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There are three moments in the annual disaster

A pandemic when events may be different. The first time was on January 3, 2020, when Robert Redfield, director of the Centers for Disease Control and Prevention, and George Fu Gao, director of the Chinese Center for Disease Control and Prevention based on US institutions Talk. Redfield has just received a report of an unexplainable respiratory virus in Wuhan.

The possibility of widespread outbreaks such as respiratory diseases has plagued the public health field for a long time.

, So Redfield was worried. Gao Zai assured him that there was no evidence of human-to-human transmission. The theory at the time was that every case was caused by animals in the "wet" market, where exotic games were sold. When Redfield learned that there were several family clusters in the 27 reported cases, he observed that everyone was unlikely to be infected by a civet cat or rac dog in a cage at the same time. He expressed his willingness to send a team from the Centers for Disease Control and Prevention to Wuhan to investigate, but Gao said he has no right to accept such assistance. Redfield made a formal request to the Chinese government and convened more than 20 experts, but received no invitation. A few days later, in another conversation with Redfield, Gao Xiang began to cry and said: "I think we are too late."

Perhaps Gao realized that this virus has spread in China since at least November. Of course, Redfield does not know that the virus already exists in California, Oregon and Washington, and will be in Massachusetts, Wisconsin, Iowa, Connecticut, Michigan, and Rhode within the next two weeks. Island state spread-well before the first official release of the case in the United States was discovered.

Redfield is convinced that if experts from the Centers for Disease Control and Prevention visit China in early January, they will know exactly what the world is facing. The new pathogen is a coronavirus, so it is considered to be only contagious, just like its cousin.

virus. This assumption is wrong. The virus in Wuhan City was originally more contagious and spread mainly through asymptomatics. Redfield told me recently: "The whole idea of ​​diagnosing cases based on symptoms, quarantining them, and tracking their contacts will not work." "You will lose 50% of the cases. Until late February, We just realized this." The first mistake was made, and the second mistake was about to happen.

Matthew Pottinger became nervous. He is one of the few survivors

The White House, perhaps because he is difficult to classify. He is proficient in Mandarin and has worked in China for 7 years, working for Reuters and

. He left the press at the age of thirty-two and joined the Marine Corps. This decision puzzled everyone who knew him. In Afghanistan, he co-authored an influential paper with the Lieutenant General

About improving military intelligence. When Trump appointed Flynn as his national security adviser, Flynn chose Pottinger as the director of Asia. The scandal dismissed Flynn almost overnight, but Bodinger stayed behind to serve the next five heads of national security. In September 2019, Trump appointed him as his deputy national security adviser. In a noisy government, he quietly became one of the most influential people shaping American foreign policy.

in

, Pottinger reported in 2003

outbreak. The Chinese concealed the news, and when the rumors emerged, the authorities minimized the severity of the disease, even though its case fatality rate was about 10%. authorities

He was eventually allowed to go to a hospital in Beijing, but it was reported that the infected patient was loaded into an ambulance or checked into a hotel until the inspector left the country. When,

Spread to Hong Kong, Hanoi, Singapore, Taiwan, Manila, Ulaanbaatar, Toronto and San Francisco. It eventually reached about thirty countries. Thanks to the heroic efforts of public health officials, and

Spread slowly-it was contained within eight months of its appearance.

The National Security Council is committed to global development and provides the president with a response plan. Last winter, Pottinger was shocked by the fact that China rarely mentioned the difference between the new coronavirus and Chinese social media. Someone posted a photo of a sign outside a hospital in Wuhan saying that the emergency room had been closed because the employee was infected. Another report stated that the crematorium was overwhelmed.

On January 14, the NSC held an interagency meeting to discuss the virus. That morning, the WHO relied on China’s assurances to tweeted that there was no evidence of human-to-human transmission. The National Security Council recommended that inspectors take body temperature measurements of all passengers from Wuhan.

The next day, President Trump signed the first phase of the US-China trade agreement and announced: “We will jointly correct the mistakes of the past and create an economically just and safe future for American workers, farmers and families.” He called President of China,

"A very, very good friend."

On January 20, the first case was discovered on the "Voice of America" ​​broadcast in the United States.

The director of the National Institute of Allergy and Infectious Diseases said: "This is a 35-year-old man working in the United States. He has been to Wuhan." Trump denied at the World Economic Forum in Davos, Switzerland. In response to this threat, he said: "This is a person from China. That's fine."

On January 23, 2020, all members of the U.S. Senate held a public debate on the second day of President Trump’s impeachment trial. This is an air freight with the expected results.

The majority leader has stated that he will curb the Democratic Party’s attempts to introduce witnesses or new evidence. He declared: "We have the right to vote."

The trial caused difficulties for the four Democratic senators who are still running for president. Once the procedure is over, on Friday night, the candidates will start participating in the weekend campaign. one of them,

From Minnesota, he recalled: "I was working as a planetarium in a small town at midnight." Then I went back to Washington and listened to the argument that one party would obviously win. McConnell announced in this sleepy theater: "In the morning, all members will hold a briefing on the coronavirus at the age of thirty." This is the first mention.

In Congress.

The briefing was held on January 24 in the hearing room of the Health, Education, Labor and Pensions Committee chaired by Republican Lamar Alexander in Tennessee. Patty Murray is an important member of the Democratic Party. She was a preschool teacher and has been a senator for 27 years. Her father cured five cents until he developed multiple sclerosis and was unable to work. Murray is only 15 years old. The family continues to live. She knows how illness can offend people financially and how the government can help.

A few days ago, she heard of the first confirmed case

In the United States, the man moved from Wuhan to her state, Washington. Murray contacted the local public health officials, and they seemed to be doing well: The man has been hospitalized, and the health officials are looking for some possible contact methods. Suddenly, they were following dozens of people. Murray said to himself, "Wow, this is a little scary. This is in my backyard."

But in the early stages of the epidemic, decisiveness is the most important, and other political figures rarely pay attention. It has been a century since the last pandemic, and it was discovered in the ditch of the pandemic.

To the tropical jungle and Eskimo villages. At that time, scientists hardly knew what a virus was. In the 21st century, infectious diseases seem to be a nuisance rather than a fatal threat. This concern is reflected in the reduction in budgets for institutions that have put the world at the forefront of fighting disease and keeping Americans healthy. The hospital is closed; there is no replenishment of the emergency equipment inventory. The specter of an unknown virus in China made some public health officials sick, but most American policymakers did not put it on the agenda.

