Diamond Annual Review 2020/21

6 7 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 2 0 / 2 1 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 2 0 / 2 1 Rising to the Challenge of COVID-19 W hen theWorld Health Organisation (WHO) declared COVID-19 a pandemic on 11 March 2020, it was largely an unknown quantity. The priorities for researchers were to learn more about the virus, how it infects and how it spreads. A structural understanding of the virus was critical for developing therapies, and the Diamond synchrotron’s X-rays, laboratories and integrated facilities, in particular the ElectronBio-Imaging Centre (eBIC) with its suite of high-end cryo-electronmicroscopes, would be crucial tools for researchers. Diamond’s first priority was to make its unique capabilities available to COVID-19 researchers. Over the past few years, Diamond has been developing technology and software for highly-automated, high-throughput beamlines, particularly for Macromolecular Crystallography (MX). This investment means that more and more experiments can be run remotely, with users sending samples to Diamond rather than visiting themselves. When the UK lockdown started, this became Diamond’s standard way of working, with beamtime reserved for research related to COVID-19. Diamond allocated beamtime via a new COVID-19 specific rapid access route and more than 60 projects have benefitted from expedited access in the last year. The many COVID-19 related research projects that Diamond has worked on, and continues to work on, are a great demonstration of the powerful synergy between Diamond and its neighbouring research institutes, the Research Complex at Harwell (RCaH) and the Rosalind Franklin Institute. The array of specialised tools and instruments at Diamond, alongwith the scientific and technical expertise of its staff, allow for many different techniques to be used, from looking at the structure of the virus and fitting drugs into it, like a tiny jigsaw puzzle, to taking direct images of the virus without its infectious component, making it possible to see how it interacts with drugs. The COVID-19 research taking place at Diamond can be loosely grouped into five strands: understanding the virus structure and function, vaccine design, the development of new drugs, the development of new therapies, and screening existing drugs as potential COVID treatments. Understanding the virus, SARS-CoV-2 By August 2020, Diamond and an international team of researchers had discovered a new and highly conserved site on SARS-CoV-2, the virus that causes COVID-19, that can be neutralised by a specific antibody. Previous studies showed that antibodies that block the virus interaction with the human receptor (ACE2) have a significant neutralising effect and can be used to save the lives of critically ill patients. This study (published in Nature Structural and Molecular Biology ) described a different target that can be bound in synergy with ACE2 blocking antibodies for a stronger neutralising effect 1 . Using eBIC, and working with a group at a hospital in Taiwan, the team identified antibodies from a convalescent patient that could create a real potential for a drug target. In November 2020, a research group led by Peijun Zhang, Director of eBIC and Professor of Structural Biology at the University of Oxford, published the results of their investigation of SARS-CoV-2 replication under near-native conditions 2 . They used a unique correlative imaging approach to depict the entire SARS-CoV-2 infected cell. Their results revealed - at the whole cell level - the profound cell changes caused by SARS-CoV-2 infection and enabled modelling of SARS-CoV-2 genome replication, virus assembly and egress pathways. Understanding the multistage infection process is critically important to help combat COVID-19. Diamond then created a highly detailed scientific animation showing how the SARS-CoV-2 virus infection mechanism works at the cellular level, see www.diamond.ac.uk/SARS-CoV-2_animation. The aim was to inform researchers and the public and share the knowledge that scientists working with Diamond had uncovered on how the virus replicates itself. This was the first time the virus had been depicted in this way, showing in detail how the virus infection mechanism operates. The animation was entirely based on the work achieved at Diamond using cryogenic electron microscopy (cryo-EM), X-ray tomography and X-ray crystallography. A research article published in the journal Cell in March 2021 is one of the most comprehensive studies of its kind so far, examining antibodies from a large cohort of COVID-19 patients 3 . Every person infected with COVID-19 has the potential to produce many antibodies that target the virus in a slightly different way. By using Diamond, applying X-ray crystallography and cryo-EM, an international research team led by scientists fromDiamond and Oxfordwere able to visualise and understand how antibodies interact with and neutralise the virus. Their results show that there are many different opportunities to attack the virus using different antibodies over a much larger area than initially thought. This has also provided a basis for understanding the effect on antibody neutralisation of mutations in several of the variant viruses which are now a cause for concern around the world. Vaccine design In April 2021, eBIC published the first images of cells exposed to the Oxford-AstraZeneca vaccine producing native-like coronavirus spikes 4 . The images showed that the spikes are highly similar to those of the virus and support the modified adenovirus used in the vaccine as a leading platform to combat COVID-19. The challenge now is to stay ahead of the mutations, and the race is on to understand the consequences of these changes and to develop new vaccine constructs tailored to the variants. Three major new science papers, published in the journal Cell in April 2021, included data collected at Diamond and provided valuable new informationabouthowpreviously infectedorvaccinated individuals respond to these new variants and antibodies 5-7 . Their conclusions indicate that even if antibody responses to the new variants are compromised, they are likely to provide some protection. In addition, T cell responses to the virus spike may not be disrupted by the mutational changes and should be able to limit spread to the lower respiratory tract and prevent severe disease. New drug development To truly defeat COVID-19, we will need a combination of vaccines and treatments for people who become infected. An attractive drug target is the so- calledmain protease of SARS-CoV-2.This protein is essential for viral replication. Work initiated in theWalsh Group at Diamond in January 2020, in collaboration with the von Delft Group, inspired a novel crowd sourcing initiative led by PostEra Inc – the COVID Moonshot. The name derives from its unprecedented aim to develop a clinically effective antiviral more rapidly than ever before, by crowdsourcing designs of new inhibitors from chemists around the world who are mining the rich ‘fragment’ data measured at Diamond. All data was released in real-time and in the open to enable worldwide collaboration and rapid progress. The COVID Moonshot asked chemists to come up with new molecules and to have a practical input towards the global efforts to combat COVID-19. Researchers submitted their designs to PostEra, who ran machine learning algorithms to triage suggestions and generate synthesis plans to enable a rapid turnaround. Promising compounds can be synthesised and tested for antiviral activity and toxicity.This is ongoing drug discovery work. Most drugs work due to a chemical interaction between the medicine compound and a protein in the body. A powerful approach to early drug (‘lead’) discovery tests whether tiny fragments of compounds are connecting to a target protein. Fragment screening is quicker and easier than testing larger compounds, and Diamond’s XChem fragment screening facility (developed in Titan Krios Electron Microscope at eBIC. Screenshot of the SARS-CoV-2 virus infection mechanism animation. Principal Beamline Scientist on I04-1/XChem, Frank von Delft.