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Is CRISPR safe? Genome editing gets its first FDA scrutiny.
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How to protect the first 'CRISPR babies' prompts ethical debate.
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Programmed Editing of Rice (Oryza sativa L.) OsSPL16 Gene Using CRISPR/Cas9 Improves Grain Yield by Modulating the Expression of Pyruvate Enzymes and Cell Cycle Proteins.
Rice (Oryza sativa L.) is one of the major crops in the world and significant increase in grain yield is constant demand for breeders to meet the needs of a rapidly growing population. The size of grains is one of major components determining rice yield and a vital trait for domestication and breeding. To increase the grain size in rice, OsSPL16/qGW8 was mutagenized through CRISPR/Cas9, and proteomic analysis was performed to reveal variations triggered by mutations. More specifically, mutants were generated with two separate guide RNAs targeting recognition sites on opposite strands and genomic insertions and deletions were characterized. Mutations followed Mendelian inheritance and homozygous and heterozygous mutants lacking any T-DNA and off-target effects were screened. The mutant lines showed a significant increase in grain yield without any change in other agronomic traits in T0, T1, and T2 generations. Proteomic screening found a total of 44 differentially expressed proteins (DEPs), out of which 33 and 11 were up and downregulated, respectively. Most of the DEPs related to pyruvate kinase, pyruvate dehydrogenase, and cell division and proliferation were upregulated in the mutant plants. Pathway analysis revealed that DEPs were enriched in the biosynthesis of secondary metabolites, pyruvate metabolism, glycolysis/gluconeogenesis, carbon metabolism, ubiquinone and other terpenoid-quinone biosynthesis, and citrate cycle. Gene Ontology (GO) analysis presented that most of the DEPs were involved in the pyruvate metabolic process and pyruvate dehydrogenase complex. Proteins related to pyruvate dehydrogenase E1 component subunit alpha-1 displayed higher interaction in the protein-protein interaction (PPI) network. Thus, the overall results revealed that CRISPR/Cas9-guided OsSPL16 mutations have the potential to boost the grain yield of rice. Additionally, global proteome analysis has broad applications for discovering molecular components and dynamic regulation underlying the targeted gene mutations.
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The energy landscape for R-loop formation by the CRISPR-Cas Cascade complex.
Clustered regularly interspaced short palindromic repeats (CRISPR) sequences and CRISPR-associated (Cas) genes comprise CIRSPR-Cas effector complexes, which have revolutionized gene editing with their ability to target specific genomic loci using CRISPR RNA (crRNA) complementarity. Recognition of double-stranded DNA targets proceeds via DNA unwinding and base pairing between crRNA and the DNA target strand, forming an R-loop structure. Full R-loop extension is a prerequisite for subsequent DNA cleavage. However, the recognition of unintended sequences with multiple mismatches has limited therapeutic applications and is still poorly understood on a mechanistic level. Here we set up ultrafast DNA unwinding experiments on the basis of plasmonic DNA origami nanorotors to study R-loop formation by the Cascade effector complex in real time, close to base-pair resolution. We resolve a weak global downhill bias of the forming R-loop, followed by a steep uphill bias for the final base pairs. We also show that the energy landscape is modulated by base flips and mismatches. These findings suggest that Cascade-mediated R-loop formation occurs on short timescales in submillisecond single base-pair steps, but on longer timescales in six base-pair intermediate steps, in agreement with the structural periodicity of the crRNA-DNA hybrid.
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Therapeutic gene editing strategies using CRISPR-Cas9 for the β-hemoglobinopathies.
With advancements in gene editing technologies, our ability to make precise and efficient modifications to the genome is increasing at a remarkable rate, paving the way for scientists and clinicians to uniquely treat a multitude of previously irremediable diseases. CRISPR-Cas9, short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9, is a gene editing platform with the ability to alter the nucleotide sequence of the genome in living cells. This technology is increasing the number and pace at which new gene editing treatments for genetic disorders are moving toward the clinic. The β-hemoglobinopathies are a group of monogenic diseases, which despite their high prevalence and chronic debilitating nature, continue to have few therapeutic options available. In this review, we will discuss our existing comprehension of the genetics and current state of treatment for β-hemoglobinopathies, consider potential genome editing therapeutic strategies, and provide an overview of the current state of clinical trials using CRISPR-Cas9 gene editing.
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CRISPR/Cas genome editing system and its application in potato.
Potato is the largest non-cereal food crop worldwide and a vital substitute for cereal crops, considering its high yield and great nutritive value. It plays an important role in food security. The CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated) system has the advantages of easy operation, high efficiency, and low cost, which shows a potential in potato breeding. In this paper, the action mechanism and derivative types of the CRISPR/Cas system and the application of the CRISPR/Cas system in improving the quality and resistance of potatoes, as well as overcoming the self-incompatibility of potatoes, are reviewed in detail. At the same time, the application of the CRISPR/Cas system in the future development of the potato industry was analyzed and prospected.
