Breathless: The Scientific Race to Defeat a Deadly Virus

by David Quammen

ProMED (as it’s commonly known) is an email service with roughly eighty thousand subscribers, devoted to detecting, gathering, and disseminating reliable information about disease events happening moment to moment anywhere in the world. It began in 1994, with a subscribership of forty, and is now run by the International Society for Infectious Diseases, a body of scientists and health care professionals. It’s free. It’s independent and apolitical. It’s relentless, encyclopedic, and sometimes arcane. If you subscribe to ProMED, you might wake up to three or four of its emails on a given morning, one informing you of lumpy skin disease (a viral affliction) among Laotian water buffalo, another reporting shigellosis (bacterial diarrhea) among children who visited a safari park in Kansas, the third updating you on the latest Ebola outbreak in the Democratic Republic of the Congo. Pollack has been part of this operation since 1997.

she does her ProMED work with the skeptical acuity of an old-school newspaper editor in Chicago—“If your mother says she loves you, get a second source.”

The Evolution and Emergence of RNA Viruses, an authoritative but concise compendium. Oddly for a text that goes so deeply into the swales and the gullies of molecular evolution, the book is clear, trenchant, and readable.

RNA viruses mutate faster than almost any other sort of creature on Earth. In fact, Burke wrote, they mutate about a thousand times faster than animals: roughly one mistake in every ten thousand bases of genome. Although the genomes of RNA viruses are relatively short, only a few thousand or twenty thousand or thirty thousand bases (compared to three billion bases for the human genome), that error rate is enough to put at least one mutation into every new virion (every viral particle) of the typical RNA virus. Result: each of those new virions is likely to be different, by at least one mutation, from its parent.

But some RNA viruses have an additional trick that further increases their capacity to evolve. They can recombine, swapping sections from one viral genome to another, like railroad trains switching cars on a siding. (Coronaviruses, for instance, recombine. Influenza viruses have their own version, called reassortment, with the breaks occurring at regular spots along their segmented genomes.) This occurs by a sort of molecular interruption during the process of replicating their genomes within the same cell. Recombination, Burke explained, “serves both to hybridize highly fit variants and to replace defective and incompetent genes.” Empty boxcars left behind, sleek Pullman cars added. In other words, recombination gives viruses major new options and clears away genetic debris. It allows them to evolve by large chunks, as well as by the tiny increments of mutation.

recombination of a different sort occurs in animals, including humans, during the production of eggs and sperm. To put it simply (and spare you a refresher on meiosis), the chromosomes in complex creatures swap sections at a crucial moment, which reshuffles the genes received from each parent into new gene combinations for the offspring. This process is called sex. Its value in evolutionary terms is to produce offspring that differ genetically from their parents and also (except identical twins) from their siblings. In other words, it adds variation among individuals to a population. Variation allows populations to evolve. RNA viruses are incapable of sex, so they achieve the same end by a different sort of recombination: swapping sections of RNA with other viruses while engaged in the delicate, naked act of genome replication.

a place considered so barren that you might be AWOL for three days and the guards could still see you leaving.

Singapore is orderly. Singapore is rigorous and affluent. By April 24, twenty-two people had died, at which point penalties for quarantine breakers stiffened: bigger fines, the possibility of jail. Taxi drivers had their temperatures checked daily. Passengers arriving at Changi Airport were also screened, as well as people traveling in buses and private automobiles. On May 20, eleven people were fined $300 each for spitting. These measures worked. On July 13, 2003, the last SARS patient walked out of Tan Tock Seng and it was over. Some people loosely say that SARS “burned out,” having killed 774 people worldwide. It didn’t burn out. As Khan told me, it was stopped.

“A disease anywhere is a disease everywhere.”

“What you learn very quickly is, there are these individuals who are just excellent at spreading to lots and lots of other individuals.” Most primary cases account for zero secondary cases. “Period. It doesn’t go anywhere. But it’s this small minority of people who are so good at transmitting to others.”

