Artificial Intelligence (AI)-enabled Cryogenic Electron Ptychography For Bio-macromolecule Imaging

Cryogenic transmission electron microscopy (cryo-EM) with single-particle analysis (SPA) is a powerful method for visualizing a wide range of biological macromolecules in three dimensions (3D) at near-atomic resolution, which can provide direct insights into function and mechanism. Despite these revolutionary advances, it remains a challenge to deal with such small, heterogeneous and/or flexible molecules or complexes. An emerging strategy is based on cryogenic electron ptychography, which has been recently demonstrated by us for phase reconstruction of biological samples under low dose conditions. Ptychography is an emerging computational microscopy technique for acquiring images with resolution beyond the limits imposed by lenses, which has been applied to high resolution x-ray imaging. Due to its high phase-sensitivity, robustness to low electron dose data and the recovery of the sample wavefunction, electron ptychography represents a potentially disruptive change in the rapidly growing field of cryo-EM. The aim of this project is to provide a new computational image restoration framework for visualizing bio-macromolecules in 3D at near-atomic resolution. You will base upon artificial intelligence (AI) and machine learning techniques and develop a completely new computational scheme to dramatically speed up the time-consuming ptychographic reconstructions from a large quantity of electron diffraction, and recover high-fidelity phase-contrast images of biological macromolecules at high resolution. Combining with SPA, this AI-enhanced ptychography would potentially reveal and examine the 3D structures of the small molecules in an unbiased and comprehensive manner. You will be exposed to diverse and interdisciplinary research areas in applied mathematics, biological macromolecules, electron microscopy and cryogenics. You will experience an internationally collaborative environment, where you will closely collaborate with international-leading electron microscopists in the Rosalind Franklin Institute, a national research institute, dedicated to developing new technologies to tackle important health research challenges. You will have access to the state-of-the-art JEOL GrandARM with aberration correction, cryo stage, which is the very first and unique purpose-built cryo-EM in the UK for this category of work. You will also work with world-leading structural biologists in the Division of Structural Biology at the University of Oxford.

Impact on Students. The primary impact will be on the 50+ PhD students trained by the Centre. They will be high-quality computational scientists who can develop and implement new methods for modelling complex systems in collaboration with scientists and end-users, who are comfortable working in interdisciplinary environments, have excellent communication skills and be well prepared for a wide range of future careers. The students will tackle and disseminate results from exciting PhD projects with strong potential for direct impact. Exemplar research themes we have identified together with our industrial and international partners: (i) design of electronic devices, (ii) catalysis across scales, (iii) high-performance alloys, (iv) direct drive laser fusion, (v) future medicine exploration, (vi) smart nanofluidic interfaces, (vii) composite materials with enhanced functionality, (viii) heterogeneity of underground systems.

Impact on Industry. Students trained by HetSys will make a significant impact on UK industry as they will be ideally prepared for R&D careers to help to address the skills shortage in science and engineering. They will be in high demand for their ability to (i) work across disciplines, (ii) perform calculations that come along with error estimates, and (iii) develop well-designed software that other researchers can readily use and modify which implements novel solutions to scientific problems. More generally, incorporating error bars into models to take account of incomplete data and insufficient models could lead to significantly enhanced adoption of materials modelling in industry, reducing trial and error, and costly/time-consuming R&D procedures. The global market for simulation software is expected to more than double from now to 2022 indicating a very strong absorptive capacity for graduates. Moreover, a recent European Materials Modelling Consortium report identified a typical eight-fold return on investment for materials modelling research, leading to cost savings of 12M Euros per industrial project.

Impact on Society. Scarcity of resources and high energy requirements of traditional materials processing techniques raise ever-increasing sustainability concerns. Limitations on jet engine fuel efficiency and the difficulties of designing materials for fusion power stations reflect the social and economic cost of our incomplete knowledge of how complex heterogeneous systems behave. High costs of laboratory investigations mean that theory must aid experiment to produce new knowledge and guidance. By training students who can develop the new methodology needed to model such issues, HetSys will support society's long term need for improved materials and processes.

There will also be a direct impact locally and regionally through engagement by HetSys in outreach projects. For example we will encourage CDT students to be involved with annual 'Inspire' residential courses at Warwick for Year 11 girls, which will show what STEM subjects are like at degree level. CDT students will present highlights from projects to secondary-school pupils during these courses and also visit local schools, particularly in areas currently under-represented in the student body, in coordination with relevant professional bodies.

Impact on collaboration. Our international partners have identified the same urgent challenges for computational modelling. We will build flourishing links with research institutes abroad with long term benefit on UK research via our links to computational science networks. Shared research projects will strengthen links between academic staff and industry R&D personnel and across disciplines. The work will also lead to accessible, robust and reusable software. The Centre will achieve cross-disciplinary academic impact on the physical and materials sciences, engineering, manufacturing and mathematics communities at Warwick and beyond, and on the generation of new ideas, insights and techniques.