A time course experiment is a widely used design in the study of cellular processes such as differentiation or response to stimuli. In this paper, we propose time course regulatory analysis (TimeReg) as a method for the analysis of gene regulatory networks based on paired gene expression and chromatin accessibility data from a time course. TimeReg can be used to prioritize regulatory elements, to extract core regulatory modules at each time point, to identify key regulators driving changes of the cellular state, and to causally connect the modules across different time points. We applied the method to analyze paired chromatin accessibility and gene expression data from a retinoic acid (RA)–induced mouse embryonic stem cells (mESCs) differentiation experiment. The analysis identified 57,048 novel regulatory elements regulating cerebellar development, synapse assembly, and hindbrain morphogenesis, which substantially extended our knowledge of cis-regulatory elements during differentiation. Using single-cell RNA-seq data, we showed that the core regulatory modules can reflect the properties of different subpopulations of cells. Finally, the driver regulators are shown to be important in clarifying the relations between modules across adjacent time points. As a second example, our method on Ascl1-induced direct reprogramming from fibroblast to neuron time course data identified Id1/2 as driver regulators of early stage of reprogramming.

Genome-wide association studies have implicated thousands of noncoding variants across common human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate that signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in cortical layer V excitatory neurons. We also show that differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in cortical layers II-III, IV, and V, as well as the dentate gyrus. Finally, we leverage these data to fine-map variants in 177 schizophrenia loci nominating variants in 104/177. We integrate these data with transcription factor binding site, chromatin interaction, and validated enhancer data, placing variants in the cellular context where they may modulate risk.

Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A, and RAD21, cohesin in somatic cells contains one of two orthologous STAG subunits, STAG1 or STAG2. How these variable subunits affect the function of the cohesin complex is still unclear. STAG1- and STAG2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either STAG1 or STAG2. Following rapid depletion of either subunit, we perform high-resolution Hi-C, gene expression, and sequential ChIP studies to show that STAG1 and STAG2 do not co-occupy individual binding sites and have distinct ways by which they affect looping and gene expression. These findings are further supported by single-molecule localizations via direct stochastic optical reconstruction microscopy (dSTORM) super-resolution imaging. Since somatic and congenital mutations of the STAG subunits are associated with cancer (STAG2) and intellectual disability syndromes with congenital abnormalities (STAG1 and STAG2), we verified STAG1-/STAG2-dependencies using human neural stem cells, hence highlighting their importance in particular disease contexts.

Peptidyl arginine deiminase 4 (PAD4/PADI4) is a posttranslational modification enzyme that converts protein arginine or mono-methylarginine to citrulline. The PAD4-mediated hypercitrullination reaction in neutrophils causes the release of nuclear chromatin to form a chromatin network termed neutrophil extracellular traps (NET). NETs were first described as antimicrobial fibers that bind and kill bacteria. However, it is not known whether PAD4 can mediate the release of chromatin DNA into the extracellular space of cancer cells. Here, we report that murine breast cancer 4T1 cells expressing high levels of PADI4 can release cancer extracellular chromatin networks (CECN) in vitro and in vivo. Deletion of Padi4 using CRISPR/Cas9 abolished CECN formation in 4T1 cells. Padi4 deletion from 4T1 cells also reduced the rate of tumor growth in an allograft model, and decreased lung metastasis by 4T1 breast cancers. DNase I treatment, which degrades extracellular DNA including CECNs, also reduced breast to lung metastasis of Padi4 wild-type 4T1 cells in allograft experiments in the Padi4-knockout mice. We further demonstrated that DNase I treatment in this mouse model did not alter circulating tumor cells but decreased metastasis through steps after intravasation. Taken together, our genetic studies show that PAD4 plays a cell autonomous role in cancer metastasis, thus revealing a novel strategy for preventing cancer metastasis by inhibiting cancer cell endogenous PAD4.

Human bone marrow stromal cells (BMSC) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key stromal cell functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key stromal cell regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSC, down-regulated upon culture, and low in non-colony-forming CD45^neg stromal cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSC. Overexpression of EGR1 in stromal cells induced potent hematopoietic stroma support as indicated by an increased production of transplantable CD34⁺CD90⁺ hematopoietic stem cells in expansion co-cultures. The improvement in bone marrow stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. Furthermore, EGR1 overexpression markedly decreased stromal cell proliferation whereas EGR1 knockdown caused the opposite effects. These findings thus show that EGR1 is a key stromal transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to co-ordinate the specific functions of BMSC in their different biological contexts.