But that SARS-CoV virus had one feature, or the absence of a feature, standing between it and a global nightmare in 2003. “Which was, for the most part, asymptomatic people didn’t transmit until they were sick. So you had time.” You could identify cases, trace contacts, and quarantine. It could be stopped, for those reasons, and it was. If the virus had been a little different, “highly transmissible, with more variable disease manifestation, harder to figure out who were silent carriers, then we may never have been able to contain SARS.”

Super-spreading events drove this outbreak, as they had driven SARS, but it was exacerbated by aspects of South Korea’s health care system. Because citizens receive cheap medical care through a national insurance plan, with few restrictions on which hospital they can visit, people often shop for treatment. The businessman visited three different hospitals after he felt sick, and was finally admitted to a fourth, in Seoul, where he was given a diagnosis of MERS.

MERS in South Korea became a textbook example of blunders that can lead to “nosocomial spread,” the term for disease transmission occurring because of, rather than in spite of, health care circumstances.

When COVID-19 arrived five years later, Khan said, “I guess maybe it was raw for them.” South Korea reacted fast to the news out of China, on January 3, 2020, with screening and quarantine measures for travelers from Wuhan. Thanks to those measures, the country’s first case was detected on January 20, 2020, in a woman from Wuhan disembarking at Incheon International Airport. The government raised its crisis-management alert level from Blue to Yellow, and then a week later from Yellow to Orange. Also, on January 27, health officials summoned representatives from twenty medical companies to meet at a train station in Seoul and discuss creation of the tools for response, including privately developed diagnostic tests, with guarantees that those tests would get fast regulatory approval. Officials of the Republic of Korea took this outbreak seriously from the start. Their response was strongly in contrast to what happened and didn’t happen, for instance, in the United States, which had its first detected case on January 19, one day before South Korea’s.

That first U.S. case was a man who had flown home to Seattle from a family visit in Wuhan, then turned up at an urgent-care clinic in Snohomish, Washington, with symptoms. His swab samples went overnight to the CDC, tested positive there, and by January 21 his blood had been sampled too. “Every day after January 22 was a day missed—by the U.S. government,” Khan told me with some frustration. January 22 was a Wednesday. Leaders of America’s health agencies could have called in Becton, Dickinson, Khan added (referring to the giant multinational medical-technology company, headquartered in New Jersey), and told them: We want nationwide testing capacity ready by next week. Didn’t happen. Failure...

The lockdown fatigue in South Korea, the second and third and fourth waves, and the variants were still to come. But at least they had started well, their initial pandemic response saving misery and lives.

The segment of interest was the gene responsible for producing the spike proteins, the complex knobs on the surface of each spherical virion, which form a corona-like fuzz and give the family its name. The spikes protrude from the envelope (exterior wrapper) of the virion. Each spike consists of three copies of an identical protein bundled together like an inverted tripod. It’s an elaborate, three-dimensional molecular feature that allows a virion to catch hold of a receptor molecule on the exterior of a cell, fuse its envelope with the cell membrane, and gain entry for its RNA genome. You often hear the simile—it’s a go-to cliché—that the spike fits to the receptor like a key to a lock, opening the cell. That’s too simple, because the spike is so intricate and dynamic, but it does capture the fact that precise matching between a spike and a cell receptor is what determines which coronaviruses can infect which cells within which particular host. Matching of spike and receptor also, therefore, affects the capacity for host switching.

Previous work, since 2003, had established that SARS-CoV uses a receptor called (never mind why) ACE2, which dangles from the exterior of certain human cells, including some lining the blood vessels, some in the small intestine, some in the heart and kidneys and other organs, and some (most fatefully) along the upper airway. ACE2 is there because it’s an enzyme that serves functions in human metabolism, one of which is to help regulate blood pressure. But incidentally it makes cells vulnerable, providing an opportunity for certain viruses.

