Social, cultural, economic, spiritual, psychological, emotional, intellectual: Everything is outside the box. And this new sheltered-in-place experience won’t fit into old containers.Photo Illustration by Africa Studio / Shutterstock

Many of us are stuck now, sheltered in our messy dwellings. A daily walk lets me appreciate the urban landscaping; but I can’t stop to smell anything because a blue cotton bandana shields my nostrils. Indoors, constant digital dispatches chirp to earn my attention. I click on memes, status updates, and headlines, but everything is more of the same. How many ways can we repackage fear and reframe optimism? I mop the wood-laminate floor of my apartment because I hope “ocean paradise” scented Fabuloso will make my home smell a little less confining. My thoughts waft toward the old cliché: Think outside the box. I’ve always hated when people say that.

To begin with, the directions are ineffectual. You can’t tell someone to think outside the box and expect them to do it. Creativity doesn’t happen on demand. Want proof? Just try to make yourself think a brilliant thought, something original, innovative, or unique. Go ahead. Do it. Right now. You can’t, no matter how hard you try. This is why ancient people believed that inspiration comes from outside. It’s external, bestowed on each of us like a revelation or prophecy—a gift from the Muses. Which means your genius does not belong to you. The word “genius” is the Latin equivalent of the ancient Greek “daemon” (δαίμονες)—like a totem animal, or a spirit companion. A genius walks beside us. It mediates between gods and mortals. It crosses over from one realm to the next. It whispers divine truth.

We are paralyzed by the prospect of chaos, uncertainty, and entropy.

In modern times, our mythology moves the daemons away from the heavens and into the human soul. We say, “Meditate and let your spirit guide you.” Now we think genius comes from someplace deep within. The mind? The brain? The heart? Nobody knows for sure. Yet, it seems clear to us that inspiration belongs to us; it’s tangibly contained within our corporeal boundaries. That’s why we celebrate famous artists, poets, physicists, economists, entrepreneurs, and inventors. We call them visionaries. We read their biographies. We do our best to emulate their behaviors. We study the five habits of highly successful people. We practice yoga. We exercise. We brainstorm, doodle, sign up for online personal development workshops. We do whatever we can to cultivate the fertile cognitive soil in which the springtime seeds of inspiration might sprout. But still, even though we believe that a genius is one’s own, we know that we cannot direct it. Therefore, no matter how many people tell me to think outside the box, I won’t do it. I can’t. 

Even if I could, I’m not sure thinking outside the box would be worthwhile. Consider the origins of the phrase. It started with an old brain teaser. Nine dots are presented in a perfect square, lined up three by three. Connect them all, using only four straight lines, without lifting your pencil from the paper. It’s the kind of puzzle you’d find on the back of a box of Lucky Charms breakfast cereal, frivolous but tricky. The solution involves letting the lines expand out onto the empty page, into the negative space. Don’t confine your markings to the dots themselves. You need to recognize, instead, that the field is wider than you’d assume. In other words, don’t interpret the dots as a square, don’t imagine that the space is constricted. Think outside the box! 

For years, pop-psychologists, productivity coaches, and business gurus have all used the nine-dot problem to illustrate the difference between “fixation” and “insight.” They say that we look at markings on a page and immediately try to find a pattern. We fixate on whatever meaning we can ascribe to the image. In this case, we assume that nine dots make a box. And we imagine we’re supposed to stay within its boundaries—contained and confined. We bring habitual assumptions with us even though we’re confronting a unique problem. Why? Because we are paralyzed by the prospect of chaos, uncertainty, and entropy. We cling to the most familiar ways of organizing things in order to mitigate the risk that new patterns might not emerge at all, the possibility that meaning itself could cease to exist. But this knee-jerk reaction limits our capacity for problem-solving. Our customary ways of knowing become like a strip of packing tape that’s accidentally affixed to itself—you can struggle to undo it, but it just tangles up even more. In other words, your loyalty to the easiest, most common interpretations is the sticky confirmation bias that prevents you from arriving at a truly insightful solution. 

At least that’s what the experts used to say. And we all liked to believe it. But our minds don’t really work that way. The box parable appeals because it reinforces our existing fantasies about an individual’s proclivity to innovate and disrupt by thinking in unexpected ways. It’s not true. 

Studies have found that solving the nine-dot problem has nothing to do with the box. Even when test subjects were told that the solution requires going outside the square’s boundaries, most of them still couldn’t solve it. There was an increase in successful attempts so tiny that it was considered statistically insignificant, proving that the ability to arrive at a solution to the nine-dot problem has nothing to do with fixation or insight. The puzzle is just difficult, no matter which side of the box you’re standing on.

Still, I bet my twelve-year-old son could solve it. Yesterday, we unpacked a set of oil paints, delivered by Amazon. He was admiring the brushes and canvases. He was thinking about his project, trying to be creative, searching for insight. “Think inside the outside of the box,” he said.  “What does that mean?” I pushed the branded, smiling A-to-Z packaging aside and I looked at him like he was crazy. “Like with cardboard, you know, with all the little holes inside.” 

He was talking about the corrugations, those ridges that are pasted between layers of fiberboard. They were originally formed on the same fluted irons used to make the ruffled collars of Elizabethan-era fashion. At first, single faced corrugated paper—smooth on one side, ridged on the other—was used to wrap fragile glass bottles. Then, around 1890, the double-faced corrugated fiberboard with which we’re familiar was developed. And it transformed the packing and shipping industries. The new paperboard boxes were sturdy enough to replace wooden crates. It doesn’t take an engineering degree to understand how it works: The flutes provide support; the empty space in between makes it lightweight. My son is right; it’s all about what’s inside the outside of the box.

Now I can’t stop saying it to myself, “Think inside the outside of the box.” It’s a perfect little metaphor. In a way, it even sums up the primary cognitive skill I acquired in graduate school. One could argue that a PhD just means you’ve been trained to think inside the outside of boxes. What do I mean by that? Consider how corrugation gives cardboard it’s structural integrity. The empty space—what’s not there—makes it strong and light enough that it’s a useful and efficient way to carry objects. Similarly, it’s the intellectual frameworks that make our interpretations and analyses of the world hold up. An idea can’t stand on its own; it needs a structure and a foundation. It needs a box. It requires a frame. And by looking at how those frames are assembled, by seeing how they carry a concept through to communication, we’re able to do our best thinking. We look at the empty spaces—the invisible, or tacit assumptions—which lurk within the fluted folds of every intellectual construction. We recognize that our conscious understanding of lived experience is corrugated just like cardboard. 

