Issmat Kassem, a microbiologist and assistant professor at the University of Georgia’s Center for Food Safety, has been worried for a while about antibiotic resistance. His research focuses on what he calls hitchhiker genes, short strings of DNA that get passed among bacteria like trading cards. For several years, he had been tracking the worldwide spread of one hitchhiker, a set of genes called mcr that defuse the effectiveness of one of the most valuable antibiotics in medicine: colistin, used on life-threatening infections when other medications fail.
The mcr genes were first found in China in 2015, in E. coli bacteria present in pigs at a slaughterhouse and pork in markets, and also in infections found in hospital patients in two provinces. Ever since, they have been popping up in people, animals, and environmental samples across the globe. That includes a half-dozen sightings in the United States, in patients in Connecticut, Michigan, New Jersey, New York, and Washington State. Every sighting constituted a potential emergency, because if the bacteria carrying mcr spread to other people—or if the genes passed into other pathogens—it could take away one of medicine’s last-resort defenses. But there was no connection between those US patients, and no known event that could explain their infection—and without those pieces of data, no easy way to set up a surveillance scheme to test how widespread its dispersal might be.
Kassem understood that he couldn’t trek door to door or farm to farm to determine whether mcr was hiding in the guts of US residents, or the animals they planned on eating—but he could go to places where gut contents end up. Last year, he collected a sample of raw sewage from the wastewater treatment plant of a mid-sized city a few hours’ drive from his university, the first step in what he thought would be an ongoing project. But immediately, in that first sample, he identified mcr, hiding not in E. coli but in a common environmental bacterium called M. morganii. The gene was stitched into an array of others that confer resistance to additional antibiotics, making the bacterium—which Kassem grew on lab plates and then sequenced—a potentially formidable foe.
Kassem’s discovery is notable for finding colistin resistance where there was no prior evidence to expect it. But it also validates the technique by which he found it: looking in wastewater for a signal of the presence of pathogens. “Sewage is like a litmus paper for whatever is circulating in a community,” he says. “Everything goes into it. So if there's any pathogen, any gene, any anything you are concerned about, that's where you should be looking.”
For more than 18 months, wastewater sampling has been a crucial tool for monitoring the Covid pandemic in parts of the US; just 10 days ago, the Centers for Disease Control and Prevention debuted a nationwide data dashboard that reports SARS-CoV-2 isolations from sewage. But researchers working in what is still a pretty small field say we should expand wastewater monitoring beyond the search for the virus that causes Covid—not only to detect known health problems emerging in new areas, but also to ring the alarm over novel pathogens that could spark the next pandemic.
Identifying water contamination is a foundational act of epidemiology: In 1854, physician John Snow tracked the source of a cholera outbreak in London by pinpointing sick households on a map and associating them with the neighborhood well they used. (Snow didn’t find cholera in the well, though; the bacterium was not identified until later that year in Italy.) Using sewage as a data source also isn’t new. Israel began using wastewater analysis in 1989 to detect whether polio had been eliminated there; when the virus was found in sewage in 2013, it provided an early warning of a flare-up in one community. In 2017, the city government of Tempe, Arizona and researchers at Arizona State University began sampling wastewater for opioid metabolites and mapping the results, hoping to identify where use was concentrated for insight into a spiraling epidemic of overdoses.
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Sewage sampling “is extremely efficient—a ‘sewershed’ may involve dozens of people living within a dorm or working in a building, to hundreds, thousands or even millions of people,” says Este Geraghty, a physician and chief medical officer of the private company Esri, which built the underlying mapping and analytics. “It's passive; nobody has to do anything except for the water utilities and the public health authorities. And it's not intrusive.”
Sewage sampling can pick up a pathogen’s presence whether or not someone’s infection has been noticed by the healthcare system—an important feature when many people don’t have health insurance, can’t access testing regimes, or are taking at-home tests whose results don’t get reported into any comprehensive system. In the case of SARS-CoV-2, it also detects the virus early. People begin shedding it in their feces before they experience its respiratory symptoms, allowing sewage detection to ring the alarm bell up to two weeks in advance of patients hitting emergency rooms.
Sewage sampling is overwhelmingly a local decision, under the purview of mayors, city councils, or wastewater authorities, which allows it to elide the politicization of the national Covid response. Local control allowed campuses such as University of California, Davis and small cities such as Somerville, Massachusetts, among many others, to set up their own testing. Big municipalities, too: New York City began allowing scientists at the City University of New York to examine samples from its wastewater plants in June 2020, formalizing it into a citywide testing regime that August.
Those sampling programs have served as early warning systems for their areas, by mapping the extent of disease spread and flagging the arrival of new variants before tests on people do. In Missouri, a sewage sampling and mapping regime run by the University of Missouri covers about 70 percent of the state. It picked up Missouri’s first occurrence of Delta in the second week of May 2021 in the tourist town of Branson, weeks before a wave of Delta cases swept hospitals. It would have taken luck to identify that variant in an individual patient; even if they had sought medical care, their isolate might not have been sequenced. But wastewater doesn’t depend on lucky choices, because every patient—and everyone else nearby—is represented in it.
