Combining high throughput metabolomics with real-time biosensors to study the oxidative state in cell culture producing recombinant proteins.

从基本的化学品到复杂的药品，今天的许多产品都是在细胞的帮助下创造出来的。与在酒精发酵中使用酵母类似，大量不同类型的细胞使我们能够制造出纯化学方法难以制造或成本过高的产品。虽然细胞培养的目标是利用细胞的复杂性进行化学或药物生产，但同样的复杂性也带来了挑战——如果我们不知道细胞在做什么，我们如何改进生产过程，以更低的成本生产新产品？拟议的研究计划的目标是改进当前的细胞培养监测方法，并深入了解细胞复杂性，特别关注药物生产。首先，有必要识别和测量细胞正在使用的化学物质（或代谢物），并确定它们是如何被使用的。就像奶牛的饲料会影响牛奶的质量和数量一样，细胞培养“饲料”对它能生产什么有深远的影响。其次，有必要让细胞与研究人员“对话”。目前，许多重要的细胞功能是肉眼和分析仪器完全看不见的。在这项研究中，我们将修改细胞，使它们根据状态发光——区分健康细胞和应激细胞以及导致它们出现问题的条件。结合具有成本效益和快速的细胞代谢物测量与快速简便的细胞状态读数将允许快速开发改进的喂养策略，用于新的和现有的产品。虽然药品或化学品的最终成本是由许多不同的因素决定的，但收集可以建立在现有知识基础上的有用数据是开发新产品和改进现有产品的一个相当大的障碍。在当今竞争激烈的环境中，降低研发和制造成本将传递给消费者。随着重要的药物专利开始到期，这对于刺激“仿制药”（在细胞培养生产中称为“生物仿制药”）的发展将特别重要。加拿大将在两个不同的方面从这项研究中获益。作为世界第十大药品市场，降低现有药品的成本和开发新产品将对加拿大人的日常生活产生切实的影响。由于加拿大也是许多利用细胞培养生产工艺的制药公司的所在地——包括礼来、默克和罗氏——降低研发的材料成本也可以促进对研究活动的进一步投资，从而有可能创造更多高技能工作岗位。

From basic chemicals to complex pharmaceuticals, many of today's products are created with the help of cells. Similar to the use of yeast in alcoholic fermentation, a large number of different cell types allow us to make products that would be too difficult or costly to manufacture through purely chemical means. While the goal of cell culture is to take advantage of cellular complexity for chemical or pharmaceutical production, the same complexity also poses a challenge - how can we improve on the production process to make new products at lower cost if we don't know what the cells are doing? The goal of the proposed research program is to improve on the current methods of cell culture monitoring and gain a deeper insight into cellular complexity with a particular focus on pharmaceutical production. First, it is necessary to identify and measure the chemicals (or metabolites) that the cells are using and determine how they are being used. In much the same way as a cow's feed will influence the quality and quantity of milk, the cell culture "feed" has a profound influence on what it is able to make. Second, it is necessary to get the cells to "talk" to the researchers. As it stands, many important cellular functions are completely invisible to both the naked eye and to analytical instruments. For this research, we will modify the cells so that they light up depending on their state - distinguishing between healthy and stressed cells as well as the conditions that are causing them problems. Combining a cost effective and rapid measurement of cellular metabolites with a quick and easy readout for cellular state will allow rapid development of improved feeding strategies for new and existing products. Although the final cost of pharmaceuticals or chemicals is dictated by many different factors, the collection of useful data that can build on existing knowledge is a considerable barrier to the development of new products and improvement of existing ones. In today's competitive environment, reducing the cost of research and development as well as manufacturing will be passed down to the consumer. This will be particularly important to spur the development of "generic" pharmaceuticals (referred to as "biosimilars" in cell culture production) as important pharmaceutical patents begin to expire. Canada stands to gain from this research on two different fronts. As the 10th largest world market for pharmaceuticals, reducing the cost of existing pharmaceutical products and the development of new ones will have a tangible effect on the everyday Canadian. As Canada is also home to a number of pharmaceutical companies that make use of cell culture production processes - including Eli Lilly, Merck, and Roche - reducing the material cost of research and development can also promote further investments into research activity, potentially generating more high skilled jobs.