The famous sociologist Erving Goffman said as much in 1974 when he published his essay on “Frame Analysis.” He encouraged his readers to identify the principles of organization which govern our perceptions. This work went on to inspire countless political consultants, pundits, publicists, advertisers, researchers, and marketers. It’s why we now talk often about the ways in which folks “frame the conversation.” But I doubt my son has read Goffman. He just stumbled on a beautifully succinct way to frame the concept of critical thinking. Maybe he was inspired by Dr. Seuss. 

When my kids were little, they asked for the same story every night, “Read Sneetches Daddy!” I could practically recite the whole thing from memory: “Now, the Star-belly Sneetches had bellies with stars. The Plain-belly Sneetches had none upon thars.” It’s an us-versus-them story, a fable about the way a consumption economy encourages people to compete for status, and to alienate the “other.” If you think inside the outside of the box, it’s also a scathing criticism of a culture that’s obsessed with personal and professional transformation—always reinventing and rebranding. 

One day, Sylvester McMonkey McBean shows up on the Sneetches’ beaches with a peculiar box-shaped fix-it-up machine. Sneetches go in with plain-bellies and they come out with stars. Now, anyone can be anything, for a fee. McBean charges them a fortune; he exploits the Sneetches’ insecurities. He builds an urgent market demand for transformational products. He preys on their most familiar—and therefore, cozy and comforting—norms of character assessment. He disrupts their identity politics, makes it so that there’s no clear way to tell who rightfully belongs with which group. And as a result, chaos ensues. Why? Because the Sneetches discover that longstanding divisive labels and pejorative categories no longer provide a meaningful way to organize their immediate experiences. They’ve lost their frames, the structural integrity of their worldview. They feel unhinged, destabilized, unboxed, and confused.

Social, cultural, economic, spiritual, psychological, emotional, intellectual: Everything is outside the box.

It should sound familiar. After all, we’ve been living through an era in history that’s just like the Sneetches’. The patterns and categories we heretofore used to define self and other are being challenged every day—sometimes for good, sometimes for bad. How can we know who belongs where in a digital diaspora, a virtual panacea, where anyone can find “my tribe”? What do identity, allegiance, heredity, and loyalty even mean now that these ideas can be detached from biology and birthplace? Nobody knows for sure. And that’s just the beginning: We’ve got Sylvester-McMonkey-McBean-style disruption everywhere we look. Connected technologies have transformed the ways in which we make sense of our relationships, how we communicate with one another, our definitions of intimacy. 

Even before the novel coronavirus, a new global paradigm forced us to live and work in a world that’s organized according to a geopolitical model we can barely comprehend. Sure, the familiar boundaries of statehood sometimes prohibited migrant foot traffic—but information, microbes, and financial assets still moved swiftly across borders, unimpeded. Similarly, cross-national supply-chains rearranged the rules of the marketplace. High-speed transportation disrupted how we perceive the limits of time and space. Automation upset the criteria through which we understand meritocracy and self-worth. Algorithms and artificial intelligence changed the way we think about labor, employment, and productivity. Data and privacy issues blurred the boundaries of personal sovereignty. And advances in bioengineering shook up the very notion of human nature.

Our boxes were already bursting. And now, cloistered at home in the midst of a pandemic, our most mundane work-a-day routines are dissolved, making it feel like our core values and deeply-held beliefs are about to tumble out all over the place. We can already envision the mess that is to come—in fact, we’re watching it unfurl in slow motion. Soon, the world will look like the intellectual, emotional, and economic equivalent of my 14-year-old’s bedroom. Dirty laundry is strewn across the floor, empty candy wrappers linger on dresser-tops, mud-caked sneakers are tossed in the corner, and the faint yet unmistakable stench of prepubescent body odor is ubiquitous. Nothing is copasetic. Nothing is in its place. Instead, everything is outside the box. 

It’s not creative, inspiring, or insightful. No, it’s disorienting and anxiety-provoking. I want to tidy it up as quickly as possible. I want to put things back in their familiar places. I want to restore order and eliminate chaos. But no matter how hard I try, I can’t do it, because the old boxes are ripped and torn. Their bottoms have fallen out. Now, they’re useless. Social, cultural, economic, spiritual, psychological, emotional, intellectual: Everything is outside the box. And this new sheltered-in-place experience won’t fit into old containers.

Jordan Shapiro, Ph.D., is a senior fellow for the Joan Ganz Cooney Center at Sesame Workshop and Nonresident Fellow in the Center for Universal Education at the Brookings Institution. He teaches at Temple University, and wrote a column for Forbes on global education and digital play from 2012 to 2017. His book, The New Childhood, was released by Little, Brown Spark in December 2018.

There are many challenges to developing a vaccine that will be successful against COVID-19.eamesBot / Shutterstock

Wayne Koff is one of the world’s experts on vaccine development, the president and CEO of the Human Vaccines Project. He possesses a deep understanding of the opportunities and challenges along the road to a safe and effective vaccine against COVID-19. He has won prestigious awards, published dozens of scientific papers, held major positions in academia, government, industry, and nonprofit organizations. But Koff, 67, has never produced a successful vaccine.

“I have been an abject failure,” he says. He smiles with a charming, self-deprecating sense of humor. “That’s what the message is.”

The real reason for Koff’s lack of success is that he spent most of his career searching for a vaccine against HIV, the virus that causes AIDS. It remains, as he and many others put it, “the perfect storm” of a viral infection resistant to a vaccine development. Almost 40 years after doctors first recognized the disease in five men in Los Angeles—and 70 million people have been infected worldwide—there are no adequate animal models. Neutralizing antibodies, the backbone of many vaccines, do not stop it, and most importantly, HIV begins its assault on the body by attacking CD4 T cells, which serve as the command center of much of the immune system.

