In January 2020, Nam Tran of the Department of Pathology and Laboratory Medicine at the University of California, Davis, and his colleagues are expanding the testing platform for seasonal flu and the common cold.
Tran, a professor of clinical pathology at the University of California, Davis School of Medicine, is following reports in China about a mysterious new respiratory virus SARS-CoV-2. Little was known about the mode of transmission or mortality of the new coronavirus at the time.
Tran noticed the speed of the virus spreading around the world. He led the laboratory's response to the 2014 Ebola outbreak and has experience in responding to the 2009 novel H1N1 swine flu pandemic. Like many people, he believes that this outbreak may be similar to the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak, which caused 774 deaths worldwide.
By late January, it became clear that the new coronavirus that caused COVID-19 was no longer in China. The Centers for Disease Control and Prevention (CDC) announced the first case of human-to-human transmission in the United States. On January 31, the World Health Organization declared a global health emergency.
Tran began discussing with colleagues in infectious diseases whether the University of California Davis Health Center would need to conduct internal COVID-19 testing.
At the time, the U.S. Food and Drug Administration authorized COVID-19 testing for emergency use and must comply with CDC guidelines. The only available test is at the Centers for Disease Control and Prevention in Atlanta, which means the sample must be sent to Georgia. This process may take several days.
In the second week of February, the CDC began issuing COVID-19 test kits, enabling public health laboratories to provide results within a few hours. But almost immediately, there was a problem with the kit, possibly due to contamination of the reagents.
The new coronavirus has been spreading quietly all the time. Its presence in the Sacramento area became widely known on February 26, when the University of California Davis Health Center announced that it had treated the country's first known case of community-transmitted COVID-19.
Then, on February 29th, everything changed. The FDA announced that it will allow diagnostic laboratories to create something that does not yet exist: their own COVID-19 test. The game started.
"March 1 was crazy," said Marcelo Prado, director of the Molecular Pathology Laboratory. "We feel as if we are racing against this virus. It is impressive to see the mobilization of resources and the number of people gathered for COVID-19 diagnostic testing. It involves our entire laboratory."
The professional testing center laboratories where Prado works usually maintain normal working hours. It is not designed to run 24 hours a day. But in the weeks following the FDA announcement, laboratory staff worked more than 16 hours a day, sometimes until the lights were really extinguished. "All the lights are programmed to go out at 2 in the morning," Prado explained. "We will have to reopen them and start working again."
The team felt incredible pressure when creating the test. "The sooner we provide diagnostic tests, the sooner medical staff can identify and isolate patients with the virus. But we basically start from scratch," Prado said.
Molecular pathology laboratories specialize in testing genomic materials—RNA and DNA—to identify pathogens such as bacteria or viruses. The laboratory can also detect genetic diseases. "We are looking for the RNA of the SARs-CoV-2 virus," Prado said.
The molecular pathology team developed a COVID-19 test on the Roche Diagnostics cobas 6800 system in just 19 days.
The COVID-19 test they created is called a reverse transcription polymerase chain reaction or RT-PCR test. The PCR test can detect genetic material. Since SARS-CoV-2 has an RNA genome, the first step is to synthesize complementary DNA, namely cDNA. The genetic material is then identified and reproduced through a series of amplification steps.
Sometimes referred to as "molecular copying," the amplification in a PCR test can be repeated dozens of times, resulting in millions of copies of the original genetic material. This method is used to detect bacteria and viruses, and can make accurate diagnosis even if only a small amount of DNA is collected.
Scott Bainbridge, head of the Department of Pathology and Laboratory Medicine, explained that the method of collecting samples for PCR testing depends on the type of disease or pathogen.
“For example, Zika virus is a blood-borne disease of mosquitoes, so we will use blood samples for PCR testing,” he said. "But for respiratory diseases like COVID-19, you will find the virus in the back of the nose or throat. So, we use cotton swabs. The test is for the RNA of the virus. It has a very high specificity. So, if you are positive , Then you have a very high probability of contracting the virus."
Last March, Bainbridge was the busiest time of his life. "Friends and family say they have nothing to do, but I have been working for a long time."
But the long days are not the biggest challenge. "The most difficult part of all of this is purchasing the necessary reagents," he said.
Reagents are an important part of PCR detection. Laboratories around the world are racing to obtain the reagents needed to expand the scale of COVID-19 testing. "The supply chain is broken," Bainbridge said.
Every time a new reagent is used, the test must be revalidated. Prado said: "As soon as we proposed the test, we found that we could not get enough supplies and reagents to maintain it."
They have to repeat this effort time and time again to hedge against shortages. "We can't stop operations. When the world is pursuing the same material, it will quickly dry up," he said.
A dedicated IT team ensures that all new test data flows smoothly to where it needs to go and provides actionable information to healthcare providers.
Bob Hamilton is the director of the Epic Beaker laboratory and the Bugsy Infection Control Information System. In addition to other functions, the team also manages laboratory orders, test results and sample processing, and identifies patients who are at risk of contracting COVID-19.
