Predictable Protein Production

包括生物制药（蛋白质药物）、蛋白质特异性探针和酶在内的特定蛋白质构成了一个增长的市场。它们的复杂性使得这些制剂和试剂具有高度的特异性，因此，例如，在杀死患病细胞的同时保持健康细胞的完整。此外，它们由20种天然氨基酸组成的事实提供了安全性的一个重要方面；它们本质上是由可以安全降解的天然化合物组成的。活细胞复杂的生产环境很好地满足了这些产品的复杂性。然而，这是有代价的：活细胞很难用简单的方法来管理，而且很难用传统的分子或全细胞聚焦生物学来理解。活细胞生产蛋白质是不可预测的，而且效率相当低，这使得生物制药比它们应有的价格更昂贵，甚至有些生物制药无法经济地生产。系统生物学是一门新近兴起的科学学科，研究复杂的细胞内分子网络如何控制整个活细胞的功能。英国在这个系统生物学领域处于世界领先地位，拥有6个政府（BBSRC+EPSRC）资助的综合系统生物学中心和3个这样的博士培训中心。其中一个研究中心，曼彻斯特大学的MCISB，也是dtc的东道主之一，已经整合了一个完整的工具集，使人们能够理解面包酵母的生长，这是最著名和最有用的活细胞之一（面包，啤酒和葡萄酒）。曼彻斯特也是生物制药卓越中心（COEBP）的所在地，该中心正在研究利用哺乳动物细胞生产生物制药。这个研究项目做了显而易见的事情：它将MCISB和COEBP结合在一起。它是在生物技术研究产业俱乐部（BRIC）的背景下这样做的，在这个俱乐部中，学者和实业家聚在一起讨论如何通过更好的工业过程实施科学和工程，从而产生对公众更好的工作。这个想法是把新的系统生物学投入到理解活细胞同时产生蛋白质的问题上。这项研究将首先在我们熟知的酵母细胞上进行，现在它产生的是蛋白质而不是啤酒，但随后，同样的方法将在哺乳动物细胞系上实施，哺乳动物细胞系产生的蛋白质较少，但形状更好。如果成功，通过对细胞工厂生产过程的数学建模，这将使英国在生物制药生产方面处于世界领先地位。为了实现最大的效率和控制，与金砖四国相关的生物工艺行业将在设计和优化各种生物制药工艺方面变得高度通用和快速。这在其他国家是不可能做到的。这种增加的多功能性可能会导致英国加工工业中生物加工的实质性增加。这个项目极具挑战性，在科学上也很有趣。一件事是，对于哺乳动物细胞，可用的信息是有限的：它们的DNA结构并不精确。因此，建模方法必须考虑到许多可能的DNA结构。这需要大量的计算机能力和程序员的熟练程度。另一个挑战是精确测量产生蛋白质的细胞的化学活性，并利用结果推断出它们的网络中哪些部分是用来产生蛋白质的。这应该使我们能够预测它们的最大效率，然后也许指导它们改进性能。因为生命是微妙的，另一个挑战是培养细胞，使它们在为我们生产“热”蛋白质时“感觉凉爽”，从而防止它们抗拒做好自己的工作。

Specific proteins including biopharmaceuticals (=protein-based medicines), protein-based specific probes, and enzymes, constitute a growth market. Their complexity allows these agents and reagents to be highly specific, and thereby, for instance, kill diseased cells whilst leaving healthy cells intact. In addition, the fact that they are composed of the 20 natural amino acids offers an important aspect of safety; they essentially consist of natural compounds that can be degraded safely. The complexity of these products is well served by the complex production environment of living cells. This comes at a price however: Living cells are difficult to manage with simple methodologies, and difficult to understand with the traditional molecule or whole cell focused biologies. Protein production by living cells is unpredictable and rather inefficient, making biopharmaceuticals more expensive than they should be, to the exent that some cannot be produced economically. Systems Biology is a recently amplified scientific discipline studying how the complex intracellular networking of molecules controls the functioning of whole living cells. The UK is among the word leaders in this Systems Biology, with its 6 government (BBSRC+EPSRC) funded Centres for Integrative Systems Biology and three such Doctoral Training Centres. One of these research centres, the MCISB at the University of Manchester, which also hosts one of the DTCs, has put together a complete tool set enabling the understanding of the growth of baker's yeast, which is one of the most famous and useful living cells (bread, beer and wine). Manchester is also home to the Centre of Excellence in BioPharmaceuticals (COEBP), in which the production of biopharmaceuticals by mammalian cells is being studied. This research project does the obvious: it brings together the MCISB and the COEBP. It does this in the context of the Biotechnology Research Industry Club (BRIC) in which academics and industrialists meet to discuss how science and engineering can be implemented to lead to work that is better for the public, through better industrial processes. The idea is to throw the new Systems Biology at the problem of understanding the living cells whilst producing proteins. This will first be done for the better known yeast cells, now producing proteins rather than beer, but immediately thereafter the same approaches will be implemented in mammalian cell lines that are known to produce less protein but in better shape. If successful, this will give Britain a world leading role in the production of biopharmaceuticals through the mathematical-modelling of the production processes that occur in the cell factories. Enabling maximal efficiency and control, the bioprocess industry associating with BRIC will become highly versatile and quick in designing and optimizing processes for a great variety of biopharmaceuticals. This could not now be accomplished in other countries. This increased versatility may lead to a substantial augmentation of bioprocessing in the UK process industry. The project is extremely challenging and interesting scientifically. One thing is that for the mammalian cells, the available information is limited: The structure of their DNA is not precisely known. Modelling methods will therefore have to be used that reckon with the many possible DNA structures. This requires substantial computer power and adeptness of the programmer. Another challenge is to measure precisely the chemical activity of the protein producing cells and use the results to deduce which parts of their networks they are using to produce the protein. This should enable us to predict their maximum efficiency and then perhaps to direct them to improved performance. Because Life is subtle, yet another challenge is to cultivate the cells in such a way that they 'feel cool' when they are producing 'hot' protein for us, thereby preventing them from resisting doing their job well.