Spanish flu was one of the most serious pandemics humanity has faced over the last century. But there are others, and some have the capacity to be even deadlier.
It arrived with the army of England’s new king. Just days earlier, tens of thousands of men had been fighting for their lives on a marshy field in Bosworth, Leicestershire. There, in the summer of 1485, the bitter rivalry between Henry Tudor and Richard III was finally resolved – with Richard III dying at the Battle of Bosworth Field.
这种疾病随着英格兰新国王的军队一起到来。几天前，成千上万的人在莱斯特郡（Leicestershire）博斯沃思（Bosworth）的沼泽地里奋战。1485年的夏天，亨利·都铎（Henry Tudor）和理查三世（Richard III）之间的激战终于见分晓——理查三世在博斯沃思原野战役（Battle of Bosworth Field）中阵亡。
Freshly styled as Henry VII, the victor led his troops on to London. Little did he know that there they would be about to face a very different kind of mortal peril.
The first sign was a feeling of general apprehension, which soon led to shivers, pains, and headaches. Then the perspiration set in. The victims would be swamped by a torrent of sweat, which led to insatiable thirst and delirium. Finally, they’d feel an overwhelming urge to sleep. If they succumbed, they’d likely end up dead. The fatality rate was up to 50%.
The army had brought with them a strange and unknown disease. Dubbed “The English Sweat”, this alarming malady swept across the city, killing 15,000 people in just six weeks. Eventually the epidemic fizzled out, but not before it had spread to Europe, leaving plenty of mourners in its wake.
亨利七世军队带来的是一种奇怪且未知的疾病。这种令人惊恐被称为“英国汗热病”（The English Sweat） 的瘟疫席卷伦敦，短短6周就导致15000人丧命。虽然瘟疫最终销声匿迹，但在此之前曾蔓延到欧洲，留下大量失去亲人的哀悼者。
And it kept coming back – the disease’s reign of terror continued through the next generation of Tudors, striking four more times over the coming century.
Henry VII’s son, Henry VIII, was petrified. During one particularly devastating outbreak, he slept in a different bed every night, presumably hoping to outmanoeuvre it. Here was a disease that could strike out of nowhere, often leading to death in a matter of hours; one chronicler wrote that you could be “merry at dinner and dedde [sic] at supper”. Even more uneasily, it seemed to have a peculiar affinity for the nobility. It killed many people at court, and nearly cut short the King’s romance with Anne Boleyn.
亨利七世的儿子亨利八世（Henry VIII）被吓坏了。在一次特别毁灭性的爆发中，他每晚睡在不同的床上，大概是想以此躲过瘟疫。这是一种可能在任何地方突然爆发的传染病，通常几个小时内就能致人死亡；一个记录者写道，你可能“晚餐时还很愉快，夜宵时就死了”。更让人不安的是，这种传染病似乎格外青睐贵族，导致宫廷里许多人死亡，还差一点就终止了国王与王后安波琳（Anne Boleyn）的风流韵事。
To this day, no one has any clear idea what caused the mysterious English Sweat. But the leading theory is that this mega-outbreak wasn’t caused by the flu, Ebola, or any of the infamous diseases we often hear about.
Instead, the culprit was a type of hantavirus – a rare family of viruses that typically infect rodents.
Not all pandemics are caused by the obvious suspects. Though the media have us whipped up into a frenzy over a select cast of superstar pathogens, the villain in the next global drama may be lurking in the unlikeliest of places; perhaps it hasn’t even been discovered yet.
“I think the chances that the next pandemic will be caused by a novel virus are quite good,” says Kevin Olival, a disease ecologist from the EcoHealth Alliance, a US-based organisation that studies the links between human and environmental health. “If you look at Sars, which was the first pandemic of the 21st Century, that was a previously unknown virus before it jumped into people and spread round the world. So there’s a precedent there – there are many, many viruses out there in the families that we’re concerned with.”
生态健康联盟（EcoHealth Alliance）的疾病生态学家奥利瓦尔（Kevin Olival）说：“我认为下一次大流行病很可能由一种新型病毒引起，如果你看看非典（Sars，也翻译为沙士），这个21世纪的第一场流行病，在进入人们视野蔓延全球之前，是一种人类从未听说过的病毒。所以是有先例的——这些病毒群里有许许多多另我们担心的病毒。” 生态健康联盟总部位于美国，专研究人类和环境健康之间的联系。
Olival is not alone. Earlier this year, Microsoft co-founder Bill Gates warned that the next pandemic could be something we’ve never seen before. He suggested that we prepare for its emergence as we would for a war.
