Even more impressive is that the automated testing lab can reportedly process (with results in four hours) up to 3,000 patient samples daily for SARS-CoV-2, the coronavirus that causes the COVID-19 illness.
“All of our laboratories do PCR every day. But for this test we need to go above and beyond to ensure accurate detection,” said Jennifer Doudna, PhD, IGI Executive Director and UC Berkeley Professor of Molecular and Cell Biology, in an IGA news release.
“We put in place a robotic pipeline for doing thousands of tests per day,” she continued, “with a pipeline for managing the data and getting it back to clinicians. Imagine setting that up in a couple of weeks. It’s really extraordinary and something I’ve never seen in my career.”
Robert Sanders, UC Berkeley’s Manager Science Communications, told Dark Daily the COVID-19 lab performs about 180 tests per day and has tested 1,000 people so far—80% of the samples came from the campus community. About 1.5% to 4% of the tests were found to be positive for the SARS-CoV-2 coronavirus among the groups tested.
“We hope other academic institutions will set up testing labs too,” he said.
How Did Berkeley Set Up a COVID-19 Diagnostic Lab So Fast?
To get up and running quickly, university officials drew from the campus and surrounding business community to equip and operate the laboratory, as well as, train researchers to do clinical analysis of patient samples.
Though the methodology to test for the coronavirus—isolating RNA from a biological sample and amplifying it with PCR—is standard fare in most research labs worldwide, including at UC Berkeley, the campus’ research labs were shuttered due to the spread of the coronavirus.
IGI reached out to the idle labs for their high-throughput PCR systems to start-up the lab. Through its partnership with University Health Services and local and national companies, IGI created an automated sample intake and processing workflow.
Additionally, several research scientists who were under government-mandated stay-at-home orders made themselves available. “My own research is shut down—and there’s not very much I can do other than stay in my home … finally I’m useful,” said PhD candidate Holly Gildea in a Berkeleyside article which noted that about 30 people—mostly doctoral students and postdoctoral researchers—are being trained to oversee the process and monitor the automated equipment.
Postdoctoral fellows Jenny Hamilton (left) and Enrique Shao (right) with an automated liquid-handling robot (Hamilton Microlab STAR), which will be used to analyze swabs from patients to diagnose COVID-19. Hamilton and Shao volunteered to train to become CLIA certified so as to process patient samples. When analyzing real samples from patients, they would be wearing full personal protective equipment (PPE), including mask, face shield, gown and gloves. (Photo and caption copyright: Max and Jules Photography/UC Berkeley.)
Federal and State Authorities Remove Hurdles
In her article, “Blueprint for a Pop-up SARS-CoV-2 Testing Lab,” published on the medRxiv servers, Doudna summarized “three regulatory developments [that] allowed the IGI to rapidly transition its research laboratory space into a clinical testing facility.
“The second was California Governor Newsom’s Executive Order N-25-20, which modified the requirements for clinical laboratory personnel running diagnostic tests for SARS-CoV-2 in a certified laboratory.
“The third was increased flexibility and expediency at the state and federal levels for certification and licensure requirements for clinical laboratory facilities under the Clinical Laboratory Improvement Amendments (CLIA) program. Under these emergency conditions, the California Department of Public Health (CDPH) was willing to temporarily extend—once the appropriate regulatory requirements have been fulfilled—an existing CLIA certificate for high-complexity testing to a non-contiguous building on our university campus.”
“These developments,” wrote Doudna, “enabled us to develop and validate a laboratory-developed test (LDT) for SARS-CoV-2, extend the UC Berkeley Student Health Center’s clinical laboratory license to our laboratory space, and begin testing patient samples.”
Lessons Learned Implementing a Pop-Up COVID-19 Testing Laboratory
“Our procedures for implementing the technical, regulatory, and data management workstreams necessary for clinical sample processing provide a roadmap to others in setting up similar testing centers,” she wrote.
Learned strategies Doudna says could aid other academic research labs transform to a “SARS-CoV-2 Diagnostic Testing Laboratory include:
Leveraging licenses from existing CLIA-certified labs;
Following FDA authorized testing procedures;
Using online HIPAA training;
Managing supply chain “bottlenecks” by using donated equipment;
Adopting in-house sample barcoding;
Adapting materials, such as sampling tubes, to work with donated equipment;
Cost of equipment and supplies (not including staff) was $550,000, with a per test cost of $24, Doudna noted.
“As the COVID-19 pandemic continues, our intention is to provide both PCR-based diagnostic testing and to advance research on asymptomatic transmission, analyze virus sequence evolution, and provide benchmarking for new diagnostic technologies,” she added.
Medical laboratory leaders understand that the divide between clinical and research laboratories is not easy to surmount. Nevertheless, UC Berkley’s IGI pulled it off. The lab marshaled resources as it took on the novel coronavirus, quickly developed and validated a test workflow, and assembled and trained staff to analyze tests with fast TAT to providers, students, and area residents. There’s much that can be learned from UC Berkeley IGI’s accomplishments.
At present, medical laboratories are collecting blood specimens for testing by authorized public health labs. However, clinical laboratories should prepare for the likelihood they will be called on to perform the testing using the CDC test or other tests under development.
