The world is in the grips of a historic pandemic, and the death toll from the COVID-19 coronavirus shows chilling numbers. Almost 120,000 people in the U.S. have died from the disease as of Monday morning, and globally the number is close to 470,000, according to the Johns Hopkins University coronavirus tracker. Total cases of the virus have soared past two million in the U.S. and almost 9 million globally.
Debates are now raging about whether U.S. states have begun to move too quickly to reopen restaurants, stores, barbershops and many other engines of life and commerce after weeks of lockdown.
But there is one area of widespread agreement, said Robert Tjian, a Howard Hughes Medical Institute investigator at the University of California, Berkeley: The safe path out of the pandemic requires enormous amounts of testing.
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In the online journal RNA, Tjian and coauthors reviewed recent advances in COVID-19 testing techniques and highlighted barriers facing widespread testing. To trace the pathogen's spread and stop the chain of transmission, it's crucial to test both for the SARS-CoV-2 virus itself and for evidence that people have previously been infected.
The countries that have so far successfully quashed their outbreaks, such as New Zealand, Taiwan, South Korea and Iceland, have done the best job of identifying cases. In contrast, the U.S. has done quite poorly.
That failing is not for lack of effort in the scientific community. Scores of researchers around the country dropped what they were doing to tackle the challenge in the U.S., authors said. In fact, in compiling the many studies described in his group's paper, Tjian was "surprised at how quickly so many labs have converted to working on COVID-19."
These labs have devised innovative new approaches for testing, as well as for overcoming the bottlenecks that hampered testing efforts early in the pandemic. Some labs, like at Berkeley, have set up their own rapid testing operations to serve local communities, quickly publishing their methods so they can be duplicated. These and many other efforts are helping to answer some of the basic questions about fighting the pandemic.
WHAT'S THE IMPACT?
SARS-CoV-2 is an especially pernicious virus. It is both highly contagious and relatively lethal, with a mortality rate that's still uncertain, but higher than that of flu – 10 times higher or more, some data suggests. But the virus' wiliest feature is that it can be spread by people who don't even know they are infected. In contrast, victims of the original SARS virus in 2003 weren't contagious until severe symptoms struck, making it easy to isolate those people and cut the chain of transmission.
One unknowingly infected person can infect dozens of others, as shown by "superspreading" events like a choir practice in Washington state, with 32 confirmed cases, or a man who visited several South Korean nightclubs, infecting more than 100 people.
In addition, testing may spot SARS-CoV-2 only when an infected person is actively producing lots of the virus. That's why authors said three types of testing are vital. People with any COVID-19 symptoms should be tested to spot new cases as soon as possible; people who have been in contact with an infected person also should be tested, even if they have no symptoms; and finally, healthcare providers should test people for antibodies to the virus to identify those who may have already been infected.
HOW TESTING WORKS
SARS-CoV-2 reproduces by getting into human cells, then hijacking the cells' machinery to make multiple copies of its genetic material, called RNA. Scientists have designed several testing methods to spot this distinctive viral RNA. The method used in almost all testing to date and considered the gold standard relies on a technique for amplifying tiny amounts of viral genes.
First, a swab collects infected cells from a person's throat, gathering bits of viral RNA. That genetic material is typically purified and then copied from RNA into complementary DNA. The DNA is then copied millions of times using a standard method known as polymerase chain reaction (PCR). Finally, a fluorescent probe is added that emits a telltale glow when DNA copies of the viral RNA are present.
PCR isn't the only viable approach. Scientists at MIT and other universities have also repurposed the gene editing technique called CRISPR to quickly detect SARS-CoV-2. CRISPR uses engineered enzymes to cut DNA at precise spots. The testing approach harnesses that ability to hunt for a specific bit of genetic code, in this case a viral RNA, using an enzyme that fluoresces when it finds the distinctive SARS-CoV-2 target. In early May, the Food and Drug Administration gave emergency authorization to the test developed by a team at MIT.
Another testing technique quickly reads each RNA "letter" of the viral genome, using a process called genetic sequencing. That's overkill for detecting the virus, but it has been particularly helpful at charting the virus's relentless march around the globe. And some researchers are experimenting with clever DNA "nanoswitches" that can flip from one shape to another and generate a fluorescent glow when they spot a piece of viral RNA.
Scientists can also see telltale signs of infection in the blood. Once people have been infected, their immune systems respond by creating antibodies designed to neutralize the virus. Antibody tests detect that immune response in blood samples using a protein engineered to bind to SARS-CoV-2 antibodies. Creating an antibody test that's both sensitive and accurate can be tricky, however.
Coronavirus testing in the U.S. has struggled to reach the levels needed, with a particular problem in accelerating the pace of testing.