Meanwhile, the WHO is so firmly convinced that they have updated their list of pathogens most likely to cause a massive, deadly outbreak to include “Disease X” – a mystery microorganism which hasn’t yet entered our radar.
Of course, finding the deadly microbes that are still in hiding, or identifying which of the obscure or exotic pathogens that we already know about may pose a threat, is no mean feat. What can be done to hunt them down? And how can we tell which ones could really take off?
Earlier this year, scientists from Johns Hopkins University published a report which aimed to answer these pressing questions. “Our research really arose because everybody in my field was just coming up with things that they thought were going to cause the next pandemic because they were scary, or because they had caused outbreaks – no one was trying to understand what it was about the pathogens that allowed them to have that potential,” says Amesh Adalja, who led the team. “People just kept taking lists [of potential concerns] that other people had made and adding to them, without any real rigour. Why is influenza at the top of the list? Why did we not think about Zika, before 2016? And why did we not think about West Nile in the United States?”
约翰霍普金斯大学（Johns Hopkins University）的科学家2018年曾发表一份报告，旨在回答上述紧迫的问题。团队负责人阿德加（Amesh Adalja）说：“我们之所以开始这个研究，是因为每个在此领域的科学家都提出他认为会导致下一次大流行病的病原体，或者因为这些病原体很可怕，或是它们已经引发过瘟疫，但没有人试图理解为什么这些病原体会有此可能。大家只是一直在接受他人列出的（潜在威胁）的病原体名单，然后做些添加，但不是很严谨。为什么流感要排在名单的首位？为什么2016年之前我们没有想到寨卡病毒（Zika）？为什么我们以前没有想到过西尼罗河病毒（West Nile）会在美国爆发？”
At the core of the research was the idea that pandemic pathogens are fundamentally weird. Out of millions of viruses on the planet, very few have ever caused a major outbreak. Together with his colleagues, Adalja identified the unusual combination of features that allowed them to do this.
First of all, pandemic pathogens are almost all viruses. This is partly because of their sheer abundance and ubiquity. They are the most numerous biological entities, stalking every ecosystem and invading every type of organism. They can traverse continents and cascade down from the sky in their trillions every day; there are about 800 million viruses on every square metre of the planet.
When you combine their large population sizes with the lightning speed at which they can copy themselves, you end up with a pace of evolution that’s unparalleled in nature. And not only does this mean that they can outsmart our immune systems, but it’s very difficult to develop effective vaccines and anti-viral treatments. While there are several broad-spectrum antibiotics which will kill a wide variety of bacteria, there aren’t yet any equivalent drugs for viruses that actually work.
One group, the RNA viruses – which have genomes made from RNA, rather than DNA – takes these characteristics to the extreme. When these super-pathogens make new copies of their genetic instructions, they don’t include a proofreading step where they check for mistakes, so mutations are common and new variants are constantly being created.
Many of the world’s most notorious pathogens fall into this category, including influenza, HIV, Sars, Mers, Zika, Ebola, polio and rhinovirus (the most prevalent cause of the common cold). But it also includes lesser-known threats, such as Enterovirus 68 – a rare relative of polio with a taste for babies, children and teenagers. It was only discovered in the winter of 1962, when four children were struck down with pneumonia in California.
No one is suggesting that this particular virus is going to suddenly start killing millions of people, but it does satisfy all the criteria – including the final condition that it can infect the respiratory tract. “These viruses are much harder to intervene upon, because breathing is an essential part of life and it’s very hard to stop people from breathing on each other. It’s not the same thing when you’re talking about blood or body fluids,” says Adalja.
After laying low in the US population, largely undetected, for several decades, Enterovirus 68 has recently been on the increase. It was linked to an outbreak of a mysterious, polio-like disorder which sprung up in the Midwest of the US in 2014 and killed four people, including a 10-year old girl. Then earlier this month, many more children in the area fell ill, experiencing a sudden paralysis of one or more limbs. So far at least 12 have tested positive for rare enteroviruses such as strain 68.
According to Adalja, enteroviruses are the sort that we should be keeping an eye on. “This group has probably been grossly underestimated in terms of its pathogenicity,” he says. “There’s no enterovirus vaccine, except for polio. And there are probably enteroviruses that we haven’t discovered yet.”
However, perhaps the most enigmatic viruses of all are those which infect other animals. The ‘zoonotic’ pathogens include all the big names, from HIV to Nipah, having caused nearly every pandemic in human history. Just like the recent avian flu outbreak, the 1918 flu pandemic, which killed between 50 and 100 million people worldwide, began in birds.
