Monster or machine? Everything we know about coronavirus after six months
We are not at war with a hidden enemy so much as at odds with a microscopic photocopier
Coronavirus: teams of scientists are racing to understand its weaknesses, develop treatments and vaccines, and accurately forecast its next moves. Illustration: Richard McGuire/New York Times
A virus, at heart, is information, a packet of data that benefits from being shared.
The information at stake is genetic: instructions to make more virus. Unlike a truly living organism, a virus cannot replicate on its own; it cannot move, grow, persist or perpetuate. It needs a host. The viral code breaks into a living cell, hijacks the genetic machinery and instructs it to produce new code – new virus.
Donald Trump, the US president, has characterised the response to the pandemic as a “medical war” and described the virus behind it as, by turns, “genius”, a “hidden enemy” and “a monster”. It would be more accurate to say that we find ourselves at odds with a microscopic photocopying machine. Not even that: an assembly manual for a photocopier, model Sars-CoV-2.
In our information age we have grown familiar with computer viruses and with memes going viral; now here is the real thing to remind us what the metaphor means
For at least six or seven months the virus has replicated among us. The toll has been devastating. Officially, close to 12 million people worldwide have been infected so far, and 540,000 have died. (The actual numbers are certainly higher.) At the end of May the United States, which has seen the largest share of cases and casualties, surpassed 100,000 deaths, one-quarter the number of all Americans who died in the second World War.
Health officials fear another major wave of infections in autumn, and a possible wave train beyond.
“We are really early in this disease,” Dr Ashish Jha, director of the Harvard Global Health Institute, says. “If this were a baseball game, it would be the second inning.”
There may be trillions of species of virus in the world. They infect bacteria, mostly, but also abalone, bats, beans, beetles, blackberries, cassavas, cats, dogs, hermit crabs, mosquitoes, potatoes, pangolins, ticks and the Tasmanian devil. They give birds cancer and turn bananas black. Of the trillions, a few hundred thousand kinds of viruses are known; fewer than 7,000 have names. Only about 250, including Sars-CoV-2, have the mechanics to infect us.
In our information age we have grown familiar with computer viruses and with memes going viral; now here is the real thing to remind us what the metaphor means. A mere wisp of data has grounded more than half of the world’s commercial aircraft, sharply reduced global carbon emissions and doubled the stock price of Zoom. It has infiltrated our language – “social distancing”, “immunocompromised shoppers” – and our dreams. It has postponed sports, political conventions and the premieres of the next Spider-Man, Black Widow, Wonder Woman and James Bond films.
The virus also has prompted a collaborative response unlike any our species has seen. Teams of scientists, working across national boundaries, are racing to understand the virus’s weaknesses, develop treatments and vaccine candidates, and to accurately forecast its next moves. Medical workers are risking their lives to tend to the sick. Those of us at home do what we can: share instructions for how to make a surgical mask from a pillowcase; send condolences; offer hope.
“We’re mounting a reaction against the virus that is truly unprecedented,” says Dr Melanie Ott, director of the Gladstone Institute of Virology in San Francisco.
So far the match is deadlocked. We gather, analyse, disseminate, probe. What is this thing? What must be done? When can life return to normal? And we hide while the latest iteration of an ancient biochemical cipher ticks on, advancing itself at our expense.
A fearsome envelope
Who knows when viruses first came about. Perhaps, as one theory holds, they began as free-living microbes that, through natural selection, were stripped down and became parasites. Maybe they began as genetic cogs within microbes, then gained the ability to venture out and invade other cells. Or maybe viruses came first, shuttling and replicating in the primordial protein soup, gaining shades of complexity – enzymes, outer membranes – that gave rise to cells and, eventually, us. They are sacks of code – double- or single-stranded, DNA or RNA – and sometimes called capsid-encoding organisms, or CEOs.
As viruses go, Sars-CoV-2 is big – its genome is more than twice the size of that of the average flu virus and about one-half larger than Ebola’s. But it is still tiny: a 10,000th of a millimetre, barely a 1,000th the width of a human hair, smaller even than the wavelength of light from a germicidal lamp. If a person were the size of Earth, the virus would be the size of a person. Picture a human lung cell as a cramped office just big enough for a desk, a chair and a photocopier. Sars-CoV-2 is an oily envelope stuck to the door.
