A novel approach to Biopharm cell line selection using advanced molecular microscopy and chemical profiling

在制药行业中，培养的细胞系在生产生物治疗药物方面具有巨大的潜力。我们对“生产者”细胞系内各种生物学过程的细胞、代谢和遗传机制的理解还不完全清楚。目前正在整个行业探索识别这些细胞属性并将其与生物处理表型联系起来的努力，以优化生物治疗生产。光学显微镜是细胞生物学中不可或缺的工具，也是以高空间和时间分辨率破译活细胞中生物分子和小分子化合物的位置、功能和相互作用的唯一实用方法。光学显微镜技术领域的进步使新一代显微镜得以开发，这种显微镜允许在不需要染色或操作的情况下可视化细胞的化学成分。相干反斯托克斯拉曼散射(CARS)，结合了拉曼光谱的化学特性和多光子显微镜的固有光学切片。该项目涉及到应用分子成像方法和图像分析能力来可视化细胞内和细胞外的代谢物，定位蛋白质表达，并确定表达外源蛋白质的关键因素。通过将这些技术应用于显示不同表型的细胞系，我们可以将基于图像的数据集与过程性能相关联，并识别细胞器丰度、蛋白质运输、分泌瓶颈和内在生化特征等细胞现象。这个为期4年的博士生项目涉及葛兰素史克和卡迪夫大学的联合专业知识，以利用专业和先进的显微镜技术更深入地了解细胞特征。这个项目旨在开发和嵌入特定的生物成像技术在细胞系发展的早期阶段。这个专业是跨学科的，因此适合物理和生命科学的毕业生。作为项目的一部分，学生将在GSK至少呆上3个月，在4年的课程中获得工业环境下的研究经验。

Cultured cell lines have great potential within the pharmaceutical industry for the production of biotherapeutics. Our understanding of the cellular, metabolic and genetic mechanisms underpinning various biological processes within "producer" cell lines are not fully understood. Current efforts to identify and link these cellular properties to bioprocessing phenotypes are being explored across the industry in order to optimise biotherapeutic production. Optical microscopy is an indispensable tool in cell biology and is still the only practical way to decipher the cellular location, function and interactions of biomolecules and small molecular compounds in living cells with high spatial and temporal resolution. Advances within the field of optical microscopy technologies have enabled a new generation of microscopes to be developed that allow the chemical components of a cell to be visualised without the need of staining or manipulation. Coherent anti-Stokes Raman scattering (CARS), combines the chemical specificity of Raman spectroscopy with the intrinsic optical sectioning of multiphoton microscopy.This project involves the application of molecular imaging methodologies and image analysis capabilities to visualise intra and extra-cellular metabolites, localise protein expression and identify key factors for expressing exogenous proteins. Through applications of these techniques to cell lines displaying differential phenotypes, we can correlate image-based data-sets with process performance, and identify cellular phenomena such as organelle abundance, protein trafficking, secretion bottlenecks and inherent biochemical profiles.This 4-year PhD studentship is a collaborative project involving the combined expertise of GSK and Cardiff University to gain deeper understanding of cellular characteristics using specialised and advanced microscopy techniques. This project aims to develop and embed specific Bio-imaging techniques within early stage cell line development.This studentship is cross-disciplinary in nature, and so would suit graduates from both the physical and life sciences. As part of the project the student will spend a minimum of 3 months at GSK, to gain research experience in an industrial setting, over the course of 4 years.