The COVID-19 outbreak requires a concerted research effort that draws on a range of different disciplines. At the Francis Crick Institute, researchers are continuing vital studies into the biology of the virus and volunteering scientific facilities, resources and expertise.
Answering key questions about the virus
How does the virus interact with our cells and how did it jump from animals to humans?
Director of Science Platforms, Steve Gamblin’s research group is looking at how a large surface spike protein on the virus interacts with a receptor in human cells. They will also use cryo-electron microscopy to look for differences in how spike proteins of related coronaviruses from bats and pangolins (a potential intermediate species) interact with human receptors.
These studies are probing the cause and effect in receptor binding specificity associated with transfer between host species.
How does the virus replicate in human cells?
Group leader Rupert Beale, a clinician scientist, is trying to understand how SARS-CoV-2, the virus that causes COVID-19, can replicate in human cells. In collaboration with scientists at The Roslin Institute, his lab will use CRISPR technologies to discover the genes that are involved.
What treatments might be most effective for people with severe symptoms?
Andreas Wack’s research group specialises in understanding why influenza (flu) viruses and other respiratory pathogens cause only mild symptoms in some people, while in others the infection can be severe and even deadly.
Using their established in vivo models of severe respiratory infection, they are testing potential anti-inflammatory treatments.
The experimental strategy is similar to antibody treatments already tested in China and Italy, and the candidates used have already been tested in humans for other diseases. So if one of these potential treatments shows promise, compounds could be rapidly produced for additional trials in people.
How does the virus spread?
Paul Bates, group leader of the Biomolecular Modelling Laboratory, has joined forces with the supercomputing firm Hadean to develop large-scale simulations to track how virus outbreaks, such as COVID-19, spread within and between cities.
The project will integrate both in-vivo and extrinsic models of virus transmission into a single, massive scale simulation. The extrinsic model will map how people interact and move around a city - from using public transport to meeting with others. Integrating this with a model that understands how the virus behaves and transmits at the individual level (immune system strength, genomic factors), will give decision makers valuable insights into how a disease spreads and help make better informed decisions on how to combat disease outbreaks.
Paul’s role will be to input to the system how susceptible an individual is to infection and the likelihood that they can pass on the virus. This means he’ll help design the simulation with our current understanding of how the virus enters human cells, multiplies within the cell and spreads to neighbouring lung cells.
He’ll be analysing protein sequences, both from the virus and the receptor cells in humans, and formulating relative binding affinities – how likely it is that the virus will stick to the human cell receptors. This work will use his expertise in simulating proteins and formulating mathematical models.
Hadean is a deep technology company that has previously partnered with Paul Bates to simulate protein-protein interactions. Their product, Aether Engine enables scientists and organisations to build spatial simulations that achieve unprecedented levels of scale and fidelity by harnessing the full force of the cloud. Underpinned by a proprietary compute model, Hadean enable any program or simulation written on it to be distributed by default.
How is COVID-19 impacting cancer treatment?
COVID-19 is creating unprecedented challenges for clinicians delivering cancer care. In the context of infection risk and social distancing, oncologists are exercising judgment in deciding whether to postpone or modify anti-cancer therapies (including immunotherapy, chemotherapy, and targeted treatments) as well as surgery. However, hard evidence to guide these decisions is limited and even contradictory.
Samra Turajlic's group is initiating a large prospective immune-monitoring trial with patients at the Royal Marsden NHS Foundation Trust.
This aims to determine the epidemiological, clinical, genomic and immunological determinants of mortality outcomes and severity of COVID-19 infection in cancer patients, across cancer types, disease stage and types of treatment.
It will shed light on the interaction between the cancer, the anti-viral immune-response and the anti-cancer therapies in a way that can guide clinical decision making to minimise risk of severe infection and maximise cancer control.
How can we find better diagnostics?
Caetano Reis e Sousa and his team are testing virus diagnostic kits, including a new diagnostic tool, that could provide a result in just 20 minutes. The new method reacts with sections of RNA in the virus and causes the test sample to change colour if it contains SARS-CoV-2, the virus that causes COVID-19. This means that, unlike conventional tests, the results don’t need complex analysis.
The team plan to compare the new tests to the conventional one to see whether they can produce similarly accurate results.
How does the virus affect the body?
While many people with coronavirus experience mild symptoms, some end up in hospital and about 20% of these people will require critical care and possibly ventilation in an intensive care unit.
Many of these patients are older or have existing health conditions, but doctors are also seeing younger, healthy individuals decline rapidly after infection.
Professor Adrian Hayday and colleagues at King’s College and Guy's and St Thomas' NHS Foundation Trust, have built a high-throughput platform, looking at patient’s blood to see how our immune system responds to coronavirus, and if there are clues to whether someone might need additional treatment.
The team are studying the differences in immune response between different groups of patients and examining how this relates to clinical outcome. They’re looking at proportions of different immune cells in order to understand why some people can’t get rid of infection after a few days and why some people enter a type of ‘immune shock’ where inflammatory cells cause the body to shut down.
