利用集合扰动进行可扩展的压缩表型筛选

IF 33.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Nuo Liu, Walaa E. Kattan, Benjamin E. Mead, Conner Kummerlowe, Thomas Cheng, Sarah Ingabire, Jaime H. Cheah, Christian K. Soule, Anita Vrcic, Jane K. McIninch, Sergio Triana, Manuel Guzman, Tyler T. Dao, Joshua M. Peters, Kristen E. Lowder, Lorin Crawford, Ava P. Amini, Paul C. Blainey, William C. Hahn, Brian Cleary, Bryan Bryson, Peter S. Winter, Srivatsan Raghavan, Alex K. Shalek
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引用次数: 0

摘要

使用生化扰动和高含量读数进行高通量表型筛选受到规模限制。为了解决这个问题,我们建立了一种汇集外源扰动并进行计算解卷积的方法,以减少所需的样本量、人力和成本。与传统方法相比,我们通过生物活性小分子库和高内容成像读出器进行基准测试,证明了压缩实验设计提高了效率。然后,我们在两个生物发现项目中应用了压缩筛选。在第一项研究中,我们利用早期胰腺癌器官组织绘制了重组肿瘤微环境蛋白配体库的转录反应图,发现了特定配体诱导的可重复表型转变,这种转变不同于典型的参考特征,并与临床结果相关。其次,我们确定了具有已知作用机制的化合物库对原发性人类外周血单核细胞免疫反应的多向性调节作用。总之,我们的方法赋予表型筛选以丰富的信息读数,以推进药物发现工作和基础生物学研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Scalable, compressed phenotypic screening using pooled perturbations

Scalable, compressed phenotypic screening using pooled perturbations

High-throughput phenotypic screens using biochemical perturbations and high-content readouts are constrained by limitations of scale. To address this, we establish a method of pooling exogenous perturbations followed by computational deconvolution to reduce required sample size, labor and cost. We demonstrate the increased efficiency of compressed experimental designs compared to conventional approaches through benchmarking with a bioactive small-molecule library and a high-content imaging readout. We then apply compressed screening in two biological discovery campaigns. In the first, we use early-passage pancreatic cancer organoids to map transcriptional responses to a library of recombinant tumor microenvironment protein ligands, uncovering reproducible phenotypic shifts induced by specific ligands distinct from canonical reference signatures and correlated with clinical outcome. In the second, we identify the pleotropic modulatory effects of a chemical compound library with known mechanisms of action on primary human peripheral blood mononuclear cell immune responses. In sum, our approach empowers phenotypic screens with information-rich readouts to advance drug discovery efforts and basic biological inquiry.

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来源期刊
Nature biotechnology
Nature biotechnology 工程技术-生物工程与应用微生物
CiteScore
63.00
自引率
1.70%
发文量
382
审稿时长
3 months
期刊介绍: Nature Biotechnology is a monthly journal that focuses on the science and business of biotechnology. It covers a wide range of topics including technology/methodology advancements in the biological, biomedical, agricultural, and environmental sciences. The journal also explores the commercial, political, ethical, legal, and societal aspects of this research. The journal serves researchers by providing peer-reviewed research papers in the field of biotechnology. It also serves the business community by delivering news about research developments. This approach ensures that both the scientific and business communities are well-informed and able to stay up-to-date on the latest advancements and opportunities in the field. Some key areas of interest in which the journal actively seeks research papers include molecular engineering of nucleic acids and proteins, molecular therapy, large-scale biology, computational biology, regenerative medicine, imaging technology, analytical biotechnology, applied immunology, food and agricultural biotechnology, and environmental biotechnology. In summary, Nature Biotechnology is a comprehensive journal that covers both the scientific and business aspects of biotechnology. It strives to provide researchers with valuable research papers and news while also delivering important scientific advancements to the business community.
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