It was formally identified on January 7th this year by scientists in China. For weeks beforehand a mysterious respiratory ailment had been circulating in the city of Wuhan. Health officials were worried that it might be a reappearance of severe acute respiratory syndrome, or Sars, an alarming viral illness that emerged abruptly in 2002, infected more than 8,000 people and killed nearly 800 in the next several months, then was quarantined into oblivion.
The scientists had gathered fluid samples from three patients and, with nucleic-acid extractors and other tools, compared the genome of the pathogen with that of known ones. A transmission electron microscope revealed the culprit: spherical, with “quite distinctive spikes” reminiscent of a crown or the corona of the sun. It was a coronavirus, and a novel one.
There are hundreds of kinds of coronaviruses. Two, Sars-CoV and Mers-CoV, can be deadly; four cause a third of common colds
In later colourised images, the virus resembles small garish orbs of lint or the papery eggs of certain spiders, adhering by the dozens to much larger cells. Recently a visual team, working closely with researchers, created “the most accurate model of the Sars-CoV-2 viral particle currently available”: a barbed, multicoloured globe with the texture of fine moss, like something out of Dr Seuss, or a sunken naval mine draped in algae and sponges.
Once upon a time our pathogens were crudely named: Spanish flu, Asian flu, yellow fever, Black Death. Now we have H1N1, Mers (Middle East respiratory syndrome), HIV – strings of letters as streamlined as the viruses themselves, codes for codes. The new coronavirus was temporarily named 2019-nCoV. On February 11th the International Committee on Taxonomy of Viruses officially renamed it Sars-CoV-2, to indicate that it was very closely related to the Sars virus, another coronavirus.
Before the emergence of the original Sars the study of coronaviruses was a professional backwater. “There has been such a deluge of attention on we coronavirologists,” says Susan Weiss, a virologist at the University of Pennsylvania. “It is quite in contrast to previously being mostly ignored.”
There are hundreds of kinds of coronaviruses. Two, Sars-CoV and Mers-CoV, can be deadly; four cause a third of common colds. Many infect animals with which humans associate, including camels, cats, chickens and bats. All are RNA viruses. Our coronavirus, like the others, is a string of roughly 30,000 biochemical building blocks called nucleotides enclosed in a membrane of both protein and lipid.
“I’ve always been impressed by coronaviruses,” says Anthony Fehr, a virologist at the University of Kansas. “They are extremely complex in the way that they get around and start to take over a cell. They make more genes and more proteins than most other RNA viruses, which gives them more options to shut down the host cell.”
How can it be neutralised?
The core code of Sars-CoV-2 contains genes for as many as 29 proteins: the instructions to replicate the code. One protein, S, provides the spikes on the surface of the virus and unlocks the door to the target cell. The others, on entry, separate and attend to their tasks: turning off the cell’s alarm system; commandeering the copier to make new viral proteins; folding viral envelopes and helping new viruses bubble out of the cell by the thousands.
“I usually picture it as an entity that comes into the cell and then it falls apart,” Ott, of the Gladstone Institute, says. “It has to fall apart to build some mini-factories in the cell to reproduce itself, and has to come together as an entity at the end to infect other cells.”
For medical researchers these proteins are key to understanding why the virus is so successful, and how it might be neutralised. For instance, to break into a cell, the S protein binds to a receptor called angiotensin converting enzyme 2, or Ace2, like a hand on a doorknob. The S protein on this coronavirus is nearly identical in structure to the one in the first Sars – “Sars Classic” – but some data suggests that it binds to the target enzyme far more strongly. Some researchers think this may partly explain why the new virus infects humans so efficiently.
Every pathogen evolves along a path between impact and stealth. Too mild and the illness does not spread from person to person; too visible and the carrier, unwell and aware, stays home or is avoided – and the illness does not spread. “Sars infected 8,000 people, and was contained quickly, in part because it didn’t spread before symptoms appeared,” Weiss notes.
By comparison Sars-CoV-2 seems to have achieved an admirable balance. “No aspect of the virus is extraordinary,” says Dr Pardis Sabeti, a computational geneticist at the Broad Institute who helped sequence the Ebola virus in 2014. “It’s the combination of things that makes it extraordinary.”