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Recent advances in universal chimeric antigen receptor T cell therapy.
While chimeric antigen receptor (CAR) T cell therapy is highly effective for hematological malignancies, its widespread use is limited by complex, patient-specific manufacturing. Universal CAR-T (UCAR-T) cells, derived from allogeneic donors, offer a potential "off-the-shelf" solution. However, their clinical translation hinges on overcoming two key immunological barriers: graft-versus-host disease (GvHD) and host-versus-graft rejection (HvGR), which compromise safety and therapeutic persistence. This review summarizes recent advances in UCAR-T cell engineering and clinical strategies designed to improve both safety and efficacy. We discuss gene-editing technologies-such as CRISPR/Cas9 and base editors-used to prevent GvHD by ablating the T cell receptor (TCR) and to evade HvGR by disrupting human leukocyte antigen (HLA) expression. We also explore the development of UCAR-T products from alternative cell sources with low intrinsic alloreactivity, such as γδ T cells. Furthermore, we detail multifaceted approaches to augment UCAR-T cell function and persistence, from the perspectives of enhancing intrinsic functions, reshaping the tumor microenvironment (TME) and overcoming tumor heterogeneity. Finally, we analyze recent clinical trial outcomes, which show promising efficacy in hematological malignancies but highlight ongoing challenges in solid tumors. The continued integration of sophisticated cellular engineering with innovative clinical strategies-such as enhanced lymphodepletion, combination therapies, and alternative administration routes-will be essential to realize the full potential of UCAR-T as a widely accessible and potent cell therapy.
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Gene Doping-in Animals? Ethical Issues at the Intersection of Animal Use, Gene Editing, and Sports Ethics.
Gene editors such as CRISPR could be used to create stronger, faster, or more resilient nonhuman animals. This is of keen interest to people who breed, train, race, and profit off the millions of animals used in sport that contribute billions of dollars to legal and illegal economies across the globe. People have tried for millennia to perfect sport animals; CRISPR proposes to do in one generation what might have taken decades previously. Moreover, gene editing may facilitate enhancing animals' capacities beyond their typical limits. This paper describes the state of animal use and engineering for sport, examines the moral status of animals, and analyzes current and future ethical issues at the intersection of animal use, gene editing, and sports. We argue that animal sport enthusiasts and animal welfarists alike should be concerned about the inevitable use of CRISPR in sport animals. Though in principle CRISPR could be used to improve sport animals' well-being, we think it is unlikely in practice to do so.
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The precise regulation of different COR genes by individual CBF transcription factors in Arabidopsis thaliana.
The transcription factors CBF1/2/3 are reported to play a dominant role in the cold responsive network of Arabidopsis by directly regulating the expression levels of cold responsive (COR) genes. In this study, we obtained CRISPR/Cas9-mediated loss-of-function mutants of cbf1∼3. Over 3,000 COR genes identified by RNA-seq analysis showed a slight but significant change in their expression levels in the mutants compared to the wild-type plants after being treated at 4 °C for 12 h. The C-repeat (CRT) motif (5'-CCGAC-3') was enriched in promoters of genes that were up-regulated by CBF2 and CBF3 but not in promoters of genes up-regulated by CBF1. These data suggest that CBF2 and CBF3 play a more important role in directing the cold response by regulating different sets of downstream COR genes. More than 2/3 of COR genes were co-regulated by two or three CBFs and were involved mainly in cellular signal transduction and metabolic processes; less than 1/3 of the genes were regulated by one CBF, and those genes up-regulated were enriched in cold-related abiotic stress responses. Our results indicate that CBFs play an important role in the trade-off between cold tolerance and plant growth through the precise regulation of COR genes in the complicated transcriptional network.
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Revisiting Risk Governance of GM Plants: The Need to Consider New and Emerging Gene-Editing Techniques.
New and emerging gene-editing techniques make it possible to target specific genes in species with greater speed and specificity than previously possible. Of major relevance for plant breeding, regulators and scientists are discussing how to regulate products developed using these gene-editing techniques. Such discussions include whether to adopt or adapt the current framework for GMO risk governance in evaluating the impacts of gene-edited plants, and derived products, on the environment, human and animal health and society. Product classification or definition is one of several aspects of the current framework being criticized. Further, knowledge gaps related to risk assessments of gene-edited organisms-for example of target and off-target effects of intervention in plant genomes-are also of concern. Resolving these and related aspects of the current framework will involve addressing many subjective, value-laden positions, for example how to specify protection goals through ecosystem service approaches. A process informed by responsible research and innovation practices, involving a broader community of people, organizations, experts, and interest groups, could help scientists, regulators, and other stakeholders address these complex, value-laden concerns related to gene-editing of plants with and for society.
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