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Gene therapy at the crossroads

doi : 10.1038/s41587-022-01346-7

Volume 40 Issue 5, May 2022

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Base editing marches on the clinic

Michael Eisenstein 

doi : 10.1038/s41587-022-01326-x

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Cosmetics: when biotech is better than nature

Emily WaltzÂ

doi : 10.1038/s41587-022-01318-x

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Climate-friendly couture

Emily Waltz 

doi : 10.1038/s41587-022-01319-w

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Drug pipeline 1Q22 � a raft of new modalities … and clinical blowups

Laura DeFrancesco 

doi : 10.1038/s41587-022-01310-5

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1Q22 � Blood in the water

Laura DeFrancesco 

doi : 10.1038/s41587-022-01314-1

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Baby’s first genome

Caroline Seydel 

doi : 10.1038/s41587-022-01306-1

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Reflections on Alnylam

John Maraganore 

doi : 10.1038/s41587-022-01304-3

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Relieving patent-eligibility barriers in biotech with a preparation or treatment method

Jir-You Wang, Yi-Fang Tsai, Tien-Hsiang Wang & Shyh-Jen WangÂ

doi : 10.1038/s41587-022-01301-6

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Forum: CRISPR screening roundtable with Stegmaier and Doench

doi : 10.1038/s41587-022-01303-4

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Sensitive identification of neoantigens and cognate TCRs in human solid tumors

Marion Arnaud, Johanna Chiffelle, Raphael Genolet, Blanca Navarro Rodrigo, Marta A. S. Perez, Florian Huber, Morgane Magnin, Tu Nguyen-Ngoc, Philippe Guillaume, Petra Baumgaertner, Chloe Chong, Brian J. Stevenson, David Gfeller, Melita Irving, Daniel E. Speiser, Julien Schmidt, Vincent Zoete, Lana E. Kandalaft, Michal Bassani-Sternberg, Sara Bobisse, George Coukos & Alexandre HarariÂ

doi : 10.1038/s41587-021-01072-6

The identification of patient-specific tumor antigens is complicated by the low frequency of T cells specific for each tumor antigen. Here we describe NeoScreen, a method that enables the sensitive identification of rare tumor (neo)antigens and of cognate T cell receptors (TCRs) expressed by tumor-infiltrating lymphocytes. T cells transduced with tumor antigen-specific TCRs identified by NeoScreen mediate regression of established tumors in patient-derived xenograft mice.

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Cell2location maps fine-grained cell types in spatial transcriptomics

Vitalii Kleshchevnikov, Artem Shmatko, Emma Dann, Alexander Aivazidis, Hamish W. King, Tong Li, Rasa Elmentaite, Artem Lomakin, Veronika Kedlian, Adam Gayoso, Mika Sarkin Jain, Jun Sung Park, Lauma Ramona, Elizabeth Tuck, Anna Arutyunyan, Roser Vento-Tormo, Moritz Gerstung, Louisa James, Oliver Stegle & Omer Ali BayraktarÂ

doi : 10.1038/s41587-021-01139-4

Spatial transcriptomic technologies promise to resolve cellular wiring diagrams of tissues in health and disease, but comprehensive mapping of cell types in situ remains a challenge. Here we present �ell2location, a Bayesian model that can resolve fine-grained cell types in spatial transcriptomic data and create comprehensive cellular maps of diverse tissues.

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Curated variation benchmarks for challenging medically relevant autosomal genes

Justin Wagner, Nathan D. Olson, Lindsay Harris, Jennifer McDaniel, Haoyu Cheng, Arkarachai Fungtammasan, Yih-Chii Hwang, Richa Gupta, Aaron M. Wenger, William J. Rowell, Ziad M. Khan, Jesse Farek, Yiming Zhu, Aishwarya Pisupati, Medhat Mahmoud, Chunlin Xiao, Byunggil Yoo, Sayed Mohammad Ebrahim Sahraeian, Danny E. Miller, David Jáspez, José M. Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A. Rubio-Rodríguez, Carlos Flores, …Fritz J. SedlazeckÂ

doi : 10.1038/s41587-021-01158-1

The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity.

