Atlas of immune cells explains how genetic variants cause disease. A new method reveals which genetic variants are most important in disease and how cells "buffer" the expression of genes critical for health. By Sarah C.P. Williams September 30, 2026 Highlights. * Geneticists have long struggled to find the mechanisms by which many disease-linked genetic variants actually cause disease. * A new atlas of more than 10 million immune cells from more than 1,100 Finnish blood donors provides a way to connect disease-associated regulatory variants with the genes they control. * The approach relies on looking at chromatin accessibility - the openness of the DNA around a certain genetic variant - and how that openness correlates with the expression of nearby genes. Scientists have identified thousands of genetic differences that change a person's risk of disease, but working out how they actually impact biology - an important step toward creating new treatments - has been much more challenging. One reason is that many of the genetic variants associated with disease aren't found in genes themselves, but within the vast stretches of DNA that regulate gene activity. Now, scientists have developed a new approach to connecting disease-linked regulatory variants to the actual genes they control. Their results, in Nature, reveal that these variants are more likely to influence disease risk if they alter chromatin accessibility - the openness of a section of the genome - in a way that then changes expression of a specific gene, compared to variants that affect only chromatin accessibility or gene expression alone. The finding could help other scientists prioritize the genetic variants that are most important in a particular disease. The research team applied their method to millions of immune cells from more than 1,100 blood donors enrolled in FinnGen, a large medical research project in Finland. The resulting atlas revealed likely molecular mechanisms by which tens of thousands of genetic variants cause hundreds of different diseases and health traits - including autoimmune hypothyroidism, inflammatory bowel disease, asthma, Alzheimer's disease, and skin cancer. The new work was led by researchers at the Broad Institute, Massachusetts General Hospital, and the Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki, in collaboration with the Finnish Red Cross Blood Service and BioBank Japan. "Immune dysregulation sits at the root of an enormous range of human diseases, from autoimmunity to cancer to neurodegeneration," said Ramnik Xavier, a co-senior author of the study, a core institute member at the Broad Institute, and Kurt Isselbacher Professor at Massachusetts General Hospital and Harvard Medical School. "What excites me about this work is that it doesn't just tell us that a gene matters; it tells us the molecular mechanism, which can point toward therapeutic strategies." The team also found that many of the genes most critical to health and survival are wired to dozens of regulatory elements in the genome at once, each contributing only a small change to gene expression. That redundancy, they found, keeps the expression of these important genes relatively stable and is also why these genes have been so hard to study using traditional methods. "One of the biggest gaps in human genetics has been between finding a disease-associated variant and understanding its function," said Mark Daly, co-senior author, an institute member at the Broad Institute, co-director of Broad's Program in Medical and Population Genetics, and founding chief of the Analytical and Translational Genetics Unit at Massachusetts General Hospital. "This atlas provides reliable evidence that we can now systematically connect genetic association signals to molecular switches affecting specific genes and cells at scale. With confirmatory editing experiments now possible, we have a path to unlocking the power of human genetics to provide novel insights into causal disease mechanisms." Open or closed. Daly, Xavier, and their colleagues had previously analyzed data from FinnGen - a research project that integrates genomic information and health records for more than 500,000 people in Finland. The 2023 study using FinnGen data pinpointed hundreds of genomic regions linked to diseases. In this new work, they wanted to connect those risk variants to their molecular consequences. In the millions of immune cells from FinnGen donors, the researchers measured both gene expression and chromatin accessibility in the same cells. This let them connect whether a genetic variant was correlated to a change in that openness in a particular cell type, and then whether that change in openness was also correlated with a change in gene expression. By collecting and analyzing this data from each of the millions of individual cells, the team had enough statistical power to show how cells maintain stable expression of genes that are important for life: by hooking these genes up to many weak regulatory switches rather than a single strong one. That explained why studies looking only at gene expression often missed the full story: a switch that matters for disease may move expression only slightly - too little for those studies to detect. "We think the body wants precise control over the expression of its most important genes; it doesn't want any single genetic variant to be able to swing that expression too far on its own," said Masahiro Kanai, first author of the study, a postdoctoral scholar at the Broad Institute and an instructor in