The virus is mutating as expected. We can still stop it.
In the final, darkest days of the deadliest year in U.S. history, the world received ominous news of a mutation in the SARS-CoV-2 coronavirus. Scientists in the U.K. had identified a form of the virus that was spreading rapidly throughout the nation. Then, on January 4, Prime Minister Boris Johnson announced a lockdown that began almost immediately and will last until at least the middle of February. “It’s been both frustrating and alarming to see the speed with which the new variant is spreading,” he said in an address, noting that “our scientists have confirmed this new variant is between 50 and 70 percent more transmissible” than previous strains.
Those figures, based on an early estimate by British government scientists in late December, made for terrifying push alerts and headlines. Though this strain of the virus (officially called “B.1.1.7”) quickly became known as “the U.K. variant,” it has already been found in 45 countries, suggesting that the opportunity to contain it with travel restrictions has passed. On January 8, Australia locked down Brisbane, a city of 2.3 million people, after discovering a single case.
Each day, B.1.1.7 is being found in more people in more places, including all around the United States. Experts have raised dire warnings that a 70 percent more transmissible form of the virus would overwhelm already severely stretched medical systems. Daily deaths have already tripled in recent months, and the virus is killing more than 3,000 Americans every day. From a purely mathematical perspective, considering exponential growth, a significantly more transmissible strain could theoretically lead to tens of thousands of daily deaths, with hospital beds lining sidewalks and filling parking lots.
To make matters worse, the warnings from Britain were followed by headlines about yet another variant, B.1.351, in South Africa. Then anotherconcerning variant was identified in Brazil. News reports speculated that these strains may resist vaccines. Some experts cautioned that the mutations could render current treatments less effective. Scott Gottlieb, the former director of the FDA, said last week: “The South Africa variant is very concerning right now because it does appear that it may obviate some of our medical countermeasures, particularly the antibody drugs.” On Tuesday, Anthony Fauci echoed that concern, calling the variant “disturbing.”
These new variants demand to be taken seriously. Skyrocketing case counts in the U.K. suggest a potential to do enormous damage, and the identification of B.1.1.7 in so many countries is noteworthy. Still, we don’t yet know whether either variant will become as dominant worldwide as they have in their respective countries. They might spread widely and cause tremendous harm. They might also do neither.
The sheer scale and capacity of this virus are challenging many things we thought we knew, but the basic laws governing its evolution are not among them. All viruses are constantly evolving and changing, just as human populations are. When a virus is spreading as widely and rapidly as SARS-CoV-2, spinning through trillions of generations each minute, adaptation is inevitable. The transmissibility of the virus will change. The severity of the disease it causes will change. Its ability to evade our immune system will change. It very well may evolve to circumvent our current vaccines.
Thanks to genetic-sequencing technology, we can watch this evolution in real time. We can see the changes in a virus’s genes before we even know what they mean for the spread of disease. Charting the course of this evolution, and assessing its significance, has quickly become a foremost challenge of the pandemic. The peril is not that the virus will suddenly change in an extraordinary way that transforms the pandemic, but that it is changing in small, ordinary ways that are playing out on a vast scale, and whose significance we may not appreciate until it’s too late.
Almost exactly a year ago, in January of 2020, a flight attendant warned the renowned Chinese virologist Zhang Yongzhen: It was time to turn off all portable electronic devices. He was sitting with his phone to his ear. On the other end of the line, his Australian collaborator Eddie Holmes was pleading with him to publish the genetic code of the novel coronavirus.
The Chinese government had forbidden this. Yongzhen was torn. The world did not yet know the cause of the rapidly spreading respiratory infection, and he seemed to have uncovered it in a sample of sputum from a severely ill person in Wuhan. Using genomic sequencing to unravel the code of the virus, he had found what appeared to be the blueprint of a new coronavirus.
He told Holmes to publish the code. When Holmes did so on Twitter, the international scientific community pounced. Within days, researchers in Thailand were able to verify that the same virus had infected patients there. Scientists at the U.S. National Institutes of Health began to work on a vaccine. The code became the backbone of the Pfizer/BioNTech and Moderna vaccines, which owe their development to the speedy identification and sharing of the genome.