How does it spread?
Sars Classic settled quickly into human lung cells, causing a person to cough but also announcing its presence. In contrast its successor tends to colonise first the nose and throat, sometimes causing few initial symptoms. Some cells there are thought to be rich in the surface enzyme Ace2 – the doorknob that Sars-CoV-2 turns so readily. The virus replicates quietly, and quietly spreads: one study found that a person carrying Sars-CoV-2 is most contagious two to three days before they are aware that they might be ill.
From there the virus can move into the lungs. The delicate alveoli, which gather oxygen essential to the body, become inflamed and struggle to do their job. The texture of the lungs turns from airy froth to gummy marshmallow. The patient may develop pneumonia; some, drowning internally and desperate for oxygen, go into acute respiratory distress and require a ventilator.
The virus can settle in still further: damaging the muscular walls of the heart; attacking the lining of the blood vessels and generating clots; inducing strokes, seizures and inflammation of the brain; and damaging the kidneys. Often the greatest damage is inflicted not by the virus but by the body’s attempt to fight it off with a dangerous “cytokine storm” of immune-system molecules.
The result is an illness with a perplexing array of faces. A dry cough and a low fever at the outset, sometimes. Shortness of breath or difficulty breathing, sometimes. Maybe you lose your sense of smell or taste. Maybe your toes become red and inflamed, as if you had frostbite. For some patients it feels like a heart attack, or it causes delusion or disorientation.
Often it feels like nothing at all; according to the Centers for Disease Control and Prevention, part of the United States department of health, 35 per cent of people who contract the virus experience few to no symptoms, although they can continue to spread it. “The virus acts like no pathogen humanity has ever seen,” the journal Science notes.
More to the point the pathogen has gone largely unseen. “It has these perfect properties to spread throughout the entire human population,” Fehr says. “If we didn’t know what a virus was” – and didn’t take proper precautions – “this virus would infect virtually every human on the planet. It still might do that.”
Data v data
On January 10th the Wuhan health commission, in China, reported that in the previous weeks 41 people had contracted the illness caused by the novel coronavirus and that one had died – the first known casualty at the time.
That day Chinese scientists also publicly released the complete genome of the virus. The blueprint, which could be simulated and synthesised in the lab, was almost as good as a physical sample, and easier for researchers worldwide to obtain. Analyses appeared in journals and on preprint servers like bioRxiv, on sites like nextstrain.org and virological.org: clues to the virus’s origin, its errors and its weaknesses. From then on the new coronavirus began to replicate not only physically in human cells but also figuratively, and likely to its own detriment, in the human mind.
Ott entered medicine in the 1980s, when Aids was still new and terrifyingly unknown. “Compare that time to today; there are a lot of similarities,” she says. “A new virus, a rush to understand, a rush to a cure or a vaccine. What’s fundamentally different now is that we have generated this community of collaboration and data-sharing. It’s really mind-blowing.”
Three hours after the virus’s code was published Inovio Pharmaceuticals, based in San Diego, in California, began work on a vaccine against it – one of more than 145 such efforts now under way around the world. Sabeti’s lab quickly got to work developing diagnostic tests. Ott and Weiss soon managed to obtain samples of live virus, which allowed them to “actually look at what’s going on” when it infects cells in the lab, Ott says.
“The cell is mounting a profound battle to prevent the virus from entering or, on entering, to alarm everyone around it so it can’t spread,” she says. “The virus’s intent is to overcome this initial surge of defence, to set up shop long enough to reproduce itself and to spread.”
With so many proteins in its tool kit the virus has many ways to counter our immune system; these also offer targets for potential vaccines and drugs. Researchers are working every angle. Most vaccine efforts are focused on disrupting the spike proteins, which allow entry into the cell. The drug remdesivir – all supplies of which the United States has bought until September – targets the virus’s replication machinery. Fehr studies how the virus disables our immune system.
“I use the analogy of Star Wars,” he says. “The virus is the Dark Side. We have a cellular defence system of hundreds of antiviral proteins” – Jedi knights – “to defend ourselves. Our lab is studying one specific Jedi that uses one particular weapon, and how the virus fights back.”