As for COVID-19, “We’re all hoping this one is going to be easier,” says Koff, a slight, bearded man with thick, curly salt-and-pepper hair. “There are research issues that still have to be addressed on a COVID vaccine. But they are a lot more straightforward than what we were dealing with in HIV.”

Let’s say we have a vaccine in 18 months. How do you make 1 billion doses or 4 billion doses or whatever it’s going to take to immunize everybody?

Koff and others started the Human Vaccines Project in 2016, modeled on the Human Genome Project. The project works with industry and academia to study the human immune system and develop vaccines, incorporating every modern-day tool, including artificial intelligence, computational biology, and big data sets. Today it is partnered with the Harvard T.H. Chan School of Public Health.

With COVID-19, Koff says, scientists “know the target is the spike protein binding site.” This is where the proteins sticking out from the virus attach to the cells in the human respiratory system. “If you can elicit antibodies against those proteins, they should be neutralizing.” He puts a strong emphasis on should. To prove antibodies will prevent infection, scientists must watch a population of people who’ve been infected for months or longer. It’s a good bet, based on similar viruses, that antibodies will appear and protect—although no one right now can predict how long and how well.

Depending on which count you use, more than 70 companies, universities, and other institutions are offering candidate vaccines. Koff says the real number of companies is lower. During the AIDS crisis, he says, “a lot of people claimed they had an experimental HIV vaccine in development. Some of those were a one-person lab who had created a paper company to attract investors.”

But even with a lower number, almost everyone involved in the search for a vaccine agrees that several different approaches from different research organizations need to proceed in parallel. The world does not have the time to bet on one horse. The race will be neither simple nor cheap.

“The probability of success, depending on whose metric is used in vaccines, is somewhere between 6 and 10 percent of candidate vaccines that make it from the animal model through licensure,” Koff says. “That process costs $1 billion or more. So you can do the math.”

Koff sees big potential problems at the outset. “In the best of all worlds, let’s say we have a vaccine in 18 months. Who knows where the epidemic is going to be then and what its impact is going to be? How do you make 1 billion doses or 4 billion doses or whatever it’s going to take to immunize everybody? Will we need one dose or two or three? These are issues people just haven’t faced before.”

COVID-19 also presents some unique dangers for vaccine safety. Based on how the virus behaves when it infects some people, there’s a chance a vaccine could dangerously overstimulate the immune system, a reaction called immune enhancement. “I’m hoping it’s more theoretical than real,” Koff says. “But that has to be addressed and it may slow down the entire process.” To ensure safety, he says, “It may mean we have to test the vaccine in a larger number of people. It’s one thing to do a 50-person trial in healthy adults as a safety signal. It’s another thing to run a trial of 4,000 or 5000 or more individuals.”

The world does not have the time to bet on one horse. The race will be neither simple nor cheap.

A virus also sometimes causes mysterious, potentially deadly blood clots. This means an experimental vaccine could hypothetically induce the same damage. “This is a bad bug,” Koff says. “We’re just starting to understand that pathogenesis.”

A big question is who should be the first volunteers for widespread vaccine testing. “Who are the high-risk groups?” asks Koff. “Is it nursing-home residents and staff, health-care workers and people on the front lines, or people someplace else like grocery stores? We must also make sure a vaccine is effective for the elderly and people in the developing world.”

Many vaccines work well in young and healthy people but not in older adults because immunity declines with age. Influenza vaccine is a prime example. Rotavirus vaccine, which protects against the deadliest killer—diarrheal disease in children—works better in the developed world. In the developing world, the virus often circulates year-round. Infants get antibodies from breast milk but not enough to prevent disease. Worse, those antibodies can make the vaccine less effective.

Another hypothetical obstacle is that a mutation in the COVID-19 virus could render a vaccine designed today less effective in the future. While the virus mutates frequently, so far there has been little change in the critical part of the spike that binds to human cells.

Of course, neither Koff nor all the others working for a COVID-19 vaccine focus solely on the potential obstacles. At one time, all vaccines against viruses either killed viruses, such as the Salk polio vaccine, or rendered them harmless, such as the Sabin polio vaccine. Now there is a multiplicity of ways to stimulate an immune response to prevent infection or reduce the consequences. These include genetically engineered protein subunits (peptides) or virus-like particles. Such approaches have led to successful vaccines against hepatitis B and human papilloma virus, which causes cervical cancer. Researchers now use “vectors”—harmless viruses attached to the protein subunits and virus particles to transmit them into the body. There are also many new adjuvants, chemicals that boost immune response to a vaccine.

Newer platforms include direct injection of messenger-RNA. M-RNA is the chemical used to translate the information in DNA into proteins in all cells. The Moderna Company, which received a $483 million grant from the U.S. government, and has begun early clinical trials, uses m-RNA to try to make the body produce proteins to protect against the COVID-19 virus. INOVIO Pharmaceuticals uses pieces of DNA called plasmids to achieve the same objective. It has also begun phase 1 studies.

“There are about eight platforms, and it would be good to see a couple vaccines in each of those advance,” Koff says. Predicting which of these most likely to succeed or fail he says would be “simply foolish.”

Many groups, including the Human Vaccines Initiative, are plotting routes to test any possible vaccine more quickly than tradition dictates with an “adaptive trial design.” Usually trials begin with a phase 1 study of some 50 healthy people to search for any immediate signs of toxicity, then moves onto about 200 people in a phase 2, still looking for hazards and a signal of immunity, and then to phase 3 in thousands of people. But the plan here is to start phases 2 and 3 even before its predecessors are finished, and keep recruiting additional volunteers so long as no danger signals arise.

Good animal models are appearing almost daily. Macaque monkeys, hamsters, and genetically engineered mice have all been infected in the laboratory and could determine whether potential vaccines exhibit various types of immunity. Members of Congress from both sides of the aisle have suggested that healthy human volunteers should be allowed to agree to be test subjects, allowing themselves to be infected. Stanley Plotkin, a vaccine researcher at the University of Pennsylvania, was among the first to suggest the idea.

Arthur Caplan, a bioethicist at New York University, says that “deliberately causing disease in humans is normally abhorrent.” But COVID-19 is anything but a normal circumstance. In this case, Caplan says, “asking volunteers to take risks without pressure or coercion is not exploitation but benefitting from altruism.” At least 1,500 people have already volunteered to be such human guinea pigs, although none of the experimental vaccines is far enough along to try such challenging experiments.