The exact sequence that Holmes tweeted is now a relic. The virus it represented is gone, replaced by many, many, many subsequent generations. New lineages have arisen in different parts of the world, and hundreds of thousands of slightly different sequences have been added to an international database. There are now thousands of unique SARS-CoV-2 genomes, each the result of myriad permutations of mutations in the code. There is no single, standard genetic code for this coronavirus, any more than there is a standard human genome.
“The term variant is misleading, in that it creates the idea that all the other viruses are the same,” explains Ramon Lorenzo Redondo, a genomic analyst at Northwestern University’s Feinberg School of Medicine. Technically, every version of the virus is a variant. Even within a single person, the virus changes and evolves many times. If you were to have your bodily fluids sequenced on different days, the viral strains would show new mutations. “Viruses operate as a cloud of mutants — a swarm of mutants,” Redondo told me.
This is not a flaw in the system, but rather the way viruses work. When it comes to reproduction, viruses are sloppy. The speed and scale of their replication come at the cost of accuracy; they operate like a spam email marketing scheme, favoring inundation over meticulous grammar. Insofar as a virus can be said to have a “goal,” the goal is to ensure as many future generations as possible. To that end, it fires off shotgun blasts of imperfect clones, gambling that a few will make their way to other cells and penetrate them.
Almost all of these accidental mutations are inconsequential: The virus still looks and functions just as its parent before it did. Over time, though, sets of mutations can layer on top of one another and accumulate, and the virus begins to function differently. Some of these differences confer an advantage of one sort or another — for example, increased transmissibility.
“What we’re observing is very expected,” Paul Turner, a professor of ecology and evolutionary biology at Yale, told me. “If a population can improve in its environment, evolution lets that happen. The virus population size is expanding, and mutations spontaneously occur.”
Although it’s not news that the virus has mutated, it’s extremely important to keep an eye on the general direction of the changes — and what they mean for the humans whose cells are being hijacked. “If you see a mutation that could allow the virus to escape detection by the immune system, or escape vaccine coverage, that’s very worrisome,” Turner said. “We don’t have evidence of that yet.”
The likelihood of these scenarios depends on a few factors. Some viruses mutate more readily than others: Influenza mutates so quickly that new strains spread around the world each year, requiring the creation of new vaccines. Measles, by contrast, mutates slowly, so people who were vaccinated decades ago are very likely still protected. “Coronaviruses typically don’t mutate very quickly,” Turner said. “I don’t see any evidence that this coronavirus is going to suddenly become like influenza. But right now there are so many people infected, and the virus is in a new environment [humans instead of bats], so I’m not surprised that evolution is pushing it to improve.”
In the long run, he believes, the spread of this coronavirus will more closely resemble measles than flu. Although we may need to update our vaccines occasionally, we won’t need to do so every year. But as long as rates of infection remain high, the coronavirus is likely to acquire, over months or years, the ability to at least partially bypass our immune responses. Second-time infections may be less severe, but their severity also depends on how the virus evolves. And we may develop immunity to one variant but not to another.
In anticipation of such complexities, Redondo and others have been creating and updating phylogenetic maps — essentially, family trees — for this coronavirus. Groups with a common ancestor are referred to as a “lineage.” A lineage is something like a human family: different individuals sharing a common ancestor. (B.1.1.7 and B.1.351 are separate lineages that evolved similar changes in their spike protein independently.)
Genetic commonalities can also define broader groups called “clades.” Last spring, a clade known as D614G came to dominate the world. This was attributed to a mutation in the spike protein that made this group more transmissible than previous strains. And this was just one part of a family tree that’s now more like a forest. “The two first clades that were defined have disappeared,” Redondo said. Right now five major clades are jockeying for dominance, he said, but the picture is constantly shifting.