During the one-hour briefing, about 20 senators appeared to listen to Anthony Fauci and Robert Redfield's speeches. The health department is reassuring. Redfield said: "We are ready for this."

That day, Pottinger called 42 people, including NSC staff and cabinet-level officials, for a meeting. China just announced

Wuhan, a city with a population of 11 million, may only mean that continuous human-to-human transmission is taking place. Indeed, Pottinger staff reported that Huanggang, another city, was also blocked. The day before, the U.S. State Department stepped up its travel advisory for travelers to Wuhan. The delegates debated how to implement another preventive measure: send all travelers from Wuhan to five U.S. airports, before that You can perform health check entries on them.

The next day, Pottinger attended the Chinese New Year Gala on Capitol Hill. Ancient diplomats, immigrants and Chinese dissidents told stories about the outbreak of the epidemic among relatives and friends. People feel scared. sounds like

again and again.

After Pottinger returned home, he dug up documents from the date of the report, looking for phone numbers from previous sources, including Chinese doctors. Then he called his brother Paul, an infectious disease doctor in Seattle. Paul has been reading about the new virus on Listservs, but he thinks

, It will be "the flash in the pot".

Matt asked if the flight from China was stopped, would the United States have more time to prepare?

Paul hesitated. Like most public health professionals, he believes that travel bans often have unintended consequences. They have stigmatized countries that are struggling to spread. Doctors and medical equipment must be able to move. Moreover, due to time constraints, the disease usually has penetrated the border anyway, rendering the entire movement meaningless. But Matt spoke firmly. Little is known about viruses

Because it spread like wildfire, embers flew from one city to another.

Paul told Matt to do everything in his power to slow down the spread of the virus, so that the United States has the opportunity to establish testing and contact tracking protocols to control the outbreak. Otherwise, the coming year may be catastrophic.

No one realizes how widespread the disease has been. Fauci told the radio interviewer

Americans do not need to be "worried or afraid", but he added that this is "a constantly changing situation."

In October 2019, the first global health and safety index appeared. This is a sober report showing that a world is largely unprepared for a pandemic. Author: "Unfortunately, the political will to accelerate the health and safety plunged into panic and long-term neglect."

. "No country is fully prepared." In terms of preparation, there is another country higher than others: the United States.

During the transition to the Trump administration, the Obama White House handed over

It is called "The Script for Early Response to High-Consequence Emerging Infectious Disease Threats and Biological Events". This is an elaborate guide to the fight against "pandemic pathogens", which contains a catalog of government resources to consult when things start to mess up.

Respiratory viruses are the most dangerous pathogens, including orthopox viruses (such as smallpox), new influenza and coronaviruses. The script pointed out that in the case of a domestic avian flu outbreak, “although countries have major powers and responsibilities in matters related to public health response beyond the declared public health emergency, the American public will seek the US government’s Action." The script outlines the conditions under which various federal agencies should participate. Questions about the severity and infectiousness of the disease should be directed to the Ministry of Health and Human Services, the Federal Emergency Management Agency and the Environmental Protection Agency. How robust is contact tracking? If the case explodes, can clinical care in the area be expanded? There are many such issues, decisions have been made and agencies appointed. The appendix describes entities such as the Pentagon’s military aviation medical evacuation team, which can be assembled to transport patients. The Ministry of Health and Human Services can convene a disaster Mor House action response team, which includes medical examiners, pathologists and dental assistants.

The Trump administration discarded Obama's script. In 2019, HHS conducted the Crimson Contagion exercise, which simulated the government's ability to contain the pandemic. The Pentagon, the National Security Council, hospitals, local and regional health departments, the American Red Cross and twelve state governments attended the meeting. This scenario imagines a group of international tourists coming to China, they are infected with a new type of influenza and spread it to all parts of the world. There is no vaccine; antiviral drugs are ineffective.

The Crimson Contagion Exercise has inspired confidence that the government is prepared to deal with this crisis. Federal agencies cannot tell who is responsible. The states are frustrated in trying to obtain sufficient resources. During the simulation, some cities ignored the CDC’s recommendation to close schools. The report concluded that the government’s policies were inadequate and "frequent conflicts." The public health emergency fund and national strategic reserves have been consumed dangerously; N95 masks and other medical necessities are in short supply, and domestic manufacturing capacity is insufficient. Congress heard a briefing on the results of the investigation, but never made it public. by the time

When it arrived, no meaningful changes had been made to address these shortcomings.

"I only like infectious diseases," John Brooks, the chief medical officer of the ward

The response team of the Centers for Disease Control and Prevention admitted to me. "I know diseases are terrible. They kill people. But something about them caught me."

Every generation fights against disease. In 1939, Brooks' mother, Joan Bertrand Brooks (Joan Bertrand Brooks), contracted polio. Her leg was covered with surgical scars, and her right leg was significantly shorter than her left leg. Brooks recalled: "She often talked about this experience-how to make fun of, insult or openly discriminate against her."

For the gay Brooks, the disease of his generation is

. He grew up near the Dupont Circle community in Washington, D.C., where there were a lot of gay people, and watched the disappearance of people he knew: "Men will get thinner, show disease, and then disappear. It's scary." Science provides no solution. And when Brooks decided to become a doctor, that was what he thought. When he was admitted to Harvard Medical School, he and his mother went to lunch to celebrate. He told me: "After that, we fell into a ten-dollar handheld computer reader. She said that she saw me married a tall Swedish woman and owned a jet plane. I was ringing with three children. Travel the world." "We laughed happily. I should ask for a refund."

In 2015, Brooks became HIV/

Each AIDS researcher is humbled by the various manifestations of the disease. Brooks said: "Every moment is different." "All these opportunistic infections have appeared. What the hell is going on? It's cool." The experience of studying HIV helped him to do a good job of various techniques. Ready,

Will appear.

CDC was established in 1946 and was formerly the Center for Infectious Diseases. Atlanta was chosen as his hometown because the city is located in the center of the so-called "malaria zone." Five years later, the United States declared malaria-free. The CDC’s mission is extended to attack other diseases: typhus, polio, rabies. In 1981, the organization (then renamed the Centers for Disease Control) reported the first known case

, In Los Angeles. Until this year, the CDC has maintained its reputation as the gold standard of public health, operates on top of politics, and has repeatedly demonstrated the value of enlightened government and the necessity of science to promote the development of civilization. In the twentieth century, the life expectancy of Americans increased by thirty years. This was largely due to advances in public health, especially vaccination.