Vibralactone, a hybrid compound derived from phenols and a prenyl group, is a strong pancreatic lipase inhibitor with a rare fused bicyclic β-lactone skeleton. Recently, a researcher reported a vibralactone derivative (compound C1) that caused inhibition of pancreatic lipase with a half-maximal inhibitory concentration of 14 nM determined by structure-based optimization, suggesting a potential candidate as a new antiobesity treatment. In the present study, we sought to identify the main gene encoding prenyltransferase in Stereum vibrans, which is responsible for the prenylation of phenol leading to vibralactone synthesis. Two RNA silencing transformants of the identified gene (vib-PT) were obtained through Agrobacterium tumefaciens-mediated transformation. Compared to wild-type strains, the transformants showed a decrease in vib-PT expression ranging from 11.0 to 56.0% at 5, 10, and 15 days in reverse transcription-quantitative PCR analysis, along with a reduction in primary vibralactone production of 37 to 64% at 15 and 21 days, respectively, as determined using ultra-high-performance liquid chromatography-mass spectrometry analysis. A soluble and enzymatically active fusion Vib-PT protein was obtained by expressing vib-PT in Escherichia coli, and the enzyme’s optimal reaction conditions and catalytic efficiency (K_m/k_cat) were determined. In vitro experiments established that Vib-PT catalyzed the C-prenylation at C-3 of 4-hydroxy-benzaldehyde and the O-prenylation at the 4-hydroxy of 4-hydroxy-benzenemethanol in the presence of dimethylallyl diphosphate. Moreover, Vib-PT shows promiscuity toward aromatic compounds and prenyl donors.

IMPORTANCE Vibralactone is a lead compound with a novel skeleton structure that shows strong inhibitory activity against pancreatic lipase. Vibralactone is not encoded by the genome directly but rather is synthesized from phenol, followed by prenylation and other enzyme reactions. Here, we used an RNA silencing approach to identify and characterize a prenyltransferase in a basidiomycete species that is responsible for the synthesis of vibralactone. The identified gene, vib-PT, was expressed in Escherichia coli to obtain a soluble and enzymatically active fusion Vib-PT protein. In vitro characterization of the enzyme demonstrated the catalytic mechanism of prenylation and broad substrate range for different aromatic acceptors and prenyl donors. These characteristics highlight the possibility of Vib-PT to generate prenylated derivatives of aromatics and other compounds as improved bioactive agents or potential prodrugs.

This protocol describes a simple single-step column purification (SSCP) of rAAV2 by gravity flow based on its affinity to heparin, without ultracentrifugation.

Alison Roman’s latest comments about Marie Kondo have not sparked joy.

In an interview with The New Consumer about her increased popularity and the avenues she might pursue to capitalize on it, the popular food columnist discussed her hesitance to put her name on a product line—citing the Japanese organization maven and Chrissy Teigen as examples of what she did not foresee in her own future.

“I have a collaboration coming out with [the cookware startup] Material, a capsule collection,” Roman said. “It’s limited edition, a few tools that I designed that are based on tools that I use that aren’t in production anywhere—vintage spoons and very specific things that are one-offs that I found at antique markets that they have made for me.”

Read more at The Daily Beast.

“I didn’t ‘sell out’ by making my dreams come true.”

PAX is history but Chris is still feeling the siren’s call of some of its best games. Alice is busy fending off aliens and hedgehogs....

Wagner Moura and Ana de Armas give strong performances in a mostly effective retelling of the life and tragic death of a celebrated Brazilian diplomat

There’s an old school charm to Sergio, documentarian Greg Barker’s narrative portrait of UN diplomat Sérgio Vieira de Mello, a dramatic retelling of a life he already brought to the screen in a 2009 documentary of the same name. Barker’s knowledge of Sérgio’s life and accomplishments is backgrounded by a clear respect for who he was and so while the film is factually detailed, as one would expect, it’s also rooted in a desire to showcase his humanity, both in and out of work, with Barker deciding to lean into full-tilt romantic tragedy, perhaps also as a way of differentiating his two Sergios.

Related: Love Wedding Repeat review – laboured Netflix romcom farce

This heartwarming documentary traces the lives of a baseball star and her partner, now in their 90s, who pretended to be ‘just good friends’ for decades

This documentary from Netflix is a real heart-soother. Directed with tremendous sensitivity and intimacy by Chris Bolan, it’s a love story about two women now in their 90s – Terry Donahue and Pat Henschel, who have been together since the 1940s.

For decades they kept up the pretence of being “just good friends” to their families before finally coming out a few years ago. Talking to outsiders, they still describe each other as “cousins”. The legacy of shame and fear among older people in the gay community is explored in the film, but the overwhelming mood here is love.

Jameela Jamil also came to Teigen and Kondo's defense, calling Roman "distasteful" and "cliche" for criticizing women of color for being successful in business.