The emergence of a new clade can be as difficult to predict as any rise to global domination. Obsolescence and dominance are determined by the qualities of the lineages, the characteristics of the host populations, and the legacies of previous microbial invaders. The fact that a lineage or clade is dominant in one place, within one group of humans, does not mean it will be in others. So far, the U.K. and South African variants are dominating local surges, but they are not expansive enough to be considered clades. The South African variant, for example, accounts for about 90 percent of the genetic sequences analyzed in the country, but remains a minor player elsewhere.
Similarly, the B.1.1.7 variant was identified in the U.K. in September, yet so far dominates only one geographic region. Although genomic testing in the U.S. is relatively sparse, “we’re doing enough sequencing that we know it’s not that common in the U.S.,” says Nathan Grubaugh, a microbial epidemiologist at the Yale School of Public Health. “This variant doesn’t seem to be more than 1 or 2 percent of cases at the moment. It’s here, and it’s very widespread, but it’s low in frequency. I think, for the most part, this is true globally.”
For now, these variants may be thought of like weeds in a garden. They have shown that they have the capacity to take over in some areas. There is a plausible mechanism that could allow them to do so elsewhere: Both the U.K. and South African variants share a mutation that manifests as a subtle change in a key site where the virus binds to human cells. But weeds take over for many reasons, and sometimes they have more to do with the garden than the weed. Human populations vary in so many ways — behaviorally, genetically, immunologically, geographically, environmentally — that the degree to which a regional surge in cases is due to a change in the virus itself is extremely difficult to discern. And that leads to some uncertainty. “We may have it wrong in the end, [and] it’s not actually more transmissible,” Grubaugh told me. “It seems to be, but we may have been fooled.”
Even if these variants are indeed as transmissible as the rising case numbers suggest, transmissibility is only one determinant of a virus’s overall potential to do harm. Sometimes viruses become more transmissible but ultimately less dangerous. And of course, each new variant is but an intermediate step toward some other form of the virus. The real challenge is understanding how any given change fits into all of these larger patterns, and what that means for us.
The plot of Michael Crichton’s 1969 novel, The Andromeda Strain, hinges on an extraterrestrial microorganism that “mutates” its way out of containment. A similar narrative device drives the film Outbreak, in which a bleed-from-the-eyes virus suddenly becomes airborne. What amounts to a lazy screenwriting cliché has loaded the word mutation with such horrifying subtext that it’s almost unusable. The process of viral evolution is much subtler, and requires a careful eye to detect. That subtlety is what makes it dangerous.
There are two basic ways that a coronavirus can become more transmissible. One is by binding more effectively to human cells. When this happens, a person who inhales viral particles becomes slightly more likely to develop an infection. The other is by replicating more efficiently, creating higher numbers of viral particles (higher “viral load”) in an infected person, so that they exhale more particles with each breath (making it statistically more likely that one of the particles will infect someone else). If a breath contains 10 percent more viral particles, it is that much more likely that one will land in someone else’s nose.
It’s unclear whether one or both of these mechanisms are at play in the U.K. and South African lineages, but we know their effects can be complex. If a person is carrying a much higher viral load, for example, they may get sick more quickly. That sounds bad — and it certainly is for that person. But a shorter asymptomatic period could ultimately make the virus easier to contain. This was the case with the first SARS coronavirus, in 2003 (SARS-CoV-1), which caused a more severe disease than SARS-CoV-2 does, but killed far fewer people in total because each case was identifiable.
By the same token, this coronavirus could evolve to cause a somewhat less severe illness — something slightly closer to that caused by the other four endemic coronaviruses. The common cold is extremely transmissible, yet rarely fatal. This makes sense from an evolutionary perspective: Viruses that kill their hosts are less likely to become dominant than those that don’t. “It could be that transmissibility correlates with being ‘kinder’ to your host,” Turner said. “We’ve observed that in other realms of virus evolution.” Natural selection would, hypothetically, favor the versions that leave people feeling well enough to be out and about, spreading the virus to other hosts.
