{"title":"Italy tests first gene-edited vines for winemaking","authors":"","doi":"10.1038/s41587-024-02478-8","DOIUrl":"https://doi.org/10.1038/s41587-024-02478-8","url":null,"abstract":"Europe’s first field trial of gene-edited vines began in northern Italy on 30 September 2024. Developed by EdiVite, a spinoff from the University of Verona, these Chardonnay vines have undergone gene inactivation to enable them to better defend themselves against downy mildew, a major fungal disease. The trial is being conducted on university land, with plans to expand to another site in the Veneto region. Researchers aim to gather initial data by 2025, with the potential for experimental winemaking in 2026.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ancient and versatile CRISPR–Cas nuclease created with ancestral sequence reconstruction","authors":"","doi":"10.1038/s41587-024-02468-w","DOIUrl":"https://doi.org/10.1038/s41587-024-02468-w","url":null,"abstract":"Ancestral sequence reconstruction enables the identification and synthesis of ReChb, an ancient form of CRISPR–Cas12a with a highly versatile functionality. ReChb can target any nucleic acid, with minimal restrictions, making it a multipurpose tool for genome editing and genetic diagnostics.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas D. Avery, Jiahe Li, Dion J. L. Turner, Mohd S. U. Rasheed, Fisher R. Cherry, Damian L. Stachura, Fátima Rivera-Escalera, David M. Ruiz, Michael J. Lacagnina, Caitlyn M. Gaffney, Clarissa Aguilar, Jingxian Yu, Yang Wang, Huan Xie, Dong Liang, Andrew J. Shepherd, Andrew D. Abell, Peter M. Grace
{"title":"Site-specific drug release of monomethyl fumarate to treat oxidative stress disorders","authors":"Thomas D. Avery, Jiahe Li, Dion J. L. Turner, Mohd S. U. Rasheed, Fisher R. Cherry, Damian L. Stachura, Fátima Rivera-Escalera, David M. Ruiz, Michael J. Lacagnina, Caitlyn M. Gaffney, Clarissa Aguilar, Jingxian Yu, Yang Wang, Huan Xie, Dong Liang, Andrew J. Shepherd, Andrew D. Abell, Peter M. Grace","doi":"10.1038/s41587-024-02460-4","DOIUrl":"https://doi.org/10.1038/s41587-024-02460-4","url":null,"abstract":"<p>Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer–Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CRISPR Nobelists surrender their own European patents","authors":"","doi":"10.1038/s41587-024-02472-0","DOIUrl":"https://doi.org/10.1038/s41587-024-02472-0","url":null,"abstract":"A strategic move by lawyers acting for Doudna and Charpentier is the latest twist in the battleground for CRISPR–Cas9 technology.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Frank Erasmus, Laura Spector, Fortunato Ferrara, Roberto DiNiro, Thomas J. Pohl, Katheryn Perea-Schmittle, Wei Wang, Peter M. Tessier, Crystal Richardson, Laure Turner, Sumit Kumar, Daniel Bedinger, Pietro Sormanni, Monica L. Fernández-Quintero, Andrew B. Ward, Johannes R. Loeffler, Olivia M. Swanson, Charlotte M. Deane, Matthew I. J. Raybould, Andreas Evers, Carolin Sellmann, Sharrol Bachas, Jeff Ruffolo, Horacio G. Nastri, Karthik Ramesh, Jesper Sørensen, Rebecca Croasdale-Wood, Oliver Hijano, Camila Leal-Lopes, Melody Shahsavarian, Yu Qiu, Paolo Marcatili, Erik Vernet, Rahmad Akbar, Simon Friedensohn, Rick Wagner, Vinodh babu Kurella, Shipra Malhotra, Satyendra Kumar, Patrick Kidger, Juan C. Almagro, Eric Furfine, Marty Stanton, Christilyn P. Graff, Santiago David Villalba, Florian Tomszak, Andre A. R. Teixeira, Elizabeth Hopkins, Molly Dovner, Sara D’Angelo, Andrew R. M. Bradbury
{"title":"AIntibody: an experimentally validated in silico antibody discovery design challenge","authors":"M. Frank Erasmus, Laura Spector, Fortunato Ferrara, Roberto DiNiro, Thomas J. Pohl, Katheryn Perea-Schmittle, Wei Wang, Peter M. Tessier, Crystal Richardson, Laure Turner, Sumit Kumar, Daniel Bedinger, Pietro Sormanni, Monica L. Fernández-Quintero, Andrew B. Ward, Johannes R. Loeffler, Olivia M. Swanson, Charlotte M. Deane, Matthew I. J. Raybould, Andreas Evers, Carolin Sellmann, Sharrol Bachas, Jeff Ruffolo, Horacio G. Nastri, Karthik Ramesh, Jesper Sørensen, Rebecca Croasdale-Wood, Oliver Hijano, Camila Leal-Lopes, Melody Shahsavarian, Yu Qiu, Paolo Marcatili, Erik Vernet, Rahmad Akbar, Simon Friedensohn, Rick Wagner, Vinodh babu Kurella, Shipra Malhotra, Satyendra Kumar, Patrick Kidger, Juan C. Almagro, Eric Furfine, Marty Stanton, Christilyn P. Graff, Santiago David Villalba, Florian Tomszak, Andre A. R. Teixeira, Elizabeth Hopkins, Molly Dovner, Sara D’Angelo, Andrew R. M. Bradbury","doi":"10.1038/s41587-024-02469-9","DOIUrl":"https://doi.org/10.1038/s41587-024-02469-9","url":null,"abstract":"<p>Science is frequently subject to the Gartner hype cycle<sup>1</sup>: emergent technologies spark intense initial enthusiasm with the recruitment of dedicated scientists. As limitations are recognized, disillusionment often sets