The CDC campus is now like a medium-sized university, with more buildings being built, including high-protection facilities for the world's most dangerous diseases. Experimental animals (mice, ferrets, monkeys) live in cages in a level 4 biosafety room. People move around them like deep-sea divers in diving suits, tied to the airflow system overhead.

The emergency operations center is a spacious and bright room, with rows of wooden tables facing the TV screen wall. This place exudes a sense of urgency and professional calm. On one side of the room, the operator classifies incoming calls. Year 2014,

During the crisis, Brooks received a call from Dallas County Judge Clay Jenkins. Thomas Eric Duncan, a Liberian citizen who went to the city, contracted the disease. Jenkins wanted advice on how to safely get in touch with Duncan's fiancé and his family. On the monitor, Brooks could see the fiance’s apartment building, which was captured by the helicopter’s camera from above. Brooks told Jenkins that as long as his family members are asymptomatic, he can safely enter the apartment: for him, choosing compassion over fear is an important public gesture. Brooks watched the footage of Jenkins escorting his family out of the complex. (Thomas Duncan eventually died; two nurses who cared for him were infected but survived.)

Brooks is working on

Epidemiology researcher Greg Armstrong's response team. Armstrong oversaw the Advanced Molecular Testing Program, which is part of the CDC Center for Emerging and Zoonotic Infectious Diseases. (Zonones, usually like coronaviruses, are caused by animals.) Human invasions into previously wild areas, coupled with climate change forcing animals to leave their traditional habitats, have caused many new diseases in humans, including Ebo Pull virus and Ebola virus.

. First of all,

-CoV-2 (known as the new virus) is a less deadly coronavirus that spreads quickly like the common cold and is sometimes asymptomatic. In fact,

-CoV-2 is more like polio. Most polio infections are asymptomatic or very mild, with fever and headache. But some are fatal. Doctors actually see polio cases about 1 in 200 infections. Stealth transmission is the reason why polio is difficult to eradicate.

When Armstrong noticed an article on the Salt Lake City website, he was training in Salt Lake City

"

. "This article is one of the first to describe the spread of this virus in humans. This development does not surprise Armstrong: "Anyone with epidemiological experience can tell you that this is between people. spread. "Then he noticed the "Patient characteristics" in Table 1, which indicated the original source of infection of the patient. Among the Chinese who contracted the virus before January 1, 26% had not touched the Wuhan wet market or had obvious respiratory tracts. Symptoms. In the following weeks, the number of people without an obvious source of infection exceeded 70%. Armstrong realized that with

Either

-Many infections of other coronavirus diseases-

-CoV-2 may be asymptomatic or mild. Contact tracking, isolation, and isolation may not be enough. These details are buried in Table 1.

Other reports of possible asymptomatic transmission have also begun to emerge. although

-CoV-2 and

with

Viruses are obviously different from viruses in two key aspects: people may be contagious before they develop symptoms, and some infected people will never show the disease. In late February, a University of Texas scientist led by Lauren Ancel Meyers

It may have a "negative sequence interval", which means that some infected people show symptoms

To their people.

The CDC's early guidance documents did not mention this possibility because the evidence of asymptomatic transmission was considered insufficient. Brooks said: "In the beginning, for each mathematical analysis that showed that the interval was shorter than the incubation period, there was no difference in other reports." "When the science changed, we changed. Our recommendations changed." But, to that point. At that time, the Centers for Disease Control and Prevention had been enveloped by the Trump administration.

Brooks told me: "Three things about this virus shocked me." "The first is that it directly infects the endothelial cells in our blood vessels. I don't know of any other human respiratory viruses that can do this. This can cause a lot. Destruction." Endothelial cells usually help protect the body from infection. When

-CoV-2 invades them, and its powerful chemical composition is dumped into the blood, causing inflammation in other parts of the body. The rupture of a single endothelial cell thickens the inner wall of the blood vessel, forming ruptures and rough spots, causing turbulence.

The second surprise is hypercoagulability-the patient has a clear tendency to thrombosis. This reminds Brooks of Michael Crichton’s 1969 novel,

"The pathogen will immediately cause blood clotting and hit the victim in a stride. "This is different," Brooks said. "The things you get are called pulmonary embolism, which is annoying. A blood clot forms-it clots into the lungs, destroys tissues, obstructs blood flow, and creates pressure that can cause heart problems. "It is puzzling that clots sometimes form in the lungs, causing acute respiratory distress. Brooks referred to an early report documenting the autopsy of the victims. Almost everyone had pulmonary thrombosis. Before the autopsy was performed. , No one suspects or even a blood clot, let alone a possible cause of death.

Brooks said: "The last one is this hyperimmune response." Most infectious diseases kill people by triggering an excessive immune system response.

Like pneumonia, it releases white blood cells and fills them with fluid, putting the patient at risk of drowning. but

It can cause physical breakdown in many ways, which is unusual. Some patients require kidney dialysis or suffer liver damage. The disease affects the brain and other parts of the nervous system, causing delusions, strokes and lasting nerve damage.

You can also do strange things to the heart. The hospital began accepting patients with heart attacks-chest pain, difficulty breathing-and preparing for emergency coronary catheterization. "But their coronary blood vessels are clean," Brooks said. "There is no barrier." Instead, the immune response inflames the heart muscle, a disease called myocarditis. "There is nothing you can do, but I hope they can succeed."

One hundred recovery

Patients with an average age of 49 years were found to have 22 cases of persistent heart problems, including myocardial scars.

Even if Brooks thinks

There are no more tricks. Another sequelae confused him: "You overcome the disease, feel better, and bit you again." In adults, this may just be a rash. But some children will develop multiple organ inflammatory syndrome. Brooks said: "They suffer from conjunctivitis, red eyes, abdominal pain, and then continue to experience cardiovascular failure."

When I was six years old, I woke up one morning and couldn't get up: I was paralyzed from the waist. It was in the era of polio. In the early 1950s, there was no cure. I remember the alarm in my mother's eyes. Our family doctor called home. He sat by the bed and took my temperature and pulse. He has no other choice. The horror of polio plagues children and parents everywhere.

