Dynamics, Control, and Design of Bacteriophage T7

描述（由申请人提供）：由自然系统编码的设计有时会通过进化进行优化，以提供由(i)个体发展和（ii）在许多环境和进化中持续生存所带来的物理问题的解决方案。然而，我们的自然系统模型，在分子和细胞尺度上，很大程度上是描述性的。我们的模型通常概括流程中涉及的部分，流程发生的时间和地点，以及流程如何工作。关于为什么系统可能以特定方式设计的约束通常是缺失的。我们也经常缺乏精确的实验数据来描述我们的系统随着时间的推移的物理状态，当我们试图模拟系统的动态行为时，利用基于细胞内部的硬球稀释气体近似的建模框架。毫不奇怪，随着我们的模型规模和复杂性的增加，它们在帮助我们预测分子和细胞系统的新扰动所导致的行为方面的效用是有限的。

DESCRIPTION (provided by applicant): The designs encoded by natural systems are sometimes optimized by evolution to provide solutions to the physical problems posed by both (i) individual development and (ii) continued viability across many environments and evolution. However, our models of natural systems, at the molecular and cellular scales, are largely descriptive. Our models typically recapitulate what parts are involved in a process, when and where a process occurs, and how the process works. Constraints due to why a system might be designed in a particular way are typically missing. We also often lack precise experimental data describing the physical state of our system over time and, when we attempt to model the dynamic behavior of the system, make use of a modeling framework that is based on a hard-sphere dilute gas approximation for the inside of a cell. Not surprisingly, as our models increase in size and complexity, their utility in helping us to predict the behavior that results from novel perturbations to molecular and cellular systems is limited. What is the best practical foundation on which to ground models for the dynamic behavior of many- component molecular and cellular systems? Can we better constrain our models of natural biological systems by exploring why the systems might be designed as we find them? Do our experiments produce enough understanding of the information encoded in natural genetic systems such that we should now expect to be able to predict their behavior? Could we replace natural living systems with engineered surrogates that are better defined and easier to model, interact with, and predict? To make progress on these questions we plan to work with a relatively well-characterized natural biological system, bacteriophage T7. Specifically, we propose to: (1) Design and construct a synthetic bacteriophage T7 genome that is based on our current understanding of the genetic elements that contribute to phage gene expression, (2) Test our models for the parts encoded on the T7 genome by characterizing the behavior of our synthetic genome relative to the behavior of the original 'wild-type1 isolate, (3) Constrain our models for how the parts of T7 produce a functioning whole by testing the hypothesis that feedback control during early and middle T7 gene expression is used to tune the allocation of expression resources across a range of uncertain cellular environments.