Koff says the key to a successful vaccine is a cooperative effort. “It’s going to take a whole different way of thinking to move this onto the expedited train,” he says. “The old dog-eat-dog, ‘I’m going to beat you to the end of the game,’ isn’t going to help us with this.” Seth Berkley, who worked with Koff at the International AIDS Vaccine Initiative, and now heads GAVI, an international vaccine organization, agrees that a COVID-19 vaccine needs a Manhattan Project approach. “An initiative of this scale won’t be easy,” Berkley says. “Extraordinary sharing of information and resources will be critical, including data on the virus, the various vaccine candidates, vaccine adjuvants, cell lines, and manufacturing advances.”

Koff has no regrets about spending so many years on an AIDS vaccine without results. He learned a great deal, he says, which he’s putting to work in the COVID-19 crisis. “The reason COVID-19 vaccines should be a lot easier is because most of the platforms, the novel approaches, and the clinical infrastructure for the testing of vaccines, came out of HIV.” He pauses. “We’re far better prepared.”

Robert Bazell is an adjunct professor of molecular, cellular, and developmental biology at Yale. For 38 years, he was chief science correspondent for NBC News.

The final outcome of COVID-19 is still unclear. It will ultimately be decided by our patience and the financial bottom line.Castleski / Shutterstock

On January 5, six days after China officially announced a spate of unusual pneumonia cases, a team of researchers at Shanghai’s Fudan University deposited the full genome sequence of the causal virus, SARS-CoV-2, into Genbank. A little more than three months later, 4,528 genomes of SARS-CoV-2 have been sequenced,1 and more than 883 COVID-related clinical trials2 for treatments and vaccines have been established. The speed with which these trials will deliver results is unknown—the delicate bаlance of efficacy and safety can only be pushed so far before the risks outweigh the benefits. For this reason, a long-term solution like vaccination may take years to come to market.3

The good news is that a lack of treatment doesn’t preclude an end to the ordeal. Viral outbreaks of Ebola and SARS, neither of which had readily available vaccines, petered out through the application of consistent public health strategies—testing, containment, and long-term behavioral adaptations. Today countries that have previously battled the 2002 SARS epidemic, like Taiwan, Hong Kong, and Singapore, have shown exemplary recovery rates from COVID. Tomorrow, countries with high fatality rates like Sweden, Belgium, and the United Kingdom will have the opportunity to demonstrate what they’ve learned when the next outbreak comes to their shores. And so will we.

The first Ebola case was identified in 1976,4 when a patient with hemorrhagic symptoms arrived at the Yambuku Mission Hospital, located in what is now the Democratic Republic of Congo (DRC). Patient samples were collected and sent to several European laboratories that specialized in rare viruses. Scientists, without sequencing technology, took about five weeks to identify the agent responsible for the illness as a new member of the highly pathogenic Filoviridae family.

The first Ebola outbreak sickened 686 individuals across the DRC and neighboring Sudan. 453 of the patients died, with a final case fatality rate (CFR)—the number of dead out of number of sickened—of 66 percent. Despite the lethality of the virus, sociocultural interventions, including lockdowns, contact-tracing, campaigns to change funeral rites, and restrictions on consumption of game meat all proved effective interventions in the long run.

That is, until 2014, when there was an exception to the pattern. Ebola appeared in Guinea, a small country in West Africa, whose population had never before been exposed to the virus. The closest epidemic had been in Gabon, 13 years before and 2,500 miles away. Over the course of two years, the infection spread from Guinea into Liberia and Sierra Leone, sickening more than 24,000 people and killing more than 10,000.

Countries that have previously battled the 2002 SARS epidemic, like Taiwan and Hong Kong, have shown exemplary recovery rates.

During the initial phase of the 2014 Ebola outbreak, rural communities were reluctant to cooperate with government directives for how to care for the sick and the dead. To help incentivize behavioral changes, sociocultural anthropologists like Mariane Ferme of the University of California, Berkeley, were brought in to advise the government. In a recent interview with Nautilus, Ferme indicated that strategies that allowed rural communities to remain involved with their loved ones increased cooperation. Villages located far from the capital, she said, were encouraged to “deputize someone to come to the hospital, to come to the burial, so they could come back to the community and tell the story of the body.” For communities that couldn’t afford to send someone to the capital, she saw public health officials adopt a savvy technological solution—tablets to record video messages that were carried between convalescent patients and their families.

However, there were also systemic failures that, in Ferme’s opinion, contributed to the severity of the 2014 West African epidemic. In Sierra Leone, she said, “the big mistake early on was to distribute [weakly causal] information about zoonotic transmission, even when it was obviously community transmission.” In other words, although there had been an instance of zoonotic transmission—the virus jumping from a bat to a human—that initiated the epidemic, the principle danger was other contagious individuals, not game meat. Eventually, under pressure from relief groups, the government changed its messaging to reflect scientific consensus.

But the retraction shook public faith in the government and bred resentment. The mismatch between messaging and reality mirrors the current pandemic. Since the COVID outbreak began, international and government health officials have issued mixed messages. Doubts initially surfaced about the certainty of the virus being capable of spreading from person to person, and the debate over the effectiveness of masks in preventing infection continues.

Despite the confused messaging, there has been general compliance with stay-at-home orders that has helped flatten the curve. Had the public been less trusting of government directives, the outcome could have been disastrous, as it was in Libera in 2014. After a two-week lockdown was announced, the Liberian army conducted house-to-house sweeps to check for the sick and collect the dead. “It was a draconian method that made people hide the sick and dead in their houses,” Ferme said. People feared their loved ones would be buried without the proper rites. A direct consequence was a staggering number of active cases, and an unknown extent of community transmission. But in the end, the benchmark for the end of Ebola and SARS was the same. The WHO declared victory when the rate of new cases slowed, then stopped. By the same measure, when an entire 14-day quarantine period passes with no new cases of COVID-19, it can be declared over.

It remains possible that even if we manage to end the epidemic, it will return again. Driven by novel zoonotic transmissions, Ebola has flared up every few years. Given the extent of COVID-19’s spread, and the potential for the kind of mutations that allow for re-infection, it may simply become endemic.

