Mesolab: A Centre for Optical Mesoscopy for Biomedical Research at the University of Strathclyde

在过去的二十年里，已经发明了几种不同的显微镜，它们可以使生物医学科学家的眼睛更敏锐，在更小的视野中显示更多的细节。我们的显微镜是最近才在英国开发出来的，它代表了横向思维：我们极大地拓宽了视野，同时保持了传统显微镜的灵敏度。这一创新使样品的体积增加了一百倍，从中可以获得亚细胞的细节。单个细胞被详细地观察到，同时，它们与整个器官或身体的三维关系也是第一次被观察到。我们的光学“中观镜”的第一个共聚焦结果是在过去的六个月里获得的，并在2012年皇家学会列文虎克讲座和《科学》杂志的一篇简介中公布。现在全世界都有强烈的兴趣，因为已经公布的图像的好处是显而易见的。有许多应用程序：这里我们将描述一个最重要的例子。其中一张图片（见《支持案例》）显示了整个小鼠胚胎5毫米长的中间光学切片。这是有史以来第一个如此大而厚的标本的共聚焦图像，在同一图像中有亚细胞细节包括单个高尔基体。该提案的参与者包括英国小鼠遗传学领域的两家顶级实验室，那里的研究人员正热切地寻求利用这些图像对小鼠胚胎中的人类基因进行表型筛选，这是现代生物医学中最重要和最大规模的活动之一。我们建议在我们的项目中也包括同样重要但完全不同的生物医学研究领域，在这些领域，光学介观镜几乎肯定会改变工作的完成方式。向MRC提出的建议是建立一个中心，Mesolab，并以成本价从新兴的制造公司Mesolens Ltd购买两个光学介镜系统（我们已经成功地利用我们在光学物理和软件开发方面的专业知识建立了原型共聚焦系统）。我们目前正在进行这项工作，得到了EPSRC知识转移协议的资助和斯特拉斯克莱德大学的支持，以及最初在剑桥MRC分子生物学实验室开发的单个Mesolens原型。在斯特拉斯克莱德大学的人力、专业知识和基础设施的大力支持下，我们将利用拟议的MRC Mesolab设施开发多光子扫描、高分辨率和快速相机成像，以及其他用于光学中介镜的成像模式，并由该公司作为我们的项目合作伙伴提供大量的物质支持和专业知识投入，以及密集的设计参与。这项开发工作将在项目的头三年内完成，但即使在这个阶段，生物医学工作也会发生，系统的生物医学用户和设计人员之间也会有协同作用。这种参与（大型显微镜制造商迄今未能实现）将是我们项目的一个关键特征。在第二阶段，这项工作将专门包括在每个应用中优化实验程序，以产生最大的生物医学效益。我们期望光学介观镜能像MRC最初开发的光束扫描共聚焦显微镜一样，为生物医学研究提供一种革命性的技术。Mesolab的创建将使科学家们能够快速获得他们已经在寻找的下一代显微镜方法。

During the last twenty years, several different microscopes have been invented which can sharpen the eyes of biomedical scientists, showing more detail in an ever-tinier field of view. Our microscope, developed only recently in the UK, represents lateral thinking: we have broadened the field of view enormously, while keeping the acuity of a conventional microscope. This innovation allows a hundred-fold increase in the volume of the specimen from which sub-cellular detail can be obtained. Individual cells are seen in detail, but so also, for the first time, is their three-dimensional relationship to the whole organ or body. The first confocal results of our optical 'mesoscope' were obtained in the last six months and announced in the 2012 Royal Society Leeuwenhoek Lecture and in a profile in the journal Science. There is now strong worldwide interest because the benefit is obvious in the images already published. There are many applications: here we will describe one of the most important as an example. One image (shown in the Case for Support) shows a median optical section of an entire mouse embryo five millimetres long. This is the first ever confocal image of such a large and thick specimen, with sub-cellular detail including individual Golgi bodies in the same image. The participants in this proposal include the two top UK labs in the field of mouse genetics, where researchers are eagerly seeking to use such images for phenotypic screening of human genes in mouse embryos, one of the most important and large-scale activities in modern biomedicine. We propose to also include in our project equally important but quite different areas of biomedical research where it is almost certain that the optical mesoscope will change the way that work is done. This proposal to the MRC is to set up a centre, the Mesolab, and purchase two optical mesoscope systems at cost from the fledgling manufacturing company Mesolens Ltd (with which we have already worked successfully using our expertise in optical physics and software development to build the prototype confocal system). We are currently pursuing this work with modest but vital EPSRC Knowledge Transfer Agreement funding and support from the University of Strathclyde, as well as a single prototype Mesolens originally developed in the MRC Laboratory of Molecular Biology, Cambridge. We will use the proposed MRC Mesolab facility to develop multi-photon scanning, high-resolution and fast camera imaging, and other imaging modes for the optical mesoscopes, with strong support in manpower, expertise and infrastructure from the University of Strathclyde and substantial input of material support and expertise and intensive design participation by the company, who will be our Project Partner. This development work will be completed within the first three years of the project, but even during this phase biomedical work will occur and there will be synergy between the collaborating biomedical users of the systems and the designers. This engagement (which the large microscope manufacturers have hitherto failed to achieve) will be a key feature of our project. In the second phase, the work will consist exclusively of optimisation of experimental procedures in each application to yield the greatest biomedical benefit. We expect optical mesoscopy to be similar to the original development of the beam-scanning confocal microscope by the MRC, in providing a transforming technology for biomedical research. The creation of the Mesolab will allow scientists rapid access to this next generation microscopy method, which they are already seeking.