Follow our live coronavirus updates here

In Carpathia, Irina Georgescu shines a light on the richness of Romanian food culture

A couple of days ago Alison Roman, critic and food enthusiast gave an interview directly trashing Chrissy Teigen’s approach to business. “What Chrissy Teigen has done is so crazy to me. She had a successful cookbook. And then it was like Boom, the line at Target. Boom, now she has an Instagram page that has […]

The post Alison Roman Is Eating Her Words, Apologizing To Chrissy Teigen appeared first on Chart Attack.

The actor, 47, on being an optimist, avoiding marriage advice and why other people make him anxious

I have so many bad habits it’s impossible to measure the worst. My son would say I don’t take enough care with how I dress, my daughter might say I work too much, and my wife that I can’t seem to help in the kitchen at all. But in my opinion I have none.

As a former kid actor, I know how hard it is to turn that attention into anything but self-destruction. The heat of the spotlight makes ordinary temperatures real cold.

In today’s film news roundup, romantic comedy “Tell Me I Love You” finds a home; the Canadian government gives COVID-19 relief funding to the Canada Media Fund and Telefilm Canada; and the cancelled Sun Valley Film Festival gives out awards. ACQUISITION Vision Films has acquired Los Angeles romantic comedy film “Tell Me I Love You,” […]

Move over, Martha Stewart and Gwyneth Paltrow. There's a new feud brewing between two leaders in the lifestyle industry. Best-selling cookbook author Alison Roman has caught the...

It seems like people who get infected with SARS-CoV-2 retain immunity, but we can’t be sure how long that immunity will last. We still lack the testing capabilities to be certain.eamesBot / Shutterstock

This story was updated post-publication to include information from a study published on the preprint server medRxiv on April 17, 2020.

With more than half a million cases of COVID-19 in the United States1 and the number of deaths increasing daily, it remains unclear when and how we might return to some semblance of pre-pandemic life. This leaves many grappling with an important question: Do you become immune after SARS-CoV-2 infection? And, if so, how long might that immunity last?

In 2019, the virus SARS-CoV-2 jumped to a human host for the first time, causing the disease COVID-19. When you become infected with a new virus, your body does not possess the antibodies necessary to mount a targeted immune response. Antibodies, proteins belonging to the immunoglobulin family, consist of four chains of amino acids that form a characteristic Y-shaped structure. Antibodies are manufactured by the immune system to bind to antigens (viral proteins) to neutralize viral infectivity.

When you inhale an aerosolized droplet containing SARS-CoV-2, the virus encounters the cells of the mucous membrane lining the respiratory tract. If effective contact is made, the virus binds to a particular receptor on these cells called ACE-2. After binding ACE-2, a host enzyme is co-opted to cleave the virus’ surface protein, called the spike protein, allowing the virus to enter the cell.

It appears that individuals with COVID-19 do create neutralizing antibodies—the basis of immunity.

Within the first few hours of infection, the body’s first line of defense—the innate immune response—is activated. The innate immune response is non-specific. When a “foreign” molecule is detected, innate immune cells signal to other cells to alter their response or prepare to combat infection.

In the following days, the adaptive immune response is activated, which is more specific. The adaptive immune response will peak one to two weeks post-infection and consists of antibodies and specialized immune cells. It is called the “adaptive” immune response because of its ability to tailor the response to a specific pathogen. Antibodies can neutralize viral infectivity by preventing virus from binding to receptors, blocking cell entry, or causing virus particles to aggregate.2 Once an infection has resolved, some of these antibodies remain in the body as immunological memory to be recruited for protection in the case of reinfection. To be immune to a virus is to possess this immunological memory.

Many vaccines work by activating the adaptive immune response. Inactivated virus, viral protein, or some other construct specific to a particular virus are introduced into the body as vaccines to initiate an immune response. Ideally, the body creates antibodies against the viral construct so that it can mount a succinct response when infected by the virus. However, in order to work effectively, a vaccine must provoke an immune response that is sufficiently robust. If the body only produces low concentrations of neutralizing antibodies, adequate immunological memory may not be sustained.

While there is still much that we have to learn about SARS-CoV-2, it appears that individuals with COVID-19 do create neutralizing antibodies—the basis of immunity. However, we don’t know for certain how long that immunity might offer protection. On the question of COVID-19 re-infection, Matt Frieman, a coronavirus researcher at the University of Maryland School of Medicine, commented in a recent interview with NPR: “We don’t know very much … I think there’s a very likely scenario where the virus comes through this year, and everyone gets some level of immunity to it, and if it comes back again, we will be protected from it—either completely or if you do get reinfected later, a year from now, then you have much less disease. That’s the hope, but there is no way to know that.”3

Immunity to a virus is measured by serological testing—patient blood is collected and analyzed for the presence of antibodies against a particular virus. Serological data is most informative when collected long-term, so the data we have been able to obtain on SARS-CoV-2 is limited. However, data on other coronaviruses that we’ve had the opportunity to study in more depth can inform our estimations on how this outbreak may evolve.