Two factors will play into the final outcome of COVID-19 are pathogenicity and virulence. Pathogenicity is the ability of an infectious agent to cause disease in the host, and is measured by R0—the number of new infections each patient can generate. Virulence, on the other hand, is the amount of harm the infectious agent can cause, and is best measured by CFR. While the pathogenicity of Ebola, SARS, and SARS-CoV-2 is on the same order—somewhere between 1 to 3 new infections for each patient, virulence differs greatly between the two SARS viruses and Ebola.

The case fatality rate for an Ebola infection is between 60 to 90 percent. The spread in CFR is due to differences in infection dynamics between strains. The underlying cause of the divergent virulence of Ebola and SARS is largely due to the tropism of the virus, meaning the cells that it attacks. The mechanism by which the Ebola virus gains entry into cells is not fully understood, but it has been shown the virus preferentially targets immune and epithelial cells.5 In other words, the virus first destroys the body’s ability to mount a defense, and then destroys the delicate tissues that line the vascular system. Patients bleed freely and most often succumb to low blood pressure that results from severe fluid loss. However, neither SARS nor SARS-CoV-2 attack the immune system directly. Instead, they enter lung epithelial cells through the ACE2 receptor, which ensures a lower CFR. What is interesting about these coronaviruses is that despite their similar modes of infection, they demonstrate a range of virulence: SARS had a final CFR of 10 percent, while SARS-CoV-2 has a pending CFR of 1.4 percent. Differences in virulence between the 2002 and 2019 SARS outbreaks could be attributed to varying levels of care between countries.

The chart above displays WHO data of the relationship between the total number of cases in a country and the CFR during the 2002-2003 SARS-CoV epidemic. South Africa, on the far right, had only a single case. The patient died, which resulted in a 100 percent CFR. China, on the other hand, had 5,327 cases and 349 deaths, giving a 7 percent CFR. The chart below zooms to the bottom left corner of the graph, so as to better resolve critically affected countries, those with a caseload of less than 1,000, but with a high CFR.

Here is Hong Kong, with 1,755 cases and a 17 percent CFR. There is also Taiwan, with 346 cases and an 11 percent CFR. Finally, nearly tied with Canada is Singapore with 238 cases and a 14 percent CFR.

With COVID-19, it’s apparent that outcome reflects experience. China has 82,747 cases of COVID, but has lowered their CFR to 4 percent. Hong Kong has 1,026 cases and a 0.4 percent CFR. Taiwan has 422 cases at 1.5 percent CFR, and Singapore with 8,014 cases, has a 0.13 percent CFR.

It was the novel coronavirus identification program established in China in the wake of the 2002 SARS epidemic that alerted authorities to SARS-CoV-2 back in November of 2019. The successful responses by Taiwan, Hong Kong, and Singapore can also be attributed to a residual familiarity with the dangers of an unknown virus, and the sorts of interventions that are necessary to prevent a crisis from spiraling out of control.

In West Africa, too, they seem to have learned the value of being prepared. When Ferme returned to Liberia on March 7, she encountered airport staff fully protected with gowns, head covers, face screens, masks, and gloves. By the time she left the country, 10 days later, she said, “Airline personnel were setting up social distancing lines, and [rural vendors] hawking face masks. Motorcycle taxis drivers, the people most at risk after healthcare workers—all had goggles and face masks.”

The sheer number of COVID-19 cases indicates the road to recovery will take some time. Each must be identified, quarantined, and all contacts traced and tested. Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars. Northwestern University economists Martin Eichenbaum et al. modeled6 the cost of a yearlong shutdown to be $4.2 trillion, a cost that proactive countries will not face. A recent Harvard study7 published in Science suggests the virus will likely make seasonal appearances going forward, potentially requiring new waves of social distancing. In other words, initial hesitancy will have repercussions for years. In the future, smart containment principles,6 where restrictions are applied on the basis of health status, may temper the impact of these measures.

Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars.

Inaction was initially framed as promoting herd immunity, where spread of the virus is interrupted once everyone has fallen sick with it. This is because getting the virus results in the same antibody production process as getting vaccinated—but doesn’t require the development of a vaccine. The Johns Hopkins Bloomberg School of Public Health estimates that 70 percent of the population will need to be infected with or vaccinated against the virus8 for herd immunity to work. Progress toward it has been slow, and can only be achieved through direct infection with the virus, meaning many will die. A Stanford University study in Santa Clara County9 suggests only 2.5 percent to 4.2 percent of the population have had the virus. Another COVID hotspot in Gangelt, Germany, suggests 15 percent10—higher, but still nowhere near the 70 percent necessary for herd immunity. Given the dangers inherent in waiting on herd immunity, our best hope is a vaccine.

A key concern for effective vaccine development is viral mutation. This is because vaccines train the immune system to recognize specific shapes on the surface of the virus—a composite structure called the antigen. Mutations threaten vaccine development because they can change the shape of the relevant antigen, effectively allowing the pathogen to evade immune surveillance. But, so far, SARS-CoV-2 has been mutating slowly, with only one mutation found in the section most accessible to the immune system, the spike protein. What this suggests is that the viral genome may be sufficiently stable for vaccine development.

What we know, though, is that Ebola was extinguished due to cooperation between public health officials and community leaders. SARS-CoV ended when all cases were identified and quarantined. The Spanish Flu in 1918 vanished after two long, deadly seasons.

The final outcome of COVID-19 is still unclear. It will ultimately be decided by our patience and the financial bottom line. With 26 million unemployed and protests erupting around the country, it seems there are many who would prefer to risk life and limb rather than face financial insolvency. Applying smart containment principles in the aftermath of the shutdown might be the best way to get the economy moving again, while maintaining the safety of those at greatest risk. Going forward, vigilance and preparedness will be the watchwords of the day, and the most efficient way to prevent social and economic ruin.

Anastasia Bendebury and Michael Shilo DeLay did their PhDs at Columbia University. Together they created Demystifying Science, a science literacy organization devoted to providing clear, mechanistic explanations for natural phenomena. Find them on Twitter @DemystifySci.

