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  • Highly targeted CRISPR delivery system advances gene editing in living animals

    Highly targeted CRISPR delivery system advances gene editing in living animals
    1st March 2024

    Enveloped viruses get their outer coat by budding from cells they’ve invaded. CRISPR-Cas9 researchers coopted this behavior to produce envelope-derived vehicles that encapsulate Cas9 proteins (dark green), guide RNA and transgenes. These loaded carriers target and invade specific types of human T-cells, where they simultaneously edit and insert new genes, turning the T-cells into cancer fighters. Credit: Jenny Hamilton, IGI/UC Berkeley

    Most approved gene therapies today, including those involving CRISPR-Cas9, work their magic on cells removed from the body, after which the edited cells are returned to the patient.

    This technique is ideal for targeting blood cells and is currently the method employed in newly approved CRISPR gene therapies for blood diseases like sickle cell anemia, in which edited blood cells are reinfused in patients after their bone marrow has been destroyed by chemotherapy. A new, precision-targeted delivery method for CRISPR-Cas9, published in the journal Nature Biotechnology, enables gene editing on very specific subsets of cells while still in the body a step toward a programmable delivery method that would eliminate the need to obliterate patients’ bone marrow and immune system before giving them edited blood cells.

    The delivery method, developed in the University of California, Berkeley, laboratory of Jennifer Doudna, co-inventor of CRISPR-Cas9 genome editing, involves wrapping the Cas9 editing proteins and guide RNAs in a membrane bubble that has been decorated with pieces of monoclonal antibodies that home in on specific types of blood cells.

    As a demonstration, Jennifer Hamilton, a CRISPR researcher in the Doudna laboratory at the Innovative Genomics Institute (IGI), targeted a cell of the immune system a T-cell which is the starting point for a revolutionary cancer treatment called chimeric antigen receptor (CAR) T-cell therapy.

    By University of California – Berkeley

    Article can be accessed on: phys.org

  • Novel RNA- or DNA-based substances can protect plants from viruses, scientists show

    Novel RNA- or DNA-based substances can protect plants from viruses, scientists show
    1st March 2024

    Credit: Uni Halle / Markus Scholz

    Individually tailored RNA or DNA-based molecules are able to reliably fight off viral infections in plants, according to a new study by the Martin Luther University Halle-Wittenberg (MLU) published in the International Journal of Molecular Sciences. The researchers were able to fend off a common virus using the new active substances in up to 90% of cases. They also developed a method for finding substances tailored specifically to the virus. The team has now patented the method.

    During a viral infection, the plant’s cells are hijacked by the virus to multiply itself. Key products of this process are viral RNA molecules that serve as blueprints for the production of proteins. “A virus cannot reproduce without producing its proteins,” explains Professor Sven-Erik Behrens from the Institute of Biochemistry and Biotechnology at MLU. For years, his team has been working on ways to disrupt this process and degrade the viral RNA molecules inside the cells.

    In the new study, the researchers describe how this can be achieved using the so-called “antisense” method. It relies on short, synthetically produced DNA molecules known as antisense oligonucleotides (ASOs). In the plant cells, the ASOs direct cellular enzymes acting as scissors towards the foreign RNA so they can degrade it.  For this process to work, it is crucial to identify a suitable target structure in the viral RNA which the enzyme scissors can attach to,” explains Behrens.

    By Tom Leonhardt, Martin Luther University Halle-Wittenberg

    Article can be accessed on: phys.org


  • Re-exposing a cancer protein to enhance immunotherapy

    Re-exposing a cancer protein to enhance immunotherapy
    23rd February 2024

    Credit: Victor Segura Ibarra and Rita Serda, PhD, National Cancer Institute, National Institutes of Health/CC BY-NC 2.0 DEED

    Successful immunotherapy for cancer involves activating a person’s own T cells to identify telltale proteins called antigens on the surface of a tumor and attack it. But some tumors have a trick: They hide themselves from the immune system by preventing their antigens from being displayed. A team led by Harvard Medical School researchers at Boston Children’s Hospital has now found a way around this defense in mice.

