The Biophysics of Mesoscale, Reversible, Biomolecular Assemblies

了解细胞在生物学中是如何工作的，可以帮助我们发现当细胞出错时会发生什么，例如在疾病中，以及我们可以做些什么来最大限度地减少甚至防止这些问题的发生，例如开发新药。要做到这一点，需要在这些结构中涉及的生物分子水平上有高水平的新见解，通过物理科学开发的先进实验技术来探测细胞中的这些结构，以及复杂的理论方法来真正了解这些结构如何通过与其他生物分子和细胞内环境相互作用形成。在这个奖学金中，我的目标是研究细菌中迷人而非凡的液滴，称为侵略者，从我们早期有前途的研究中，我们现在知道它是对施加在细胞上的一系列压力条件的反应，并帮助它们在苛刻的条件下生存下来。只是在过去的十年中，我们才意识到生物分子液滴对广泛的细胞过程是多么普遍和重要。这种液滴通过一种称为相分离的现象形成，类似于水蒸气冷凝形成水液体时发生的过程，但控制生物分子液滴如何在细胞中形成的物理规则比非生物过程复杂得多，并且对这些驱动物理机制知之甚少。在这里，我的目标是开发和使用新型的实验技术和理论建模，以确定支持细菌侵袭体形成的物理规则是什么，以及细胞环境在这一过程中所起的作用。我的目标是使用这些物理规则来建立如何“调整”侵略者形成的条件，以使特定的生物分子选择性富集到侵略者中，因为这将使一个雄心勃勃的机会，使用侵略者作为这些选定的成分的纯化容器。我将在该项目的后期阶段利用这些见解，通过选择性富集来工程化含有高含量重组治疗性生物分子的侵袭体，以期在扩大工业水平生产的方法方面取得早期进展，以大幅改善这种复杂药物产品的纯化方法。这样一个令人兴奋的医疗保健技术的发展可能会产生广泛的影响，以改善生产的一系列重组疗法用于对一系列人类疾病和健康障碍。这个奖学金将使我能够建立我一直在努力，因为我成为一个独立的学术二十年：改变了我们对使用先进的新自制技术可以检测和量化的看法，这些技术主要集中在光学显微镜上，并在改善医疗保健技术方面开辟了新的进展。作为物理和生命科学界的桥梁，我将利用这一奖学金巩固我作为生命物理学全球领导者的地位，使我能够将我的视野扩展到下一代生命物理学研究人员，在生物分子相分离研究的一个关键新兴领域，为英国北方的卓越动力所播种，这将使学术研究界和通过开发更好、更有效、最终更便宜的药物制造方法，帮助创造新的就业机会，并最终帮助提高国家在日益老龄化的人口中的医疗保健问题。

Understanding how cells in biology really work can help us to find out what happens when cells go wrong, for example in diseases, and what we can then do to minimise or even prevent these problems from occurring, such as developing new drugs. To do this requires a high level of new insight at the level of the biomolecules involved in such structures, enabled through advanced experimental technologies developed from the physical sciences to probe these structures in cells, as well as complex theoretical methods to really understand how these structures form through interacting with other biomolecules and the environment inside the cell. In this fellowship, I aim to investigate fascinating and remarkable liquid droplets in bacteria called aggresomes that, from our early promising research, we now know form in response to a range of stress conditions imposed on cells, and help them to survive harsh conditions such as are imposed. It is only in the past decade that we have become aware of how ubiquitous and important biomolecular liquid droplets are to a wide range of cell processes. Such droplets form through a phenomenon known as phase separation, similar to the process that occurs when water vapour condenses to form water liquid, but the physical rules that govern how biomolecular liquid droplets form in cells are much more complex than non-biological processes and much is not unknown about these driving physical mechanisms. Here, I aim to develop and use new types of experimental technology and theoretical modelling to determine what the physical rules are that underpin the formation of bacterial aggresomes, and the role in this process played by the cell environment. I aim to use these physical rules to establish how to "tune" the conditions of aggresome formation to enable selective enrichment of specific biomolecules into aggresomes, since this will enable an ambitious opportunity to use aggresomes to act as purification vessels for these selected components. I will capitalise on these insights in the later stages of the project by applying selective enrichment to engineer aggresomes that contain a high content of a recombinant therapeutic biomolecule, with a view to making early progress in scaling up methods for industrial-level production to substantially improve the method of purification for such complex pharmaceutical products. Such an exciting healthcare technology development may have wide ranging impact for improving the production of a range of recombinant therapeutics used against a range of human diseases and health disorders.This fellowship will enable me to build on what I have been working towards since becoming an independent academic for two decades: changing our perception of what we can detect and quantify using advanced new home-built technologies focused around light microscopy, and opening up new inroads in improved healthcare technology. Bridging the physical and life sciences communities, as I am uniquely placed to do, I will use this fellowship to cement my position as a global leader in the physics of life, allowing me to extend my vision to the next generation of physics of life researchers, seeding a northern UK powerhouse of excellence in a key emerging area of biomolecular phase separation research that will benefit both the academic research community and the national economy, helping to create new jobs and ultimately helping to elevate the nation's problems of healthcare in an increasingly aging population through the development of better, more efficient, and ultimately cheaper drug manufacturing methods.