“Our results provide the strongest evidence to date,” Shi’s team wrote, “that Chinese horseshoe bats are natural reservoirs of SARS-CoV,” and that intermediate hosts might not be necessary for SARS-like coronaviruses to pass from bats to humans. “They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.” Six years before the pandemic, Zhengli Shi was saying: People, get ready.

The sample in which Shi’s team found one of those nine, especially notable in light of its later history, was given the number 4991. The sample number is distinct from the label assigned to any genomic sequence that may come from that sample, just as gazpacho is distinct from a cucumber; and the genomic sequence of a virus is distinct from any live virus that is grown, just as the genomic sequence of a lion is distinct from a live lion that might walk into your laboratory—but those distinctions got lost amid later criticisms of Zhengli Shi’s work. Sample 4991, which came from an intermediate horseshoe bat (Rhinolophus affinis), contained just enough material for Shi’s group, two years later, when they had better equipment, to pull out and sequence a near-complete genome. They named that genome RaTG13, from Ra as in Rhinolophus affinis, TG as in Tongguan the town, and 13 as in 2013, the year the sample was collected. Why should you care? Because these relatively simple facts of variant naming would later bring accusations of sinister obfuscation against Zhengli Shi, and RaTG13 would become the single most important, and most poorly understood, piece of data amid the controversy over the origin of the virus.

A furin cleavage site is a sort of trigger within the spike protein of a coronavirus (or an equivalent protein in other viruses) that enhances the capacity of the virus to latch on to and enter cells. First the spike catches hold of a receptor protein on the exterior of the cell, such as ACE2. Then the cleavage site comes into play. It’s located at the junction between the two major lobes of the spike, and when it’s triggered, the spike changes shape—like a Transformer robot metamorphosing suddenly into a truck—so that the spike is “cleaved,” split open, in a way that allows it to fuse with the membrane of the cell. This enables the viral genome to squirt into the cell and begin replicating itself. What triggers the furin cleavage site is the touch of a furin molecule. Furin is an enzyme with important functions, never mind what, and our bodies are full of it. So the furin cleavage site is well suited for triggering, by bodily furin, and helping the virus to penetrate cells. Some viruses possess furin cleavage sites as part of their cell-entry machinery, and those sites seem to help make them highly virulent in humans. SARS-CoV had no such site, and that virus, fortunately, was not very efficiently contagious. So the inclusion of a furin cleavage site in the new coronavirus caused Bob Garry some concern, on the grounds that it might make the thing better able to spread.

Ngl i love that he doesn't try on some of these

“I wrote pipelines to analyze the FASTQs that came off the Illumina machine,” he said. Then he explained what the hell that meant. A pipeline is a series of procedural steps in validating and analyzing data. An Illumina machine is a sequencer. FASTQs are… never mind.

Wong posted this on Virological, signing only with a nonsense username he had favored since his boyhood, “torptube.”

They were candid: the genome of SARS-CoV-2 as it had emerged in Wuhan carried coding for two notable features that required explaining. These two features were unexpected, insofar as they hadn’t been seen before in other known SARS-like coronaviruses (although they were not unique among coronaviruses generally, and they had parallels in other viruses too). Both features lay on the spike protein, the cell grabber. The first was the receptor-binding domain. The second was the furin cleavage site, which allowed the spike to cleave, and thereby fuse to the cell membrane, in response to a tickle from the host’s furin. The effect of both features was to make the virus more capable of infecting humans.

The first scenario was genetic manipulation in a laboratory. Andersen and his coauthors dismissed that one, on grounds that the main body of the SARS-CoV-2 genome bore no resemblance to any virus backbone ever known to have been used in viral engineering, and that the RBD was an anomalous concoction of which the effectiveness couldn’t have been foreseen. Only one form of trial and error could have produced it, they judged, a form that is tireless, blind, and infinitely persistent: evolution by natural selection.

