Control-Theoretic Approaches in Systems Biology: sensitivity conservations as performance constraints

这项拟议中的研究探讨了生活的“设计原则”。过去，人们经常将工程设计的自动反馈系统与活的有机体进行比较。实验技术的最新进展允许通过全面观察最基本的生物反馈系统--生化和基因调控网络--来严格测试这些比较。这项拟议的研究解决了自动反馈系统理论的一个特殊方面：灵敏度守恒。一般而言，提高健壮性意味着降低系统敏感度--使系统免受不可预见的干扰。控制工程界已经认识到，在许多情况下，系统结构强加了灵敏度守恒，因此无法实现灵敏度降低。当这一约束到位时，系统工程师仅限于设计反馈，这些反馈将重新分配敏感度，以改善系统行为，例如通过将敏感度从干扰危险的组件上转移出来。由于灵敏度是守恒的，这必然会在其他部件中引入额外的灵敏度。敏感性限制同样适用于生物分子的“设计空间”。它们已被应用于代谢途径，以便更好地了解它们的调节。我和其他人最近的工作表明，这些限制存在于一系列生化和遗传网络中。这项拟议的研究旨在探索这些限制在哪里发生，它们采取什么形式，以及从实验上验证它们的后果。这将导致对细胞调控的更好理解，从而加强旨在通过化学(例如药物)或遗传(例如基因工程)改变细胞行为的策略。这些类型的操作是目前在一系列生物技术方向上努力的关键，包括人类健康和疾病、生物制造、农业和环境生物修复。

The proposed research addresses the 'design principles' of life. In the past, comparisons have often been made between engineered automatic feedback systems and living organisms. Recent advances in experimental techniques allow the rigorous testing of these comparisons, through the comprehensive observation of the most fundamental of biological feedback systems: biochemical and gene-regulatory networks. The proposed research addresses a particular aspect of the theory of automatic feedback systems: conservation of sensitivity. Generally, improving robustness means reducing system sensitivity -- insulating a system from unforeseen perturbations. The control engineering community has identified that in many cases, system structure imposes a conservation of sensitivity, so sensitivity reduction cannot be achieved. When this constraint is in place, the system engineer is limited to designing feedback that will redistribute sensitivity to improve system behaviour, for instance by shifting sensitivity away from components to which perturbations are dangerous. Because sensitivity in conserved, this will necessarily introduce additional sensitivity in other components. Sensitivity constraints apply in the biomolecular 'design space' as well. They have been applied to metabolic pathways in order to better understand their regulation. Recent work by myself and others indicates that these constraints are in place in a range of biochemical and genetic networks. The proposed research aims to explore where these constraints occur, and what forms they take, as well as to experimentally verify their consequences. This will result in a better understanding of cellular regulation, and thus enhance strategies that aim to alter cellular behaviour, either chemically (e.g. with drugs), or genetically (e.g. genetic engineering). These types of manipulations are key to current efforts in a range of biotechnological directions, including human health and disease, biomanufacturing, agriculture, and environmental bioremediation.