“It doesn’t matter whether you’re testing the right people, because wastewater is comprehensive,” says Marc Johnson, a molecular virologist and professor in the University of Missouri School of Medicine who directs the program and collaborates with wastewater researchers in other states. “Whether they've been tested, whether they've been vaccinated, whether they believe in the virus—as long as they poop and use a toilet connected to municipal wastewater, they're part of the sample.”
The New York testing regime—which is run by John Dennehy, a virologist and professor of biology at Queens College of the City University of New York, and Monica Trujillo, a microbiologist and associate professor at CUNY’s Queensborough Community College—flagged the arrival of Omicron in the city on November 21, four days before its existence was announced by South African scientists and 10 days before the city’s first recognized case. That finding provided more than just situational awareness. Omicron infections don’t respond to two of the three monoclonal antibody treatments that can arrest the course of Covid if delivered early—so picturing where the variant was occurring allowed healthcare officials to route resources where they would do the most good.
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There are enough Covid-detecting wastewater efforts running now that the CDC’s new dashboard contains data from 471 points of analysis, including municipal sewage systems, university water treatment facilities, and the labs of academic researchers. “CDC is supporting 37 states, four cities and two territories to help develop wastewater surveillance systems in their communities,” Amy Kirby, team lead for the National Wastewater Surveillance System, said in a media briefing announcing the system. “The real power of this program will be more evident in the coming weeks when hundreds more testing sites will begin submitting data.”
That many sites might sound comprehensive, but as analyst Betsy Ladyzhets revealed in her newsletter Covid-19 Data Dispatch, almost half of them are clustered in three states: Johnson’s Missouri network, plus Ohio and Wisconsin. Another seven states—California, Colorado, New York, North Carolina, Texas, Utah, and Virginia—have enough sampling sites to deliver a usable picture of the virus’s movement in their territories. But most states do not, and 18 of them have no wastewater analysis sites at all. “While the CDC’s new wastewater tracker offers a decent picture of national Covid-19 trends,” she wrote, “it’s basically useless for local data in the majority of states.”
Those data gaps are a warning of where the Covid response is still flying blind, but they also represent an opportunity. They are places where low-cost, low-effort detection systems, designed from the start to to report the same sets of data, could be installed in existing wastewater plants to build a cohesive network. Building out wastewater detection is one goal of the Rockefeller Foundation’s new Pandemic Prevention Institute, which aims to knit disparate data streams into global detection networks.
“We’ve been seeing this done here, in Ghana, in Bangladesh, all over India, at the UK Health Security Administration,” says Samuel Scarpino, the Institute’s managing director of pathogen surveillance and affiliate faculty at Northeastern University, where he worked on the Somerville city project. “But there's nobody pulling all of that information together, layering it with the clinical genomes, layering it in with the epidemiological data and trying to look at the big picture. It’s that stitching-together piece that’s still the biggest gap.”
The real promise of wastewater surveillance, though, is what detection systems might deliver once they can broaden their scope beyond the grind of tracking Covid. Kassem’s mcr find suggests how utilities could track antibiotic-resistant bacteria. Some cities, such as Houston and Tulsa, and some private companies, such as Biobot, which spun out of the Massachusetts Institute of Technology, have begun scanning sewage for influenza, sussing out clues of flu season’s arrival and potentially measuring its intensity. Ultimately, researchers hope that wastewater analysis could deliver intelligence on the advent of previously unknown pathogens, including ones that seem candidates for causing future pandemics.
New work from the CUNY team shows an early glimpse of that possibility, while also revealing the difficulties involved in identifying what an aberrant signal means. For a year, the group has been finding what they call “novel cryptic SARS-CoV-2 lineages,” variations of the virus that do not exist in the shared international databases where sequencing results are recorded. “Not only have they not been seen anywhere in New York City or the United States, they have never been observed in clinical samples anywhere in the world,” Dennehy says. “They have only been detected in wastewater—tantalizing hints of some unknown strains, whose origin we can't pinpoint at this point.”
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New York City isn’t the only location that has registered these odd variations; Johnson has seen some in Missouri, and collaborators in other states have found localized clusters as well. So far, no one can offer a reliable explanation of where they came from. Hypotheses include that they could have arisen among immunocompromised patients carrying the virus over a long period of time, or among people residing in long-term care facilities, which could explain why the sequences were confined to specific areas. They might also have come from urban animals, particularly rodents—though sampling of rats conducted by the US Department of Agriculture found no sign of the variants.
Being unable to identify the source of those sequences doesn’t mean that expanding sewage surveillance is impossible. But it does indicate that the big task for wastewater epidemiology will be to understand a complex ecosystem, and untangle the relative influence of all of the substances that comprise it.
“We are at the beginning. We are not at a point where we are building on something that is already known,” says Trujillo, of the New York team. “If we want wastewater surveillance to be a tool, we need to do some of this basic work.”
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