References

1. Genomic epidemiology of novel coronavirus - Global subsampling. Nextstrain www.nextstrain.org.

2. Covid-19 TrialsTracker. TrialsTracker www.trialstracker.net.

3. Struck, M. Vaccine R&D success rates and development times. Nature Biotechnology 14, 591-593 (1996).

4. Breman, J. & Johnson, K. Ebola then and now. The New England Journal of Medicine 371 1663-1666 (2014).

5. Baseler, L., Chertow, D.S., Johnson, K.M., Feldmann, H., & Morens, D.M. THe pathogenesis of Ebola virus disease. The Annual Review of Pathology 12, 387-418 (2017).

6. Eichenbaum, M., Rebell, S., & Trabandt, M. The macroeconomics of epidemics. The National Bureau of Economic Research Working Paper: 26882 (2020).

7. Kissler, S., Tedijanto, C., Goldstein, E., Grad, Y., & Lipsitch, M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science eabb5793 (2020).

8. D’ Souza, G. & Dowdy, D. What is herd immunity and how can we achieve it with COVID-19? Johns Hopkins COVID-19 School of Public Health Insights www.jhsph.edu (2020).

9. Digitale, E. Test for antibodies against novel coronavirus developed at Stanford Medicine. Stanford Medicine News Center Med.Stanford.edu (2020).

10. Winkler, M. Blood tests show 14%of people are now immune to COVID-19 in one town in Germany. MIT Technology Review (2020).

On January 5, six days after China officially announced a spate of unusual pneumonia cases, a team of researchers at Shanghai’s Fudan University deposited the full genome sequence of the causal virus, SARS-CoV-2, into Genbank. A little more than three months later, 4,528 genomes of SARS-CoV-2 have been sequenced,1 and more than 883 COVID-related clinical trials2 for treatments and vaccines have been established. The speed with which these trials will deliver results is unknown—the delicate bаlance of efficacy and safety can only be pushed so far before the risks outweigh the benefits. For this reason, a long-term solution like vaccination may take years to come to market.3

The good news is that a lack of treatment doesn’t preclude an end to the ordeal. Viral outbreaks of Ebola and SARS, neither of which had readily available vaccines, petered out through the application of consistent public health strategies—testing, containment, and long-term behavioral adaptations. Today countries that have previously battled the 2002 SARS epidemic, like Taiwan, Hong Kong, and Singapore, have shown exemplary recovery rates from COVID. Tomorrow, countries with high fatality rates like Sweden, Belgium, and the United Kingdom will have the opportunity to demonstrate what they’ve learned when the next outbreak comes to their shores. And so will we.

The first Ebola case was identified in 1976,4 when a patient with hemorrhagic symptoms arrived at the Yambuku Mission Hospital, located in what is now the Democratic Republic of Congo (DRC). Patient samples were collected and sent to several European laboratories that specialized in rare viruses. Scientists, without sequencing technology, took about five weeks to identify the agent responsible for the illness as a new member of the highly pathogenic Filoviridae family.

The first Ebola outbreak sickened 686 individuals across the DRC and neighboring Sudan. 453 of the patients died, with a final case fatality rate (CFR)—the number of dead out of number of sickened—of 66 percent. Despite the lethality of the virus, sociocultural interventions, including lockdowns, contact-tracing, campaigns to change funeral rites, and restrictions on consumption of game meat all proved effective interventions in the long run.

That is, until 2014, when there was an exception to the pattern. Ebola appeared in Guinea, a small country in West Africa, whose population had never before been exposed to the virus. The closest epidemic had been in Gabon, 13 years before and 2,500 miles away. Over the course of two years, the infection spread from Guinea into Liberia and Sierra Leone, sickening more than 24,000 people and killing more than 10,000.

Countries that have previously battled the 2002 SARS epidemic, like Taiwan and Hong Kong, have shown exemplary recovery rates.

During the initial phase of the 2014 Ebola outbreak, rural communities were reluctant to cooperate with government directives for how to care for the sick and the dead. To help incentivize behavioral changes, sociocultural anthropologists like Mariane Ferme of the University of California, Berkeley, were brought in to advise the government. In a recent interview with Nautilus, Ferme indicated that strategies that allowed rural communities to remain involved with their loved ones increased cooperation. Villages located far from the capital, she said, were encouraged to “deputize someone to come to the hospital, to come to the burial, so they could come back to the community and tell the story of the body.” For communities that couldn’t afford to send someone to the capital, she saw public health officials adopt a savvy technological solution—tablets to record video messages that were carried between convalescent patients and their families.

However, there were also systemic failures that, in Ferme’s opinion, contributed to the severity of the 2014 West African epidemic. In Sierra Leone, she said, “the big mistake early on was to distribute [weakly causal] information about zoonotic transmission, even when it was obviously community transmission.” In other words, although there had been an instance of zoonotic transmission—the virus jumping from a bat to a human—that initiated the epidemic, the principle danger was other contagious individuals, not game meat. Eventually, under pressure from relief groups, the government changed its messaging to reflect scientific consensus.

But the retraction shook public faith in the government and bred resentment. The mismatch between messaging and reality mirrors the current pandemic. Since the COVID outbreak began, international and government health officials have issued mixed messages. Doubts initially surfaced about the certainty of the virus being capable of spreading from person to person, and the debate over the effectiveness of masks in preventing infection continues.

Despite the confused messaging, there has been general compliance with stay-at-home orders that has helped flatten the curve. Had the public been less trusting of government directives, the outcome could have been disastrous, as it was in Libera in 2014. After a two-week lockdown was announced, the Liberian army conducted house-to-house sweeps to check for the sick and collect the dead. “It was a draconian method that made people hide the sick and dead in their houses,” Ferme said. People feared their loved ones would be buried without the proper rites. A direct consequence was a staggering number of active cases, and an unknown extent of community transmission. But in the end, the benchmark for the end of Ebola and SARS was the same. The WHO declared victory when the rate of new cases slowed, then stopped. By the same measure, when an entire 14-day quarantine period passes with no new cases of COVID-19, it can be declared over.

It remains possible that even if we manage to end the epidemic, it will return again. Driven by novel zoonotic transmissions, Ebola has flared up every few years. Given the extent of COVID-19’s spread, and the potential for the kind of mutations that allow for re-infection, it may simply become endemic.

