A mystery disease wound its way through the Mission this January, wreaking runny noses and headaches upon its victims. But when doctors had patients test for likely diseases — Covid-19, flu, respiratory syncytial virus (RSV) — results turned up negative for all three.
What was ailing them? Chan Zuckerberg Biohub scientists used metagenomic sequencing to find out.
In metagenomic sequencing, scientists run the genetic code of a sample gathered from a patient’s nostrils against the genetic codes of other pathogens, viruses, and microbes to identify the mystery agent or biological source. This means that once a sample is sequenced, the Chan Zuckerberg Biohub runs the genetic code of a patient’s sample against an open-source database of genetic codes documented by the National Center for Biotechnology Information. The latter tracks the genetic code of thousands of viruses, fungi and bacteria from all over the world.
The specificity — matching a genetic code against a database of other illnesses — could also become a powerful tool in precision public health, doctors said.
Doctors typically make a diagnosis by asking a patient about their symptoms and forming an educated guess about the cause. A doctor then orders a specific test to confirm their hypothesis; if the results are positive, mystery solved. If they’re negative, then it’s either back to the drawing board, or the patient goes undiagnosed and potentially untreated for any specific illness.
“It’s hard to guess, right? There’s a lot of things it could be,” said Genay Pilarowski, a scientist with Chan Zuckerberg Biohub. “That’s where metagenomics come into play. You don’t have to know what you’re looking for to find it, which is unique.”
The cutting-edge technique became a local tool when Joe DeRisi, president of the Chan Zuckerberg Biohub and long involved in Covid-19 testing in the community, directed his team to use metagenomic sequencing to research a Mission mystery.
In January, workers at the Unidos en Salud health site at 24th and Capp streets, a collaboration between the Latino Task Force and the University of California, San Francisco, found patients coming in with respiratory symptoms that suggested the three prominent respiratory viruses: The flu, respiratory syncytial virus (RSV) or Covid-19. But, they tested negative for all three. What did they have?
Scientists at ChanZuckerberg BioHub collected roughly six dozen of the samples, and Pilarwoski sequenced them.
The results revealed that 44 percent of the patients had a form of rhinovirus, the untreatable source of the common cold, and 44 percent had seasonal coronavirus, which is endemic and generally more mild than Covid-19, according to the U.S. Centers for Disease Control and Prevention. About 7 percent had adenovirus, which can cause sore throats or bronchitis; 5 percent had metapneumovirus, a common respiratory virus like a common cold.
Interestingly, the data corroborated how more metapneumovirus hospitalizations showed up in recent hospital data, wrote UCSF associate professor of medicine Dr. Carina Marquez in an email.
Marquez was also impressed that the results identified a majority of viruses that could cause disease.
“Most of what we know right now about circulating respiratory viruses is from hospital or urgent care surveillance, but it is important to know what is going on in the community,” Marquez said. “Data on what viruses are circulating in local communities can help direct and tailor resources and public-health interventions.”
Pilarowski agreed. When doctors know their patients are infected with flu, for example, they prescribe oseltamivir; Covid-19 patients are prescribed Paxlovid. “The worst case would be if we had something going around that is treatable or has a therapeutic,” Pilarowski said, but without identifying the cause, “we could never help people connect with follow-up care.”
A local lab will determine the biological source through a catch-all test called “metagenomic sequencing.”
“We clearly haven’t found a way to communicate to the public how important it is, and we have to keep trying,” said Diane Jones.
“This information was a call to action for all of us,” said UCSF professor of medicine Dr. Diane Havlir.
Moreover, identifying disease makes it easier to procure or develop novel treatments, DeRisi added. Rhinovirus C, which accounted for 21 percent of Mission residents’ illness, can be dangerous for the elderly, young and immunocompromised, DeRisi said. It currently has no treatment. But, neither did Covid-19 before public awareness grew, he said.
“It’s not like we can’t make them,” DeRisi said. But “no one is going to make a vaccine, no one is going to make a drug for something that they don’t know is there,” DeRisi said.
Knowledge about disease can alter public-health policy, too. Pilarowski’s previous work researching Binax tests — rapid Covid-19 tests — at 24th and Capp revolutionized San Francisco’s testing and isolation policy by offering real-time transmission data.
Metagenomic sequencing may discover new pathogens and prepare health systems to combat them. For example, South African scientists used metagenomic sequencing to first discover the Covid-19 omicron variant. Learning the differences between Covid-19 strains — Delta was more deadly, omicron more contagious — has affected people’s personal behaviors, too.
But metagenomic sequencing is not broadly accessible, nor a timely technology, yet. Chan Zuckerberg’s efforts are still in the research stage.
Metagenomic sequencing is less prevalent, in part because of the cost, and in part due to lack of access to the necessary, cutting-edge technology. For example, it costs about $5,000 to process a plate of samples, Pilarowski said, whether that plate has 90 or 300 samples.
Another challenge is collecting enough samples to make processing a plate cost-effective. DeRisi’s team collected samples in January, though it took time. Analysis and results weren’t ready until this week.
Right now, ChanZuckerberg is still using metagenomic sequencing as a research tool.
Still, DeRisi’s team plunges forward. They are sequencing samples to look for common bacteria in the Mission. It’s unclear when the results will be ready, but he’s excited to look at the “bigger landscape, and process new batches of data.”
Joe DeRisi serves on the nonprofit board of Mission Local.