4 December 2020
In her role as co-founder of the Human Cell Atlas (HCA), EMBO Member and Gold Medallist Sarah Teichmann coordinates a network of hundreds of researchers around the world. As the first ominous hints that SARS-CoV-2 was no ordinary coronavirus appeared in early 2020, the HCA community mobilised. “If you have a pre-existing community,” Teichmann says, “people know each other, and they are very willing to collaborate”. From her laboratory at the Wellcome Sanger Institute in Cambridge, Teichmann asked her fellow researchers to use their published and unpublished data to generate a map delineating where in the body a panel of genes involved in viral uptake were expressed.
It soon became clear from the pooled data that one of the reasons for SARS-CoV-2’s rapid transmissibility was the presence of the viral receptor ACE2 and its associated protease TMPRSS2 on cells in the nose, mouth, upper airways and eyes; this may explain why some respiratory viruses like SARS-CoV-2 and influenza, whose receptors are more highly expressed in the upper airways, are far easier to catch. Due to the public health implications, the results were fast-tracked into print in a much-cited paper in April 2020.
More recent data show there is good concordance between the consortium’s predictions of where the virus would enter, and where it is actually found. “A good example is if you map the oral cavity from healthy donors and COVID-19 patients,” says Teichmann. “There are cells in the salivary glands that have high expression of ACE2, and when we stain in tissue sections you can see the virus sitting there.”
To accompany their ongoing COVID-19 work, the HCA community now maintains an open access data portal, containing reference data from many more healthy tissues, together with single cell mapping of patient sample data, and spatial mapping data from infected post-mortem tissue. The portal has become an invaluable resource, accessed tens of thousands of times. “It’s really helped me get through this terrible year to know that we’ve been able to contribute something useful,” Teichmann says.
In contrast to the HCA, the group leaders responsible for setting up and running the Vienna Biocenter’s impressively efficient SARS-CoV-2 testing programme had no prior experience in the field, but simply felt that they needed to help. “We had the instruments, we had extensive expertise in molecular biology, and we thought we should pool our brainpower and equipment,” says one of them, Andrea Pauli.
Three parallel initiatives were set up: an RT-qPCR pipeline for in-house testing and monitoring, led by Johannes Zuber, and also involving Stefan Ameres; next generation sequencing, led by Ulrich Elling, Luisa Cochella and Alex Stark; and RT-LAMP, led by Julius Brennecke and Pauli. Interestingly, all seven are either EMBL alumni, present or past EMBO Young Investigators, or EMBO Members. They were joined by many other volunteers from the Vienna Biocenter research community.
Neither Pauli nor Brennecke had worked on anything related to LAMP (loop-mediated isothermal amplification) technology before. “I’m a zebrafish embryologist and Julius works on RNA biology in flies, and to be honest, I didn’t even know what LAMP was in March!” Pauli laughs. However, LAMP proved to be the best solution to developing a cheap and robust assay that could also be used in lower- and middle-income countries, where uncertain supply chains and limited equipment make testing for SARS-CoV-2 especially challenging.
The assay costs less than 1€ per reaction, and only requires simple reagents and a waterbath set at 63ºC. An open-access version with home-made enzymes is available, and Pauli hopes it will be adopted not only in Austria, where diagnostics labs and hospitals are now recommended to use it for testing, but worldwide.
Of the testing programme in general, Pauli emphasises that it was a team effort: “The whole campus has come together, from the directors, particularly Harald Isemann (managing director of the IMP), to the students and technicians running the assays. To some extent, the pandemic pushed us apart, but this project has really brought us together.”
Five years ago, EMBO Member Eric Vivier co-founded Marseille Immunopôle, a federation dedicated to the research and development of immunotherapy antibodies and cell therapies. Vivier believes its members have been crucial for the rapid development of a potential anti-COVID-19 drug, now in phase 2 clinical trials. “Even though we were not working in inflammation or virology, we knew that being experts in immunology could help to describe the impact of the disease on the immune system”, he says. “Then we went one step further by trying to repurpose drugs.”
Alerted in March to the worsening situation in Marseille’s intensive care units, Vivier hit upon the idea of an immunomonitoring programme for seriously ill patients that specifically looked at 40 molecules for which drugs had already been developed in other contexts. “It turned out that one of these molecules was not just interesting, it was phenomenal”, says Vivier. The Explore COVID-19 group, recruited from Immunopôle members, rapidly analysed 82 patient samples provided by local hospitals, and showed that levels of soluble complement factor C5a were exactly commensurate with the severity of the disease. C5a and its receptor C5aR1 have a key role in initiation and maintenance of several inflammatory responses, and the high levels of both suggested a role in the acute respiratory distress syndrome suffered by COVID-19 patients. The paper describing these results, submitted less than a month after the first sample was collected, was published in Nature in July.
In addition to his academic research, Vivier is also Chief Scientific Officer of Innate Pharma, which had acquired Avdoralimab, an anti-C5a drug which had already passed phase 1 trials, some years previously. Aided by a French government grant, Innate has provided the drug gratis to be tested against placebo in an ongoing double-blind randomised trial. Results are yet to be published, but Vivier is cautiously optimistic. “This is a potential path,” he says. “I’m not saying that it’s definitely going to work—it may not—but we may provide some treatments for patients who need them. And that would be extraordinary.”