In 2016, Michael Letko moved from New York City to Hamilton, Montana—a town of 4,800 nestled between Blodgett Canyon and Highway 93 at the southern end of the Bitterroot Valley.
During the state’s earliest days, a strange, deadly disease emerged from these dark lodgepole pine forests, striking down settlers with a black rash and raging infection. Scientists eventually named it Rocky Mountain spotted fever, and they named the facility they built to study the bacteria responsible for the fever (and the ticks that carry it) the Rocky Mountain Laboratory. In 1937, the lab became part of the National Institutes of Health, evolving into a national vaccine factory when the US entered World War II. This is where, in 2008, the NIH opened its first biosafety level 4 laboratory—the highest level there is for biological containment facilities. Today, more than 400 scientists like Letko work inside the red-roofed complex, conducting research on some of the nastiest pathogens known to humans.
Letko arrived in the lab of virologist Vincent Munster, eager to work on some of these germs. Munster studies virus ecology—how they live in different hosts and sometimes jump between species. He often sends research fellows to places like the Democratic Republic of Congo, Trinidad and Tobago, and Jordan to collect blood samples or fecal swabs from bats and camels, which his team then studies back in the lab’s maximum containment facilities. Bats are of particular interest because they’ve evolved a unique ability to coexist with viruses, including ones particularly likely to transfer to humans. SARS, MERS, the Marburg virus, Nipah, and perhaps even Ebola all started in bats.
Letko wasn’t really that kind of scientist. He’d spent his PhD a block off of Central Park in Manhattan, studying a protein produced by HIV and modeling its molecular structure to understand how it shuts down the host’s immune response. He had gotten really good at figuring out the shapes of viral proteins and how those molecular grooves and pockets grant access to cells or fend off attacks. But it wasn’t until 2017, when he met a Belgian student visiting Munster’s lab, that he had an idea for what to do with this talent.
The Belgian student had spent his whole PhD on a virus discovery project, sequencing bat samples like the ones Munster’s team brings back from the field. Many of the genomes he’d put together came from coronaviruses, one of the most abundant families in the viral kingdom. After the SARS outbreak of 2003, scientists realized that maybe they should pay more attention to them, given their ability to jump between species. This new urgency—combined with the arrival of new sequencing technologies catalyzed by the Human Genome Project—kicked off a viral discovery boom. Over the next decade and a half, scientists uncovered a massive trove of coronaviruses circulating in wild animal populations around the world.
Search “coronavirus” on GenBank, a public repository for genomes, and today you’ll find more than 35,000 sequences. Alpaca coronaviruses. Hedgehog coronaviruses. Beluga whale coronaviruses. And, of course, lots and lots of bat coronaviruses.
But very few people have carried out the downstream laboratory work—figuring out how these coronaviruses behave, how they get into the bodies of their hosts, and how likely it is that they could make the hop to humans. “I realized just how much data there is and how little we know about all of it,” says Letko.
He was particularly haunted by a coronavirus called HKU4-CoV. A sequence of its spike protein was published in February 2007 by a team of Chinese researchers who’d discovered it in the blood of bats they’d collected from caves deep in Guangdong province. It was one of hundreds of sequences published during the sequencing boom to no fanfare. Then, five years later, MERS broke out in Saudi Arabia. When scientists sequenced the new MERS virus, they noticed that the protein it used to attack human cells looks almost exactly like the one HKU4-CoV uses. When other researchers looking at relatives of the MERS virus tested the bat virus, they realized that it, too, was capable of infiltrating human cells through the same receptor. But back then, no one had made the link between HKU4-CoV’s protein sequence and its ability to infect humans. “If that data had been available at the time of the MERS outbreak, scientists would have had a head start at figuring out how it’s transmitted and what drugs might work against it,” says Letko.