    The findings suggest a strategy for developing add-on treatments that make cancer immunotherapies more effective. The key lies in a protein called prosaposin, the team reported in Science. Tumor tissue contains a large percentage of dying cells that shed little capsules, or vesicles, containing the tumor antigens. Immune cells called dendritic cells absorb these vesicles, process the antigens, and sprout pieces of the antigens on their surface, which teaches T cells to recognize and attack the antigens. The researchers found that without prosaposin, dendritic cells can’t break down the vesicles and present the tumor antigens to the immune system as a teaching tool. Specifically, the dendritic cells need proteins called saposins that form from prosaposin, the team discovered.

    “We found that saposins are needed to digest these vesicles and free the tumor antigen for display to the immune system,” explained senior author Florian Winau, HMS associate professor of pediatrics in the Program in Cellular and Molecular Medicine at Boston Children’s.

    By Nancy Fliesler, Harvard Medical School

    Article can be accessed on: MedicalXpress

  • Researchers discover that a rare fat molecule helps drive cell death

    Researchers discover that a rare fat molecule helps drive cell death
    16th February 2024

    Illustration of a diPUFA phospholipid, a type of lipid with two polyunsaturated fatty acyl tails, breaking through a cell’s outer lipid layer as the cell Credit: Nicoletta Barolini/Columbia University

    Columbia researchers have found that a rare type of lipid is a key driver of ferroptosis, a form of cell death discovered by Columbia professor Brent Stockwell. The findings, appearing in Cell, provide new detail on how cells die during ferroptosis and could improve understanding of how to stop ferroptosis in contexts where it is harmfully occurring in neurodegenerative diseases, for example or induce it in contexts where it could be useful, such as using it to kill dangerous cancer cells.

    The new research found that a rare type of lipid with two polyunsaturated fatty acyl tails, called a diPUFA phospholipid, was present in a range of contexts where ferroptosis was occurring, including in aging brains and Huntington disease-affected brain tissue. The finding indicates that the lipid is efficient at promoting ferroptosis.

    The research was conducted by professors in Columbia’s Department of Biological Sciences, Department of Chemistry, and the Columbia University Irving Medical Center.

    Stockwell first discovered ferroptosis in 2012, when he found that certain cells were dying because their lipid layers were collapsing an unusual form of cell death that differs from the most common kind, which begins with the cell forming blisters on its outer surface. Since that discovery, researchers in Stockwell’s lab and elsewhere have continued to investigate ferroptosis, discovering that it can occur naturally in aging cells, in pathological contexts, and can be induced to treat disease.

    By Columbia University

    Article can be accessed on: phys.org

  • Improving accuracy of molecular quantification in high throughput sequencing

    Improving accuracy of molecular quantification in high throughput sequencing
    9th February 2024

     Credit: Nature Methods (2024). DOI: 10.1038/s41592-024-02168-y

    A team at NDORMS has developed a new approach to significantly improve the accuracy of RNA sequencing. They have pinpointed the primary source of inaccurate quantification in both short and long-read RNA sequencing, and have introduced the concept of “majority vote” error correction leading to a substantial improvement in RNA molecular counting. Accurate sequencing of genetic material is crucial in modern biology, particularly for comprehending and addressing diseases linked to genetic anomalies. However, current methodologies encounter substantial constraints.

    In a landmark study, an international consortium of researchers, led by Adam Cribbs, Associate Prof. in Computational Biology, and Jianfeng Sun, Postdoctoral Research Associate at the Botnar Institute, University of Oxford, have developed an innovative method to correct errors in PCR amplification a widely used technique used in high-throughput sequencing. By pinpointing PCR artifacts as the primary source of inaccurate quantification, the researchers, address a long-standing challenge in generating accurate absolute counts of RNA molecules, which is crucial for various applications in genomics research. The study is published in the journal Nature Methods.

    The researchers focused on Unique Molecular Identifiers (UMIs), which are random oligonucleotide sequences used to remove biases introduced during PCR amplification. While UMIs have been widely adopted in sequencing methods, the study reveals that PCR errors can undermine the accuracy of molecular quantification, particularly across different sequencing platforms.