I'm very lucky. After about a day, I can move my legs again. I am not sure what caused my short-term paralysis, but the memory is still there. Soon after the polio vaccine invented by Jonas Salk came out, in 1955, I was vaccinated with millions of other children.

Therefore, when I entered Building 40 on the main campus of the National Institutes of Health in Bethesda, Maryland, I became personally interested. Dr. Barney S. Graham, Deputy Director of the Vaccine Research Center, Director of the Viral Etiology Laboratory and Translational Science Core, works on the second floor. He studied how viruses cause diseases and designed vaccines.

The first thing about Graham is that he is a lot: He is six-foot-five, has a gray goatee and simple style. Graham’s boss is

Anthony Fauci told me: "He knows vaccinology better than anyone I know."

The bookshelf in Graham's office contains color 3D printouts of viruses he has worked with (including Ebola, Zika and influenza). I'm studying"

"This is a novel about a deadly pandemic that I published earlier this year. Graham helped me design a fictional virus and then formulate a vaccine for it. In the process of our cooperation, I gradually Learn that researchers like Graham are essentially problem solvers. Last year, he solved one of the most important problems in modern science. He was the first chief architect

Vaccines authorized for emergency use. Manufactured by Moderna and Pfizer, they differ only in the delivery system.

Graham's wall is a map of Kansas where he grew up. His father is a dentist and his mother is a teacher. During his childhood, they lived on a pig farm. Barney and his brother did a lot of farming. He learned a lot about veterinary medicine together with animals. At Rice University, he majored in biology. He received his medical degree from the University of Kansas, where he met his wife, psychiatrist Cynthia Turner-Graham. In 1978, during an infectious disease tour at the medical school, he stayed at the NIH for a while, where he first met Fauci. "When I came back, Cynthia noticed my excitement," Graham recalled. People are willing to fight against each other's ideas. She thought I would come here. "

First, he and Cynthia must complete the residence. They want to go to the same town, which is a problem faced by many professional couples, but because Cynthia is black, their situation is more complicated. She suggested to Nashville: He could apply to Vanderbilt School of Medicine, or to Meharry Medical College, a historic black institution. Tennessee only recently repealed the prohibition against interracial marriage.

On Christmas Eve, Graham drove back to Kansas from Maryland and stopped at Vanderbilt. To his surprise, Thomas Brittingham, the housing project director, was in his office and was willing to meet him immediately. After the interview, Graham told Brittingham: "I know this is the South. I want to marry a black woman. If this makes a difference, I can't come here." Brittingham said, "Close the door." He Welcome Graham on the spot. Cynthia was accepted in Meharry, so they moved to Nashville.

By 1982, Graham had become the chief resident of Nashville General Hospital. That year, he saw a patient infected with five diseases at the same time, including cryptococcal meningitis and herpes simplex. This is a mystery: most infections are isolated incidents. The medical staff was terrified. Graham realized that he was treating Tennessee's first

patient. He said: "We let him live for three weeks."

This ruthless, elusive disease will change millions of lives, and many will end because of it. Immunology, and then a field that was just getting started, was changed by this battle. Graham said: "It took us a few years to learn that HIV is a virus." He began vaccine trials. "It wasn't until the mid-90s that we had a decent treatment. There were some very difficult years. Almost everyone died."

In 2000, the National Institutes of Health (NIH) recruited Graham to create a vaccine evaluation clinic. He insisted on keeping a research laboratory. The laboratory can accommodate 20 scientists, mainly researching vaccines against three respiratory viruses: influenza, coronavirus and a highly infectious virus called respiratory syncytial virus (RSV), which will eventually play a role in the development of influenza viruses Key role

vaccine.

RSV can cause wheezing pneumonia in children, and more children under five years of age than any other disease are sent to the hospital. RSV is the last childhood infectious disease without a vaccine, and it kills as many elderly people as seasonal flu. It is extremely contagious. In order to prevent its spread in the pediatric ward of the hospital, staff must wear gloves, masks and goggles. If any of these items is omitted, RSV will surge. like

, It is dispersed in droplets and contaminated surfaces. In the 1960s, a clinical trial of a potential RSV vaccine sickened children and caused two deaths-a syndrome called vaccine-enhanced disease. Graham spent most of the twenty years trying to solve the mystery of the cause of RSV, but the technology he needed is still under development.

In 2008, he was lucky. Jason McLellan, a postdoc who studies HIV, was squeezed out of the structural biology laboratory upstairs. Despite extraordinary technological advancements and novel design theories, facts have proven that HIV is not harmful to vaccine solutions. McClellan recalled: "I think let's try a virus that is easier to treat." "Barney thinks RSV is very suitable for a structure-based vaccine."

The vaccine trains the immune system to recognize the virus and fight it. Using imaging techniques, structural biologists can understand the outlines of viruses and their proteins, and then copy these structures to make more effective vaccines. McLellan said of his field: "Structurally, we can determine function-like seeing how a car with four wheels and doors implies its function to transport people."

The surface of RSV particles has a protein called F. On top of the protein, a spot called an epitope acts as a landing pad for antibodies, allowing the virus to be neutralized. But when a virus invades a cell, something extraordinary happens. The F protein swells like an erection, burying the epitope and effectively hiding it from the antibody. Somehow, McClellan had to prevent F protein from erecting.

Until recently, one of the main imaging tools used by vaccinologists, the cryo-electron microscope, was not enough to show tiny viral proteins. McClellan said: "The whole field is called speckle theory." As a solution, he has accumulated expertise in X-ray crystallography. In this way, the virus or even the protein on the virus will be crystallized and then hit by the X-ray beam to form a scatter pattern, such as a bullet gun explosion. The structure of a crystalline object can be determined based on the distribution of electrons. McClellan showed me the "atomic interpretation" of the F protein of the RSV virus-the visualization is like a lot of oddities. This requires a leap of imagination, but in that dark world, Graham and McClellan and their team manipulated the F protein, mainly by cloning the F protein and inserting mutations that bound the F protein. McClellan said: "It contains a lot of art."

In 2013, Graham and McLellan published "

,"in

, Showing how they stabilize the F protein so that it can be used as an antigen, which is part of the vaccine that triggers an immune response. The antibody can now attack the F protein and make the virus disappear. Graham and McLellan calculated that their vaccine can be given to pregnant women and provide enough antibodies for the baby to last until the first six months (critical period). This thesis opened a new front in the fight against infectious diseases. In subsequent papers

, The research team announced that it has established a "clinical proof of structure-based vaccine design concept", heralding the "era of precision vaccinology." The RSV vaccine is currently in phase III human trials.

