Transforming molecular biophysics with mass photometry

了解生物分子、药物和其他分子如何协同工作是生命科学中最重要的研究领域之一--这是我们理解基础生物学和开发新药的核心。然而，可能很难获得关于这些不同交互作用的准确信息。要实现这一点，我们需要具有三个关键功能的工具。它们应该：i)高度灵敏和准确，ii)能够捕捉随时间的变化，而不仅仅是静态快照，以及iii)能够在蛋白质的自然环境中或在类似的条件下工作。近几十年来，在开发这类工具方面进行了大量工作，研究人员在这一领域取得了巨大进展。尽管如此，现在可用的工具中没有一个包含了我们迫切需要的所有三个功能。我们的团队已经开发出一种全新的工具，可以解决这个问题，有可能彻底改变我们研究分子相互作用的方式。我们称这种方法为“质量光度法”(MP)，因为它使用光(在显微镜中)来测量液体样品中分子的质量。根据分子散射的光量，我们可以非常准确地计算出它的质量。这项技术是继基于重力的方法和质谱学之后的第三种测量质量的方法。MP已经吸引了大学和制药行业的同事们的高度兴趣。它还导致了一家成功的衍生公司Refeyn的创建。然而，为了充分发挥这一尖端技术的潜力，我们需要做出关键的改进。对于这项研究，我们制定了四个关键方面的改进目标：1.测量分辨率；2.测量精度；3.MP适用的样品浓度范围；以及4.我们如何分析数据和处理我们获得的图像。正是这些改进将使MP成为研究生物分子结构和功能的一种潜在的革命性方法。我们将在五年内在牛津大学化学系开展这项工作。我们的团队将由奖学金持有人和四名博士后研究人员组成，他们将指导和监督这项研究，他们将与两名博士生一起领导对四个目标中的每一个目标的研究。我们的最终目标是将MP从一种概念验证技术提升为一种被广泛接受的变革性工具，供生命科学领域的研究人员使用--从从事生物发现研究的人员到开发药物和临床诊断的人员。为支持这一目标，我们还将在研究金期间开展两项主要的协作/外联活动。首先，我们将与一家大型制药公司合作，探索MP如何支持他们的药物开发工作。其次，我们将在我们的大学系运营一个MP设施，它将向所有研究人员开放，以最低的成本在他们自己的项目中使用。这两项活动将帮助我们验证我们的技术，在不同的应用程序上测试MP，收集MP用户的反馈，并将我们的技术及其可以做的事情传播给更广泛的研究社区。这一奖学金将使Philipp Kukura能够在他十年前成为一名独立学者以来一直致力于的基础上再接再厉：改变我们对我们可以用光测量的东西的看法，并在诊断、生物发现和药物开发方面开辟新的领域。他将利用这一奖学金作为先进光学和生命科学界的桥梁，巩固他作为该领域全球领导者的地位，与下一代研究人员分享他的愿景，并在牛津创建MP动力中心。最终，这不仅将有利于研究界，也将有利于英国经济，因为它将创造当地就业机会，提振英国一流的生命科学产业，并促进健康。

Understanding how biomolecules, drugs and other molecules work together is one of the most important areas of study in the life sciences - central to our understanding of basic biology and to developing new drugs. However, it can be difficult to obtain accurate information about these different interactions. To make this possible, we need tools that have three key features. They should be: i) highly sensitive and accurate, ii) able to capture changes over time rather than only static snapshots, and iii) able to operate in the natural environment of proteins or in comparable conditions. In recent decades, much work has gone into developing such tools and researchers have made huge progress in this area. Still, none of the tools available now encompasses all three of the features we urgently need. Our group has developed a completely new tool that could solve this problem, with the potential to revolutionise how we study molecular interactions. We call the approach 'mass photometry' (MP) because it uses light (in a microscope) to measure the mass of molecules in a liquid sample. From the amount of light scattered by a molecule, we can calculate its mass with a very high level of accuracy. This technology amounts to only the third way of measuring mass, after gravity-based methods and mass spectrometry.MP has already attracted high levels of interest from fellow researchers working in universities and in the pharmaceutical industry. It has also led to the creation of a successful spinout company, Refeyn. Still, for the potential of this cutting-edge technology to be fully realised, we need to make critical improvements. For this fellowship, we have set objectives to improve four key aspects: 1. Measurement resolution; 2. Measurement precision; 3. The range of sample concentrations for which MP is applicable; and 4. How we analyse the data and process the images we obtain. It is these improvements that will transform MP into a potentially revolutionary approach for studying biomolecular structure and function. We will conduct this work over five years at the University of Oxford's Department of Chemistry. Our team will consist of the fellowship holder, who will guide and oversee the study, and four postdoctoral researchers, who will lead research on each of the four objectives alongside two PhD students. Our ultimate goal is to advance MP from a proof-of-concept technology to a well-accepted, transformative tool for researchers working across the life sciences - from those doing biological discovery research to those developing drugs and clinical diagnostics. In support of that goal, we will also engage in two major collaborative/outreach activities for the duration of this fellowship. First, we will work with a major pharmaceutical company, exploring how MP can support their drug development work. Second, we will operate a MP facility in our university department, which will be open to all fellow researchers to use in their own projects at minimal cost. These two activities will help us validate our techniques, test MP on different applications, gather feedback from MP users, and spread the word about our technology and what it can do to the broader research community. This fellowship will enable Philipp Kukura to build on what he has been working towards since becoming an independent academic a decade ago: changing our perception of what we can measure with light, and opening up new inroads in diagnostics, biological discovery and drug development. Bridging the advanced optics and life sciences communities, he will use this fellowship to solidify his position as the global leader in this field, share his vision with the next generation of researchers, and create an MP powerhub in Oxford. Ultimately, this will not only benefit the research community, but the UK economy as well, with the creation of local jobs, boosting the UK's prime life sciences industry and advancing health.