Can the US ramp up coronavirus testing? California will provide clues.

In some ways, California is a US leader in grappling with the covid-19 pandemic. It enacted early and aggressive social distancing policies that slowed the spread the disease and kept the death rate low, particularly among areas hit early by the outbreak.

But the state has lagged others on testing and must significantly expand its capacity before it can reopen without risking major additional outbreaks.

The unmet need is enormous," says Fyodor Urnov, a director of the Innovative Genomics Institute at the University of California, Berkeley, who has continually fielded calls from emergency responders, health clinics, and state agencies, all looking for ways to test patients and essential workers.

The number of tests that the nation's most populous state needs to conduct before relaxing stay-at-home orders is staggering. Governor Gavin Newsom announced late last month that California would have to be able to carry out between 60,000 and 80,000 tests per day, up from 25,000 on average during the last seven days. The state hasn't set a specific deadline for hitting that goal, nor has it said specifically how it hopes to meet it and how much it will cost.

At least half of those tests will be required just to support California's contact tracing program, in which health workers will attempt to diagnose and isolate everyone an infected patient may have exposed.

Achieving California's target will require locking in necessary supplies and equipment, getting tests to where they're needed, and marshaling armies of trained medical workers to administer them across the state. Testing sites will need to ramp up in dense urban centers as well as sprawling rural areas, both of which house large populations of undocumented residents who may fear being identified by government officials.

The low end of Newsom's goal, 60,000 tests, is in line with an earlier estimate by Harvard researchers that the US will need to conduct at least 152 tests per 100,000 people per day to lift lockdowns safely. So California's efforts to achieve this benchmark for its nearly 40 million residents and kick-start its economy, the world's fifth largest, could help light the path for other regions struggling to get ahead of the outbreak-or underscore just how difficult it's going to be.

Expanding test sites

Among states, California trails only New York in total testing numbers, at nearly 690,000 to around 960,000, according to data from COVID Tracking Project as of Sunday. But it lags many others, including Connecticut, Florida, Massachusetts, Michigan, Pennsylvania, and Tennessee, in terms of tests per million people, according to a recent Vox analysis. New York has conducted three times as many tests per capita.

Most experts say California's biggest bottleneck right now is getting tests to patients or patients to tests, a process complicated by regulatory restrictions, supply constraints, and a shortage of trained personnel.

For starters, a physician needs to requisition every test. And the primary test today can be conducted only by trained medical personnel, who must wear personal protective equipment and use nasopharyngeal swabs, all of which are running critically low.

The state has been trying to speed up and scale up testing on several fronts, including aggressively recruiting health-care workers and expanding test sites.

Governor Newsom recently announced plans to add nearly 90 new sites across the state, primarily in communities that have been underserved to date.

OptumServe, a testing company based in Eden Prairie, Minnesota, will open 80 new sites across the state in the coming weeks. And Verily agreed to set up six more in partnership with the Community Organized Relief Effort (CORE), which is conducting outreach efforts to ensure migrant farmworkers and other marginalized groups can be tested. The Alphabet subsidiary is now operating 12 sites in California, including locations in Bakersfield and East San Jose that opened on Monday, and will add three more in the next two or three weeks.

In mid-March Verily set up an online screening portal where Californians can note their symptoms, enabling physicians to rapidly evaluate whether they're eligible for testing under current guidelines. If so, they can drive to one of Verily's testing sites, roll down their window, tilt back their head, and steel themselves for a nasal swab that will reach the far wall of their upper throat.

Within days, they'll get either an email saying the test was negative or a phone call from a health-care professional informing them it was positive. They will also be looped into the state's contact tracing effort at that point.

Verily's covid-19 site already works in English and Spanish, and the company is adding additional languages.

We are actively exploring different ways that we can increase the accessibility of our system to different populations and needs," the company said in a statement to MIT Technology Review.

If all these new sites can screen 200 people a day, it will add up to only about 19,000 daily tests. But other health centers throughout the state are increasing tests as well, including primary care providers like One Medical, college systems such as Berkeley's University Health Services, and community clinics like Family Health Centers of San Diego.

In addition, California recently authorized its Medicaid programs to provide free coronavirus testing and care for uninsured or undocumented patients. It has also made specific efforts to direct supplies to low-income community health clinics.

Ensuring equipment and supplies

Many nations, states, and cities across the world are all trying to ramp up testing at the same time, which is putting serious strains on global supplies and equipment.

California has relied upon its extensive biomedical research facilities, while applying a combination of direct appeals and increased in-state production to keep the necessary supply chains open, says Christina Kong, a professor of pathology at Stanford Medical Center who serves on the state testing task force.

Last month, Newsom said he'd had a phone call with President Donald Trump, who had committed to provide California with hundreds of thousands of nasal swabs per week. In addition, state staff or task force members have been working directly with companies like Abbott and Roche to add more high-volume testing machines and secure the reagents and other materials required to process samples.