First, we can look to the coronaviruses that are known to cause the common cold. Following infection with one of these coronaviruses, disease is often mild; therefore, the concentration of antibodies detected in the blood is low. This is because mild disease often indicates a less robust immune response. Interestingly, it is not the virus itself that causes us to feel sick, but, rather, our body’s response to it. Typically, the sicker we feel, the stronger the immune response; therefore, after a cold, we are often only protected for a year or two against the same virus.4 While SARS-CoV-2 wouldn’t necessarily act like these common coronaviruses, the body’s response to these coronaviruses serves as a point of reference upon which to make predictions in the absence of virus-specific data.

We can also look to coronaviruses that are known to cause severe disease, such as SARS-CoV, which caused the 2002-2003 outbreak of SARS in China. One study discovered that antibodies against SARS-CoV remained in the blood of healthcare workers for 12 years after infection.5 While it is not certain that SARS-CoV-2 will provoke a response similar to that of SARS-CoV, this study provides us with information that can inform our estimates on immunity following COVID-19 and provide hope that immunity will provide long-term protection.

If immunity to SARS-CoV-2 diminishes as it does for common cold coronaviruses, it is likely that wintertime outbreaks will recur.

Scientists have also been working to analyze antibodies in samples from individuals infected with SARS-CoV-2. A research group in Finland recently published a study detailing the serological data collected from a COVID-19 patient over the course of their illness.6 Antibodies specific to SARS-CoV-2 were present within two weeks from the onset of symptoms. Similarly, another recent report analyzing patients with confirmed COVID-19 indicated that it took approximately 11-14 days for neutralizing antibodies to be detected in blood.7 Both of these studies, while preliminary, suggest that the basis for immunity is present in patients infected with SARS-CoV-2.

Another report looked at the possibility for recurrence of COVID-19 following re-infection with SARS-CoV-2.8 In this study, rhesus macaques were infected with SARS-CoV and allowed to recover after developing mild illness. Once blood samples were collected and confirmed to test positive for neutralizing antibodies, half of the infected macaques were re-challenged with the same dose of SARS-CoV-2. The re-infected macaques showed no significant viral replication or recurrence of COVID-19. While macaques “model” human immunity, not predict it, these data further support the possibility that antibodies manufactured in response to SARS-CoV-2 are protective against short-term re-infection.

We can also analyze a virus’ structure, and the information gained from sequencing the viral genome, when trying to predict its behavior. All viruses continually undergo mutation in the process of rapid replication. They lack the necessary machinery to repair changes incurred to the genetic sequence (we as humans also incur mutations to our genetic sequence daily, but we have more sophisticated genetic repair mechanisms in place). The occurrence of significant genetic changes to the viral genome that result in viable genetic changes to a virus is termed antigenic variation. We see a lot of antigenic variation in influenza viruses (thus the need to create new vaccines each year); but the coronaviruses seem to be relatively stable antigenically.4 This is because most coronaviruses have an enzyme that allows them to correct genetic errors sustained during replication. The more stable a virus remains over time, the more likely that antibodies manufactured in response to infection or vaccination will remain effective at neutralizing viral infectivity.

All this considered, it appears that immunity is retained following SARS-CoV-2 infection. So too, that immunity might persist long enough to warrant the implementation of vaccination. However, we still have much to learn about this virus, and whether there may be some cross-immunity between SARS-CoV-2 and other coronaviruses. The widespread variation in patient immune responses adds an additional layer of complexity. We still don’t have a good understanding of why people have different responses to viral infection—some of this variation is owed to genetic variation, but how and why some people have more robust immune responses and more severe disease is still unknown.4 In some cases, individuals show a high immune response because the concentration of virus is high. In other cases, individuals show a high immune response because they differ in some aspect of immune regulation or efficiency. However, as levels of immunity increase generally across a population, the population approaches what is called “herd immunity”—when the percentage of a population immune to a particular virus is sufficiently high that viral load drops below the threshold required to sustain the infection in that population.9

How the pandemic will evolve in the coming months is uncertain. Outcomes depend on a myriad of factors—the duration of immunity, the dynamics of transmission and how we mitigate those dynamics through social distancing, the development of therapeutics and or vaccines, and the ability of healthcare systems to handle COVID-19 caseloads. If immunity to SARS-CoV-2 diminishes as it does for common cold coronaviruses, it is likely that wintertime outbreaks will recur in coming years.10 Whether immunity to other coronaviruses might offer some cross protective immunity to SARS-CoV-2 will also play a role, albeit to a lesser extent. Widespread serological testing to assess the duration of immunity to SARS-CoV-2 is imperative, but many countries still lack this capability.

