Late last week, Charles Chiu’s lab at UC San Francisco received a shipment of test tubes from the California Department of Public Health. This wasn’t out of the ordinary. For almost a year, Chiu, an infectious disease doctor, has been collaborating with the state agency to conduct genetic sequencing on samples from people who’ve tested positive for the coronavirus that causes Covid-19. Like all viruses, SARS-CoV-2 mutates as it moves through a population. Most of these mutations are trivial and don’t change how the virus behaves. But by making a record of these mutations, scientists can track the coronavirus’s spread and better understand the origins of different outbreaks.
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Chiu had been assisting with this kind of genetic detective work for months. This time, though, he had reason to think his team was about to find something new.
Two of the samples belonged to members of a household in Big Bear, California, who got sick after one of them had contact with a traveler who had recently returned from the United Kingdom. And during standard diagnostic testing, something strange had happened to both samples. The test detected bits of a protein that protects the virus’s genome, but not the spike protein SARS-CoV-2 uses to invade cells. That meant that whatever strain had infected these people had probably acquired at least one mutation in the virus’s spike protein gene. Mutations in that location are one signature of the new, seemingly more contagious variety of the coronavirus that has been rapidly spreading in the UK and now around the world.
By Saturday, Chiu’s lab had sequencing results. And sure enough, those two samples turned up 23 telltale mutations in the spike protein. Both people had been infected with the UK variant, known as B.1.1.7. At the time, there were fewer than 10 such cases in the US, following an initial discovery of the UK variant in Colorado on December 29. As of January 8, at least 52 people have been confirmed to have contracted the new strain, according to data from the Centers for Disease Control and Prevention. So far, it has shown up in New York, Florida, and Georgia, in addition to California and Colorado.
Chiu thinks the real picture is actually far worse. “I suspect it’s circulating in nearly every state in the US,” he says. “It’s just that other states don’t have the same sequencing capabilities.”
Since the beginning of the pandemic, coronavirus sequencing has been a patchy, ad hoc affair, dominated by areas with big biomedical research institutions that are staffed by scientists eager to investigate the virus’s evolution. States like California and Colorado are sequencing and uploading hundreds of viral genomes every week, according to the latest data from an international virus-sharing database known as GISAID. But others have only done a few dozen—total. North Dakota, which for the month of November held the ignominious record for the worst outbreak in the US, has yet to sequence a single sample. On a national level, the US simply hasn’t built out a robust, coordinated, genomic surveillance system capable of keeping tabs on problematic new mutations wherever they might arise. The result is not just scarce sequencing. It’s a monitoring system missing huge chunks of the country.
“We are really behind in terms of having geographically representative data,” says Kelly Wroblewski, the director of infectious disease for the Association of Public Health Laboratories. She sees the failure as the inevitable outcome of the Trump administration’s decision to leave nearly every aspect of the coronavirus response up to individual states—from ramping up diagnostic testing to rolling out vaccines. “There was no national sequencing plan, because there has not been a national much-of-anything plan,” she says.
Of the more than 21.5 million Covid-19 cases officially reported in the US, samples from just 59,438 people, or less than 0.3 percent, have been sequenced and analyzed for variants, according to GISAID. By contrast, the UK is regularly sequencing more than 10 percent of its Covid-19 cases. That allowed British public health officials to monitor in real time as the B.1.1.7 variant went from being a rare find at the beginning of December to dominating new infections three weeks later. The Brits might be an outstanding example in this regard, but they’re not alone. According to a recent Washington Post analysis, 42 other countries have sequenced more cases than the US, despite the fact that Americans account for a quarter of all coronavirus infections globally.
“What the US is doing right now is completely inadequate,” says Chiu. He thinks American government officials should be setting their sights on that 10 percent threshold. But the effort will undoubtedly be complicated by the fractured US health care system. In the UK, which has a single nationalized health service and a supporting microbiology service, it’s relatively easy to flow samples and data. In the US, the private sector still dominates the testing market. In order for a sample to show up in Chiu’s lab, he says, it has to go from a commercial lab to the county lab and then to the state lab before it gets to him. That can take weeks—if it even happens at all. Often, by the time a public health department epidemiologist comes across a case they want to investigate with genetics, the original sample has already been discarded. “The rate-limiting step isn’t sequencing; it’s really getting the sample,” says Chiu. “That’s why we have to empower state and county labs to do it in-house, so we can get the data out faster.”
