24 Mar 2020

While science groups worldwide are grappling with the logistics of shutting down to comply with the social distancing required to slow the spread of COVID-19, neurodegenerative disease researchers are asking how they can help. And help they can. One lab at Imperial College London is poised to double current SARS-CoV-2 testing capability in the U.K. Paul Freemont and colleagues have repurposed their high-throughput, robotic rtPCR technology to crank out up to 10,000 tests per day. As of writing, the whole of the U.K. was completing about 10,000 tests a day, though that is set to scale up rapidly in the coming weeks, Freemont said.

Working with the National Health Service, Freemont expects the test will be accredited and approved in the next two days. The system would then be up and running at St. Mary’s Hospital, London, by Friday. “At that point we could be accounting for half of the total national capacity,” said Freemont, a group leader at the U.K. Dementia Research Institute.

Remarkably, this pivot from dementia research to virus testing has taken but nine days. “It’s indicative of how rapidly we can scale up and provide new platforms,” Freemont told Alzforum. Bart De Strooper, director of the U.K. DRI, told Alzforum that the institute has applied for acute funding to help Freemont and other researchers adapt to fight the coronavirus. “I’m proud of how our institute has responded to the crisis,” he said.

Freemont heads the Section of Structural & Synthetic Biology in the Department of Infectious Disease at Imperial College. He uses structural and synthetic DNA tools to develop diagnostic tests for infectious agents. As part of the Healthy Homes initiative at the Care Research & Technology Center at DRI, his lab has adopted these tools to develop tests for urinary tract infections that can be used in dementia care settings. People with dementia can be unaware or unable to communicate that they have a UTI, making their diagnosis difficult in the early stages. Freemont and colleagues use polymerase chain reaction (PCR) technology to amplify and detect DNA from bacteria that commonly cause these infections. This test recently identified two people with asymptomatic UTIs in a small dementia cohort. Because the test identifies specific bacteria, it can help guide treatment with appropriate antibiotics. “We can increase the knowledge base for doctors so that they can tailor treatment more effectively,” said Freemont.

With the arrival of COVID-19, however, priorities changed. The U.K. government issued a call for labs that have high-capacity PCR to help with testing and Freemont, who co-directs the London Biofoundry, stepped up. The Biofoundry is a facility to accelerate and commercialize synthetic biology technology. It has suites of robotic equipment for scaling up procedures such as PCR. “We focused all of our efforts into working with NHS frontline testing in Northwest London to see how we can bring our expertise in robotic workflow to bear to increase the number of tests that can be done,” said Freemont.

With 384-well plate reverse transcriptase PCR capability, an initial test platform processes 2,000 samples a day. Freemont said their robotic system is modular and scalable. The U.K. government hopes to process 25,000 samples per day using a centralized testing site, said Freemont, but that will take some weeks to establish.

The rtPCR test uses oligonucleotide primers identified as suitable by the U.S. Centers for Disease Control and Prevention. Freemont said he wanted to ensure the test aligned with others being conducted. Because live virus can’t be used as a test material, he amplifies synthetic coronavirus RNA sequences that are packaged into bacteriophage envelopes. “We can do a lot with these synthetic viral particles,” he said. The test is now being run in parallel with NHS-approved tests to ensure the workflow and the quality are comparable. “Assuming our validation goes according to plan, we should be able to process up to 10,000 samples per day by the end of this week,” Freemont said.

Freemont also has a CRISPR-Cas13a test in development. This is based on guide RNAs that recognize and bind the coronavirus sequence. This hybrid then activates Cas13a, which begins to digest any RNA in sight. Cas activity can be detected by adding an RNA containing a quenched fluorophore. Once that RNA has been chewed up by Cas13a, the probe fluoresces. Developing this rapidly to support testing in the U.K. was not feasible, but Freemont thinks it might be useful for countries where the pandemic lags behind and which lack the infrastructure for high-throughput rtPCR. It can also be adapted as a “one-pot shop,” where all the reagents and enzymes necessary for the RNA amplification and CRISPR are put into one tube and only the patient sample needs to be added.

Other technologies being studied at the Care Research & Technology Center might help the medical community fight the pandemic as well. David Sharp, DRI co-director at Imperial College, usually spends his days developing a variety of sensors and wearables that can be used to monitor dementia patients in home settings. Sensors that relay blood oxygenation could help doctors monitor people with COVID-19 or who are at risk for developing it. “The situation is getting to the point where a lot of people may need to be monitored at home,” said Freemont.

Strange as it may seem at first blush for dementia research labs to be in the thick of coronavirus research, De Strooper thinks it’s only right. “I strongly believe the DRI should be involved in the fight against coronavirus because it is our patients who are most threatened,” he said.—Tom Fagan

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