An update from the Head of Department, Professor Gerard Evan, regarding the coronavirus (COVID-19) pandemic.
COVID-19 research in the Department of Biochemistry
We are all doing our bit to fight the COVID-19 scourge. For most of us this simply means staying at home and keeping safe and healthy by limiting interactions with others, social distancing and exercise. It is no mean accomplishment to cope with a national lockdown: the social isolation is unnatural for most of us and there is only so much TV anyone can bear. No one should underestimate the fortitude and commitment that the lockdown requires from each of us; it is tough, painful, and for some frightening and lonely. And it is every bit as important as developing virus screens and assays and kits, and is just as essential to preserving our health service and protecting the vulnerable.
One easy thing we can all do is help the epidemiologists who are trying to understand the pandemic and plot its future course by participating in the COVID Symptom Tracker programme: this iOS and Android app allows you to enter your COVID-19 status, along with some important diagnostic symptoms, and report that status anonymously back daily to Tim Spector and his epidemiology team at Guy's and St Thomas's Hospitals. The website shows the encouraging downward impact of the lockdown on new cases of COVID-19, as well as having a lot of other useful information.
However, our Department is a leading research institution so, not surprisingly, several enterprising faculty proposed research projects to adapt innovative technologies and approaches to the screening, assay and, potentially, treatment of COVID-19. These COVID-specific proposed projects went through a pretty strict review process by an external (outside the Department) review group that sought to balance their risk (principally, risk of COVID exposure while working in, and travelling to and from, the Department) with realistic chances of the project leading to improved disease diagnosis, detection or treatment. On that basis I approved them as appropriate for the Department of Biochemistry. Katy Pitts and Nick Smith then did fabulous jobs sorting out where each project could be safely located within our buildings and setting up the complex web of organisation and resourcing that each project entailed. Nick, Katy and I are satisfied that the permitted projects do indeed address truly innovative approaches and/or design of immediately translatable technologies.
Like many of the world's most threatening viruses (such as Zika, Ebola, SARS, MERS, CHIKV, Dengue, Influenza and HIV), the SARS-CoV-2 virus that causes COVID-19 has a genome made of RNA rather than DNA. Potentially, this offers us several novel therapeutic vulnerabilities that we can hopefully exploit for COVID-19 treatment. For example, virus RNA genomes spontaneously adopt regions of stable 3D structures that play obligate roles in virus infection, propagation and tropism. Dependencies that arise from unusual biology may serve as chinks in the virus's armour, with broad implications for managing the diseases such RNA viruses cause.
Ben Luisi and his team are using their renowned skills in structural biology to address whether a specific structured RNA element in the SARS-CoV-2 genome might be a new therapeutic target for treating the virus. His target is a conserved 48-nucleotide stem loop structure contained in the 3' UTRs of all viral protein-coding transcripts and found also in the SARS, MERS and other coronaviruses and astroviruses (which cause gastroenteritis). While the role of this RNA element in the virus lifecycle is unknown, its remarkable conservation suggests a fundamental role. So Ben is trying both to determine that role and to deduce the 3D structure of the RNA stem loop with the goal of identifying drugs that target it.
Omer Ziv is from the Gurdon Institute but is about to start working in the Biochemistry Department on another aspect of the SARS-CoV-2's distinctive RNA genome. His previous work has shown that many such RNA genomes anneal to complementary sequences in host cell RNAs and that these interactions appear to be critical for productive virus replication. Omer has developed a novel technology called 'COMRADES' that he uses to identify these key interactions between viral and host cell RNA, and he has teamed up with Professor Friedemann Weber, an expert on coronaviruses at the Institute of Virology in Justus-Liebig University in Giessen, Germany to identify such interactions in SARS-CoV-2.
A more general interactome map of the interactions between SARS-CoV-2 RNAs and host cell proteins is underway in a collaboration between Kathryn Lilley's Group and the newly arrived MRC Toxicology Unit led by Anne Willis and using the full might of the University's Proteomics Facility.
Florian Hollfelder is studying the interactive 'dialogue' between host lung epithelial cells and SARS-CoV-2 using a novel ultra-high throughput analysis of gene expression to identify mechanisms by which the virus replicates and evades local immunity. Another Hollfelder project seeks the converse; to map how clades of adaptive antibody-producing immune B lymphocytes undergo positive selection and potentiation during virus infection. A third endeavour seeks to meet the urgent need for assays with which to screen the population for SARS-CoV-2 infection using synthetic idiotypes generated in DARPINs (modified protein scaffolds derived from a class of ankyrin repeat protein).
Meanwhile, Marko Hyvönen has a team using bespoke tools and expertise to produce large quantities of the SARS-CoV-19 spike and capsid proteins for use in development of antibody tests to determine who has, and has not, been infected.
In a similar vein, our new Sir Henry Dale fellow Alex Borodavka will be working with Paul Digard and Dr Eleanor Gaunt of the Roslin Institute to generate recombinant rotaviruses expressing 14-20 amino acid epitopes of SARS-CoV-2. These recombinant viruses will be used in antigenicity tests on animal models with a view to generating a future SARS-CoV-19 vaccine.
And last but not least, Luca Pellegrini made the observation that DNA polymerase alpha/primase, a host cell enzyme needed for cell DNA replication, is potently targeted by the SARS-CoV-2 viral Nsp1 protein, a likely virulence factor that modulates host innate immune responses. As yet, it is unclear to what end this interaction is mission critical for the virus, but it might just reveal a completely novel strategy for treating COVID-19 infections.
I should say that all of these projects are possible only because of the willingness, courage and expertise of a number of research associates, graduate students and core technical, maintenance and facility staff. We will be shining the spotlight on them in a coming newsletter.
Publications and presentations
Meanwhile, great science waits for no one. Many laboratories continue to hold their regular lab meetings and discussion groups using remote software such as Teams or Zoom, and I guess that those lucky enough to have a lot of writing up to do or who are engaged in in silico analysis may not even have noticed that the rest of the world is on hold.
Take a look at a lovely review from the Owen/Mott laboratory in the journal Peptide Science on "Therapeutic peptides targeting the Ras superfamily", a ground-breaking paper in Nature Methods on "Genetic tool development in marine protists: emerging model organisms for experimental cell biology" from an international consortium that has Ellen Nisbet, Chris Howe and Ross Waller as members, and a fascinating paper in Nature Communications on restoring proliferation in adult heart cells from Cathy Wilson, who has just moved to take up a lectureship in the Department of Pharmacology.
And finally, great kudos and thanks to Rhys Grant for his tireless work in helping to recruit some 1,600 people to his COVID-19 volunteers project. The volunteers are now working on all our behalves at the Milton Keynes and Anne McLaren building testing facilities, and also with various projects as part of the COG-UK consortium. As I said at the beginning of this message, we are all doing our bit to fight the COVID-19 scourge.
That's all for now. Please take care and stay safe,
Gerard