A recent study looking at serological data from 3,300 symptomatic and asymptomatic individuals in California estimates that there may be as many as 48,000-81,000 people who have been infected with SARS-Cov-2 in Santa Clara County, which is 50- to 85-fold more cases than we previously thought.11 This small-scale survey emphasizes the importance of serological testing in determining the true extent of infection.

The continuation of rigid social distance also hangs in a balance—one-time social distancing measures may drive the SARS-CoV-2 epidemic peak into the fall and winter months, especially if there is increased wintertime transmissibility.10 New therapeutics, vaccines, or measures such as contact tracing and quarantine—once caseloads have been reduced and testing capacity increased—might reduce the need for rigid social distancing. However, if such measures are not put in place, mathematical models predict that surveillance and recurrent social distancing may be required through 2022.10 Only time will tell.

Helen Stillwell is a research associate in immunobiology at Yale University.

References

1. The COVID Tracking Project https://covidtracking.com/data/us-daily (2020).

2. Virology Blog: About Viruses and Viral Disease. Virus neutralization by antibodies. virology.ws (2009).

3. GreenfieldBoyce, N. Do you get immunity after recovering from a case of coronavirus? NPR (2020).

4. Racaniello, V., Langel, S., Leifer, C., & Barker, B. Immune 29: Immunology of COVID-19. Immune Podcast. microbe.tv (2020).

5. Guo, X., et al. Long-Term persistence of IgG antibodies in SARS-CoV infected healthcare workers. bioRxiv (2020). Retrieved from doi: 10.1101/20202/02/12/20021386

6. Haveri, A., et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020. Euro Surveillance 25, (2020).

7. Zhao, J., et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clinical Infectious Diseases (2020). Retrieved from doi: 10.1093/cid/ciaa344

8. Bao, L., et al. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv (2020). Retrieved from doi: 10.1101/20202.03.13.990226

9. Virology Blog: About Viruses and Viral Disease. Herd immunity. virology.ws (2008).

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

11. Bendavid, E., et al. COVID-19 antibody seroprevalence in Santa Clara County, California. medRxiv (2020). Retrieved from doi: 10.1101/2020.04.14.20062463

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).

We called Greg Carr the other day to talk about the spread of the coronavirus in Africa. Carr, who has been featured in Nautilus, is the founder of the Gorongosa Restoration Project, a partnership with the Mozambique government to revive Gorongosa National Park, that environmental treasure trove at the southern end of the Rift Valley. The 1,500 square-mile park, about the size of Rhode Island, was first given animal refuge status in the 1920s by the Portuguese, and for years was a favorite of European tourists. But in 1983 civil war broke out and the park became a no-man’s land. The place was poached to death, closed up and didn’t reopen until 1992.

Renewal began in 2004 and in 2008 the government signed a restoration agreement with Carr’s foundation. The agreement, which lasts through 2043, envisions a “human rights park” that will restore both ecosystems and economic vitality. After 11 years of rebuilding infrastructure, reintroducing animals, including hippos and wildebeests, and working with local communities, Gorongosa is thriving again. The park now serves as a model for future conservation. Today some 200,000 people live around the park in a “sustainable development zone” that includes education, employment opportunities, and health service. About 700 people have full time jobs in the park; another 300, part time. Naturalist E.O. Wilson calls Gorongosa “a window on eternity.”

“If there’s one thing the rest of the world can learn from Africans, it would be their resilience.”

Carr is a 60-year-old entrepreneur and philanthropist who grew up in Idaho and in his mid twenties co-founded Boston Technology, a voice mail company. By the time he turned 40 he had amassed his fortune and couldn’t see the fun in doing it all over again, and so turned to philanthropy. These days he’s in Idaho Falls, on the phone six hours a day, getting the latest reports from his staff in the park, now closed until further notice.

The coronavirus news from Mozambique is mixed, as it is in much of sub-Saharan Africa. With the exception of South Africa, with over 7,500 confirmed cases of COVID-19 and 148 deaths, some countries below the Equator have fewer than 100 cases. As of May 6, there were just 81 cases in Mozambique and no deaths. If these numbers don’t blow up, the quick explanation might hold that the median age in Sub Saharan Africa is under 20, just 17.6 in Mozambique; population density is low (103 people per square mile); and there’s relatively limited direct contact with heavily infected countries in other parts of the world. 