    By Adam Cribbs, University of Oxford

    Article can be accessed on: phys.org


  • Scientists uncover a crucial link between cholesterol synthesis and cancer progression

    Scientists uncover a crucial link between cholesterol synthesis and cancer progression
    5th February 2024

    Credit: Babita Madan

    Scientists led by a team at Duke-NUS Medical School have made a breakthrough in understanding the mechanisms that influence cancer cell growth and development. Publishing in the Journal of Clinical Investigation, the researchers illuminate the previously hidden role of a novel enzyme, called fatty acid hydroxylase domain containing 2 (FAXDC2), revealing its pivotal role in cholesterol synthesis and cancer progression. The study details the cascade of molecular events beginning from the suppression of FAXDC2 to the disruption of normal cholesterol synthesis to altered cancer fates, highlighting a potential vulnerability in cancer cells that could be targeted for therapeutic intervention.

    “Our journey into the cellular drivers of cancer started with an exploration of the Wnt signaling pathway, a crucial player in cell growth and development,” explained Assistant Professor Babita Madan, first author of the study from Duke-NUS’ Cancer & Stem Cell Biology (CSCB) Program.

    “It was during these studies that we stumbled upon the enzyme FAXDC2, which emerged as a central figure in controlling cancer and stem cells. Our discovery suggests that FAXDC2’s activity, or its suppression, has profound implications for cellular growth and differentiation, painting a complex picture of the relationship between cancer biology and cholesterol synthesis.”

    The research began with a deep dive into the Wnt signaling pathway, known for its critical role in the regulation of both normal and cancer cell growth. Wnt signaling is a key signaling pathway that regulates growth and development and maintaining brain, skin, hair and intestinal cells.

    By  Federico Graciano, Duke-NUS Medical School

    Article can be accessed on: MedicalXpress

  • Researchers create genetic atlas detailing early stages of zebrafish development

    Researchers create genetic atlas detailing early stages of zebrafish development
    19th December 2023

    Credit: J. Swan and K. Tabor, NICHD/NIH

    Researchers at the National Institutes of Health have published an atlas of zebrafish development, detailing the gene expression programs that are activated within nearly every cell type during the first five days of development, a period in which embryos mature from a single cell into distinct cell types. These diverse cells become tissues and organs that form juvenile fish capable of swimming and looking for food. The findings are published in Developmental Cell.

    “Perhaps surprisingly, tiny zebrafish provide us with significant insight into human development and disease. Many of the gene expression programs that direct embryonic growth are similar across fish, people, and other animals,” said Christopher McBain, Ph.D., scientific director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which conducted the work. “Since zebrafish are visibly transparent, fertilize eggs externally, and are easy to study genetically, they represent a unique and effective way to model human disease.”

    The process of embryonic development is orchestrated by instructions in DNA that direct different programs of gene expression within individual cells, which give different cell types their unique functional characteristics. To create the atlas, the study team used a method called single-cell RNA sequencing to identify gene expression programs over the course of five days, with samples taken every two to 12 hours.

    By NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

    Article can be accessed on: MedicalXpress

  • Peroxidase gene found to confer drought tolerance in soybean

    Peroxidase gene found to confer drought tolerance in soybean
    1st December 2023

    Credit: IGDB

    A research team led by Prof. Tian Zhixi of the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences, in collaboration with Prof. Ma Junkui from the Industrial Crop Institute of Shanxi Agriculture University/Shanxi Academy of Agricultural Sciences, identified the drought tolerance value of 585 soybean accessions covering the major growing areas of the world to mine the genes and corresponding beneficial alleles in soybean germplasm.

    The paper entitled “Natural allelic diversities of GmPrx16 confer drought tolerance in soybean” was published in Plant Biotechnology Journal on Nov. 22. A significant locus on chromosomes 16 was detected by genome-wide association study (GWAS). Further analysis showed that a peroxidase harboring a nonsynonymous SNP was the occasional gene in the locus, and the nonsynonymous mutations resulted in peroxidase activity differences between the two GmPrx16 haplotypes. Furthermore, overexpression of GmPrx16 in Dongnong No.50 could improve the peroxidase activity and enhance the drought tolerance in soybean, but GmPrx16 RNAi transgenic lines reduced the peroxidase activity and showed a drought-sensitive phenotype. Interestingly, overexpression of GmPrx16 could improve salt tolerance in soybean at the same time, suggesting multiple applications of GmPrx16 in breading abiotic tolerant soybean.