in; some scientists turn away, disappointed in the inability of the new technology to deliver on initial promise, while others persevere and further develop the technology. Although the value (or not) of a new technology usually becomes clear with time, appropriate benchmarks can be invaluable in highlighting strengths and areas for improvement, substantially speeding up technology maturation. A particular challenge in computational engineering and artificial intelligence (AI)/machine learning (ML) is that benchmarks and best practices are uncommon, so it is particularly hard for non-experts to assess the impact and performance of these methods. Although multiple papers have highlighted best practices and evaluation guidelines<sup>2,3,4</sup>, the true test for such methods is ultimately prospective performance, which requires experimental testing.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"What will it take to get miRNA therapies to market?","authors":"","doi":"10.1038/s41587-024-02480-0","DOIUrl":"https://doi.org/10.1038/s41587-024-02480-0","url":null,"abstract":"The Nobel Prize in medicine was awarded for the discovery of miRNA, but miRNA therapeutics have a long way to go before they outcompete other therapies.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew J. Szarzanowicz, Lucas M. Waldburger, Michael Busche, Gina M. Geiselman, Liam D. Kirkpatrick, Alexander J. Kehl, Claudine Tahmin, Rita C. Kuo, Joshua McCauley, Hamreet Pannu, Ruoming Cui, Shuying Liu, Nathan J. Hillson, Jacob O. Brunkard, Jay D. Keasling, John M. Gladden, Mitchell G. Thompson, Patrick M. Shih
{"title":"Binary vector copy number engineering improves Agrobacterium-mediated transformation","authors":"Matthew J. Szarzanowicz, Lucas M. Waldburger, Michael Busche, Gina M. Geiselman, Liam D. Kirkpatrick, Alexander J. Kehl, Claudine Tahmin, Rita C. Kuo, Joshua McCauley, Hamreet Pannu, Ruoming Cui, Shuying Liu, Nathan J. Hillson, Jacob O. Brunkard, Jay D. Keasling, John M. Gladden, Mitchell G. Thompson, Patrick M. Shih","doi":"10.1038/s41587-024-02462-2","DOIUrl":"https://doi.org/10.1038/s41587-024-02462-2","url":null,"abstract":"<p>The copy number of a plasmid is linked to its functionality, yet there have been few attempts to optimize higher-copy-number mutants for use across diverse origins of replication in different hosts. We use a high-throughput growth-coupled selection assay and a directed evolution approach to rapidly identify origin of replication mutations that influence copy number and screen for mutants that improve <i>Agrobacterium</i>-mediated transformation (AMT) efficiency. By introducing these mutations into binary vectors within the plasmid backbone used for AMT, we observe improved transient transformation of <i>Nicotiana benthamiana</i> in four diverse tested origins (pVS1, RK2, pSa and BBR1). For the best-performing origin, pVS1, we isolate higher-copy-number variants that increase stable transformation efficiencies by 60–100% in <i>Arabidopsis thaliana</i> and 390% in the oleaginous yeast <i>Rhodosporidium toruloides</i>. Our work provides an easily deployable framework to generate plasmid copy number variants that will enable greater precision in prokaryotic genetic engineering, in addition to improving AMT efficiency.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Josh Tycko, Mike V. Van, Aradhana, Nicole DelRosso, Hanrong Ye, David Yao, Raeline Valbuena, Alun Vaughan-Jackson, Xiaoshu Xu, Connor Ludwig, Kaitlyn Spees, Katherine Liu, Mingxin Gu, Venya Khare, Adi Xiyal Mukund, Peter H. Suzuki, Sophia Arana, Catherine Zhang, Peter P. Du, Thea S. Ornstein, Gaelen T. Hess, Roarke A. Kamber, Lei S. Qi, Ahmad S. Khalil, Lacramioara Bintu, Michael C. Bassik
{"title":"Development of compact transcriptional effectors using high-throughput measurements in diverse contexts","authors":"Josh Tycko, Mike V. Van, Aradhana, Nicole DelRosso, Hanrong Ye, David Yao, Raeline Valbuena, Alun Vaughan-Jackson, Xiaoshu Xu, Connor Ludwig, Kaitlyn Spees, Katherine Liu, Mingxin Gu, Venya Khare, Adi Xiyal Mukund, Peter H. Suzuki, Sophia Arana, Catherine Zhang, Peter P. Du, Thea S. Ornstein, Gaelen T. Hess, Roarke A. Kamber, Lei S. Qi, Ahmad S. Khalil, Lacramioara Bintu, Michael C. Bassik","doi":"10.1038/s41587-024-02442-6","DOIUrl":"https://doi.org/10.1038/s41587-024-02442-6","url":null,"abstract":"<p>Transcriptional effectors are protein domains known to activate or repress gene expression; however, a systematic understanding of which effector domains regulate transcription across genomic, cell type and DNA-binding domain (DBD) contexts is lacking. Here we develop dCas9-mediated high-throughput recruitment (HT-recruit), a pooled screening method for quantifying effector function at endogenous target genes and test effector function for a library containing 5,092 nuclear protein Pfam domains across varied contexts. We also map context dependencies of effectors drawn from unannotated protein regions using a larger library tiling chromatin regulators and transcription factors. We find that many effectors depend on target and DBD contexts, such as HLH domains that can act as either activators or repressors. To enable efficient perturbations, we select context-robust domains, including ZNF705 KRAB, that improve CRISPRi tools to silence promoters and enhancers. We engineer a compact human activator called NFZ, by combining NCOA3, FOXO3 and ZNF473 domains, which enables efficient CRISPRa with better viral delivery and inducible control of chimeric antigen receptor T cells.