Still, many experts fear chaos is inevitable. Underlying conditions in Mozambique include implacable poverty and a 60-year history of colonial and civil wars. On another front, in early April, in northern Mozambique, an Isis group shot or beheaded 52 young people because they refused to be recruited. Add a 48 percent literacy rate for women, 60 percent for men. The country also suffers the world’s eighth-highest incidence of HIV; 1.5 million people have contracted the virus and nearly 40,000 people have died. Finally, a large number of Mozambicans go to South Africa for work and then return. Testing is rare in the entire country.

In March, CDC Africa sent out a national directive requiring social distancing. “People are going to pay more attention to that in the cities than they are in rural Mozambique, at least until the virus really comes,” Carr said the other day. “Now, if you live in rural Mozambique, you don’t have the luxury of saying, ‘I’m isolating at home.’ People have to go out every day, to get food and water, from 40 to 60 liters a day, they have to tend to their farms. The idea of social distancing is a bit impossible for these folks.” He added, “Schools are closed and we are making our own masks for people. We all know there’s no treatment per se or certainly vaccine. If this hits, we’ll only be able to offer people Tylenol and soup.”

Cases in Mozambique could shoot up as mine workers continue to return home from their jobs in South Africa. “In my opinion,” said Carr, “Mozambique does not have the capacity to deal with this type of pandemic, as there are few qualified health personnel and the high level of poverty leads people to resist isolating themselves, as they look for alternatives to take care of their families. Our Gorongosa teams are in the field, spreading prevention messages, distributing masks and water purification.” 

Berta Barros, head nurse at Gorongosa, told Carr recently she has three main worries: lack of COVID-19 test kits, lack of healthcare professionals to respond to sick patients, and shortage of medications for treatment. “Mozambique has a population close to 30 million and we only have 34 ventilators,” Barros said. “It’s beyond impossible to work and choose who to save.”

Carr often talks about Mozambique as though he was Mozambican. “We’re very practical people,” he’ll say. “We’re not really theoretical. We’re just going to work our way through this.” He shies away from broad, open-ended questions about Africa, much less cultural comparisons and grand conclusions. “Africa is more than 1 billion people in 54 countries with, what, 2,500 languages? To make a statement like, ‘Africa is this…’ Frankly, I just think a lot of it is complete baloney.”

At the same time, says Carr, “If there’s one thing the rest of the world can learn from Africans, it would be their resilience. We’ve had five years of war in Mozambique and then last year we had a cyclone that killed nearly 1,000 people. I didn’t even mention the two droughts we had in the last seven years and the armyworm that came through and ate everybody’s maize. These people had their homes washed away in a flood last year, lost everything. So they rebuild their homes and then someone says, ‘Hey, there might be a virus coming through.’ It’s just one thing after another.”

What impact might the pandemic have on animals in the park? What effect will it have on just recovered antelope populations, for example, and the inevitable increase in poaching as tourism subsides? How many resources will need to be taken away from the war on other diseases to fight this? Impossible to say. But an anecdote came to Carr’s mind that suggests the vagaries of death in Southern Africa. “I got a call from a dear friend of mine yesterday, a Mozambique good friend, who said her aunt had just died. I said, ‘Wow, do you think it was COVID?’ She goes, ‘No, she’d been suffering for a while with a bad kidney.’ Life is tough in Africa. Do we know for sure this woman didn’t also have COVID and that contributed? Maybe. The truth about Africa is that disaster is hardly news. Malaria is the most prolific killer. And when they turn 50, people die and often no one knows exactly what the cause was. It’s just the way life is.”

Mark MacNamara is an Asheville, North Carolina-based writer. His articles for Nautilus include “We Need to Talk About Peat” and “The Artist of the Unbreakable Code.”

When I worked as a TV reporter covering health and science, I would often be recognized in public places. For the most part, the interactions were brief hellos or compliments. Two periods of time stand out when significant numbers of those who approached me were seeking detailed information: the earliest days of the pandemic that became HIV/AIDS and during the anthrax attacks shortly following 9/11. Clearly people feared for their own safety and felt their usual sources of information were not offering them satisfaction. Citizens’ motivation to seek advice when they feel they aren’t getting it from official sources is a strong indication that risk communication is doing a substandard job. It’s significant that one occurred in the pre-Internet era and one after. We can’t blame a public feeling misinformed solely on the noise of the digital age.

America is now opening up from COVID-19 lockdown with different rules in different places. In many parts of the country, people have been demonstrating, even rioting, for restrictions to be lifted sooner. Others are terrified of loosening the restrictions because they see COVID-19 cases and deaths still rising daily. The officials deciding what to open, and when, seldom offer thoughtful rationales. Clearly, risk communication about COVID-19 is failing with potentially dire consequences.

