Studying biology one molecule at a time by combining optical tweezers, fluorescence microscopy and microfluidics.

我们研究计划的目的是培育新的更好的科学研究方法。我们的目标是让剑桥大学的科学家和更广泛的英国科学界的科学家接触到一种新的重要技术，这种技术正在改变我们设计和实施实验的方式。传统上，分子生物学家通过检查含有大量被研究分子的样本来了解蛋白质和DNA等分子在细胞内的工作方式。这种类型的“生物化学重建”实验在为我们提供我们现在拥有的细胞世界的分子图像方面发挥了重要作用。这些实验的一个重要限制是，因为它们考虑的是被研究的大量分子，它们只能告诉我们它随时间的平均性质。然而，分子行为的重要方面只有在单独考虑分子时才能理解。重要的例子包括ATP合成酶（一种产生富含能量的ATP分子的酶）是如何工作的，以及鞭毛是如何推动细菌前进，帮助它们有目的地游泳的。我们打算获得的仪器类似于一套镊子，用来操纵非常微小的物体。为了能够精确地处理像单个分子这样小的东西，镊子是由激光控制的，因此该仪器被称为“光学镊子”。通过能够用镊子抓住和探测单个分子，我们可以探测和了解它们的机械特性，这对于确定分子在细胞内的行为方式非常重要。这项新技术的科学应用非常广泛，包括了解保护我们基因组免受损害的蛋白质如何与DNA相互作用，以及细胞如何将蛋白质货物从一个细胞器运输到另一个细胞器。反过来，这些知识最终可以被利用来理解当这些重要的细胞过程在疾病中被破坏时，我们会发生什么，以及如何设计合理的治疗干预策略。

The purpose of our research proposal is to foster new and better ways to do science. We aim to empower scientists at the University of Cambridge and in the wider UK scientific community by giving them access to a new and important technology, that is transforming the way in which we design and carry out experiments.Traditionally, molecular biologists have learnt about the way molecules such as proteins and DNA work inside cells by examining samples that contain a very large number of the molecules under study. This type of 'biochemical reconstitution' experiments have been instrumental in providing us with the molecular picture of the cellular world that we now have.One important limitation of these experiments is that, because they consider a large population of the molecule under study, they can only tell us about its average properties over time. However, important aspects of molecular behaviour can only be understood when the molecules are considered individually. Important examples include how ATPase synthase, the enzyme that generates the energy-rich molecule ATP, works and how flagella propel bacteria forward, helping them swim in a purposeful way. The instrument that we intend to acquire is akin to a set of tweezers to manipulate very tiny objects. To be able to handle something as small as a single molecule accurately and precisely, the tweezers are controlled by by laser light, hence the instrument name as 'optical tweezers'. By being able to grip and probe individual molecule with the tweezers, we can probe and understand their mechanical properties, which are important to determine the way molecules behave inside the cells.The scientific applications of this new technology are very wide, and include understanding how proteins that protect our genome from damage interact with DNA, and how cells transport their protein cargoes from one organelle to another. In turn, such knowledge can be eventually exploited to understand what happens to us when such important cellular processes are disrupted in disease, and how to design rational strategies to intervene therapeutically.