These battles, fought on the field of biochemistry, strain the alphabet to describe. The Jedi in this analogy are particular enzymes (poly-ADP-ribose polymerases, or Parps, if you must know) that are produced in infected cells and wield a molecule that attaches to certain invading proteins – “We don’t know what these are yet,” Fehr says – and disrupts them. In response the virus has an enzyme of its own that sweeps away our Jedi like dust from a Star Wars sandcrawler.
Carolyn Machamer, a cell biologist at Johns Hopkins school of medicine, is studying the later stages of the process, to learn how the virus manages to navigate and assemble itself within a host cell and depart it. Among the research topics listed on her university webpage are coronaviruses but also “intracellular protein trafficking” and “exocytosis of large cargo”.
How does the virus work without leaving traces in some people, but in others there’s a giant reaction? That’s the biggest question currently, and the most urgent
On entering the cell, components of the virus set up shop in a subregion, or organelle, called the Golgi complex, which resembles a stack of pancakes and serves as the cell’s mail-sorting centre. Machamer has been working to understand how the virus commandeers the unit to route all the newly replicated viral bits, scattered throughout the cell, for final assembly.
The subject was “poorly studied”, she concedes. Most drug research has focused on the early stages, like blocking infection at the very outset or disrupting replication inside the cell. “Like I said, it hasn’t gotten a whole lot of attention,” she says. “But I think it will now, because I think we have some really interesting targets that could possibly yield new types of drugs.”
The line of inquiry dates back to her postdoctoral days. She was studying the Golgi complex – “The organelle is really bizarre” – even then. “It’s following what you’re interested in; that’s what basic science is about. It’s, like, you don’t actually set out to cure the world or anything, but you follow your nose.”
For all the attention the virus has received, it is still new to science and rich in unknowns. “I’m still very focused on the question: How does the virus get into the body?” Ott says. “Which cells does it infect in the upper airway? How does it get into the lower airway, and from there to other organs? It’s absolutely not clear what the path is, or what the vulnerable path types are.”
And most pressing: Why are so many of us asymptomatic? “How does the virus manage to do this without leaving traces in some people, but in others there’s a giant reaction?” she says. “That’s the biggest question currently, and the most urgent.”
Mistakes are made
Even a photocopier is imperfect, and Sars-CoV-2 is no exception. When the virus commandeers a host cell to copy itself, invariably mistakes are made, an incorrect nucleotide swapped for the right one, for instance. In theory such mutations, or an accumulation of them, could make a virus more infectious or deadly, or less so, but in a vast majority of cases they do not affect a virus’s performance.
What’s important to note is that the process is random and incessant. Humans describe the contest between host and virus as a war, but the virus is not at war. Our enemy has no agency; it does not develop “strategies” for escaping our medicines or the activity of our immune systems.
Unlike some viruses Sars-CoV-2 has a proofreading protein – NSP14 – that clips out mistakes. But errors still slip through. The virus acquires two mutations a month, on average, which is less than half the error rate of the flu – and increases the possibility that a vaccine or drug treatment, once developed, will not be quickly outdated. “So far it’s been relatively faithful,” Ott says. “That’s good for us.”
By March at least 1,388 variants of the coronavirus had been detected around the world, all functionally identical as far as scientists could tell. Arrayed as an ancestral tree, these lineages reveal where and when the virus spread. For instance, the first confirmed case of Covid-19 in New York was announced on March 1st, but an analysis of samples revealed that the virus had begun to circulate in the region weeks earlier. Unlike early cases on the US west coast, which were seeded by people arriving from China, these cases were seeded from Europe, and in turn seeded cases throughout much of the country.
The roots can be traced back still further. The first known patient was hospitalised in Wuhan on December 16th, 2019, and first felt ill on December 1st; the first infection would have occurred still earlier. Sometime before that the virus, or its progenitor, was in a bat – the genome is 96 per cent similar to a bat virus. How long ago it made that jump, and acquired the mutations necessary to do so, is unclear. In any case, and contrary to certain conspiracy theories, Sars-CoV-2 was not engineered in a laboratory.