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Multiscale PHATE identifies multimodal signatures of COVID-19

Manik Kuchroo, Jessie Huang, Patrick Wong, Jean-Christophe Grenier, Dennis Shung, Alexander Tong, Carolina Lucas, Jon Klein, Daniel B. Burkhardt, Scott Gigante, Abhinav Godavarthi, Bastian Rieck, Benjamin Israelow, Michael Simonov, Tianyang Mao, Ji Eun Oh, Julio Silva, Takehiro Takahashi, Camila D. Odio, Arnau Casanovas-Massana, John Fournier, Yale IMPACT Team, Shelli Farhadian, Charles S. Dela Cruz, …Smita KrishnaswamyÂ

doi : 10.1038/s41587-021-01186-x

As the biomedical community produces datasets that are increasingly complex and high dimensional, there is a need for more sophisticated computational tools to extract biological insights. We present Multiscale PHATE, a method that sweeps through all levels of data granularity to learn abstracted biological features directly predictive of disease outcome.

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A knowledge graph to interpret clinical proteomics data

Alberto Santos, Ana R. Colaço, Annelaura B. Nielsen, Lili Niu, Maximilian Strauss, Philipp E. Geyer, Fabian Coscia, Nicolai J. Wewer Albrechtsen, Filip Mundt, Lars Juhl Jensen & Matthias MannÂ

doi : 10.1038/s41587-021-01145-6

Implementing precision medicine hinges on the integration of omics data, such as proteomics, into the clinical decision-making process, but the quantity and diversity of biomedical data, and the spread of clinically relevant knowledge across multiple biomedical databases and publications, pose a challenge to data integration.

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scJoint integrates atlas-scale single-cell RNA-seq and ATAC-seq data with transfer learning

Yingxin Lin, Tung-Yu Wu, Sheng Wan, Jean Y. H. Yang, Wing H. Wong & Y. X. Rachel WangÂ

doi : 10.1038/s41587-021-01161-6

Single-cell multiomics data continues to grow at an unprecedented pace. Although several methods have demonstrated promising results in integrating several data modalities from the same tissue, the complexity and scale of data compositions present in cell atlases still pose a challenge.

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Generating lineage-resolved, complete metagenome-assembled genomes from complex microbial communities

Derek M. Bickhart, Mikhail Kolmogorov, Elizabeth Tseng, Daniel M. Portik, Anton Korobeynikov, Ivan Tolstoganov, Gherman Uritskiy, Ivan Liachko, Shawn T. Sullivan, Sung Bong Shin, Alvah Zorea, Victòria Pascal Andreu, Kevin Panke-Buisse, Marnix H. Medema, Itzhak Mizrahi, Pavel A. Pevzner & Timothy P. L. SmithÂ

doi : 10.1038/s41587-021-01130-z

Microbial communities might include distinct lineages of closely related organisms that complicate metagenomic assembly and prevent the generation of complete metagenome-assembled genomes (MAGs).

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Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues

Calum Gabbutt, Ryan O. Schenck, Daniel J. Weisenberger, Christopher Kimberley, Alison Berner, Jacob Househam, Eszter Lakatos, Mark Robertson-Tessi, Isabel Martin, Roshani Patel, Susan K. Clark, Andrew Latchford, Chris P. Barnes, Simon J. Leedham, Alexander R. A. Anderson, Trevor A. Graham & Darryl ShibataÂ

doi : 10.1038/s41587-021-01109-w

Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated ‘flip–flops’ between methylated and unmethylated states.

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Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing

Andrew V. Anzalone, Xin D. Gao, Christopher J. Podracky, Andrew T. Nelson, Luke W. Koblan, Aditya Raguram, Jonathan M. Levy, Jaron A. M. Mercer & David R. LiuÂ

doi : 10.1038/s41587-021-01133-w

The targeted deletion, replacement, integration or inversion of genomic sequences could be used to study or treat human genetic diseases, but existing methods typically require double-strand DNA breaks (DSBs) that lead to undesired consequences, including uncontrolled indel mixtures and chromosomal abnormalities.

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Partitioning RNAs by length improves transcriptome reconstruction from short-read RNA-seq data

Francisca Rojas Ringeling, Shounak Chakraborty, Caroline Vissers, Derek Reiman, Akshay M. Patel, Ki-Heon Lee, Ari Hong, Chan-Woo Park, Tim Reska, Julien Gagneur, Hyeshik Chang, Maria L. Spletter, Ki-Jun Yoon, Guo-li Ming, Hongjun Song & Stefan CanzarÂ

doi : 10.1038/s41587-021-01136-7

The accuracy of methods for assembling transcripts from short-read RNA sequencing data is limited by the lack of long-range information. Here we introduce Ladder-seq, an approach that separates transcripts according to their lengths before sequencing and uses the additional information to improve the quantification and assembly of transcripts.