A big part of maintaining credibility is to admit to uncertainty—something politicians are loath to do.

Peter Sandman is a foremost expert on risk communication. A former professor at Rutgers University, he was a top consultant with the Centers for Disease Control in designing crisis and emergency risk-communication, a field of study that combines public health with psychology. Sandman is known for the formula Risk = Hazard + Outrage. His goal is to create better communication about risk, allowing people to assess hazards and not get caught up in outrage at politicians, public health officials, or the media. Today, Sandman is a risk consultant, teamed with his wife, Jody Lanard, a pediatrician and psychiatrist. Lanard wrote the first draft of the World Health Organization’s Outbreak Communications Guidelines. “Jody and Peter are seen as the umpires to judge the gold standard of risk communications,” said Michael Osterholm of the Center for Infectious Disease Research and Policy at the University of Minnesota. Sandman and Lanard have posted a guide for effective COVID-19 communication on the center’s website.

I reached out to Sandman to expand on their advice. We communicated through email.

Sandman began by saying he understood the protests around the country about the lockdown. “It’s very hard to warn people to abide by social-distancing measures when they’re so outraged that they want to kill somebody and trust absolutely nothing people say,” he told me. “COVID-19 outrage taps into preexisting grievances and ideologies. It’s not just about COVID-19 policies. It’s about freedom, equality, too much or too little government. It’s about the arrogance of egghead experts, left versus right, globalism versus nationalism versus federalism. And it’s endlessly, pointlessly about Donald Trump.”

Since the crisis began, Sandman has isolated three categories of grievance. He spelled them out for me, assuming the voices of the outraged:

• “In parts of the country, the response to COVID-19 was delayed and weak; officials unwisely prioritized ‘allaying panic’ instead of allaying the spread of the virus; lockdown then became necessary, not because it was inevitable but because our leaders had screwed up; and now we’re very worried about coming out of lockdown prematurely or chaotically, mishandling the next phase of the pandemic as badly as we handled the first phase.”

• “In parts of the country, the response to COVID-19 was excessive—as if the big cities on the two coasts were the whole country and flyover America didn’t need or didn’t deserve a separate set of policies. There are countless rural counties with zero confirmed cases. Much of the U.S. public-health profession assumes and even asserts without building an evidence-based case that these places, too, needed to be locked down and now need to reopen carefully, cautiously, slowly, and not until they have lots of testing and contact-tracing capacity. How dare they destroy our economy (too) just because of their mishandled outbreak!”

• “Once again the powers-that-be have done more to protect other people’s health than to protect my health. And once again the powers-that-be have done more to protect other people’s economic welfare than to protect my economic welfare!” (These claims can be made with considerable truth by healthcare workers; essential workers in low-income, high-touch occupations; residents of nursing homes; African-Americans; renters who risk eviction; the retired whose savings are threatened; and others.)

In their article for the Center for Infectious Disease Research and Policy, Sandman and Lanard point out that coping with a pandemic requires a thorough plan of communication. This is particularly important as the crisis is likely to enter a second wave of infection, when it could be more devastating. The plan starts with six core principles: 1) Don’t over-reassure, 2) Proclaim uncertainty, 3) Validate emotions—your audience’s and your own, 4) Give people things to do, 5) Admit and apologize for errors, and 6) Share dilemmas. To achieve the first three core principles, officials must immediately share what they know, even if the information may be incomplete. If officials share good news, they must be careful not to make it too hopeful. Over-reassurance is one of the biggest dangers in crisis communication. Sandman and Lanard suggest officials say things like, “Even though the number of new confirmed cases went down yesterday, I don’t want to put too much faith in one day’s good news.” 

Sandman and Lanard say a big part of maintaining credibility is to admit to uncertainty—something politicians are loath to do. They caution against invoking “science” as a sole reason for action, as science in the midst of a crisis is “incremental, fallible, and still in its infancy.” Expressing empathy, provided it’s genuine, is important, Sandman and Lanard say. It makes the bearer more human and believable. A major tool of empathy is to acknowledge the public’s fear as well as your own. There is good reason to be terrified about this virus and its consequences on society. It’s not something to hide.

Sandman and Lanard say current grievances with politicians, health officials, and the media, about how the crisis has been portrayed, have indeed been contradictory. But that makes them no less valid. Denying the contradictions only amplifies divisions in the public and accelerates the outrage, possibly beyond control. They strongly emphasize one piece of advice. “Before we can share the dilemma of how best to manage any loosening of the lockdown, we must decisively—and apologetically—disabuse the public of the myth that, barring a miracle, the COVID-19 pandemic can possibly be nearing its end in the next few months.”

