Model-based design for synthetic (micro)biology

我的研究项目包括开发和分析细胞生物学的计算机模型，以帮助研究细胞行为和预测干预的效果。拟议的研究涉及将这种建模方法应用于微生物生物学。这些看不见的生物对人类活动的主要方面产生了影响，从食品生产到健康，从环境到制造业。我们将使用计算机模型来提高我们对单个微生物细胞和微生物种群行为的理解，目的是使对微生物的操纵能够造福人类。我们建议针对三个短期目标开展研究活动： 我们的第一个目标是研究通过传递改变微生物行为的遗传元素来操纵环境中微生物种群的策略。我们的动机是有可能抑制抗药性细菌的数量，要么使它们对抗生素敏感，要么直接杀死它们。我们将调查一些这样的操纵策略在实验室人群中的表现，并将建立计算机模型，以巩固我们对它们行为的理解，并提供对潜在应用中的表现的预测。 我们的第二个目标是开发相互作用的微生物种群的计算机模型。在大多数自然环境中，微生物存在于由大量相互作用的物种组成的生态系统中。研究界直到最近才开始了解这些组装的复杂性。我们已经在实验室中获得了简单的两种物种群落的视频显微镜。通过开发这些相互作用的种群的计算机模型，我们将朝着产生对自然微生物生态的机械描述迈出重要的第一步。这些描述将使我们能够预测干预这些系统对改善健康、农业和环境的影响。 我们的第三个目标是利用光合作用微生物的光敏系统。这些细胞可以被重新连接，以允许通过光控制一系列细胞活动。这种光遗传系统可以通过时变的光输入对细胞活动进行前所未有的控制。我们已经建立了一个计算机控制的光激发系统，可以用来探索这个系统。利用计算机模型，我们将确定为探测细胞行为提供最大信息量的光输入。然后，我们将研究在代谢工程中使用该系统进行时间控制，目的是提高药物和其他有用化学品的生物制造效率。 这项工作将提高我们操纵微生物的能力，对我们有利，有助于解决健康、农业、制造业和环境方面的一系列紧迫问题。

My research program involves the development and analysis of computer models of cellular biology, to aid in investigations of cellular behaviours and for prediction of the effects of interventions. The proposed research involves applying this modelling approach to the biology of microbes. These unseen organisms have impact on major aspects of human activity, from food production to health, from the environment to manufacturing. We will use computer models to improve our understanding of the behaviour of individual microbial cells and of microbial populations, with the goal of enabling manipulation of microbes to benefit humanity. We propose research activities targeted toward three short-term aims: Our first aim is to investigate strategies for manipulation of microbial populations in the environment by delivery of genetic elements that alter their behaviour. We are motivated by the possibility of suppressing populations of antibiotic resistant bacteria, either by rendering them antibiotic-susceptible, or by killing them outright. We will investigate the performance of a number of such manipulation strategies in laboratory populations, and will build computer models to consolidate our understanding of their behaviour and to provide predictions of performance in potential applications. Our second aim is to develop computer models of interacting microbial populations. In most natural environments, microbes occur in ecologies consisting of large numbers of interacting species. The research community has only recently begun to understand the complexities of these assemblies. We have acquired video microscopy of simple two-species communities in the lab. By developing computer models of these interacting populations, we will be taking an important first step toward generating mechanistic descriptions of natural microbial ecologies. These descriptions will allow us to predict the effect of intervention in these systems toward improvements in health, agriculture, and the environment. Our third aim takes advantage of light-sensing systems from photosynthetic microbes. These can be re-wired' to allow control by light of a range of cellular activities. This optogenetic' system allows unprecedented control of cellular activity by time-varying light inputs. We have built a computer-controlled light excitation system with which we can explore this system. Using a computer model, we will identify light inputs that provide maximum informativeness for probing cellular behaviours. We will then investigate the use of this system for temporal control in metabolic engineering, with the goal of improving efficiency in biomanufacturing of drugs and other useful chemicals. This work will result in improvements in our ability to manipulate microbes to our advantage, contributing to solving a range of pressing problems in health, agriculture, manufacturing, and the environment.