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Engineering the amoeba Dictyostelium discoideum for biosynthesis of a cannabinoid precursor and other polyketides

Christin Reimer, Johann E. Kufs, Julia Rautschek, Lars Regestein, Vito Valiante & Falk HillmannÂ

doi : 10.1038/s41587-021-01143-8

Aromatic polyketides are natural polyphenolic compounds with a broad spectrum of pharmacological activities.

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CLUSTER guide RNAs enable precise and efficient RNA editing with endogenous ADAR enzymes in vivo

Philipp Reautschnig, Nicolai Wahn, Jacqueline Wettengel, Annika E. Schulz, Ngadhnjim Latifi, Paul Vogel, Tae-Won Kang, Laura S. Pfeiffer, Christine Zarges, Ulrike Naumann, Lars Zender, Jin Billy Li & Thorsten StafforstÂ

doi : 10.1038/s41587-021-01105-0

RNA base editing represents a promising alternative to genome editing. Recent approaches harness the endogenous RNA-editing enzyme adenosine deaminase acting on RNA (ADAR) to circumvent problems caused by ectopic expression of engineered editing enzymes, but suffer from sequence restriction, lack of efficiency and bystander editing.

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Conformation-locking antibodies for the discovery and characterization of KRAS inhibitors

Christopher W. Davies, Angela J. Oh, Rana Mroue, Micah Steffek, John M. Bruning, Yang Xiao, Siyu Feng, Sangeeta Jayakar, Emily Chan, Vidhyalakshmi Arumugam, Sean Carlo Uribe, Jake Drummond, Alexandra Frommlet, Cheng Lu, Yvonne Franke, Mark Merchant, Hartmut Koeppen, John G. Quinn, Sushant Malhotra, Steve Do, Lewis Gazzard, Hans E. Purkey, Joachim Rudolph, Melinda M. Mulvihill, …Marie EvangelistaÂ

doi : 10.1038/s41587-021-01126-9

Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. To facilitate the discovery and characterization of such inhibitors, we created a screening platform to identify conformation-locking antibodies for molecular probes (CLAMPs) that distinguish and induce rare protein conformational states.

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Optogenetic control of RNA function and metabolism using engineered light-switchable RNA-binding proteins

Renmei Liu, Jing Yang, Jing Yao, Zhou Zhao, Wei He, Ni Su, Zeyi Zhang, Chenxia Zhang, Zhuo Zhang, Haibo Cai, Linyong Zhu, Yuzheng Zhao, Shu Quan, Xianjun Chen & Yi YangÂ

doi : 10.1038/s41587-021-01112-1

RNA-binding proteins (RBPs) play an essential role in regulating the function of RNAs in a cellular context, but our ability to control RBP activity in time and space is limited. Here, we describe the engineering of LicV, a photoswitchable RBP that binds to a specific RNA sequence in response to blue light irradiation.

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A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo

Ao Dong, Kaikai He, Barna Dudok, Jordan S. Farrell, Wuqiang Guan, Daniel J. Liput, Henry L. Puhl, Ruyi Cai, Huan Wang, Jiali Duan, Eddy Albarran, Jun Ding, David M. Lovinger, Bo Li, Ivan Soltesz & Yulong LiÂ

doi : 10.1038/s41587-021-01074-4

Endocannabinoids (eCBs) are retrograde neuromodulators with important functions in a wide range of physiological processes, but their in vivo dynamics remain largely uncharacterized. Here we developed a genetically encoded eCB sensor called GRABeCB2.0.

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Author Correction: Engineered promoters enable constant gene expression at any copy number in bacteria

Thomas H. Segall-Shapiro, Eduardo D. Sontag & Christopher A. VoigtÂ

doi : 10.1038/s41587-022-01300-7

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Publisher Correction: Diabetes cell therapies take evasive action

Elie Dolgin 

doi : 10.1038/s41587-022-01322-1

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Publisher Correction: Bio-leather gears up to wow fashion industry

Emily Waltz 

doi : 10.1038/s41587-022-01329-8

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First-quarter biotech job picture

Michael Francisco 

doi : 10.1038/s41587-022-01313-2

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