2012,

Coronavirus emerged in Saudi Arabia. Working with it is very dangerous: a third of the infected people die. Ominously, this is the second new type of coronavirus in ten years. Coronavirus has infected humans for eight centuries, but before that

They only cause the common cold. The distant past, cold viruses and

, And human beings resisted over time.

Like RSV, the coronavirus protein stretches as it invades the cell. Graham said: "This looks like a spike, so we call it a spike." The spike is large, elastic and covered in sugar, which makes it difficult to crystallize, so X-ray crystallography is not an option. Fortunately, around 2013, McLellan called it the "resolution revolution" of cryo-electron microscopy, allowing scientists to see microorganisms as small as one-tenth of a meter. In the end, vaccinologists can really see what they are doing.

Graham and McLellan used these high-power lenses to modify

Stabbed in protein to create a vaccine. It works well in mice. They are making a version for humans, but then

Hundreds of people have been killed, it is gradually disappearing, posing a direct threat to mankind, and research funding is gradually decreasing. Graham felt frustrated and realized that this reaction was short-sighted, but he knew his energy was not wasted. About twelve virus families are known to infect humans, and the one developed by Graham’s laboratory can conquer RSV and

It may be transferred to many of them.

What is the best way to deliver modified proteins? Graham knew that Moderna, a biotechnology startup in Cambridge, Massachusetts, had encoded a modified protein on a strip of genetic material called messenger RNA. The company has never put vaccines on the market, but focused on providing treatments for rare diseases, and the profits of these diseases are not enough to arouse Big Pharma's interest. But Moderna's Messenger-RNA platform is powerful.

In mice, Graham has proven that structure-based vaccines can be effective

There is also Nipah, a particularly deadly virus. In 2017, Graham arranged a pandemic prevention demonstration project,

Nipah uses Moderna's Messenger-RNA platform as a prototype for human vaccines. About three years later, when he was about to start human trials on the Nipah vaccine, he heard the news from Wuhan.

Graham called McLellan, who happened to be in Park City, Utah, and he thermoformed his snowboard boots onto his feet. McLellan has become a star in structural biology and was recruited to the University of Texas at Austin, where he can use cryo-electron microscopes. Someone who knows Graham very well is needed to detect the urgency in his voice. He suspects that the SARS cases in China are caused by the new coronavirus, and he is trying to obtain the genome sequence. This is an opportunity to test their concepts in the real world. Are McClellan and his team willing to "return to the game" and help him develop a vaccine?

"Of course," McClellan said.

"We got the sequence on Friday night, January 10," Graham told me. They have been posted online by the Chinese. "We woke up on the eleventh day and started designing proteins."

Nine days later, the coronavirus officially arrived in the United States.

Downloaded at Graham and McLellan

-CoV-2, they designed a modified protein. The key enabler is that they already know how to change the spike proteins of other coronaviruses. On January 13, they handed over the plan to Moderna for manufacturing. Six weeks later, Moderna began shipping vials of vaccine for clinical trials. Graham told me that the development process is "historical." Usually, it takes years or even decades from formulating a vaccine to preparing a product for testing: the process prioritizes safety and cost over speed.

Graham must make several key decisions when designing a vaccine, including where to start encoding the spike protein sequence on the messenger RNA. Making the wrong choice may make the vaccine less effective or worthless. He asked his colleagues for advice. Everyone said that the final decision is up to him-no one has more experience in designing vaccines. He made a choice. Then, after Moderna had started the manufacturing process, the company sent back some preliminary data, which made him worry that he would be a drag on his work.

Graham panicked. Considering his usual composure, his wife Cynthia was shocked. She said: "This is a crisis of confidence I have never seen before." Much depends on the rapid development of a safe and effective vaccine. Graham's laboratory developed rapidly. If his vaccine is effective, it could save millions of lives. If it fails or is delayed, it will be Graham's fault.

After testing the vaccine in animals, it became clear that Graham's design choice was correct. The first human trial started on March 16. A week later, Moderna began to expand production to one million doses per month.

Since 2016,

The Biomedical Advanced Research and Development Bureau has been operated. This department is a department of HHS, responsible for taking medical countermeasures in the event of bioterrorism or a pandemic. According to the whistleblower's complaint, Bright received an email from Mike Bowen, an executive at Prestige Ameritech, Texas, the largest manufacturer of surgical masks in the United States on January 22. Bowen writes that he has 4 "new" N95 production lines not in use. He added: “It will be very difficult and very expensive to reactivate these machines, but it can be achieved under severe circumstances and with the help of the government.” Bowen wrote in another letter: “We are the last large-scale mask in the country. The company... My phone is ringing now, so I don’t need government affairs. I just want to tell you that if things really get worse, I can help you protect our infrastructure. I am a patriot first, Next is the merchant."

Bright is already worried about a possible shortage of personal protective equipment in the national strategic reserve. He also believes that the diagnosis method for the Wuhan virus is not enough. On January 23, at an HHS leadership meeting with Secretary of State Alex Azar, he warned that “the virus may already be here-we just don’t have a test to know.” Many Trumps Government officials seem determined to ignore scientists who share bad news.

On January 25, Bowen wrote to Bright again, stating that his company is "receiving a large number of requests from China and Hong Kong" for masks. This is shocking intelligence. About half of the masks used in the United States come from China. Bowen said that if this supply stops, American hospitals will run out. Bright continued to push for immediate action on the mask, but he found that HHS did not respond. On January 27, Bowen wrote: "I think we are in trouble. The world."

On the same day, Matt Pottinger convened a meeting of cabinet officials and representative agencies at the White House. The participants were divided into four camps. There are public health agencies (Redfield, Fauci, Azar) that are data-driven personnel, and currently they have no data. The other group-Acting White House Chief of Staff,

If drastic measures are taken, economic losses will be caused, and officials from the management, budget office and the Ministry of Transportation are fully focused. The State Council faction is mainly concerned with logistical issues, such as the extradition of Americans from Wuhan. Finally, there is Pottinger, who believes that the virus is not only a medical and economic challenge, but also a national security threat. He now wants to take dramatic action.