Over the last decade, public health labs have built up their sequencing capacities as part of their role in tracking outbreaks of foodborne illness across the US. Every state lab, as well as a handful of large regional ones, has the technology readily available, according to Wrobleski. But they haven’t been able to deploy it widely during the pandemic because they’ve had their hands full just trying to conduct basic diagnostic tests and contact tracing, she says. And until a few weeks ago, they hadn’t been given marching orders to do anything differently.
But that’s finally starting to change.
In mid-December, the CDC released $15 million to public health labs around the country to boost sequencing outputs nationwide. That was part of a multipronged effort now underway at the agency to increase both the number of coronavirus variants being characterized and the locations from which they’re being drawn. The money will help states participate in a dedicated SARS-CoV-2 Strain Surveillance program, dubbed NS3, which the CDC launched in November. When the program is fully operational, public health labs will be expected to send 10 randomly selected coronavirus samples to the CDC’s labs in Atlanta every other week. The samples should represent patients from different age, racial, and ethnic groups, as well as the geographic diversity of each state. In addition to sequencing them, CDC scientists will also use the samples to build up a centralized strain library that they can dip into to perform additional tests.
“Sequencing will tell us a lot, but it can’t tell us everything,” says Gregory Armstrong, who leads the CDC’s Office of Advanced Molecular Detection. For example, one of the things public health experts are concerned about is how well people with existing immunity gained through a previous bout with Covid-19 will be able to fend off infections with this new UK strain. To test it, scientists have to be able to assess how well the antibodies found in the blood of Covid-19 survivors attack and neutralize the B.1.1.7 version of the virus. Another alarming possibility is that the vaccines that have been developed and authorized so far won’t be as effective against emerging strains. “We need to have a library of variants in order to get those answers,” says Armstrong.
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The NS3 program, which Armstrong expects to be fully up and running by the end of the month, will help with that. But it won’t get the US as much genetic data as public health officials need to track the progress of B.1.1.7 and other emerging strains, like an alarming one that originated in South Africa, through the American populace. That’s why the CDC is also bringing large commercial testing labs on board. In December, the agency signed contracts with LabCorp and Illumina, and it is in the process of negotiating further deals with others that have the capacity to acquire and sequence samples from all around the country. In addition, since September the CDC has granted about $8 million to academic sequencing centers and is currently seeking to bring additional sites online. Data from all these efforts is continuously analyzed by CDC scientists and uploaded to public databases like GISAID for other researchers to use.
These new efforts are designed to boost the efforts of scientists like Chiu, who since the early stages of the pandemic has been part of a CDC-led coalition of more than 160 research institutions, non-governmental organizations, and public health agencies called Spheres (Sequencing for Public Health Emergency Response, Epidemiology, and Surveillance). The federal initiative aims to help scientists agree on data and quality standards, but it doesn’t foot the bill for actual lab work. And it hasn’t been able to keep pace with the pandemic.
“We feel very strongly that we haven’t been sequencing enough,” says Armstrong. “That’s why we’re taking these steps right now to scale things up.” In December, labs throughout the US were sequencing about 3,000 viral genomes per week. He’s optimistic that by combining the forces of public, academic, and commercial labs, the nation can get up to 6,500 viral genomes per week by the end of January.
Wrobleski speculates that the newfound urgency at the CDC comes from a collision of forces—the surfacing of more transmissible, and possibly more dangerous, new strains right as the beleaguered public health agency wriggles free of the political meddling of the Trump administration. Whatever the reason, the window to get it right is closing, says Chiu. “The point of doing surveillance is to find these rare variants and, in doing so, make sure they continue to be rare. If we do it now, we can hopefully still prevent these variants from blowing up and becoming the predominant lineage. That would be a disaster.”
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