Two factors will play into the final outcome of COVID-19 are pathogenicity and virulence. Pathogenicity is the ability of an infectious agent to cause disease in the host, and is measured by R0—the number of new infections each patient can generate. Virulence, on the other hand, is the amount of harm the infectious agent can cause, and is best measured by CFR. While the pathogenicity of Ebola, SARS, and SARS-CoV-2 is on the same order—somewhere between 1 to 3 new infections for each patient, virulence differs greatly between the two SARS viruses and Ebola.

The case fatality rate for an Ebola infection is between 60 to 90 percent. The spread in CFR is due to differences in infection dynamics between strains. The underlying cause of the divergent virulence of Ebola and SARS is largely due to the tropism of the virus, meaning the cells that it attacks. The mechanism by which the Ebola virus gains entry into cells is not fully understood, but it has been shown the virus preferentially targets immune and epithelial cells.5 In other words, the virus first destroys the body’s ability to mount a defense, and then destroys the delicate tissues that line the vascular system. Patients bleed freely and most often succumb to low blood pressure that results from severe fluid loss. However, neither SARS nor SARS-CoV-2 attack the immune system directly. Instead, they enter lung epithelial cells through the ACE2 receptor, which ensures a lower CFR. What is interesting about these coronaviruses is that despite their similar modes of infection, they demonstrate a range of virulence: SARS had a final CFR of 10 percent, while SARS-CoV-2 has a pending CFR of 1.4 percent. Differences in virulence between the 2002 and 2019 SARS outbreaks could be attributed to varying levels of care between countries.

The chart above displays WHO data of the relationship between the total number of cases in a country and the CFR during the 2002-2003 SARS-CoV epidemic. South Africa, on the far right, had only a single case. The patient died, which resulted in a 100 percent CFR. China, on the other hand, had 5,327 cases and 349 deaths, giving a 7 percent CFR. The chart below zooms to the bottom left corner of the graph, so as to better resolve critically affected countries, those with a caseload of less than 1,000, but with a high CFR.

Here is Hong Kong, with 1,755 cases and a 17 percent CFR. There is also Taiwan, with 346 cases and an 11 percent CFR. Finally, nearly tied with Canada is Singapore with 238 cases and a 14 percent CFR.

With COVID-19, it’s apparent that outcome reflects experience. China has 82,747 cases of COVID, but has lowered their CFR to 4 percent. Hong Kong has 1,026 cases and a 0.4 percent CFR. Taiwan has 422 cases at 1.5 percent CFR, and Singapore with 8,014 cases, has a 0.13 percent CFR.

It was the novel coronavirus identification program established in China in the wake of the 2002 SARS epidemic that alerted authorities to SARS-CoV-2 back in November of 2019. The successful responses by Taiwan, Hong Kong, and Singapore can also be attributed to a residual familiarity with the dangers of an unknown virus, and the sorts of interventions that are necessary to prevent a crisis from spiraling out of control.

In West Africa, too, they seem to have learned the value of being prepared. When Ferme returned to Liberia on March 7, she encountered airport staff fully protected with gowns, head covers, face screens, masks, and gloves. By the time she left the country, 10 days later, she said, “Airline personnel were setting up social distancing lines, and [rural vendors] hawking face masks. Motorcycle taxis drivers, the people most at risk after healthcare workers—all had goggles and face masks.”

The sheer number of COVID-19 cases indicates the road to recovery will take some time. Each must be identified, quarantined, and all contacts traced and tested. Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars. Northwestern University economists Martin Eichenbaum et al. modeled6 the cost of a yearlong shutdown to be $4.2 trillion, a cost that proactive countries will not face. A recent Harvard study7 published in Science suggests the virus will likely make seasonal appearances going forward, potentially requiring new waves of social distancing. In other words, initial hesitancy will have repercussions for years. In the future, smart containment principles,6 where restrictions are applied on the basis of health status, may temper the impact of these measures.

Countries that failed to act swiftly, which allowed their case numbers to spiral out of control, will pay in lives and dollars.

Inaction was initially framed as promoting herd immunity, where spread of the virus is interrupted once everyone has fallen sick with it. This is because getting the virus results in the same antibody production process as getting vaccinated—but doesn’t require the development of a vaccine. The Johns Hopkins Bloomberg School of Public Health estimates that 70 percent of the population will need to be infected with or vaccinated against the virus8 for herd immunity to work. Progress toward it has been slow, and can only be achieved through direct infection with the virus, meaning many will die. A Stanford University study in Santa Clara County9 suggests only 2.5 percent to 4.2 percent of the population have had the virus. Another COVID hotspot in Gangelt, Germany, suggests 15 percent10—higher, but still nowhere near the 70 percent necessary for herd immunity. Given the dangers inherent in waiting on herd immunity, our best hope is a vaccine.

A key concern for effective vaccine development is viral mutation. This is because vaccines train the immune system to recognize specific shapes on the surface of the virus—a composite structure called the antigen. Mutations threaten vaccine development because they can change the shape of the relevant antigen, effectively allowing the pathogen to evade immune surveillance. But, so far, SARS-CoV-2 has been mutating slowly, with only one mutation found in the section most accessible to the immune system, the spike protein. What this suggests is that the viral genome may be sufficiently stable for vaccine development.

What we know, though, is that Ebola was extinguished due to cooperation between public health officials and community leaders. SARS-CoV ended when all cases were identified and quarantined. The Spanish Flu in 1918 vanished after two long, deadly seasons.

The final outcome of COVID-19 is still unclear. It will ultimately be decided by our patience and the financial bottom line. With 26 million unemployed and protests erupting around the country, it seems there are many who would prefer to risk life and limb rather than face financial insolvency. Applying smart containment principles in the aftermath of the shutdown might be the best way to get the economy moving again, while maintaining the safety of those at greatest risk. Going forward, vigilance and preparedness will be the watchwords of the day, and the most efficient way to prevent social and economic ruin.

Anastasia Bendebury and Michael Shilo DeLay did their PhDs at Columbia University. Together they created Demystifying Science, a science literacy organization devoted to providing clear, mechanistic explanations for natural phenomena. Find them on Twitter @DemystifySci.