That was the second scenario: natural selection acting on the virus, within its animal host, before spillover into humans. The pangolin coronavirus was important evidence here, demonstrating that an RBD almost identical to the RBD in SARS-CoV-2 could evolve—because it had evolved—in a wild animal. And of course the cross-border trade in live pangolins for meat and medicine, with thousands of the animals passing from trader to buyer to butcher to consumer, provided plenty of opportunities for a pangolin virus to spill into some person.

In the third scenario, a progenitor form of the virus had passed by spillover from an animal host into one or more persons, and then, during some period of slow, inefficient, unrecognized transmission among humans, acquired its nifty cleavage site by evolutionary steps that vastly improved its mediocre transmissibility. This period of sputtering, unnoticed human infection might have happened in October and November of 2019, possibly stretching back even earlier.

Scenario four was the most intricate. It imagined that some team of scientists had performed “passaging” experiments with a SARS-like coronavirus—that is, intentionally infecting a series of laboratory animals, each animal given the virus in the form that emerged from a previous animal, and thereby inviting the virus to adapt better and better to those animals as it went. Or the virus might have been similarly passaged not in live animals but in cultured cells, dish by dish, using laboratory-captive strains of once human (or at least once primate) cells.

“If the cruise ship epidemic is a microcosm of the community outbreak scenario,” Yuen and his colleagues concluded in their published report, “then individuals with or without pneumonia could carry the virus for a long period but remain asymptomatic.” And they could do more than carry it; they could spread it. To me he said, “That is very important. That is why you cannot control a pandemic”—could not control this pandemic, anyway—“because there’s so much asymptomatic cases spreading infection around.” Think of it, he said: we found nine positives from the Diamond Princess, six of them asymptomatic. Taking that as a very rough guide, he said, for each case you identify from symptoms, “there’s at least another two cases.” Spreading the virus invisibly through your ship, your city, your country. By the time symptoms appear, in fact, the load of virus in a person’s nose and throat has already risen to its peak.

tonal italics—“…anthropomologize,

“I’m a hybrid. I’m a virus that causes very, very little harm, doesn’t give many people symptoms.” Highly capable of transmission, mild in most infected persons, invisible in many, therefore lulling the host population and its more doltish, obdurate leaders toward complacency. “At the same time that I can be absolutely deadly to a large number of people, who happen to be vulnerable.” “Yeah,” I said admiringly. “And that’s the nefarious, insidious nature of this virus.”

doing what viruses do: obeying what I call the three Darwinian imperatives, which govern all creatures that replicate by way of variable genomes, whether they are viruses or fennel plants or rats or dandelions or kangaroos. Those imperatives are 1) copy yourself as abundantly as possible, 2) expand yourself in geographical space, and 3) extend yourself in time.

The oceans alone may contain more virions than there are stars in the observable universe. Mammals may carry at least 320,000 different viruses. When you add the viruses infecting nonmammalian animals, plants, terrestrial bacteria, and every other possible host, the total comes to… lots. And beyond the big numbers are big consequences of a sort we wouldn’t expect: many of those viruses bring adaptive benefits, not harms, to life on Earth, including human life.

There are two lengths of DNA that originated from viruses and now reside in the genomes of humans and other primates, for instance, without which—an astonishing fact—successful pregnancy would be impossible. There’s viral DNA, nestled among the genes of terrestrial animals, that helps package and store memories in tiny protein bubbles. Still other genes co-opted from viruses contribute to the growth of embryos, regulate immune systems, resist cancer—important effects only now beginning to be understood. Viruses, it turns out, have played crucial roles in launching major evolutionary transitions.

each viral particle consists of a stretch of genetic instructions (written either in DNA or RNA) packaged inside a protein capsule, known as a capsid. The capsid, in some cases, is surrounded by a membranous envelope (like the caramel on a caramel apple), which protects it and helps it catch hold of a cell. A virus can copy itself only by entering a cell, or at least injecting its genome, and commandeering the 3-D printing machinery that turns genetic information into proteins.