“We need to be vigilant and understand everything related to the testing and the virus,” said Bodhraj Acharya, PhD, Manager of Chemistry and Referral Testing at the Laboratory Alliance of Central New York, in an exclusive interview with Dark Daily. “If the situation comes that you have to do the testing, you have to be ready for it.”
The current criteria for determining PUIs include clinical features, such as fever or signs of lower respiratory illness, combined with epidemiological risks, such as recent travel to China or close contact with a laboratory-confirmed COVID-19 patient. The CDC notes that “criteria are subject to change as additional information becomes available” and advises healthcare providers to consult with state or local health departments if they believe a patient meets the criteria.
Bodhraj Acharya, PhD (above), is Manager of Chemistry and Referral Testing at the Laboratory Alliance of Central New York. In an exclusive interview with Dark Daily, he stressed the importance that medical laboratories be prepared. “We need to be vigilant and be active and understand everything related to this virus and the testing. That’s the role of clinical laboratory scientists, to be ready because this can become a pandemic anytime. It can spread and tomorrow the CDC could announce it is disseminating the test to designated laboratories.” (Photo copyright: Laboratory Alliance of Central New York.)
Test Kit Problems Delay Diagnoses
On Feb. 4, the FDA issued a Novel Coronavirus Emergency Use Authorization (EUA) allowing state and city public health laboratories, as well as Department of Defense (DoD) labs, to perform presumptive qualitative testing using the Real-Time Reverse Transcriptase PCR (RT-PCR) diagnostic panel developed by the CDC. Two days later, the CDC began distributing the test kits, a CDC statement announced. Each kit could test 700 to 800 patients, the CDC said, and could provide results from respiratory specimens in four hours.
However, on Feb. 12, the agency revealed in a telebriefing that manufacturing problems with one of the reagents had caused state laboratories to get “inconclusive laboratory results” when performing the test.
“When the state receives these test kits, their procedure is to do quality control themselves in their own laboratories,” said Nancy Messonnier, MD, Director of the CDC National Center for Immunization and Respiratory Diseases (NCIRD), during the telebriefing. “Again, that is part of the normal procedures, but in doing it, some of the states identified some inconclusive laboratory results. We are working closely with them to correct the issues and as we’ve said all along, speed is important, but equally or more important in this situation is making sure that the laboratory results are correct.”
During a follow-up telebriefing on Feb. 14, Messonnier said
that the CDC “is reformulating those reagents, and we are moving quickly to get
those back out to our labs at the state and local public health labs.”
Above is a picture of CDC’s laboratory test kit for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CDC is shipping the test kits to laboratories CDC has designated as qualified, including US state and local public health laboratories, Department of Defense (DOD) laboratories, and select international laboratories. The test kits are bolstering global laboratory capacity for detecting SARS-CoV-2. (Photo and caption copyright: Centers for Disease Control and Prevention.)
Serologic Test Under Development
The current test has to be performed after a patient shows
symptoms. The “outer bound” of the virus’ incubation period is 14 days, meaning
“we expect someone who is infected to have symptoms some time during those 14
days,” Messonnier said. Testing too early could “produce a negative result,”
she continued, because “the virus hasn’t established itself sufficiently in the
system to be detected.”
Messonnier added that the agency plans to develop a serologic test that will identify people who were exposed to the virus and developed an immune response without getting sick. This will help determine how widespread it is and whether people are “seroconverting,” she said. To formulate this test, “we need to wait to draw specimens from US patients over a period of time. Once they have all of the appropriate specimens collected, I understand that it’s a matter of several weeks” before the serologic test will be ready, she concluded.
“Based on what we know now, we believe this virus spreads
mainly from person to person among close contacts, which is defined [as] about
six feet,” Messonnier said at the follow-up telebriefing. Transmission is
primarily “through respiratory droplets produced when an infected person coughs
or sneezes. People are thought to be the most contagious when they’re most
symptomatic. That’s when they’re the sickest.” However, “some spread may happen
before people show symptoms,” she said.
The virus can also spread when people touch contaminated surfaces and then touch their eyes, nose, or mouth. But it “does not last long on surfaces,” she said.
Where the Infection Began
SARS-CoV-2 was first identified during an outbreak in Wuhan, China, in December 2019. Soon thereafter, hospitals in the region “were overwhelmed” with cases of pneumonia, Dr. Acharya explained, but authorities could not trace the disease to a known pathogen. “Every time a new pathogen originates, or a current pathogen mutates into a new form, there are no molecular tests available to diagnose it,” he said.
So, genetic laboratories used next-generation sequencing, specifically unbiased nontargeted metagenomic RNA sequencing (UMERS), followed by phylogenetic analysis of nucleic acids derived from the hosts. “This approach does not require a prior knowledge of the expected pathogen,” Dr. Acharya explained. Instead, by understanding the virus’ genetic makeup, pathology laboratories could see how closely it was related to other known pathogens. They were able to identify it as a Betacoronavirus (Beta-CoVs), the family that also includes the viruses that cause SARS and Middle East Respiratory Syndrome (MERS).
This is a fast-moving story and medical laboratory leaders are advised to monitor the CDC website for continuing updates, as well as a website set up by WHO to provide technical guidance for labs.