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.

Show has proven to be a hit for Netflix

While plenty of young drama is played for shock or laughs, the anticipated BBC3 adaptation of Sally Rooney's best-selling book lingers on what goes unsaid between its adolescent lovebirds. And there is lots of humping, says arts columnist Fiona Sturges

Show promises a 'funny and hopeful look at the search for love, sex and connection during this time of social distancing'

Food writer Alison Roman accused Teigen of having people 'run a content farm' for her

(Orchid Classics)
Natalya Romaniw (soprano), Lada Valešová (piano)
The on-the-rise soprano excels in this deeply personal Russian-Czech recital

Born in Swansea of Ukrainian descent, the outstanding young soprano Natalya Romaniw was singing – stunningly – the title role of Puccini’s Madam Butterfly at English National Opera when Covid-19 restrictions forced the abrupt termination of the run. She should also have performed the title role of Dvořák’s water nymph, Rusalka, at Garsington Opera this summer, where she made an impact in Tchaikovsky’s Eugene Onegin in 2016 and Smetana’s The Bartered Bride last summer. Disappointing for her at this turning point of her career, and for her growing number of fans.

Romaniw’s new album, Arion: Voyage of a Slavic Soul – dedicated to the memory of her Ukrainian grandfather, “my great musical inspiration”, explores repertoire by the Russians Tchaikovsky, Rimsky-Korsakov and Rachmaninov, and the Czechs Dvořák, Janáček and Novák. The pianist Lada Valešová captures the varied colours of the piano writing expertly, an equal and supportive partner. These 28 songs, especially the folk-rich examples by Janáček and Novák, suit Romaniw’s generous, big-toned voice, its timbre flecked and speckled with character and emotion. The eight songs by Dvořák grouped as Love Songs, Op 83, melancholy and lyrical, make us even more impatient to hear her Rusalka when the time comes.

Renowned Bollywood actor Rishi Kapoor has died of cancer aged 67.

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AS Roma have announced that their players and coaching staff will forgo four months' salary to ease the financial strain on the club due to the coronavirus pandemic.

Arsenal loanee Henrikh Mkhitaryan wants to remain at AS Roma beyond his current loan spell, according to Giallorossi coach Paulo Fonseca.

AS Roma head coach Paulo Fonseca has reiterated his desire to keep Manchester United defender Chris Smalling at the club beyond the end of his current loan stint.

Arsenal loanee Henrikh Mkhitaryan has pleaded with the club to allow him join AS Roma on a permanent basis.

Move over, Martha Stewart and Gwyneth Paltrow. There's a new feud brewing between two leaders in the lifestyle industry. Best-selling cookbook author Alison Roman has caught the...

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You might have expected a sharper look at the underbelly of the so-called 'golden age' from the creator of American Horror Story, and more recently, The Politician.

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Lady Gaga reveals more details about her delayed new album, "Chromatica," which features collaborations with Ariana Grande, Elton John and Blackpink.

A Romanian man pleaded guilty today before U.S. District Judge Matthew F. Kennelly in Chicago to one count each of wire fraud and conspiracy for his role in moving and hiding the illicit proceeds of an international fraud scheme.

A Bulgarian national pleaded guilty today in U.S. District Court in the District of Columbia for his role in laundering money for a transnational criminal group based in Eastern Europe.

A Romanian man was sentenced today to 48 months in prison for his role in moving and hiding the illicit proceeds of an international fraud scheme.

An ongoing Internet fraud scheme conducted by several networks of organized cyber criminals in Romania and the United States has been disrupted as a result of a series of law enforcement actions coordinated since 2010 between Romanian and U.S. law enforcement, including numerous arrests and searches that took place yesterday in Romania.

Adrian-Tiberiu Oprea, 27, of Constanta, Romania; Iulian Dolan, 27, of Craiova, Romania; Cezar Iulian Butu, 26, of Ploiesti, Romania; and Florin Radu, 23, of Rimnicu Vilcea, Romania, were charged in a four-count indictment filed in the District of New Hampshire with conspiracy to commit computer fraud, wire fraud and access device fraud.

Adrian-Tiberiu Oprea, 28, of Constanta, Romania, was extradited to the United States and appeared in federal court in New Hampshire today, to face federal charges relating to his alleged participation in an international multimillion dollar scheme to remotely hack into and steal payment card data from hundreds of U.S. merchants’ “point of sale” computer systems.

Two Romanian nationals pleaded guilty today to participating in an international, multimillion-dollar scheme to remotely hack into and steal payment card data from hundreds of U.S. merchants’ computers.