If the host cell is unlucky, many new virions are manufactured, they come busting out, and the cell is left as wreckage. That sort of damage—such as what SARS-CoV-2 causes in the epithelial cells of the human airway—is partly how a virus becomes a pathogen.

But if the host cell is lucky, maybe the virus simply settles into this cozy outpost, either going dormant or back-engineering its genome into the host’s genome, and bides its time. This second trick is what retroviruses, such as HIV-1, do. It carries many implications for the mixing of genomes, for evolution, even for our sense of identity as humans. Eight percent of the human genome consists of viral DNA that has been inserted into our lineage, over millions of years, in this way. That’s a very different take on the trope of “I, Virus.” Both you and I, as well as Tony Fauci and everyone else, are 8 percent viral in our genomes. An...

Let’s say some of the long molecules (probably RNA) started to replicate. Serving as templates of selfness, pulling in small molecules from their environment to fit where appropriate, they made copies of themselves. Darwinian natural selection would have begun there, as those molecules—the first genomes—reproduced, mutated, and evolved. Groping for competitive edge, some may have found or created protection within membranes and walls, leading to the first cells. These cells gave rise to offspring by fission, splitting in two. They split in a broader sense too, diverging to become Bacteria and Archaea, two of the three domains of cellular life. The third, Eukarya, arose sometime later. That one includes us and all other creatures (animals, plants, fungi, certain microbes such as amoebas and diatoms) composed of cells with complex internal anatomy, such as a nucleus neatly holding the genome. Those are the three great limbs on the tree of life as presently drawn: Bacteria, Archaea, Eukarya.

There are three leading hypotheses to explain the evolutionary origin of viruses, known to scientists in the field as viruses-first, escape, and reduction. Viruses-first is the idea that viruses came into existence before cells, somehow assembling themselves directly from that primordial cookery of self-replicating molecules. The escape hypothesis posits that genes or stretches of genomes leaked out of cells, became encased within protein capsids, and went rogue, finding a new niche as parasites. The reduction hypothesis suggests that viruses originated when some cells downsized under competitive pressure (it being easier to replicate if you’re small and simple), shedding genes until they were reduced to such minimalism that only by parasitizing cells could they replicate and perpetuate their lineages.

Maybe viruses did originate by reducing from ancient cells, but cells of a sort no longer present on Earth. That is, not from either the Bacteria or the Archaea domains, or even from whatever cellular ancestor those two shared, but from Microbe Lineage X, still another domain of life that went extinct… except for its remnant form, viruses. That’s a little like the paleontologist’s cheerful reminder: Dinosaurs didn’t go completely extinct; they’re still here, but we call them birds. Abergel and Claverie don’t speak of Microbe Lineage X. They refer instead, in their papers, to a kind of “ancestral protocell” that might have been different from—and in competition with—the universal common ancestor of all cells known today.

But two things, to Chen’s group, seemed clear. First, there are a lot of coronaviruses potentially dangerous to humans circulating among various wild animals—bats, palm civets, camels, pangolins, who knows what else. Secondly, and for the sake of wildlife conservation as well as human health, it is important to reduce disruptive contact between people and wild animals, either captured or farmed, that risks spillover of such viruses. When you have Malayan pangolins, abducted from elsewhere in southern Asia, trafficked across the border, sobbing out their last breaths at a rescue center in a major Chinese city, something is wrong, and not just for the pangolins.

During late autumn 2019, a group of scientists led by Elisabetta Tanzi, an expert on viral diseases at the University of Milan, investigated what seemed to be an outbreak of measles. They saw thirty-nine suspected cases in patients who later tested negative—for measles, anyway. Each patient was sampled by oropharyngeal swab (a gentle dab to the back of the throat, not the kind that goes way up your nose and seems to tweak your brain), and the swab specimens stored. Months passed, the pandemic began, and it occurred to these scientists to retest those measles swabs for SARS-CoV-2. They found one positive specimen, taken from a four-year-old boy who lived near Milan. He had begun coughing on November 21. He got worse and, a week later, with vomiting and respiratory troubles, he was brought to an emergency room, and then developed a measles-like rash. But it wasn’t measles. According to the PCR testing of his swab, as eventually reported by Tanzi and her colleagues, it was SARS-CoV-2. Italy’s first recognized case of COVID-19 occurred three months later.

