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Immune checkpoint inhibitors rev up the immune system's response to tumors, but many tumors are able to resist their effects. In a preclinical study in Nature, a Broad/MGH team led by Robert Manguso and Russell Jenkins has found they augment these treatments by blocking the action of a gene called TBK1 in cancer cells, suggesting that TBK1 could be an important target for overcoming #immunotherapy resistance.
For reasons unknown, nearly one percent of patients with chronic lymphocytic leukemia progress to a more aggressive cancer, Richter's syndrome. New research from the labs of Gaddy Getz and Catherine Wu reveals for the first time the genomic differences between these two cancers, the molecular pathways by which Richter's emerges, and its subtypes -- all of which helps reveal opportunities for earlier diagnosis and better treatment.
Variation in our brains helps make us unique — and yet scientists don’t know how human brains vary at the cellular and molecular levels. Now, researchers are working to create an “atlas” of that variation. “Biological variation among human brains is vast and fascinating and includes so many things that we care about,” said Steven McCarroll, who co-leads the project along with Evan Macosko. “It’s the difference between health and illness and the difference between joy and despair. It's really important to us to understand the human brain as a dynamic entity.” Read more in a new Q&A story with McCarroll and Macosko:
In a new study of DNA from over 1 million people, scientists with the international CARDIoGRAMplusC4D consortium discovered 68 new genome sites linked to increased risk for CAD, bringing the total to more than 250. They also developed a systematic and disease-tailored approach to pinpoint 220 candidate causal genes underlying the associated sites and verified one of these through genome-editing and cell-based experiments. The work provides a more complete picture of the genetic roots of CAD, outlines a list of genes and genetic variants for future study, and demonstrates an analytical framework for identifying causal genes that can be used to enhance genome-wide association studies of other diseases.
The cell relies on a certain set of "essential" genes to carry out basic functions for survival (transcription, translation, cell division, etc.). Luke Funk, Paul Blainey, and colleagues teamed up with Kuan-Chung Su, Iain Cheeseman and others at Whitehead Institute to explore more than 5,000 essential human genes' functions using a massive, CRISPR-based, pooled optical screening approach. Their method, described in Cell, allows researchers to both see which gene in a given cell is disrupted and measure microscopically the disruption's functional impact, enabling predictions about how genes work and operate together.
Less than two percent of the human genome is made up of genes that code for proteins, with the remaining 98 percent being non-coding and involved in regulating gene expression. Scientists have now found that changes in the non-coding regions of the genome can have clinical consequences. In a new study, researchers at the Broad and Massachusetts General Hospital have discovered that structural variants in the non-coding region near a gene called MEF2C — a transcription factor that has been linked to neurodevelopmental disorders (NDDs) — can mimic the effects of changes in the gene itself. The project, led by Kiana Mohajeri, Rachita Yadav, and Michael Talkowski, is the first to describe the long-range effects of coding and non-coding MEF2C variants in human neuronal cell lines, and suggest both indirect and direct disruptions of the gene can have similar downstream effects.
In a #WhyIScience Q&A, computer scientist Victoria Popic talks about her journey through industry and academia, how machine learning can enhance our understanding of the human genome, and the beauty behind good code. "Computer science also involves some art and creativity — writing beautiful code is an art in itself."
The study of proteins is more than just a research tool — Broad researchers are showing that it has potential to impact patient care, too. They’re developing better analytical methods that work on patient samples and using those and other approaches to find early markers of severe disease, design personalized medicines, and track how patients respond to treatment. With each new improvement or technology, scientists gain more insight into the role of key proteins in disease, moving proteomics closer to the clinic. “Clinical proteomics is still a work in progress, and to improve approaches and throughput, we’ll need a lot of incremental steps,” said Steven Carr, senior director of Broad’s Proteomics Platform. “The potential these methods have to impact patients — to lead to new therapeutic interventions or better use of existing therapies — is really exciting. And that’s already started happening.”
Led by teams at the Broad and the Wellcome Sanger Institute, an international consortium of researchers has identified 10 new genes that elevate or lower a person’s risk of Crohn’s disease, a form of inflammatory bowel disease. The findings point to key cells and biological pathways that contribute to a person’s susceptibility to Crohn’s disease, and could help researchers develop new treatments.
The MPCproject is a first-of-its-kind data-gathering initiative launched in 2018 by collaborators at the Broad and Dana-Farber Cancer Institute to better understand the genetics and biology of Metastatic Prostate Cancer, which can drive different patterns of disease. It falls under the larger umbrella of Count Me In, an initiative that launched its first project in 2015 with the goal of giving cancer patients from diverse geographical, racial, and socioeconomic backgrounds opportunities to participate in research that has often excluded them. In a paper published in Cell Genomics, MPCproject researchers have reported the results of the first four years of the project. With the help of patient advocates, the team has successfully partnered with over 1,000 men with MPC across the United States and Canada and established that their new approach can make cancer discoveries.