    GmDRF1 and GmDRF2 could bind to the promoter of GmPrx16 and regulate the expression level of GmPrx16, proposing the working model of GmPrx16: drought stress induces the expression of GmDRF1 and GmDRF2, GmDRF1 and GmDRF2 physically interact with the promoter of GmPrx16, and promote its expression, thereby influencing the accumulation of ROS and regulating drought tolerance in soybean.

    By Zhang Nannan, Chinese Academy of Sciences

    Article can be accessed on: phys.org

  • Potential new treatment for COVID-19 is made from plants

    Potential new treatment for COVID-19 is made from plants
    1st December 2023

    The novel coronavirus SARS CoV-2 is responsible for the COVID-19 global pandemic. A new form of monoclonal antibody therapeutic to treat the disease is described in a new study, which graces the cover of Plant Biology Journal. Credit: Jason Drees

    In new research, Shawn Chen, a researcher with Arizona State University’s Biodesign Center for Immunotherapy, Vaccines and Virotherapy and School of Life Sciences, describes an innovative therapy for COVID-19. The method highlighted in the study uses transient expression in tobacco plants to develop and produce a monoclonal antibody, or mAb. The study highlights the potential of synergizing antibody cocktails with the addition of monoclonal antibodies that do not directly hinder ACE2 binding to the receptor-binding domain. The study also underscores the potential of plant-based monoclonal antibody expression platforms in therapeutic development against the ever-evolving SARS-CoV-2 pandemic. Plant-made COVID-19 therapies have several advantages over other production platforms. Plants can produce large quantities of therapeutic proteins in a relatively short amount of time, making them ideal for scaling up production. They are inexpensive to grow and maintain, making them a cost-effective alternative to traditional protein expression systems. Because plants are not natural hosts for human pathogens, their use reduces the risk of contamination with infectious agents.

    Finally, plant-based expression systems can be rapidly reprogrammed to produce new therapeutics in response to emerging pathogens such as SARS-CoV-2, making them an attractive option for pandemic response.

    By Richard Harth, Arizona State University

    Article can be accessed on: MedicalXpress

  • CAR-T cell therapy leads to long-term remission in lupus while maintaining vaccine response

    CAR-T cell therapy leads to long-term remission in lupus while maintaining vaccine response
    8th November 2023

    Credit: CC0 Public Domain

    New research at ACR Convergence 2023, the American College of Rheumatology’s annual meeting, demonstrates that CAR-T cell therapy could lead to sustained suppression of autoantibodies in treatment-resistant lupus while maintaining a robust response to vaccines. Systemic lupus erythematosus (SLE, lupus) is a complex autoimmune disease marked by the production of autoantibodies to nucleic acid DNA and nuclear protein autoantigens and is associated with dysfunctional B cells. It mainly affects women and is more common and severe in people who are Black, Hispanic, or Asian. Lupus can lead to a wide range of systemic problems varying in severity, including skin, kidney, lung, joints, and heart disease and complications during pregnancy. The disease often requires lifelong treatment with immunosuppressive or immunomodulatory drugs, and a considerable number of patients don’t respond to them. One theoretical option for these patients is chimeric antigen receptor (CAR)-T cell therapy, which is successfully used to treat refractory blood cancers by destroying malignant cells. “We were intrigued by the possibility that a deep B cells depletion exerted by CAR-T cells could lead to permanent eradication of the autoimmune disease,” says Georg Schett, MD, a rheumatologist at the University Hospital Erlangen in Germany. CAR-T cells are created by removing some of a patient’s white blood cells, including immune system T cells, and genetically altering them in a lab to produce chimeric antigen receptors (CARs). The modifications allow the treated T cells to recognize and destroy antigens on the surface of target pathogenic cells after they are infused back into the patient.

    By American College of Rheumatology

    Article can be accessed on: MedicalXpress