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ylenia Jabalera, Igor Tascón, Sara Samperio, Jorge P. López-Alonso, Monika Gonzalez-Lopez, Ana M. Aransay, Guillermo Abascal-Palacios, Chase L. Beisel, Iban Ubarretxena-Belandia, Raul Perez-Jimenez
{"title":"A resurrected ancestor of Cas12a expands target access and substrate recognition for nucleic acid editing and detection","authors":"Ylenia Jabalera, Igor Tascón, Sara Samperio, Jorge P. López-Alonso, Monika Gonzalez-Lopez, Ana M. Aransay, Guillermo Abascal-Palacios, Chase L. Beisel, Iban Ubarretxena-Belandia, Raul Perez-Jimenez","doi":"10.1038/s41587-024-02461-3","DOIUrl":"https://doi.org/10.1038/s41587-024-02461-3","url":null,"abstract":"<p>The properties of Cas12a nucleases constrict the range of accessible targets and their applications. In this study, we applied ancestral sequence reconstruction (ASR) to a set of Cas12a orthologs from hydrobacteria to reconstruct a common ancestor, ReChb, characterized by near-PAMless targeting and the recognition of diverse nucleic acid activators and collateral substrates. ReChb shares 53% sequence identity with the closest Cas12a ortholog but no longer requires a T-rich PAM and can achieve genome editing in human cells at sites inaccessible to the natural FnCas12a or the engineered and PAM-flexible enAsCas12a. Furthermore, ReChb can be triggered not only by double-stranded DNA but also by single-stranded RNA and DNA targets, leading to non-specific collateral cleavage of all three nucleic acid substrates with similar efficiencies. Finally, tertiary and quaternary structures of ReChb obtained by cryogenic electron microscopy reveal the molecular details underlying its expanded biophysical activities. Overall, ReChb expands the application space of Cas12a nucleases and underscores the potential of ASR for enhancing CRISPR technologies.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sairam Behera, Severine Catreux, Massimiliano Rossi, Sean Truong, Zhuoyi Huang, Michael Ruehle, Arun Visvanath, Gavin Parnaby, Cooper Roddey, Vitor Onuchic, Andrea Finocchio, Daniel L. Cameron, Adam English, Shyamal Mehtalia, James Han, Rami Mehio, Fritz J. Sedlazeck
{"title":"Comprehensive genome analysis and variant detection at scale using DRAGEN","authors":"Sairam Behera, Severine Catreux, Massimiliano Rossi, Sean Truong, Zhuoyi Huang, Michael Ruehle, Arun Visvanath, Gavin Parnaby, Cooper Roddey, Vitor Onuchic, Andrea Finocchio, Daniel L. Cameron, Adam English, Shyamal Mehtalia, James Han, Rami Mehio, Fritz J. Sedlazeck","doi":"10.1038/s41587-024-02382-1","DOIUrl":"https://doi.org/10.1038/s41587-024-02382-1","url":null,"abstract":"<p>Research and medical genomics require comprehensive, scalable methods for the discovery of novel disease targets, evolutionary drivers and genetic markers with clinical significance. This necessitates a framework to identify all types of variants independent of their size or location. Here we present DRAGEN, which uses multigenome mapping with pangenome references, hardware acceleration and machine learning-based variant detection to provide insights into individual genomes, with ~30 min of computation time from raw reads to variant detection. DRAGEN outperforms current state-of-the-art methods in speed and accuracy across all variant types (single-nucleotide variations, insertions or deletions, short tandem repeats, structural variations and copy number variations) and incorporates specialized methods for analysis of medically relevant genes. We demonstrate the performance of DRAGEN across 3,202 whole-genome sequencing datasets by generating fully genotyped multisample variant call format files and demonstrate its scalability, accuracy and innovation to further advance the integration of comprehensive genomics. Overall, DRAGEN marks a major milestone in sequencing data analysis and will provide insights across various diseases, including Mendelian and rare diseases, with a highly comprehensive and scalable platform.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":46.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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