“Those scenarios are so unlikely as to be impossible,” says Dr Robert Garry, a microbiologist at Tulane University, in New Orleans, and an expert on emerging diseases. In March a team of researchers including Garry published a paper in Nature Medicine comparing the genome and protein structures of the novel virus with those of other coronaviruses. The novel distinctions were “most likely the result of natural selection”, they concluded. “Our analyses clearly show that Sars-CoV-2 is not a laboratory construct or a purposefully manipulated virus.”
Who has it, or had it, and who does not? A firm grasp of the virus’s whereabouts – using diagnostic tests, antibody tests and contact tracing – is essential to our bid to return to normal life
In our species the virus has found prime habitat. It seems to do most of its replicating in the upper respiratory tract, Garry notes: “That makes it easier to spread with your voice, so there may be more opportunities for it to spread casually, and perhaps earlier in the course of the disease.”
And there we have it: an organism, or whatever the right word is, ideally adapted to human conversation, the louder the better. Our communication is its transmission. Consider where so many outbreaks have begun: funerals, parties, call centres, sports arenas, meatpacking plants, cruise ships, prisons. In February a medical conference in Boston led to more than 70 cases in two weeks. In Arkansas several cases were linked to “a high-school swim party that I’m sure everybody thought was harmless”, Governor Asa Hutchinson said. After a choir rehearsal in Mount Vernon, in Washington state, 28 members of the choir fell ill. Not even song is safe any more.
The virus has no trouble finding us. But we are still struggling to find it; a recent model by epidemiologists at Columbia University, in New York, estimated that for every documented infection in the United States 12 more go undetected. Who has it, or had it, and who does not? A firm grasp of the virus’s whereabouts – using diagnostic tests, antibody tests and contact tracing – is essential to our bid to return to normal life. But humanity’s immune response has been uneven.
In late May, in an open letter, a group of former White House science advisers warned that, to prepare for an anticipated resurgence of the pandemic later this year, the federal government needed to begin preparing immediately to avoid the “extraordinary shortage of supplies” that occurred this spring.
“The virus is here, it’s everywhere,” Dr Rick Bright, former director of the Biomedical Advanced Research and Development Authority, told the US Senate in mid-May. “We need to unleash the voices of the scientists in our public health system in the United States, so they can be heard.” Right now, he added, “there is no master coordinated plan on how to respond to this outbreak.”
Sars-CoV-2 virus has no plan. It doesn’t need one; without a vaccine the virus is here to stay.
“This is a pretty efficient pathogen,” Garry says. “It’s very good at what it does.”
The next wave
“The virus spreads because of an intrinsic, latent quality in the culture,” the media theorist Douglas Rushkoff, who two decades ago coined the phrase “going viral”, wrote recently. “Both biological and media viruses say less about themselves than they do about their hosts.”
To know Sars-CoV-2 is to know ourselves in reflection. It is mechanical, unreflecting, consistently on-message – the purest near-living expression of data management to be found on Earth. It is, and does, and is more. There is no “I” in a virus.
We are exactly its opposite: human, and everything that implies. Masters of information, suckers for misinformation; slaves to emotion, ego and wishful thinking. But also inquiring, wilful, optimistic. In our best moments we strive to learn, and to advance more than our individual selves.
“The best thing to come out of this pandemic is that everyone has become a virologist in some way,” Ott says. She has a regular trivia night with her family in Germany, over Zoom. Lately the topic has centred on viruses, and she has been impressed by how much they know. “There’s so much more knowledge around,” she says. “A lot of wrong info around, also. But people have become so literate, because we all want it to go away.”
Sabeti agrees, up to a point. She expresses a deep curiosity about viruses – they are “formidable opponents to understand” – but says that, this time around, she has found herself less interested in the purely intellectual pursuit.
“For me right now, the place that I’m in, I really just most want to stop this virus,” she says. “It’s so frustrating and disappointing, to say the least, to be in this position in which we have stopped the world, in which we’ve created social distancing, in which we have created mass amounts of human devastation and collateral damage because we just weren’t prepared.
“I don’t care to understand it,” she says. “For me, it’s… I get up in the morning and my motivation is just: Stop this thing, and figure out how to never have this happen again.” – New York Times