data into such a single view, however, is a complex process. In response, DR Mani, Steven Carr, and colleagues in the Proteomics Platform and Cancer Program present PANOPLY, a cloud-based statistical and machine learning analytical platform that brings a host of tools and pipelines together in Terra and that transforms multi-omic cancer data into biologically meaningful findings. Learn more in Nature Methods and a Broad tweetorial.
Establishing a diagnostic test in crisis conditions
During the early COVID-19 outbreaks in the Boston area, a team including Bennett Shaw, Jacob Lemieux, Broad institute member Pardis Sabeti, colleagues at MGH including Melis Anahtar, Eric Rosenberg, John Branda, and Sarah Turbett, and other collaborators set up an emergency-use laboratory-developed test at MGH to diagnose SARS-CoV-2 by March 13, 2020, becoming the fourth hospital in the US to gain FDA approval and laying the foundation for subsequent viral genomics efforts. This diagnostic guided hospital care of the most critically ill patients and allowed patients to enroll in clinical trials early on. In Journal of Clinical Pathology, the team describes this process, providing a roadmap for laboratories to rapidly develop and validate testing in crisis conditions. Read more in Tweetorials from Shaw and Yolanda Botti-Lodovico.
Genomic clues from a dengue outbreak
Senegal saw its largest outbreak of dengue virus to date in 2018. Through surveillance of patients with fevers of unknown cause, Katherine Siddle, Pardis Sabeti, and colleagues, including many from the Université Cheikh Anta Diop de Dakar in Senegal, sequenced and analyzed dengue virus genomes from 17 previously undetected cases. In Scientific Reports, the team identified three co-circulating serotypes, whose sequences were most similar to those from West Africa, suggesting local circulation of the virus. The findings show the dengue virus was more widespread than previously thought, accounting for 10 percent of undiagnosed fevers in the region.
GoPhAST-R picks up speed
Faster and more accurate clinical antibiotic susceptibility testing could ensure that patients promptly receive the right antibiotic instead of broad-spectrum ones, which promote antimicrobial resistance. GoPhAST-R identifies the best antibiotic within hours by detecting genotypic and phenotypic markers of antibiotic resistance in a bacterium’s transcriptional signature. IDMP associate member Roby Bhattacharyya and colleagues first developed the method to recognize the signature of individual antibiotics. Now he, Melanie Martinsen, and Alexis Jaramillo Cartagena show in Antimicrobial Agents and Chemotherapy that these transcriptional signatures can be generalized to predict the susceptibility of all antibiotics within a class. This advance could enable easier clinical translation of GoPhAST-R.
How macrophages help drive glioblastoma
Patients with glioblastoma have a high mortality rate and few effective treatment options. Postdoctoral scholar Toshiro Hara, institute member Mario Suvà in the Epigenomics Program, and colleagues used single-cell RNA sequencing and functional experiments to study the interactions between glioblastoma and the microenvironment in mice and human tumors. They found that macrophages trigger a transition of glioblastoma cells to a mesenchymal-like state. They observed this state in some of the macrophages as well. The state was associated with increased T cell abundance and cytotoxicity, suggesting a possible therapeutic strategy. Read more in Cancer Cell.
Mitochondrial priming can determine apoptosis prior to p53 activation
TP53 is the most frequently mutated tumor-suppressor gene and a common target of cancer treatments. Although scientists know activation of the tumor protein p53 can either halt the cell cycle or promote cell death, the mechanisms leading to each response remain unknown. Now, Francisco Sánchez-Rivera, associate member Anthony Letai and senior associate member Tyler Jacks of the Cancer Program, and colleagues have demonstrated that the degree of mitochondrial priming, or a cell’s propensity to undergo apoptosis, can determine cell fate prior to p53 activation. The results could help scientists guide cancer cells with functional p53 towards apoptosis by increasing priming through genetic manipulation or drug treatment. Learn more in PNAS.
Turn down the heat
Lymphatic vessels influence the functions of their surrounding tissues, but it’s unclear how. A team led by Jin Li and Erwei Li (Beth Israel), and institute member Evan Rosen in the Epigenomics Program performed single-cell transcriptional profiling of human and mouse adipose tissue and found high expression of neurotensin in lymphatic endothelial cells, which is reduced by cold exposure and norepinephrine. The team’s experiments showed that neurotensin reduces adaptive thermogenesis in brown fat cells, with anti-thermogenic and obesity-promoting actions mediated by neurotensin receptor 2. The work suggests that targeting this system could one day help treat obesity or other metabolic diseases. Read more in Cell Metabolism.
DNA repair mechanism from mice improves knock-in models
CRISPR-Cas9 shines at creating genetic knockout models of disease. But creating knock-in models — by cutting DNA and inserting a new gene — is tricky, as the cell's mechanisms for repairing cut DNA can be imperfect or cause mutations. Jonathan Wilde, institute member Guoping Feng of the Stanley Center for Psychiatric Research, and colleagues have found a way to significantly increase the efficiency of gene knock-ins by leveraging RAD51, a DNA repair factor that promotes a mechanism found in early mouse embryos called interhomolog repair (IHR). Surprisingly, this method resulted in mice that were homozygous for the knock-in gene without affecting knock-in efficiency. Read more in Cell.