This information should tell us a lot about what the virus does to people and what we do to the virus. Moreover, the results may be used by doctors to predict who will need intensive care and get them the treatment they need faster. A better understanding of our immune response could aid in the development of treatments and vaccines.
How do we know who's been infected with COVID-19?
Most current tests for COVID-19 detect the presence of the virus by looking for its RNA component. It is also important to be able to identify the proportion of people who have been infected and cleared the virus, and may have some degree of immunity. This will help build scientific understanding of the outbreak and guide public health decisions.
The Crick/UCLH/UCL serology initiative has developed a blood test to indicate whether someone has been infected with SARS-CoV-2. Initial results suggest that this procedure has higher levels of accuracy than other tests. It also appears to be highly scalable, with the potential to carry out thousands of tests a day.
The test is based on the use of cells expressing the SARS-CoV-2 Spike protein being analysed by flow cytometry. The flow cytometry process detects an antibody response to SARS-CoV-2 in patients’ blood. Importantly, a second stage of the process uses neutralisation tests to see how effectively the antibodies will stop the virus from being able to infect cells.
The Crick’s expertise in flow cytometry and neutralisation assays, offering a high level of accuracy, provides powerful insights into patients’ immune response to infection.
The information from our tests will used to quickly determine the effectiveness of candidate vaccines. It will also be used for research studies seeking to establish levels of infection across large groups of people, as well as to help doctors make treatment decisions for patients who are seriously ill.
How is the Crick helping to create PPE?
With a high demand for personal protective equipment (PPE), the Crick’s Making STP is using their equipment and expertise to produce face shields for frontline NHS workers.
They’re using a laser cutter to create the two key parts of the shields: acrylic frames and disposable plastic front windows. Whilst the cutter creates a batch, a member of the team who is wearing PPE themselves, assembles the face shields.
The shields are being delivered weekly to St Pancras Hospital for distribution to North London hospitals. The team has committed to create at least 320 face shields a week, one for each front-line nurse at the hospital.
Meanwhile, group leader Lucia Prieto-Godino, along with researchers at the University of Sussex, has reviewed hardware and 3D printing blueprints. In a PLoS Biology review paper, the team described free and open source hardware designs for a range of products, from DIY facemasks to 3D printed valves which can regulate airflow in ventilator tubes.
The freely available blueprints they’ve reviewed could provide a method to quickly produce personal protective equipment, ventilators and test kits.
Curating sequencing data
Offering assistance in emergency COVID-19 testing
Almost 300 scientists at the Crick with relevant expertise have offered their services to the NHS as volunteers, carrying out essential diagnostic tests in the lab. We've partnered with University College London Hospital to set up a testing service for patients and NHS staff, and hope to roll out the testing service to more London hospitals. The service recently opened a new drive-through coronavirus swabbing facility for NHS staff at the British Library.
The new location, operated by University College London Hospitals (UCLH) NHS Foundation Trust and its diagnostic partner Health Services Laboratories (HSL), will help streamline the hospital’s testing process, allowing more people to be tested faster. Positioning the drop-in service next door to the Crick means the swabbing and testing process can be as streamlined as possible, with testing taking place in our newly repurposed laboratories, so that NHS staff get the results quickly and know whether it’s safe for them to return to work.
The temporary facility will be located at the rear of the Library’s building at St Pancras, which is currently closed to the public, and service is by appointment only. Invited NHS staff will be able to drive onto and off the site.
As demands on PHE’s testing infrastructure continue to grow, Crick staff's laboratory skills including PCR methods will be invaluable in the Government’s fight against the coronavirus pandemic by helping to increase the number of tests that can be conducted by Public Health England and the NHS.
Offering expertise and resources
Curating sequencing data
Researchers from across the world are sequencing the genetic code of SARS-Cov-19, the virus that causes COVID-19, to see how it is evolving and mutating. Lots of viruses don’t have the machinery to check their genetic sequences when they are copied, allowing errors to creep in.
This is what allows flu to evolve and change each year so that a new vaccine is needed.
To see these patterns of evolution, researchers need access to hundreds of sequences and a central repository that they can deposit the sequences. One of these databases, the Global Initiative on Sharing All Influenza Data (GISAID), has close links to the Crick and currently holds over 700 genomes.
Science and Technology Platform head, Aengus Stewart is helping to curate the sequences as they are submitted to the database.
This involves looking at the data as it comes in making sure essential patient information is included and checking data integrity before it’s released to the database and researchers all over the world.
Working in containment conditions
The Crick hosts one of the international World Influenza Centres (WIC). Researchers in the WIC are world-leading specialists in handling, growing and characterising the Influenza virus. They have expertise in the protocols and facilities required for high level containment work on viruses.
As part of the Crick’s response to the Coronavirus outbreak, the WIC stands ready to provide advice and training in relevant protocols particularly with respect to safe use of high-level containment facilities.