For three weeks, the United States has not succeeded in sending medical experts to China. In the absence of precise information, the public health team does not want to make a decision on the quarantine area or travel ban, but the Chinese will not provide it. When Pottinger made a proposal to reduce travel from China, economic advisers mocked it as being too big. Travel prohibits excessive trade-Seriously consider with China that in addition to personal protective equipment, China also produces many important drugs that the United States depends on. It is foreseeable that public health representatives are also resistant: the travel ban has slowed the speed of emergency assistance, and in any case, the virus has found a way to spread. Moreover, at least 14,000 passengers from China arrive in the United States every day: there is no way to isolate all these people. These arguments will be combined with other public health views that were eventually overturned by the pandemic. Countries that implement strict quarantine travel bans, such as Vietnam and New Zealand, keep infectious diseases at a manageable level.

The State Department's withdrawal of Americans, especially diplomats in Wuhan, angered the Chinese. WHO Director-General Tedros Adhanom Ghebreyesus said the United States had overreacted. In order to appease the Chinese, the 747 aircraft sent to collect Americans was filled with 18 tons of PPE, including masks, dresses and gauze. This is a decision that many people regret, especially when inferior substitutes are later sold back to the United States at a huge price.

The morning after the meeting, Bodinger talked with the Chinese doctor who was treating the patient. People are infected and there is no way to know how and where it happened-a stage of infection known as community transmission.

Pottinger asked: "This will

? "

The doctor said: "Don't think 2003-more like 1918." The flu lasted for two years and caused 4 to 100 million deaths.

On January 28, National Security Adviser Robert O'Brien brought Pottinger into the Oval Office, where the President’s Office briefed them daily. According to the participants’ records during the same period, the informant mentioned the virus, but did not list it as a major threat. O'Brien warned the president: "This will be the biggest national security threat you will face." Trump asked if the outbreak resembled

, The briefer’s answer is unclear.

Pottinger stood up and reviewed what he had heard from the source. The most shocking thing was that more than half of the spread of this disease was caused by asymptomatic carriers. However, every day thousands of people fly from China to the United States

"Should we stop traveling?" Trump asked.

"Yes," Pottinger suggested.

Pottinger left the Oval Office and walked into the Situation Room, where the newly formed Coronavirus Task Force was meeting. People are annoyed with him. Fauci said: "It is unusual for asymptomatic people to cause epidemics in respiratory diseases." This is certainly true.

. He still hopes that American scientists will report from China to obtain more data. CDC's Redfield believes that it is too early to take destructive action. He said that there are only a few cases outside of China, while in the United States, the spread of pathogens is not so fast. The public health team united. They suggested: "Let the data guide us."

Pottinger pointed out that the Chinese continue to block such efforts: "We don't have reliable data!"

At the same time, economic advisers are crazy-the travel ban will kill the aviation industry and shut down the global supply chain. Larry Kudlow, the president's chief economic adviser, has been questioning the severity of the situation. He cannot compare the prediction of the end of the world with the stock market. "Is the money stupid?" He wanted to know. "Is everyone asleep? It's hard for me to believe this." (Kudlow doesn't remember making this statement.)

Pottinger realized he needed a backup, so he brought

He is a rude economic adviser who had conducted trade negotiations with China. Many White House officials regard Navarro as a liar, but he is known to be one of the president’s favorites because he advocates tariff wars and other nationalist measures. Navarro warned the organization: "We must seal the border now. This is a black swan incident and you are rolling the dice in a progressive way."

Within minutes, Navarro had an argument with everyone in the room. He pointed out that the new virus is spreading faster than seasonal flu or

. The possible economic costs and loss of life are shocking. Azar argued that the travel ban may cause overreactions. No progress was made at that meeting, but Navarro worked so hard that Mulvaney banned him from participating in future meetings.

Then the data surfaced and the argument changed. In mid-January, a Chicago woman returned from a trip to China. Within a week, she was hospitalized

. On January 30, her husband, who had never been to China, tested positive. Fauci, Redfield and others in the public health department changed their minds: in the United States, human-to-human transmission is clearly happening.

Trump was informed of the news. The timing couldn't be worse for him. His fierce trade war with China came to a halt. Since then, despite signs of cover-ups, he has always praised Xi Jinping's handling of this infectious disease. The travel ban will severely hurt the mouth. However, Trump agreed to announce the news the next day.

This is a bold gesture, but incomplete. The government blocked non-Americans from China, but American citizens, residents and their family members can enter freely. Travelers from the Wuhan area were quarantined for two weeks, but unlike Taiwan, Australia, Hong Kong, and New Zealand, which strictly enforce quarantine, the United States has hardly enforced its regulations, and the leak soon became obvious.

In 1989, Dr. Howard Markel (Howard Markel) was a graduate student at Johns Hopkins University, specializing in pediatrics and medical history. He just lost his wife to cancer, a month after their first anniversary. Markel started volunteering locally

clinic. He found that the work of helping his peers facing the death of their peers or peers was extremely consoling—"This is the most spiritually exciting work I have done in my entire clinical career."

Markle’s patients often ask him: "Doctor, do you think I will be quarantined because of HIV?" He will answer that it is not suitable for this disease. However, he realized that these people were as afraid of being turned away like leprosy patients, so he began to study the "use and abuse of isolation." His first book was about two epidemics that occurred in New York City in 1892. One of them was typhus and the other was cholera. The outbreak of Jewish immigration was the chief culprit, and many Jews were sent to the isolation island.

In the early 2000s, Markel studied "escape" communities that were basically closed during the 1918 influenza pandemic, including Gunnison, Colorado and a school for the blind in Pittsburgh. All survived the infectious disease almost unscathed. In 2006, Markel continued his 1918 influenza research with CDC's Martin Cetron. He is now the Director of the Global Immigration and Quarantine Division of the CDC. The George W. Bush administration asked Cetron and Markel to help determine the best way to manage the early wave of a pandemic without a vaccine or treatment. They considered traditional public health measures such as school closures, public gatherings bans, and business closures. Markel called a dozen researchers-he joked: "The Manhattan Project for Histor (Manhattan Project for Histor)," and he compiled more than one hundred archives.