THE U.S. TRACK RECORD
Even as the virus rampaged through Wuhan, China, in January and started to infect Americans in February or earlier, the U.S. government failed to adequately prepare for the spreading pandemic, authors said.
The Trump Administration declined to use a PCR-based test developed by the World Health Organization, for example, and a test produced by the U.S. Centers for Disease Control and Prevention turned out to be faulty. The lack of a coordinated national effort left states, companies and university labs scrambling to fill the gap.
As labs and states in the U.S. raced to boost their testing capabilities, they ran into bottlenecks and roadblocks. For example, only a few supply houses were providing the reagents needed for the PCR reactions, and supplies were inadequate at best. Even basic equipment, like the swabs used for collecting samples, was hard to find. It turned out that the major producer of swabs approved by the CDC was a factory in northern Italy, a region among those hardest hit by the virus.
Without sufficient testing, there was a "tragic data gap undermining the U.S. pandemic response," wrote health service researcher Eric C. Schneider in a commentary in the May 15 issue of The New England Journal of Medicine. Instead of being able to test every person with symptoms and all those they had been in contact with, as countries like South Korea did, the shortage meant reserving tests for hospitalized patients and for helping prevent healthcare workers from transmitting COVID-19.
The lack of data on case numbers has made it challenging to model the path of the pandemic, and, as a result, it has been difficult to anticipate where emergency medical services, hospital beds and ventilators are most needed.
By mid-May, the testing capacity in the U.S. had finally risen from a few thousand a day to about 300,000 a day. Still, that's far short of what's needed. The Harvard Roadmap to Pandemic Resilience estimates, for example, that the country will require testing at a rate of "20 million a day to fully remobilize the economy." To safely reopen, "we need massive testing capacities (that) don't currently exist," said Georgetown's Gostin, one of the authors of the report.
Scientists around the world have responded to the challenges posed by the novel coronavirus. The Berkeley group, for example, dramatically boosted its testing capacity and reduced costs to near $1 per test with improvements such as skipping one step – RNA purification – and making their own reagents. The research team has made their home-brewed test freely available to any lab that wants to replicate it.
Meanwhile, groups at Rutgers, Yale and other centers have eliminated the need for throat swabs by showing that saliva samples work just as well. That opens the door to home testing wider, since spitting into a tube and mailing it to a lab is far easier than swabbing.
Progress is also being made in testing for antibodies. Most of the dozens of so-called serology tests initially on the market didn't have the sensitivity and specificity to pick out only those antibodies directed at SARS-CoV-2. The challenge is that the tests require using copies of a viral protein that binds to the antibodies. One key to solving that problem, it turns out, is using mammalian cells to make the viral protein with the precise shape needed to home in on just the SARS-CoV-2 antibodies.
TAMING THE PANDEMIC
The basic strategy for overcoming COVID-19 is identifying infected people, finding and testing anyone they came in contact with, and quarantining infected people. That's not practical for big cities or entire countries, given the staggering numbers of needed tests, logistical challenges, and thorny privacy issues. But there are clever ways to cast a wider net without so many individual tests.
One is lumping together many samples in a pool, so that large groups of people can be monitored with only one test. Then, if the virus does show up in the pool, public health officials can test the individuals in that group to pinpoint the infections.
Perhaps even more powerful is monitoring sewage. The virus can appear in a person's feces within three days of infection – far earlier than the onset of first symptoms. Scientists could use the standard PCR test on sewage samples to detect the virus. And by collecting samples from specific locations, such as manholes, scattered throughout a community, it would be possible to narrow down the location of any infections to a few blocks or even individual buildings, like an apartment complex or a college dorm.
Tjian and others are now figuring out how these approaches might be used to safely reopen a university or a business. Large-scale testing efforts would be labor intensive and expensive, but far cheaper than locking down a whole economy – and far safer than reopening without adequate testing, as some states are now doing. And as scientists continue to increase testing capacities and create cheaper and better tests, this strategy may soon be within reach.
THE LARGER TREND
Testing is slowly becoming more widely available in the U.S., but a new challenge is accuracy: According to a Dartmouth-led paper published this month in The New England Journal of Medicine, more emphasis should be placed on addressing the inaccuracy of diagnostic tests, which play a key role in containing the pandemic.
Diagnostic tests, which generally involve a nasopharyngeal swab, can be inaccurate in a couple of ways. For one, a false-positive result mistakenly identifies someone as being infected, which can lead to consequences including unnecessary quarantine and contact tracing, with the latter needlessly eating up resources that are required to track the progression of the disease.
False-negative results, by contrast, are much more impactful because infected people who are asymptomatic may not be isolated and can consequently go on to infect others.