Florianópolis has been called “the best place to live in Brazil,” although not because housing prices are a bargain. Besides offering lifestyles for the rich and famous, it thrives on information technology enterprises and tourism. There are beaches. There are stately colonial-era churches and elderly fig trees and women selling handmade lace in the streets, plus an abundance of bars and restaurants. There is an old public market. There is sun. The airport is not huge but connects well with the world through São Paulo, Rio, and Buenos Aires. People go there from everywhere.

David Rodríguez-Lázaro went back to his “normal life,” he told me, using wastewater data to study foodborne infections, and in particular the underappreciated problem of antimicrobial resistance among bacteria. “It will kill us slowly,” he said, about the resistant-bacteria problem. “Not quickly, as SARS-CoV-2.”

To complicate things further, a group of scientists in Boston analyzed satellite images of Wuhan, archived from before the pandemic, and reported a big increase in hospital occupancy starting in August 2019, as deduced from crowded parking lots at the hospitals. These scientists also analyzed symptom-related internet searches around that time, through the Chinese technology company Baidu, and found that “cough” and “diarrhea” were trending. Their study was another preprint, and though it went up on a Harvard University website, it took immediate flak for its assumptions and methodology, and it seems never to have progressed to publication.

A virus is attenuated by passaging it repeatedly through nonhuman cells in a laboratory, causing it to accumulate mutations that render it harmless to people but still alarming to human immune systems.

They knew that the first confirmed case in the United States was detected in Snohomish County, Washington, on January 19, 2020, in that man who flew home from a family visit in Wuhan. They knew that some evidence pointed toward the Snohomish man as perhaps America’s Patient Zero, and that he might have infected others, who infected others, in chains of cryptic transmission during late January and early February of 2020, from which the virus spread to California and British Columbia and Connecticut and onward, making the Seattle area the epicenter of the North American epidemic. The Snohomish man’s viral genome sequence, designated WA1, as in “Washington case 1,” became an object of close scrutiny.

They performed computer simulations, based on the data they had, of how transmissions may have occurred to produce the trees of relatedness they saw. They drew inferences. The Snohomish case probably did not spark the outbreaks in California, Connecticut, and elsewhere. Rather, that case was likely a dead end, with no onward transmission, thanks to quick, firm containment measures taken in Washington. And the Bavarian case probably did not spark the outbreak in Italy or anywhere else. It led to about fifteen other cases, after which the spread was contained. Both the WA1 strain and the BavPat1 strain of the virus were successfully squelched, in the judgment of Worobey and his colleagues.

The public health response to the WA1 case in Washington state and the particularly impressive response to an early outbreak in Germany delayed local COVID-19 outbreaks by a few weeks and bought crucial time for U.S. and European cities, as well as those in other countries, to prepare for the virus when it finally did arrive. A few weeks might seem a small difference in response time, but it wasn’t. “The value of detecting cases early, before they have bloomed into an outbreak, cannot be overstated in a pandemic situation.”

One victim in Santa Clara County was Patricia Dowd, a fifty-seven-year-old auditor, who died in her San Jose kitchen on February 6 and was found by her daughter slumped at the breakfast bar. Dowd had been suffering flulike symptoms. Her infection was not linked to COVID-19 at the time, because of the absence of local testing capacity and the advisory declaration about who could be tested. Her death seemed mystifying, possibly caused by a heart attack, and only clarified months later when tissue samples tested positive for SARS-CoV-2. Patricia Dowd was probably the first American to die of COVID-19.