Research Roundup: July 10, 2020

First precision mitochondrial DNA editor, social factors and COVID-19, a gene drive tuner, and more

Erik Jacobs
Credit: Erik Jacobs

Welcome to the July 10, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

New molecular tool precisely edits mitochondrial DNA

In Nature, a team led by Beverly Mok, core institute member and Merkin Institute for Transformative Technologies in Healthcare director David Liu, and collaborators at the University of Washington describes a new type of molecular editor that can make C•G-to-T•A changes in mitochondrial DNA. The tool, engineered from a bacterial toxin, enables precise edits to the human mitochondrial genome for the first time, according to the team, opening the door to a better understanding of genetic changes associated with cancer, aging, and more. Learn more in news stories from Broad and HHMI, and coverage in STAT, New Scientist, and Chemical & Engineering News.

Learnings from the lung cancer proteome

Studies of lung cancer's genome have fueled great strides in patient care, but the genome provides only one layer of information about cancer cells' inner workings. By integrating genomics with comprehensive proteomics, however, Shankha Satpathy, Michael Gillette, institute scientist and Proteomics Platform senior director Steven Carr, and collaborators in the NCI's Clinical Proteomics Tumor Analysis Consortium have identified new treatment opportunities and revealed insights into lung cancer biology, smoking- vs. nonsmoking-related tumor features, and host/tumor interactions that go beyond what the genome can teach us. Learn more in Cell and in stories from Broad and the NCI

Increased COVID-19 risk associated with race 

COVID-19 disproportionately affects historically disadvantaged populations. Aniruddh Patel, Manish Paranjpe, associate member Amit Khera of the Program in Medical and Population Genetics (MPG), and colleagues investigated associations between race, socioeconomic factors, and COVID-19 hospitalizations among 418,794 participants of the UK Biobank, 549 of whom had been hospitalized. They found that both Black and Asian participants were at greater risk of COVID-19 hospitalization than white participants. Reporting in the International Journal for Equity in Health, the researchers write that whether this increased risk relates to differences in biologic factors, testing, hospitalization patterns, or other disparities in social determinants of health warrants further study.

DNA origami for potential viral vaccines

Vaccines can activate B cell responses by presenting antigens in specific ways. To learn more about the most effective antigen arrangements and other vaccine design parameters, associate member Mark Bathe and colleagues designed DNA that can fold into virus-like particles and then coated them with an engineered HIV antigen. The team found, to their surprise, that spacing the antigens apart on the particles led to stronger B cell responses in vitro than packing them as closely together as possible. The study, in Nature Nanotechnology, could potentially guide HIV vaccine development, and the team is adapting the approach to develop a potential vaccine for SARS-CoV-2. Read coverage in MIT News.

Genetic underpinnings of Huntington disease 

Huntington disease (HD) is caused by an expanded CAG trinucleotide repeat in the HD gene, HTT. A recent genome-wide association study of HD revealed genes involved in DNA maintenance processes as modifiers of onset, including multiple signals in a chromosome 15 region containing the DNA repair gene FAN1. Reporting in the American Journal of Human Genetics, MPG associate member Jong-Min Lee and colleagues carried out a detailed genetic, molecular, and cellular investigation of the modifiers at this locus. Their findings confirm that somatic CAG repeat expansion is a therapeutic target in HD and that several genetic variants act by different means through FAN1 to influence HD onset. 

A change of heart

The protein components of the mitochondrial calcium uniporter (MCU) are known, but it's phospholipid requirements are not. Using yeast mutants, a team led by institute member and Metabolism Program co-director Vamsi Mootha and collaborators at Texas A&M found that cardiolipin, a common mitochondrial membrane phospholipid, is required for MCU stability and function. Cells and cardiac tissue from patients with Barth syndrome, an inherited cardiolipin deficiency, are deficient in MCU. Described in PNAS, the work points to impaired mitochondrial calcium signaling in Barth syndrome pathogenesis, and shows that yeast mutants can be used to reveal the lipid requirements of membrane proteins. 

No small change

Methods to modify bases at specific sites in cellular RNAs could help uncover the functions of those changes in biology and disease. Christopher Wilson, Peter Chen, Zhuang Miao, and David Liu developed a targeted RNA methylation (TRM) system involving catalytically inactivated Cas13 tethered to methyltransferases, which enables site-directed N6-methyladenosine (m6A) installation in target transcripts in both the cytoplasm and nucleus. Described in Nature Biotechnology, TRM operates on a range of RNA targets with low off-targeting activity, alters cellular processing of RNA in a methylation-dependent manner, and may advance m6A biology by illuminating the modifications’ functional consequences.

Putting the brakes on gene drives

CRISPR-based gene drives can push a gene or genetic element to spread rapidly throughout a population, and hold great promise for combatting crop pests or vector-borne diseases. But their inheritance is hard to control, which is why associate members James Walker of the Cancer Program and Amit Choudhary of the Chemical Biology and Therapeutics Science Program and colleagues have been working on a gene drive that can be turned on and off using a modified Cas9 enzyme and trimethoprim, a common antibiotic. Writing in Cell Reports, they discuss how their system can tune a gene drive-fueled element's transmission from parents to offspring.

PD-1 is involved in immune memory

PD-1 regulates dysfunctional T cells in cancer and chronic infection and is the target of several cancer immunotherapies. Institute member Arlene Sharpe and collaborators have found that PD-1 signals are also needed for T cell memory. Mice lacking PD-1 or PD-L showed impaired CD8+ T cell memory after acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. The findings suggest that PD-1-blocking immunotherapies could affect immune memory responses in patients. Read more in Cell Reports.