From Bacterial Chemotaxis to the Prediction of Complex Networks: The Oxford Integrative Systems Biology Centre

生命不仅源于单个分子，还源于它们之间的动态相互作用。全球在基因组测序上花费了大量的时间和金钱，随后是转录组学、蛋白质组学和代谢组学测量的高通量方法。然而，细胞是复杂的网络和通路系统。分子生物学的一个长期目标必须是获得一个测序的基因组，并能够模拟细胞内的活动，最终形成一个复杂的有机体。有了准确和可靠的模型，就有可能在从药品和保健到粮食生产和生物修复的一系列活动中取得重大进展。方法可以是自顶向下、自底向上或通过精确定义有限的输入和输出，同时忽略中间的细节。目标是在特定的生长条件下建立一个精确的细胞动态活动模型，当许多蛋白质可能存在但不活跃时，只有在激活时才与目标蛋白质或DNA相互作用（所谓的“sensome”或“interactome”）。迄今为止，没有一种技术能够可靠地说明哪些蛋白质在什么时候是活跃的，或者哪些蛋白质与哪些蛋白质相互作用。即使是最近的发展，例如，快速通量引导酵母两种杂交系统告诉你什么可以相互作用，而不是什么在体内和何时相互作用。我们认为最好的方法是首先关注有限数量的可处理和重要的生物系统，例如，细菌组氨酸蛋白激酶（HPK）依赖的化学感觉途径或酵母细胞周期途径的特定部分，并为这些系统开发可靠的预测模型。例如，通过细菌化学感觉途径，模型可以通过具有复杂途径的物种进行测试，然后扩展到选定细菌物种的HPK途径的总补体。长期目标是将这些方法应用到更复杂的高等生物体中，并最终将这些模型扩展到一般的感觉系统，随着项目的发展，每个模型都将进行生物学测试。这些研究不仅将导致对信号通路复杂相互作用网络的理解，而且还将导致对特征基序的识别，可能为抗菌素提供新的靶点。

Life arises not just from individual molecules, but from their dynamic interactions. A great deal of time and money has been spent globally on sequencing genomes, followed by high-throughput methods for transcriptomic, proteomic and metabolomic measurement. Cells, however, are complex systems of networks and pathways. A long term goal of molecular biology must be to take a sequenced genome and be able to model the intracellular activities of a cell, and ultimately a complex organism. The availability of accurate and robust models has the potential to enable major advances in a range of activities ranging through pharmaceuticals and health care to food production and bioremediation. Approaches can be top down, bottom up or through accurate definition of limited inputs and outputs whilst ignoring the intervening detail. The goal is an accurate model of the dynamic activities of a cell under a specific set of growth conditions, when many proteins may be present but not active, only interacting with target proteins or DNA when activated to do so (the so-called 'sensome' or 'interactome'). None of the techniques available to date can reliably say which proteins are active when or which interact with which. Even recent developments in, for example, fast through-put guided yeast two hybrid systems tell you what can interact, not what does interact in vivo and when. We believe the best way forward is to initially focus on a limited number of tractable and important biological systems, for example, the bacterial histidine protein kinase (HPK) dependent chemosensory pathway or a defined section of the yeast cell cycle pathway, and to develop a reliable, predictive model for those systems. With, for example the bacterial chemosensory pathway, models can be tested through to species with complex pathways and these then extended to the total complement of HPK pathways in selected bacterial species. The long term goal is to carry these approaches to more complex pathways in higher organisms, and eventually to extend the models to sensory systems in general, with each model tested biologically as the programme develops. These studies will lead not only to an understanding of the complex interactive networks of signalling pathways, but also to the identification of signature motifs, possibly providing new targets for antimicrobials.