INSPIRE: Minimal adaptive and replicating cell

INSPIRE项目由数学和物理科学理事会化学部门的生命过程化学项目、生物科学理事会分子和细胞生物科学部的分子生物物理集群、数学和物理科学理事会物理部的生命系统物理学项目以及数学和物理科学理事会的综合活动办公室。生命系统的两个基本特征是精确复制和适应不断变化的环境条件的能力。携带遗传信息的分子DNA结构的发现，仅仅为描述遗传密码的复制提供了一个框架。然而，专注于分离的DNA并不能深入了解维持细胞活力所需的整个机制是如何从母细胞传递到子细胞的。这是由其他蛋白质分子组成的网络完成的，这些蛋白质分子在复制、细胞分裂和适应过程中通过化学反应传递信息。这些单独的分子成分是如何在一个能够复制、适应不断变化的环境并在嘈杂拥挤的环境中稳健运行的系统中相互作用和发挥作用的？活细胞发挥功能所需的最小复杂度是多少？是什么决定了这样一个生命系统的分子组成的长度尺度？我们的目标是建立一个定量的概念框架来回答这些问题，这样处理信号、适应和高保真复制的能力就可以用物理和化学定律来描述，并以细菌为例进行研究。本研究的跨学科方法包括整合物理、化学和信息论概念，并期望为不同背景的学生和博士后提供一个多功能的训练基地。为了实现拟议研究的主要目标，有必要通过创建来自各个领域的新模型和新想法来开辟新路。将通过结合酶促反应的粗粒度模型、小分子和蛋白质合成耦合反馈效应的方法以及非平衡过程的计算，开发一种综合方法。这些想法将用于探索适应环境波动的组织原则，细胞大小控制，以及促进体内平衡的各种因素之间的竞争。这些新概念将用于提供一个新的框架，说明一个简单的细菌是如何多用途的，足以应对恶劣的环境波动（高盐度或高渗透压），并适应嘈杂的环境。分析这种行为需要将控制理论与通过化学反应网络实现的信号传输的潜在随机方面结合起来。此外，关于细胞形状和大小（微米量级）如何出现的关键问题，将基于它们使用反馈来维持蛋白质平衡和控制代谢物浓度的概念进行探索。这里提出的问题是根本性的，即使部分得到回答，也可能对我们理解生命系统的功能产生深远的影响。这些研究的一个总体长期目标是开始提供框架，最终设计和控制宏观细胞行为的基本组成部分。

This INSPIRE project is co-funded by the Chemistry of Life Processes Program in the Chemistry Division in the Directorate for Mathematical and Physical Sciences, the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences, the Physics of Living Systems Program in the Physics Division in the Directorate for Mathematical and Physical Sciences and the Office of Integrative Activities in the Directorate for Mathematical and Physical Sciences.The two fundamental characteristics of living systems are their ability to replicate with precision and adapt to changing environmental conditions. The discovery of the structure of DNA, the molecule that carries genetic information, provided only a framework for describing how the genetic code is copied. However, focusing on DNA in isolation does not provide insights into how the entire machinery, needed to sustain the viability of the cell, is conveyed from the mother to the daughter cell. This is accomplished by networks of other protein molecules that transmit information through chemical reactions both in the process of replication, cell division, and adaptation. How do theses individual molecular components interact and function in a system that is capable of replicating, adapting to changing environment, and operating robustly in noisy crowded milieu? What is the minimum level of complexity needed for a living cell to function? What sets the length scale of such a living system in terms of the molecular constituents? The goal is to develop a quantitative conceptual framework to answer these questions so that the ability to process signals, adapt, and replicate with high fidelity can be described using the laws of physics and chemistry and using a bacterium as a case study. The interdisciplinary approach to this research involves integrating physics, chemistry, and information theory concepts, and is expected to provide a versatile training ground for students and postdoctoral fellows with diverse backgrounds.In order to achieve the major objectives of the proposed research it is necessary to break new ground by creating new models and ideas coming from a variety of fields. An integrated approach will be developed by combining coarse-grained models of enzymatic reactions, ways of coupling feedback effects due to synthesis of small molecules and proteins, and accounting for non-equilibrium processes. These ideas will be used to explore the organization principles for adaptation to environmental fluctuations, cell size control, and competition between various factors that promote homeostasis. These new concepts will be used to provide a new framework on how a simple bacterium is versatile enough to respond to harsh environmental fluctuations (high salinity or osmolarity) and adapt in a noisy environment. Analyzing such behavior will require combining control theory and the underlying stochastic aspects of signal transmission achieved through chemical reaction networks. In addition, the key question of how cell shape and size (on the order of a micron) emerge will be explored based on the notion that they use feedback to maintain proteostasis and keep the concentrations of metabolites in check. The questions raised here are fundamental and even if answered partially could have far-reaching implications in our understanding of how living systems function. An overarching long term goal of these studies is to begin to provide the framework to eventually design and control macroscopic cell behavior in terms of its underlying components.