In 1918, Americans faced the same confused choices as they do today. 25 cities have closed schools once; 14 times have done so twice, and Kansas City twice. More than half of the cities "Shuangfeng"-suffered two waves of flu. "They raised the threshold prematurely because the locals were upset," Markle, now a professor at the University of Michigan, told me. "Each of them acted as their own control group. After the measures were taken, the cases fell. After the measures were lifted, the cases rose." After Philadelphia allowed free loan marches, the number of cases increased sharply. In contrast, St. Louis canceled all parades and local officials broadcast a unified message. The city’s health commissioner published a column to warn citizens of this threat, immediately shut down entertainment venues and ban public gatherings. The death rate in St. Louis is half that of Philadelphia. By quickly implementing several non-pharmacological interventions, a city can greatly reduce the peak of infection—on the chart, it looks more like a rainbow than a skyscraper. Markel compares each intervention with a slice of Swiss cheese; the first layer itself is full of loopholes and cannot function, but the multiple layers have a profound impact. The formula is "early, layered, long".

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In 2007, the author declared: “We have not found any city with a second peak of influenza, and the first set of non-pharmaceutical interventions is still effective.” In the century since 1918, technology has undergone tremendous changes, but containment The tools of the new pandemic have not changed. Before treatment or vaccines, masks, staying away from social places and frequent hand washing are still the only reliable ways to limit infection.

One night, Markel and Cetron were in Atlanta to talk about their studies and ordered Thai food. When their dinner arrived, Markel opened his Styrofoam container: instead of staring at the fluffy noodle pile, he stared at the horizontal gelatinous substance. "Look," Markle said. "As we tried to do, they flattened the curve." A slogan was born.

By January 20, ten days after the Chinese announced their genetic sequence

-CoV-2, CDC created a diagnostic test for this. According to reports, Secretary Azar boasted to Trump that this was "the fastest time we created a test" and promised to prepare more than one million tests within a few weeks. (Azar denies this.) But the FDA did not approve it until February 4. Then everything really fell apart.

The test of fiasco marks the second chance of failure for the United States to control the spread. The CDC has decided to manufacture test kits and distribute them to public health laboratories in accordance with the Emergency Use Authorization of the US Food and Drug Administration. According to Redfield, the CDC published its blueprint for testing and encouraged laboratories to request FDA approval to create their own tests. But Scott Becker, CEO of the Public Health Laboratory Association, told me that the laboratory was not aware of any changes in the agreement. They have been waiting for the CDC to provide the test as before.

At the Coronavirus Task Force meeting, Redfield announced that CDC will send a limited number of test kits to five "outpost cities." Pottinger was stunned: why not send them anywhere? He learned that CDC conducted tests, but did not conduct large-scale tests. To do this, you have to go to companies like Roche or Abbott, which have a wealth of experience and capabilities that can perform millions of tests every month. Pottinger realized that CDC is like a microbrewery, not Anheuser-Busch.

At the time, Azar, a former executive of the pharmaceutical company Eli Lilly and Company, led the coronavirus task force. He agreed with Pottinger's view that the test suite needs to be widely distributed, but nothing has changed. Everyone in the task force understands the severity of the crisis. They attend meetings every weekday and hold conference calls on weekends. North Korea and Iran have not received such concentrated attention. However, the government has never completed the critical task of limiting the epidemic. There is a clear difference between what Hazard said on private occasions or working group meetings and what he said to the president. He asked Redfield and the Centers for Disease Control and Prevention (CDC) to postpone the test and assured Trump that the crisis was under control.

The bottleneck restrictions imposed by the CDC meant that testing was initially limited to symptomatic patients from China or in close contact with an infected person. Even the medical staff who have developed

Symptoms of similar symptoms are difficult to check when treating patients because the CDC has very limited capabilities.

Pottinger often keeps in touch with his brother, Paul, an infectious disease doctor in Seattle.

"Do you have enough test kits?" Matt asked him.

"We don't use any CDC kits," Paul replied. "They came too slowly." They were also not approved to screen asymptomatic patients. On the contrary, Seattle doctors designed a "self-made" diagnostic platform, but their testing capabilities are "far below demand." Paul frantically developed the triage procedure-guessing which cases are

And tried to isolate these patients to prevent them from infecting everyone in the hospital.

But there is a bigger problem.

Microbiologists are keenly aware of the danger of pollution. The viral DNA may stay on the surface for hours or days, thereby contaminating the test material. Scientists at the Centers for Disease Control and Prevention clean the instruments every day. Ou Zhenyi, a Taiwanese microbiologist who retired from the Centers for Disease Control and Prevention in 2014, told me that although he was testing the baby for HIV, he refused to let the janitor enter his laboratory and wipe the floor himself. In some laboratories, the person who left the last night turns on the ultraviolet light to kill DNA that may fall on the floor or laboratory bench. A new pathogen is like an improvised bomb: a wrong decision can be fatal.

Stephen Lindstrom, a microbiologist in Saskatchewan who oversees the development of the CDC test kit, is known for his ability to work under pressure. Scientists at the Centers for Disease Control and Prevention began to work 16 hours a day. The Center for Disease Control and Prevention’s biotechnology core facility is responsible for production for testing such as influenza, HIV and

. In order to save time, Lindstrom required the core facility to simultaneously produce components and templates for coronavirus fragments and use them to generate positive controls for the CDC test. However, as soon as the kit was packaged and mailed, the last-minute quality control program discovered a problem that could cause the test to fail 33% of the time. Decided-maybe Lindstrom or his boss-still have to send the kit. according to

, Lindstrom said to colleagues: "It will either disappoint me or it will disappoint me." (The CDC did not ask Lindstrom to comment.)

Almost immediately, the public health laboratory realized that something was wrong with the kit. The laboratory is required to perform a negative control for the test (for example, using sterile water), and the test always shows false positives.

The CDC detection kit has three sets of primers and probes, all of which are tiny nucleic acid fragments that can find a segment of RNA in the virus and replicate until it reaches a detectable level. There are two targets

-CoV-2, if the virus mutates, one-third will detect any coronavirus. The third component failed. The public health laboratory quickly discovered this. Scott Becker communicated with CDC on their behalf on February 9th, seeking permission to use the test without the third part. "I remained silent on the radio," he told me. Later, he learned that the internal CDC review showed that it had not passed the quality control inspection before sending the test kit. Becker said: "That's intuition."

In 2009, Matt Pottinger made the final deployment of the Marine Corps in Kabul. When he walked through the tunnel connected to the American Embassy, ​​he passed a young woman and then suddenly walked around. Her name is Yan Yang. She is working with the Afghan government to improve HIV testing. Yen recalled: "It's like seven o'clock in the evening." "He came to me and asked me if I knew where the office of XX company was. I thought I was pretty sure that XX office was closed now. Just talking." Matt and Yen got married in 2014.

