High Precision Charge and Size Spectrometry on Biomolecules and Molecular Complexes in Solution

科学的历史与测量的历史密不可分。正如19世纪荷兰诺贝尔奖获得者、超导电性发现者卡默林格-昂内斯所说：“通过对知识的测量”。在过去几十年的生物物理科学中，这些话在几乎所有的研究领域中听起来都更真实，在生物物理科学中，测量自然界分子构件的属性的技术的发展和完善带来了一波前所未有的知识浪潮，并对支撑生命的结构和机制进行了洞察。构成生命的一整套分子构件是巨大的，没有一种单一的方法可以为科学家们可能想要问的无数问题提供答案。任何采用不同物理方法的新技术都可以为问题带来新的曙光，揭示出在此之前一直完全看不到的重要方面。这种不断改进和提高测量技术的过程在科学发展中起着决定性的作用，并支撑着新知识的不断创造。大小、质量和电荷是表征生物分子的两个基本物理性质。虽然长期以来，分子质量的测量都是以原子级别的精度进行的，但我的实验室最近开发了一种新的实验方法来测量生物分子的电荷，其精度比单一的基本电荷更高。由于到目前为止还没有能够提供这种测量的技术，我们预计能够为现有的生物分子信息主体增加一个重要的新维度。我们新方法的一个重要方面是，与大多数其他测量技术不同，我们能够获得溶液中单个分子的性质，而不限于观察样本中多个分子所有响应的总和所产生的平均值。这一点之所以重要，是因为与常识相反，某种生物分子不一定与其所有邻居完全相同。事实上，由于许多不同的原因，一个给定的分子物种可以以略有不同的状态存在。这种多种多样的状态往往带有物种生物功能的重要特征，而这种特征在以高度平行的方式进行的“单分子”测量中被揭示出来。以快速和高精度的方式进行此类测量的能力仍处于初级阶段。我们将开发的技术旨在为生物、生物物理和生物医学科学的科学家提供一种测量工具，使他们能够前所未有地深入了解生物分子的性质，如蛋白质在溶液中的性质。除了研究实验室，许多医学诊断测试关键依赖于敏感和可靠地检测特定蛋白质的存在，无论是游离的还是与患者提取的样本中的特定分子伙伴结合的蛋白质。例如，在传染病中，对患者是否接触过病原体的测试依赖于检测血液中循环的称为“抗体”的分子。这是通过检查患者血清中的抗体是否在反应管中与用作分子诱饵的抗原结合来完成的。提供一种测量工具，对样品中分子级物质的大小和电荷进行高精度测量，不仅将给生物学研究带来革命性的变化，还将使具有前所未有灵敏度的检测工具掌握在医学测试实验室手中，不断寻找更快、更便宜和更准确的诊断技术。例如，从传染病暴发期间社会需求的角度来看，捍卫社会结构和经济稳定、维护社会契约的新技术的重要性怎么强调都不为过。

The history of Science is inextricably linked to the history of measurement. As immortalised in the words of the 19th century Dutch Nobel Laureate Kamerlingh-Onnes, discoverer of superconductivity: "Through measurement to knowledge". In scarcely any field of research have these words rung more true than in the biophysical sciences of the last few decades, where the development and refinement of technologies to measure the properties of the molecular building blocks of nature have brought a wave of unprecedented knowledge and insight into the structure and mechanisms underpinning life. The suite of molecular building blocks that make up life is vast, and no single approach offers the answers to the myriad questions scientists may wish to ask. Any new technique that takes a different physical approach can shed new light on a problem, revealing important aspects of it that until then remained entirely out of view. This process of endless improvement and enhancement of measurement techniques plays a defining role in scientific development and underpins the continuous creation of new knowledge. Size, or mass, and electrical charge are two fundamental physical properties that characterise biological molecules. While molecular mass has long been measured with atom-level precision, my laboratory recently developed a new experimental approach to measure the electrical charge of biological molecules with a precision better than a single elementary charge. Since techniques capable of delivering such measurements have been hitherto unavailable, we anticipate being able to add an important new dimension to the existing body of information on biomolecules. An important aspect of our new approach is that unlike most other measurement techniques we are able to access the properties of individual molecules in solution, and are not limited to observing an average value resulting from the sum of all responses of a multitude of molecules in sample. The reason why this matters is that contrary to common sense, a biological molecule of a certain kind is not necessarily identical to all its neighbours. In fact a given molecular species can exist in slightly different states for a number of different reasons. This multitude of states often carries an important signature of the biological function of the species, and such signatures are revealed in "single molecule" measurements performed in a highly parallel fashion. The ability to perform these sorts of measurements in a rapid and highly accurate fashion is still in its infancy.The technology we shall develop aims to offer scientists in the biological, biophysical and biomedical sciences a measurement tool that will offer unprecedented insight into properties of biomolecules such as proteins in solution. Beyond the research laboratory, many medical diagnostic tests rely crucially on the ability to sensitively and reliably detect the presence of particular proteins, either free or bound to specific molecular partners in a patient-derived sample. For example in infectious diseases, a test for whether a patient has had exposure to a pathogen or not relies on detecting molecules called "antibodies" circulating in the bloodstream. This is done by checking whether the antibodies in the patient's serum bind in a reaction tube to antigens used as 'molecular bait'. The availability of a measurement tool to deliver high precision measurements of size and electrical charge on molecular scale matter in a sample will not only revolutionise biological research, but will also put detection tools offering unprecedented sensitivity into the hands of medical testing laboratories continuously on the look-out for faster, cheaper and more accurate diagnostic technologies. Viewed through the lens of societal needs during an outbreak of an infectious disease for example, the importance of new technologies that defend the stability of social structures and economies, upholding the social contract, cannot be overstated.