De novo sequencing of the Chinese Hamster Ovary (CHO) cell genome

中国仓鼠卵巢 (CHO) 细胞基因组的从头测序

• 批准号: BB/I010610/1
• 负责人: David James
• 金额: $ 10.85万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI010610%2F1
• 关键词: De; novo; sequencing; Chinese; Hamster

The engineering paradigm of measure, model, manipulate and manufacture underpins the design of products, processes and structures with reliable, predictable performance. The design process requires a detailed knowledge of what the interacting components are, how they interact and the forces (rules) that govern those interactions. This is why it was possible to send a man to the moon in 1969 (i.e. to predict functional performance based on known physical interactions) but not to cure cancer (unpredictability deriving from complex, unknown components and interactions). Accordingly, as we enter a new age of biological engineering, the extent to which it will be possible to engineer complex biological systems for human benefit will ultimately depend upon the extent of our knowledge of those systems - the rules that govern how the complex biological system functions - or malfunctions in the case of disease. To engineer any biological system effectively we need a basic blueprint - knowledge (or design principles) that helps us to understand specifically how that organism is functionally equipped. For biological engineers this primary information is an organism's complete DNA sequence (it's genome). For simple organisms such as bacteria the genome is relatively simple - only about 6000 genes (functional genetic units) in Escherichia coli for example. In human cells there are over 30,000 genes and a large amount of 'non-coding' DNA involved in regulation of these genes. Using microbial genome sequence information, bioengineers can for the first time truly engage in the engineering design process. New ways of measuring and modelling the complexity of simple bacterial systems have emerged (this is 'systems biology') which enables us to (genetically) manipulate cells and manufacture novel products and processes using new tools (this is 'synthetic biology'). Importantly, bioengineers can now predict the functional capability of simple bacteria growing in vitro using computer models. Similar approaches are now being developed for inherently more complex mammalian cells. This project is designed to provide a much needed genomic resource for academic and industrial bioscientists and bioengineers in the UK concerned with the production of a new generation of recombinant DNA derived medicines made by made by genetically engineered cells in culture - biopharmaceuticals. Biopharmaceuticals are proving to be revolutionary treatments for many serious diseases such as rheumatoid arthritis and a range of cancers. We want to determine the genome sequence of an extremely important type of 'cell factory' that is used to make these bio-medicines; the Chinese hamster ovary (CHO) cell. Most (60-70%) biophamaceuticals are currently made by genetically engineered CHO cells in culture as well as the vast majority of those in development. However, despite the huge industrial and scientific importance of this cell type, we still do not have the CHO cell's genome sequence: The fundamental informatic resource necessary to utilise new systems and synthetic biology tools to understand and engineer the function of this cell factory. To address this problem we have formed a consortium of the UK's leading academic groups involved in research into CHO cell based manufacturing systems based at the Universities of Kent, Manchester and Sheffield, and four key industrial partners involved in biopharmaceutical manufacturing in the UK. In this project we will utilise the most advanced DNA sequencing technology available to rapidly sequence, assemble and annotate the CHO cell genome. We will establish a network to disseminate this information and to determine how we might most effectively harness this resource for future engineering strategies to improve CHO-cell based production processes. This project is necessary for, and will lead to, cutting-edge applied research underpinning new biopharmaceutical manufacturing technology.

测量、建模、操作和制造的工程范例支持具有可靠、可预测性能的产品、工艺和结构的设计。设计过程需要详细了解交互组件是什么、它们如何交互以及管理这些交互的力(规则)。这就是为什么有可能在1969年将人送上月球(即根据已知的物理相互作用预测功能性能)，但无法治愈癌症(复杂、未知的组件和相互作用产生的不可预测性)。因此，随着我们进入生物工程的新时代，设计复杂的生物系统以造福人类的可能性最终将取决于我们对这些系统的了解程度--管理复杂生物系统如何运作的规则--或疾病情况下的故障。为了有效地设计任何生物系统，我们需要一个基本的蓝图--知识(或设计原则)，帮助我们具体了解生物体是如何配备功能的。对于生物工程师来说，这些主要信息是生物体的完整DNA序列(即基因组)。对于细菌等简单的生物来说，基因组相对简单--例如，在大肠杆菌中只有大约6000个基因(功能遗传单位)。在人类细胞中，有超过30,000个基因和大量的“非编码”DNA参与这些基因的调控。利用微生物基因组序列信息，生物工程师第一次能够真正从事工程设计过程。测量和模拟简单细菌系统复杂性的新方法已经出现(这是“系统生物学”)，它使我们能够(从基因上)操纵细胞，并使用新工具制造新的产品和过程(这是“合成生物学”)。重要的是，生物工程师现在可以使用计算机模型来预测体外生长的简单细菌的功能能力。类似的方法现在正在为天生更复杂的哺乳动物细胞而开发。该项目旨在为英国学术界和工业界的生物科学家和生物工程师提供急需的基因组资源，这些科学家和生物工程师致力于生产由基因工程细胞在培养中制造的新一代重组DNA衍生药物-生物制药。事实证明，生物制药是许多严重疾病的革命性治疗方法，如类风湿性关节炎和一系列癌症。我们想要确定一种非常重要的‘细胞工厂’的基因组序列，这种‘细胞工厂’用于制造这些生物药物：中国仓鼠卵巢(CHO)细胞。目前，大多数(60%-70%)生物药物是由培养中的基因工程CHO细胞以及绝大多数处于开发中的细胞制造的。然而，尽管这种细胞类型具有巨大的工业和科学重要性，我们仍然没有CHO细胞的基因组序列：这是利用新系统和合成生物学工具了解和设计这个细胞工厂的功能所必需的基本信息资源。为了解决这一问题，我们成立了一个联盟，由肯特大学、曼彻斯特大学和谢菲尔德大学的英国领先学术团体和四个参与英国生物制药制造的关键工业合作伙伴组成，这些团体参与了基于CHO细胞的制造系统的研究。在这个项目中，我们将利用现有的最先进的DNA测序技术来快速对CHO细胞基因组进行测序、组装和注释。我们将建立一个网络来传播这一信息，并确定如何最有效地利用这一资源，用于未来的工程战略，以改进基于CHO-CELL的生产工艺。该项目对支撑新的生物制药制造技术的尖端应用研究是必要的，并将导致这一研究。