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，对我们理解基础生物学和开发新药至关重要。然而，很难获得关于这些不同相互作用的准确信息。为了实现这一点，我们需要具有三个关键特性的工具。它们应该是：i)高度敏感和准确，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或类似条件下操作。近几十年来，人们在开发这些工具方面做了大量工作，研究人员在这一领域取得了巨大进展。然而，目前没有一个可用的工具包含我们迫切需要的所有三个特性。我们的团队开发了一种全新的工具，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（在显微镜下）来测量液体样品中分子的质量。根据一个分子散射光的数量，我们可以非常精确地计算出它的质量。这项技术相当于测量质量的第三种方法，仅次于重力法和质谱法。MP已经引起了在大学和制药行业工作的研究人员的高度兴趣。它还催生了一家成功的衍生公司Refeyn。然而，为了充分发挥这项尖端技术的潜力，我们需要做出重大改进。对于这项奖学金，我们设定了四个关键方面的改进目标：测量分辨率;2. 测量精度;3. 适用于MP的样品浓度范围；和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MP转化为研究生物分子结构和功能的潜在革命性方法。我们将在牛津大学化学系进行为期五年的研究。我们的团队将由奖学金获得者组成，他将指导和监督研究，以及四名博士后研究员，他们将与两名博士生一起领导四个目标的研究。我们的最终目标是将MP从一种概念验证技术发展成为一种被广泛接受的变革性工具，适用于生命科学领域的研究人员——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。为了支持这一目标，我们还将在本奖学金期间开展两项主要的合作/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部门运营一个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，并传播我们的技术及其对更广泛的研究社区的作用。这项奖学金将使Philipp Kukura能够在他十年前成为独立学者以来的工作基础上继续努力：改变我们对光可以测量的东西的看法，并在诊断、生物发现和药物开发方面开辟新的突破口。连接先进的光学和生命科学界，他将利用这笔奖学金巩固他在这一领域的全球领导者地位，与下一代研究人员分享他的愿景，并在牛津创建一个MP权力中心。最终，这不仅有利于研究界，也有利于英国经济，创造当地就业机会，促进英国主要的生命科学产业和促进健康。

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.