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

从基础化学品到复杂的药物，今天的许多产品都是在细胞的帮助下创造出来的。与酒精发酵中酵母的使用类似，大量不同的细胞类型使我们能够生产出通过纯化学手段生产的太难或太昂贵的产品。虽然细胞培养的目标是利用细胞的复杂性来生产化学或制药产品，但同样的复杂性也构成了一个挑战--如果我们不知道细胞在做什么，我们如何改进生产工艺，以更低的成本制造新产品？拟议的研究计划的目标是改进目前的细胞培养监测方法，并更深入地了解细胞的复杂性，特别是药物生产。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，细胞培养的“饲料”也会对牛奶的产量产生深远的影响。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无论是肉眼还是分析仪器都是完全看不见的。在这项研究中，我们将修改细胞，使其根据状态而发光-区分健康和压力下的细胞以及导致它们出现问题的条件。结合经济高效和快速的细胞代谢物测量与细胞状态的快速读数，将允许快速开发针对新产品和现有产品的改进的喂养策略。尽管药品或化学品的最终成本由许多不同的因素决定，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转嫁到消费者身上。随着重要的药品专利开始到期，这对于刺激“仿制”药品(在细胞培养生产中被称为“生物仿制药”)的发展尤为重要。加拿大将从这项研究中从两个不同的方面受益。作为全球第十大药品市场，降低现有药品的成本和开发新的药品将对加拿大人的日常生活产生切实的影响。由于加拿大也有许多利用细胞培养生产过程的制药公司-包括礼来公司、默克公司和罗氏公司-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，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.