Topologic properties of metabolic networks

在过去的几十年里，生物医学研究界已经在生物世界的广泛范围内获得了大量有价值的数据。几乎所有这些努力都反映了研究重要生物学问题的简化分析方法，在这种方法中，生物学家通常故意将他们的分析限制在具有相对较少组成部分的定义良好的系统中，含蓄地试图将生物现象归结为单个分子的行为。然而，尽管这些方法很有价值，但离散的生物学功能不能仅仅归因于单个分子。相反，生物系统的健壮行为在很大程度上源于其各种建筑成分（即细胞网络）之间的复杂相互作用。在这个应用程序中，我们建议进行一个高度集成的程序，在这个程序中，我们将以定量的方式检查维持细胞正常功能所需的复杂代谢网络的结构。这一目标将得到最近两项科学发展的帮助：提供代谢网络详细连接图的综合途径基因组数据库的出现，以及在理解和量化复杂（非生物）网络拓扑结构方面的理论进步。这项研究代表了理论物理学家（a . -L.）Barabasi)，内科分子生物学家（Z. N. Oltvai）和细菌分子遗传学家（B. L. Wanner）。我们的目标有三个：(1)我们将定量分析模式生物（如大肠杆菌）复杂代谢和遗传网络的结构和功能活性；(2)我们将研究干扰中心代谢网络中蛋白质水平的影响，以帮助建立模型，并测试从这些模型的计算机模拟中进化出来的规则，包括检查它们对靶向突变的耐受性；(3)在大肠杆菌生理组的研究中，我们将尝试了解代谢网络中发生的动态变化，以响应不断变化的环境。了解活细胞中各种代谢网络组分之间的相互作用原理以及代谢网络的一般大规模特征不仅将为基础生物学提供重要贡献，而且还将适用于转化研究，如药物靶标鉴定。

Over the past several decades, the biomedical research community has acquired an enormous amount of valuable data across a wide spectrum of the biological world. Nearly all these efforts reflect reductive, analytical approaches to investigating important biological questions, in which biologists typically have deliberately restricted their analyses to well-defined systems with relatively few components, implicitly attempting to reduce biological phenomena to the behavior of individual molecules. Yet, despite the value of these approaches, a discrete biological function cannot be attributed only to individual molecules. Instead, the robust behavior of biological systems arises to a large extent from complex interactions among its various building constituents (i.e., cellular networks). In this application, we propose to conduct a highly integrated program in which we will examine in quantitative terms the structure of complex metabolic networks that are required to maintain the proper function of a cell. This goal will be aided by two recent scientific developments: the emergence of integrated pathway-genome databases providing detailed connectivity maps of metabolic networks, and by theoretical advances in comprehending and quantifying the topology of complex (non-biological) networks. This research represents a unique collaboration between a theoretical physicist (A. -L. Barabasi), a physician-molecular biologist (Z. N. Oltvai), and a bacterial molecular geneticist (B. L. Wanner). Our aims are threefold: (1) We will analyze in quantitative terms the structure and functional activity of complex metabolic and genetic networks of model organisms, such as Escherichia coli; (2) We will examine the effects of perturbing the levels of proteins in central metabolic networks to aid in model building and to test rules that evolve from computer simulations of these models, including examining their tolerance to targeted mutations; and (3) We will attempt to develop an understanding of the dynamic changes that take place in metabolic networks in response to a changing environment, in studies of the Escherichia coli physiome. Understanding the principles of interactions among various metabolic network components of a living cell and the generic large-scale feature of metabolic networks will not only provide an important contribution to basic biology, but will also have applicability to translational research, such as pharmaceutical target identification.