Major changes in the severity of the disease — in either direction — are unlikely, but the scale at which this virus is operating means that small differences in things like transmissibility are amplified, and can manifest as significant changes in how many people get sick. Experts widely agree that playing it safe in the coming weeks is prudent. Oliver Pybus, a professor of evolution and infectious diseases at the University of Oxford, emphasizes that understanding why B.1.1.7 took over the U.K. “is extremely scientifically difficult.” He has been at the forefront of identifying and tracking the variant, but says huge questions remain unanswered. “There’s still considerable uncertainty as to the long-term consequences” of B.1.1.7, Pybus told me. “We don’t even know whether this lineage truly originated in the U.K., with so many countries not doing this surveillance.”
Though much of the world is now on alert for this particular variant, Pybus said that very few places are sequencing genomes as comprehensively as the U.K. is. In some places, institutions are sampling but not sharing findings in the public domain. Both elements are crucial. Testing with PCR or antigen tests alone is no longer sufficient. Positive tests must be followed by analyses of the genomes of the virus. The more genomes we have, the more effectively we can identify anomalous patterns, both to raise alarms early and to avoid raising false ones.
The U.S. is especially far behind the U.K. in this regard. Without a baseline level of genomic surveillance, Yale’s Grubaugh told me, we do not know if a city like New York would be as devastated by B.1.1.7 as London has been. The forecast for any given variant depends on context that we lack. “I don’t think any one state is doing enough sequencing yet,” Grubaugh said. “Sequencing is the most important thing. We don’t have a big organized project like in the U.K. What we have is a bunch of individual labs, mostly at academic medical centers.” Sporadic sequencing is arguably as bad as none at all, in that it can fail to represent how and why variants are spreading. And focusing too narrowly on hunting one particular variant can mean failing to notice other, possibly more consequential warning signs.
The hunt for any one variant also introduces selection bias, making it hard to know if the variant is truly spreading more readily than others, or if we are just looking harder for it. After finding a person carrying B.1.1.7 in New York last week, for example, state health officials sequenced the genomes of nearby cases — an approach that is likely to find a disproportionate number of B.1.1.7 cases. Without constant, widespread surveillance testing, Pybus said, it’s difficult to discern an accurate overall picture.
“The field of genomic epidemiology is going through its adolescence in public, developing in full view of the most extraordinary event of the century,” Pybus told me. The ability to identify new viral lineages before we even understand how they will affect people may allow epidemiologists to warn of consequential variants — but may undermine their credibility when strains don’t prove as dangerous as headlines predict.
Even if we cannot contain this particular variant, we’re learning from its spread. Preventing more virulent strains from becoming dominant — when they inevitably do arise — may be possible if we can track genomic patternsmore widely, so that we have the context needed to determine whether a strain is indeed uniquely dangerous. If we can take steps to contain a new threat early enough, it may never become widespread. If we miss these opportunities, we risk repeating the kind of mistake that allowed the original SARS-CoV-2 strain to escape China in the first place.
Last week, Eddie Holmes reflected on the fateful moment when he tweeted the virus’s original genetic code. It was a moment of triumph for collaborative science, but the work was just beginning. The triumph must be repeated daily. “What worries me most of all is if politics gets in the way of data sharing and science,” he told Medscape. “Step one has to be immediate, rapid, open data sharing. Speed is of the essence in a pandemic. Any barrier to working together makes this a much less safe world. That should be the lesson of this outbreak.”
The changing genetic code of the coronavirus will not nullify our fundamental strategies for ending the pandemic. With better data, we can keep our vaccines and antibody treatments up to date and our shutdown measures as minimal as possible, and we can sever any ominous new chains of transmission. The spread of new variants is a stark reminder that we all have an immediate part to play in this. If you carry the virus, it will mutate within you. You could be the person in whom a new, even more threatening variant emerges. You could seed the entire world with it. But no matter how the virus mutates, the same basic preventive measures — the unglamorous ones we’ve been lectured about for nearly a year — will still have the power to ensure that you don’t.
All Rights Reserved for James Hamblin