References

1. Genomic epidemiology of novel coronavirus - Global subsampling. Nextstrain www.nextstrain.org.

2. Covid-19 TrialsTracker. TrialsTracker www.trialstracker.net.

3. Struck, M. Vaccine R&D success rates and development times. Nature Biotechnology 14, 591-593 (1996).

4. Breman, J. & Johnson, K. Ebola then and now. The New England Journal of Medicine 371 1663-1666 (2014).

5. Baseler, L., Chertow, D.S., Johnson, K.M., Feldmann, H., & Morens, D.M. THe pathogenesis of Ebola virus disease. The Annual Review of Pathology 12, 387-418 (2017).

6. Eichenbaum, M., Rebell, S., & Trabandt, M. The macroeconomics of epidemics. The National Bureau of Economic Research Working Paper: 26882 (2020).

7. Kissler, S., Tedijanto, C., Goldstein, E., Grad, Y., & Lipsitch, M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science eabb5793 (2020).

8. D’ Souza, G. & Dowdy, D. What is herd immunity and how can we achieve it with COVID-19? Johns Hopkins COVID-19 School of Public Health Insights www.jhsph.edu (2020).

9. Digitale, E. Test for antibodies against novel coronavirus developed at Stanford Medicine. Stanford Medicine News Center Med.Stanford.edu (2020).

10. Winkler, M. Blood tests show 14%of people are now immune to COVID-19 in one town in Germany. MIT Technology Review (2020).

Lead image: Castleski / Shutterstock

Visitors' health status will be checked on a smartphone app before they enter the park. Once inside, they will be required to wear face masks at all times unless they are eating.

Florida health officials have halted the publication of up-to-the-minute death statistics related to the coronavirus pandemic that have, by law, been compiled by medical examiners in the state.

“Recognize that there are going to be social distancing practices at the airport. So there’s no running to the gate at the last minute,” said Sara Nelson, the international president of the Association of Flight Attendants-CWA in an interview with Yahoo News.

While many parts of our economy remain shuttered and other sports continue to wait for the go ahead to resume play, courses in all 10 provinces will soon be open for business.

The Ontario government paved the way Friday, easing restrictions on pro sports teams by allowing them to open their training facilities providing they follow their league's "established health and safety protocols" in response to COVID-19.

The Canadian Olympic Committee CEO talks about state of Canadian sport during COVID-19 and how funding will help keep sport organizations afloat.

The Washington Capitals placed Brendan Leipsic on unconditional waivers on Friday, two days after it was revealed the forward made misogynistic comments in a private group chat. The team said the move was made with the intention of terminating Leipsic's contract.

Team training facilities have been closed, other than for approved rehab, since the league suspended play March 12 due to the global pandemic.

The team says that after working closely with the local government, infectious disease experts and public health authorities, players will be allowed to access the OVO Athletic Centre starting next week.

When the season opened on April 11 after a three-week delay, only players, team personnel and cheerleaders were allowed in the stadium.

In the long run, it could protect us from future COVID-19 outbreaks. To get there, we need an effective vaccine.

Starting Monday, “park ambassadors” will be stationed at Ottawa’s busiest parks to provide information about what's permitted under pandemic rules.

A new meme imagines a walking down all sorts of aisles after coronavirus-related lockdowns end

A silver chain has taken center stage in Hulu's adaptation of Sally Rooney's "Normal People"

Nintendo is no longer repairing the Wii video game console, which was released in 2006 and let players swing controllers to impact action on screen.

Classic casual games such as Solitaire, sudoku, crossword puzzles and pinball live on smartphones and tablets as the mobile gaming audience expands.

One gurdwara in Kent is delivering hundreds of meals daily to hospitals, care homes and vulnerable

• Coronavirus – latest updates
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They start at 4am, chopping vegetables, mixing spices, soaking legumes, kneading chapati dough. Scores of volunteers are split into five teams working in shifts: cooking, packing, delivering, cleaning and answering the phones.

By the end of the day, at least 850 meals have been delivered to staff at five nearby hospitals, care homes and vulnerable individuals. Some days, the number hits 1,000.

Handing out contracts out to firms like Serco and G4S is now second nature to those in power. We need to rebuild state capacity

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The coronavirus pandemic has revealed a lot about British society – the fragility of the economy, the insecure situation so many workers find themselves in – but it has also shone a light on the state itself. Many comparisons have been made between the current mobilisation of state resources and the second world war. But while that crisis involved a ramping up of public sector capacity, this one is being managed by a state that believes itself to be utterly dependent on the private sector.

First, there are the outsourcing giants, shadowy corporations who have been handed numerous contracts over the past 20 years. Matt Hancock has put Serco in charge of the phonelines for contact tracing, a vital part of the government’s public health strategy. This is a company that mismanaged data at a GP surgery, and failed to train staff properly for a breast cancer hotline service. Along with G4S, it claimed money from the government for tracking prisoners who were later found to be dead.

A small flock of shorebirds contaminated with oil after touching down on a northern Alberta tailings pond is expected to be released back into the wild within a week.

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This article contains major spoilers for the first episode of 'Killing Eve' series three

Mayim Bialik, Debra Messing, Finn Wolfhard and many others joined

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Whether or not the Ingrams were cheating on 'Who Wants to Be a Millionaire?', the resulting outrage was rooted in the same dynamics that have come to dominate social discourse in the years since, says Adam White

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Test your knowledge

As ITV's three-part miniseries Quiz recreates Ingram's scandalous quiz show victory – are you able to get all the the answers right without cheating?

Mario Lopez, Elizabeth Berkley and Mark-Paul Gosselaar are among the show's returning cast members

'Reasons to be Cheerful with Matt Lucas' will start on 26 April

'Never, ever, ever, ever intended to make anyone feel uncomfortable – ever. It's just not who I am'

US talk show host previously said she returned to the air to support her crew, who she said she 'loves and misses'

The pair will reunite for BBC's 'Big Night In'

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A cornucopia of huge pop names came together for an unprecedented cultural and technological event

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Reality TV star went on a rant after she was criticised for travelling while experiencing Covid-19 symptoms

Comedian was sat on a stool at the other side of the studio to his hosts

The heavily tattooed comedian was spotlighted in a segment on the BBC current affairs programme because of his volunteering work

Smollett was re-indicted in February after being charged with fabricating a racially motivated assault