“I work with a group of talented people who combine laboratory equipment with Beaker and Bugsy. We build orders and tests in the beaker, and send the results to doctors and elsewhere,” Hamilton said. "In the case of COVID-19, we must also send the results to the California Department of Public Health and other health agencies."
As the COVID-19 test was ready in March last year, the IT team worked from 7 am to 10 pm, or sometimes in the middle of the night, if that was the time to verify the test on a specific machine.
"Our team is incredible. We have a feeling that what we are doing is crucial," Hamilton said. "The most important thing for us is to ensure that doctors receive accurate and timely results so that they can treat patients."
Many other departments have also helped expand the scale of COVID-19 testing. Tran mobilized the microbiology laboratory, special chemistry and hematology laboratories.
Scientists from the California National Primate Research Center and the Center for Immunology and Infectious Diseases also joined the work to isolate, characterize, and cultivate the coronavirus from a patient treated at the University of California, Davis, to validate the test.
Once upon a time, as the supply chain stretched, Tran needed transmission media tubes and swabs. He contacted Gerhard Bauer, director of the Good Manufacturing Practices Laboratory at the Regenerative Therapy Institute at the University of California, Davis.
Bauer is able to manufacture tubes and swabs in a GMP laboratory, approximately 1,200 per week. The microbiology laboratory conducted a sterility test on the container.
At the same time, the pathology clinical trial team worked hard to obtain samples from volunteers to verify these new tubes in accordance with FDA requirements to confirm that they are suitable for COVID-19 testing.
"This is a comprehensive mobilization of clinical laboratories, spanning at least four professional laboratory departments-this would not be possible without our amazing clinical laboratory scientists," Tran said. "We validated two tests at the same time and plan to validate the third platform based on our Roche Diagnostics cobas 6800 system platform."
On March 19, the University of California Davis Health Center provided a patient with the first internal COVID-19 test, and all the hard work came together. This milestone achievement was only 19 days after the FDA's first announcement.
But there is no time to rest. They can only test 20 patients per day, which is obviously not enough to deal with the growing epidemic.
"Completing the first project gave me a sigh of relief, but we knew we needed to move it to a faster and more automated system," Tran said.
On March 28th, they started using the Roche system. On April 3, the University of California, Davis announced that it will speed up testing capabilities. The Roche 6800 can run up to 400 tests per day, and more than 1,000 tests per day thereafter.
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"Laboratories are usually performed behind the scenes, and we are sometimes taken for granted because our tests are always fast and available," Professor and Head of the Department of Pathology and Laboratory Medicine and Medical Director of the Health Clinical Laboratory at the University of California, Davis Lydia Pleotis Howell said. "Suddenly, we were pushed into the spotlight because there was a much-needed laboratory test that did not yet exist."
Howell said her department has received tremendous support to help them obtain the resources they need. She also attributed the department’s support before the pandemic to part of their success. "As a research university, before COVID-19, we had excellent equipment, such as Roche Diagnostics cobas 6800."
"Laboratories are usually performed behind the scenes, and we are sometimes taken for granted because our tests are always available quickly." — Lydia Pleotis Howell, Professor and Head of the Department of Pathology and Laboratory Medicine
She is extremely proud of the pathology staff. "Patient care is usually suspended until the provider has key test results," Howell said. "Our results are correct, which is crucial. Although we may not see their faces, these are our patients."
From March 2020 to the end of March 2021, the University of California Davis Health Center conducted more than 100,000 COVID-19 clinical tests. During this period, more than 31 million people in the United States were infected and more than 500,000 people died.
But other medical needs have not stopped. Between March 1, 2020 and February 28, 2021, the University of California Davis Health Center also processed more than 2.8 million non-COVID-19 tests.
Although the pandemic is not over, more than 200 million doses of vaccine have been vaccinated. There is a feeling that life will gradually begin to return to normal.
But the impact of the virus may last for several years, which is why Tran and his colleagues are trying to predict the current pandemic and post-pandemic needs.
For example, the department is building a sample database from COVID-19 patients to find potential clues about why long-distance patients continue to experience symptoms.
"We are validating our existing routine tests to understand how they perform in these long-distance patients," Tran said. "The biomarkers commonly used to evaluate patients with heart attacks, heart failure, inflammatory diseases, and coagulation disorders are being evaluated throughout laboratory services."
He also believes that it may be necessary to monitor antibody levels and T cell activity in the future. COVID-19 specific antibodies and T cells are produced in response to infections or vaccines. But it is not clear how long these antibodies and T cells will stay in the body to fight future infections.
"We may need an antibody test. It provides more than a simple'yes' or'no' answer. We may need to test how many antibodies someone has in their body in order to get them back to work or school. Or a certain level." Antibodies may mean they need to be vaccinated again. This is still unresolved and depends on other research and guidance from the CDC. "
However, much of the content about the new virus that will spread around the world in 2020 is still unknown, and new variants will continue to add new chapters to the story.
This is why he and the other members of the pathology team are ready to adapt and cope, as they have done repeatedly over the past year. "We are making scientific discoveries in real time," Tran said.
Lisa Howard (Lisa Howard) is a senior public information officer at the University of California, Davis Health Center and previously worked in the research office. Contact her via email or phone, 916-752-6394.
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