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

拟议的研究解决了生命的“设计原则”。过去，人们经常将工程自动反馈系统与生物体进行比较。通过对最基本的生物反馈系统：生化和基因调控网络的全面观察，实验技术的最新进展允许对这些比较进行严格的测试。提出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。一般来说，提高健壮性意味着降低系统灵敏度——使系统免受不可预见的扰动。控制工程界已经认识到，在许多情况下，系统结构施加了灵敏度守恒，因此不能实现灵敏度降低。当这个约束存在时，系统工程师只能设计反馈来重新分配灵敏度以改善系统行为，例如，通过将灵敏度从干扰危险的组件中移开。因为灵敏度是守恒的，这必然会在其他组件中引入额外的灵敏度。灵敏度限制也适用于生物分子的“设计空间”。它们已被应用于代谢途径，以便更好地理解它们的调控。我和其他人最近的工作表明，这些限制在一系列生化和遗传网络中都存在。拟议的研究旨在探索这些限制发生在哪里，它们采取什么形式，以及实验验证它们的后果。这将导致对细胞调控的更好理解，从而增强旨在改变细胞行为的策略，无论是化学上的（例如用药物）还是基因上的（例如基因工程）。这些类型的操作是当前一系列生物技术方向努力的关键，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.