medicine at the Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School. "So instead of relying on one strong switch, these genes are controlled by many weaker ones. We call this regulatory buffering, because it dampens the effect of any single chromatin change before it reaches gene expression, like a shock absorber." From signal to mechanism. The researchers chose to build their atlas from immune cells because immune dysregulation is at the root of many seemingly different diseases affecting different tissues. Across eight broad types of immune cells, the team carried out the full analysis of chromatin accessibility and gene expression for thousands of different disease-linked genes. They then traced the precise molecular mechanisms behind several disease-linked genetic variants. One, inside a gene called TNRC18, had been flagged in the 2023 FinnGen study as being linked to inflammatory bowel disease, with no known mechanism. The new data show the variant reduces TNRC18 expression in T cells, and it does this most strongly in a subset called T helper 1 cells, pushing those cells toward a more inflammatory state. Another example, involving the genes IL4R and IL21R, helped explain why one variant lowers the risk of asthma while another variant in the same genetic region instead raises the risk of autoimmune hypothyroidism. The thyroid-risk variant turns up IL21R, the receptor for an immune signal called IL-21, and mice lacking that receptor on their T cells are protected from the same thyroid complication. The finding points toward blocking IL-21 as a potential way to treat a similar thyroid complication that can occur as a side effect of cancer immunotherapy. The team has made its data and methods freely available to spur new research. They caution that many of the connections they've mapped are still hypotheses rather than confirmed mechanisms. They are now working to profile immune cells from diseased tissue directly rather than relying only on samples from healthy individuals. "This is a launching pad for future research," said Daniel Graham, a study co-author and an institute scientist at Broad. "There's a lot of reason to be optimistic about the power of using this type of data to uncover mechanisms of disease." Paper cited: Kanai M, Delorey TM, et al. Population-scale immune multiome atlas reveals regulatory disease mechanisms. Nature. Online September 30, 2026. DOI: 10.1038/s41586-026-11078-2 Support for the study was provided in part by the National Institutes of Health (DK043351, DK062432, R00HG012222, R01HG014518), the Klarman Cell Observatory, the FinnGen Project, the Department of Molecular Biology at MGH, the Masason Foundation, JSPS KAKENHI (25H01057), AMED (JP24km0405217, JP24ek0109594, JP24ek0410113, JP24kk0305022, JP223fa627001, JP223fa627002, JP223fa627010, JP223fa627011, JP22zf0127008, JP24tm0524002, JP24wm0625504, JP24gm1810011), JST Moonshot R&D (JPMJMS2021, JPMJMS2024), Ono Pharmaceutical Foundation for Oncology, Immunology, and Neurology, a Baelz Research Grant, and the RIKEN TRIP initiative (AGIS).

MIT scientists develop technique to track gene activity over time in individual cells. On September 1, the Broad Institute of MIT and Harvard announced a new method for tracking gene activity in cells over time. Previously, scientists had to destroy cells to access their RNA, providing only a one-time snapshot of a cell's genetic activity. The new technique allows living cells to report their own transcriptomes, enabling analysis without cell death. Detailed in the journal Cell, the method involves virus-like particles that cells use to package and release RNA into the surrounding culture medium. Researchers can repeatedly sample this medium to observe changes in gene activity in the same cell population as they develop or respond to stimuli. This approach has been tested on various cellular models, offering insights into disease progression and drug effects. Paul Blainey, a senior author of the study and a professor at MIT, emphasized the importance of developing practical tools for the scientific community. The concept, once considered science fiction, demonstrates the potential of long-term, high-risk research. The effort began over a decade ago, aiming to create a non-destructive RNA sequencing method. The team drew inspiration from retroviruses, which naturally package RNA genomes for cell-to-cell transmission. They engineered cells to produce a retroviral protein capable of encapsulating cellular RNA. This protein helps form virus-like particles that release RNA into the culture medium, allowing scientists to sequence the RNA without harming the cells. Co-first author Mohamad Najia highlighted the broader applicability of this molecularly encoded solution compared to traditional methods involving robotics or mechanical biopsies. The study, led by Najia, Jacob Borrajo, and Anna Le, demonstrated the method's effectiveness in various cell types, including human cancer and stem cells. The researchers also tested the method on complex systems like human endothelial cell spheroids and organ-on-a-chip devices. The technique revealed short-term transcriptional changes and gene expression dynamics related to tissue formation. Collaborating with MIT's Linda Griffith, they showed the method's utility in monitoring gene activity in organ models. The Broad team is exploring further applications and refining the technique for single-cell studies. They encourage scientists interested in cellular and tissue changes over time to adopt their innovative method.