Meanwhile, Stanford has been working directly with Carbon of Redwood City, California, on an effort to 3D-print nasal swabs. The university is conducting a head-to-head comparison study to determine whether printed versions of the long, flexible swabs work as well as the standard ones, which are primarily produced overseas.

If we can just manufacture them locally, we don't have to rely on finding sources of swabs that are outside the country," Kong says.

Fathom, an advanced manufacturing company based in Oakland, started printing nasal swabs last week on HP printers, using designs that originated through the same coalition of academic groups and private industry. It is producing 100,000 a week but could ramp up to a million, company principal Rich Stump said in an email. He expects Fathom to begin distributing swabs to California facilities in the coming weeks.

The Innovative Genomics Institute at the University of California, Berkeley, installed a liquid-handling robot, the Hamilton STARlet, to analyze swabs from patients tested for covid-19.MAX & JULES PHOTOGRAPHY/UC BERKELEY

Kong and her Stanford colleague James Zehnder both say that California is now in a relatively strong position when it comes to processing tests.

In early March, Berkeley's Innovative Genomics Institute scrambled to set up a diagnostics lab dedicated to processing coronavirus tests, installing robotic systems capable of screening more than a thousand patient samples per day.

The University of California, San Francisco, also established a lab, launched with funding from the Chan Zuckerberg Initiative. As of mid-April, it could process more than 2,600 samples per day and return results within 24 hours. Researchers there have been offering to run samples for free for all the state's county health departments.

UC Davis, UC San Diego, and various private diagnostics companies have all set up or expanded labs as well.

Getting to 80,000 tests per day with all those groups scaling up should be relatively easy," says Zehnder, a professor of pathology at the Stanford University Medical Center.

Alternate routes

But even if the tests themselves won't be a problem, finding the medical professionals to conduct them could be. One way to ease personnel constraints is by conducting different types of tests.

San Dimas-based startup Curative launched in January to develop improved diagnostics for sepsis but pivoted to coronavirus testing as the outbreak reached the US. The company's tests rely on samples of oral fluid, including sputum produced by asking the patient to cough.

Patients can administer their own tests by swabbing the inside of their mouths, as long as they do it under the supervision of someone who has been trained in the procedure by a doctor, according to Fred Turner, the startup's chief executive.

That means they can do it at a drive-up test site with their windows rolled up, place the swab in a vial, and drop it into a container. It's not as uncomfortable as the nasal tests, doesn't require workers with the same level of training, and avoids the use of swabs that are in high demand. It also eliminates direct interaction with a health worker, which reduces the need for protective equipment.

The company has conducted more than 125,000 tests and now has the capacity to do 10,000 a day. At this point, it's supplying the vast majority of the testing for Los Angeles, which is part of the reason the city was able to begin offering free tests to all city and county residents last week.

But how reliable are these tests?

The company points to a recent Yale study that suggests saliva samples may be better than nasal swabs as an indicator of coronavirus infection. But the study hasn't been peer reviewed, and the method is still not the one preferred by health authorities. Some researchers, including Kong, say it's not yet clear whether these test are as accurate as the nasal swabs, particularly for early or asymptomatic cases.

Turner says they've secured regulatory approvals to produce and distribute the tests, including emergency use authorization under the Food and Drug Administration. Curative is now seeking authorization to allow people to self-administer the tests at home.

Beyond brute force'

Others believe California may need to shift to different technologies on the processing side as well.

The standard test relies on a technique known as PCR (polymerase chain reaction), which requires a series of time-consuming steps to produce many copies of the viral genetic material. But recent research advances could streamline the testing process, as several leading genomic pioneers argued in MIT Technology Review last week. They describe using DNA sequencing, genetic engineering, industrial automation, and advanced computation" to speed up testing, potentially by orders of magnitude.

Sri Kosuri, one of the authors and an associate professor at UCLA, says he hopes the state can just brute force" its way to 60,000 tests per day. But he believes California may need to conduct far more than that: many businesses want to require weekly or even daily testing to keep their workforce healthy as they get back to business.

Reaching that kind of scale could require broader shifts in the way we conduct coronavirus testing, including rethinking how we collect and handle specimens, validating these kinds of advanced testing technologies, and getting them approved by regulators.

Since it's not clear how many tests will really be required, or what technologies it will take, we should be making multiple bets right now, Kosuri says.

Bolstering capacity will allow California to loosen its criteria for testing, expanding beyond sick patients and front-line health workers to those who may be harboring the virus but don't have symptoms. It's only when health authorities can effectively identify those people, and prevent them from spreading the disease, that a state can really get ahead of the outbreak.

There's no way to imagine controlling this highly contagious virus without having those kinds of testing and tracing abilities in place," Zehnder says.

Whether California can pull this off-with all its wealth, expertise, and biomedical resources-will be a test case worth watching.