They lead a very different American life. He grew up in Massachusetts. His parents divorced when he was young, and he mainly lived with his mother and stepfather. His father J. Stanley Pottinger was a lawyer in the Nixon administration. Matt is proficient in languages ​​and majored in Mandarin and Japanese at the University of Massachusetts in Amherst. This is how he came to China as a reporter.

Yen was only six months old when her family left Vietnam in 1979, and her father secretly built the ship in his sugar factory. At sea, the Duong family (68 in total) were shot. A storm almost capsized the ship. The pirates robbed them. Finally, the family arrived at a refugee camp in Indonesia. Six months later, Duongs was sponsored by four American churches on Long Island and eventually lived in Hampton. Yan's mother cleans the house and sews clothes, and then finds a job in a bakery. Her father paints the house and works in construction. In the end, they saved enough money to send the yen to boarding school.

Yen, influenced by science, fell in love with studying viruses. She received a PhD in pharmacology from the University of California, Davis. In 2007, she became a virologist at the CDC, where she developed a global standard test to measure the incidence of HIV. If the family stayed in Vietnam, the ship sank in a storm, the pirates killed them, or they were not taken in by Americans who wanted to help them get a chance, none of this would happen. Allow freedom.

Yen Pottinger, now a senior laboratory consultant at Columbia University, told her husband that she thought something was wrong with the test kit. Yen explained to Matt that once the Chinese publish the genetic sequence of the virus on the Internet, primers will be easy to design. She told him: "This is a very standard task." But

-CoV-2 is an RNA virus that is "sticky" and easily sticks to any surface. Contamination is the only reasonable explanation for the failure of the test suite. Perhaps a trace amount of virus template has entered the primers and probes. She said: "Pollution has killed many great scientists," which is why the primitive laboratory environment is essential.

On February 10, the FDA learned that ten laboratories using CDC test kits had reported failures. The CDC assured the FDA that it can quickly resolve the third part of the problem. The Trump administration, and Azar in particular, insisted on continuing to use the CDC test suite. Although FDA rules generally require that any procedure that grants emergency use authorization must be used exactly as designed, the agency could have allowed public health laboratories to use CDC test kits without a third component, which is their requirement. Even without the test suite, the test suite can work to a large extent, but the FDA said it does not have CDC data to justify the simple solution. CDC wants to stick to its original design. In addition, university scientists, hospital researchers, and commercial laboratories are eager to develop their own tests, but are hindered by the bureaucratic challenge of obtaining emergency use authorization.

On February 12, CDC estimated that it would take a week to re-manufacture the third part. Six days later, Redfield notified Azar that this might continue until mid-March. As of February 21, only seven laboratories in the United States can verify the validity of the test. Redfield admitted that he did not know when the new test kit was ready.

On Saturday, February 22, the FDA sent Dr. Timothy Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health, to CDC to investigate what went wrong with the test. When he arrived, there was no one to receive him and he was turned away. The next day, he was allowed to enter the building, but was forbidden to enter any laboratory. It's still the weekend. Stenzel called. After he was finally allowed to visit the laboratory where the test kit was manufactured, he discovered a problem: In a laboratory, researchers were analyzing patient samples in the same room where the test components were assembled. The test is so sensitive that even if a person walks into the room without putting on a lab coat, they may carry the virus on their clothes, which can confuse the test. according to

, An FDA official called the CDC laboratory "dirty." This is the lowest point in the history of the Pride Institution.

According to an internal FDA account, CDC staff "informed Dr. Stenzel that Dr. Stephen Lindstrom (who supervised another laboratory during the manufacturing process) instructed them to allow the positive and negative control materials to occupy the laboratory The same physical space, even if it violates their written agreement." The clear solution is to transfer part of the test manufacturing to two external contractors. Within a week, tens of thousands of tests are available. But the United States has never made up for the lost February.

I recently asked Redfield, a round-faced man with a white Amish-style beard, how the pollution happened and whether anyone was responsible for the damaged kit. He replied vaguely: "A newer person did not follow the agreement." This could also be a design flaw that ruined the result. He admitted that both of these errors could happen. He said: "When we conducted an internal review, I was unhappy and admitted that the CDC should not mass-produce test kits: "We are not a manufacturing plant. He insisted: "At any time

The test is not applicable to public health laboratories. You just need to send it to CDC", but CDC cannot handle thousands of tests.

CDC is not entirely responsible for delays. The FDA may have authorized the version of the test kit without the problematic part of the third part, and has relaxed its control of tests developed by other laboratories. Until February 26, the FDA did not allow public health laboratories to use CDC test kits without the third component. Only on February 29, other laboratories can continue their own tests.

Secretary Azar held the FDA accountable for the lack of alternative tests. A senior government official told me: "The FDA is no longer flexible, but more regulated. The FDA actually banned illegal

Tested in the United States. FDA Commissioner Stephen Hahn said: "That is incorrect. "He also pointed out that more than 300 tests have been approved. But by the end of February, there was only one other test. Regardless of whether the delay was mainly caused by the CDC or the FDA, Azar supervised both agencies.

Without a test suite, contact tracking is blocked. If contact tracing is not carried out, there will be no obstacles on the road to spread. The United States has never conducted a sufficiently reliable test nationwide once, and the results can be obtained within two days. In contrast,

, Thanks to the universal public insurance and the outbreak from 2015

Providing free, fast testing and investing heavily in contact tracing helps close the chain of infection. The country has recorded about 50,000 cases

. Now, the number of daily reports in the United States is more than four times that number.

The President said to the American people on February 27: “One day, it’s like a miracle and it will disappear.” At that time, there were only 15 known cases.

In the United States, almost all travelers or people close to them are involved.

As Trump made his promise, 175 employees of the biotech company Biogen are returning home from a meeting held at the Boston Marriott Hotel. Many of the participants traveled from other states or foreign countries. They gathered in the banquet hall for two days, shared the crowded elevator, and exercised in the gym. Soon, many people fell ill.

Researchers at Massachusetts General Hospital and the extensive research institutes at MIT and Harvard University believe

-CoV-2 may have been introduced to the meeting by one person. In the end, about a hundred people attended the meeting. The virus strain they infected has abnormal mutations, allowing researchers to track its spread. in

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, Researchers report that in the United States alone, th