CRISPR pooled libraries: optimizing knockout library design. * Laura Drepanos Computational Associate III, Broad Institute of MIT and Harvard BIOGRAPHY * Andrew Hempstead, PhD Associate Director of Scientific Engagement and Success, Addgene BIOGRAPHY Date & Time Date: July 22, 2026 Time: 9:00 AM PT, 12:00 PM ET CRISPR-Cas9 knockout pooled libraries have allowed researchers to conduct screens to identify genes important in varying cellular functions for further study. Addgene has played an important role in the dissemination of this technology, distributing CRISPR pooled libraries to thousands of researchers around the world. The Genetic Perturbation Platform (GPP) at the Broad Institute of MIT and Harvard has recently developed the Julianna and Jacquere knockout pooled libraries for screens in human and mouse cells. These pooled libraries have balance off-target and on-target considerations for an optimized design. This webinar will be co-presented by Addgene and the GPP. Addgene will provide a introduction to CRISPR pooled libraries, the landscape of types available, their applications, and design considerations. The Doench Lab will then describe the considerations for the construction of these new pooled libraries, a comparison to other available tools, and their work to validate the new optimized libraries. We'll conclude with information about how to access these new resources, including their availability as ready-to-use lentiviral preparations. At Addgene, we are committed to supporting researchers both by providing the high-quality materials you need and by equipping you with the knowledge and resources to use them successfully. If you are new to using pooled libraries, or embarking on a CRISPR screen in your lab, this webinar provide you with the information you need to use an optimized tool for your research. Learning Objectives: * Describe CRISPR pooled libraries and their research applications * Identify considerations for CRISPR-Cas9 knockout library design * Explain the optimization of the Julianna and Jacquere pooled libraries You May Also Like Sep 2, 2026, 09:00 AM PDT C.E. CREDITS Las infecciones congénitas continúan siendo una causa importante de morbimortalidad fetal y neonatal, lo que hace fundamental contar con estrategias diagnósticas oportun... Speaker: Dr. Daniel Aguirre Chavarría 8 Sept 2026 10:30am IST |1:00pm SGT | 2:00pm KST | 3:00pm AEST | 6:00pm NZDT Understanding the tissue microenvironment in tumour samples is an important factor for predicting response to different treatment regimens. Highly multiplexed imaging of tenfolds of protein... Speaker: Charlotte Stadler, PhD, Adyary Fallarero, PhD, MBA Sep 8, 2026, 07:00 AM PDT Circulating calprotectin has emerged as a sensitive and clinically valuable biomarker reflecting inflammatory activity across a range of rheumatic diseases. Unlike traditional acute-phase ma... Speaker: Dirk Föll, Univ.-Prof., Dr., Marija Jelusic, Prof., MD, MSc, PhD, Tomáš Milota, Assoc. Prof., MD, PhD Sep 8, 2026, 08:00 AM PDT Understanding how cells consume oxygen is fundamental to biology, yet most researchers capture this only at a single time point, missing the full metabolic picture. The Resipher measures oxy... Speaker: Dr. William Hotham, PhD, MRes, BSc (Hons) Sep 15, 2026, 07:00 AM PDT C.E. CREDITS The Plachta lab has pioneered the use of live-imaging approaches to discover how the preimplantation embryo forms in real time. Our recent findings help to transform the field of preimplanta... Speaker: Nicolas Plachta, Ph.D Sep 15, 2026, 08:00 AM PDT Join us for an interactive webinar focused on the practical analysis of Next Generation Flow(TM) measurable residual disease (MRD) in Multiple Myeloma through a real case example. We will... Speaker: Javier Pérez Peña, PhD