Enter the virus hunters – scientists like Olival who travel the globe, looking for the source of the next pandemic. During the first phase of the US government’s disease surveillance program, from 2009-2014, “we found about a thousand new viruses”, he says. What is the undiscovered pool of viruses? “Oh, we estimate that it could be in the millions. There are probably millions of viruses out there that infect other mammals and could potentially infect people.”
With such an intimidatingly large number of missing viruses in the wild, sifting the ones that will stay in other animals from the ones that could become global killers poses a significant problem. But there are some clues. For example, scientists can look out for genes that might allow a virus to latch onto human cells and sneak inside, or uncover which animals tend to carry it, since most people are much more likely to come into contact with, say, chickens than they are eagles.
“I think it’s one of the most exciting scientific issues right now in the field, moving from the genetic sequence of a virus to saying what is its potential infectivity of humans or other animals and what is the potential pathogenicity,” Olival says. “It’s still a bit of a holy grail, moving from the sequence to some sort of definitive answer – and every group of bugs is going to be different, in terms of which markers and genes to look at.”
Back in 2017, Olival and colleagues from the EcoHealth Alliance decided to investigate where the most dangerous undiscovered pathogens are most likely to be hiding. The team examined thousands of viruses known to infect mammals, including 188 which are also known to infect humans.
One not-so-surprising finding was that the next pandemic will probably emerge from bats. No one knows why, but bats are absolutely riddled with nasty viruses. They’re known to be the source of many, many human pandemics, including Sars, which we picked up from cave-dwelling bats in China, as well as Ebola.
Another predictor that emerged is the range of animals they can infect – and here an obscure group of viruses called the ‘bunyaviruses’ rose to the top of the list. They have a wide variety of potential victims, from insects to plants, which means they’re likely to be able to adapt to infect humans, too. Intriguingly, the family of viruses suspected to have caused the medieval sweating disease, the hantaviruses, belong to the bunyavirus group.
“These are viruses that most people have never heard of, but they rank quite highly in terms of their potential for pathogenicity,” says Olival.
Once a potential pathogen has been discovered, perhaps the greatest challenge is getting the authorities to take it seriously. According to Stephen Morse, an epidemiologist at Columbia University, this is even problematic with notorious viruses like Ebola; exotic new bunyaviruses wouldn’t stand a chance.
一旦发现一个潜在的病原体，也许最大的挑战是让政府部门能认真对待。哥伦比亚大学（Columbia University）流行病学家莫尔斯（Stephen Morse）认为，对待像埃博拉病毒这样臭名昭著的病毒甚至都存在这个问题，奇异的新布尼亚病毒就更不用说了。
“I hate to say that it could have been prevented, but the first report of the 2014 Ebola outbreak in West Africa by the WHO said, in the usual bland language, that a rapidly evolving – that should have been a red flag – outbreak of Ebola had occurred, with 43 cases. And that’s a large number,” says Morse. It was months before they mounted a response, by which time it had already made its way into cities.
“I think we are better able to respond to pandemics today than ever, but part of the problem is mobilising the resources and political will to take them seriously,” he says. “I feel the greatest problem is not so much the pathogen – it’s complacency.”
Finally, no list of obscure pandemic threats would be complete without a mention of smallpox. Though the virus has only been extinct in the wild since 1977, the sheer terror of the disease has largely been forgotten.
Here’s a quick reminder: during its 3,000-year dominion, the smallpox virus killed hundreds of millions of people, including several European kings and queens and nearly the entire population of native North Americans. The mummified head of Egyptian pharaoh Ramesses V bears its characteristic pockmarks, as did the Soviet dictator Joseph Stalin, who required that all photographs of his face were edited to disguise them – he would reportedly have the creators of unflattering images shot.
这里有一个快速提示：在天花病毒3000年的肆虐期间，杀死人类数亿人，包括一些欧洲的国王和王后，以及几乎全部北美原住民人口。埃及法老拉美西斯五世（Ramesses V）的木乃伊头上留着痘疤，这是出过天花的特征，苏联独裁者斯大林（Joseph Stalin）也一样，他要求所有他脸部的照片都要进行编辑来掩饰那些痘疤——据报道，他会枪毙那些真实照片的拍摄者。
Smallpox has most of the ingredients you need for a major pandemic: it’s caused by a virus, and though it is unusual in having a genome made from DNA, it belongs to a family that can evolve rapidly and move easily between different animal species. Crucially, the smallpox pathogen is transmitted by breathing in droplets of particles suspended in the air. Though there haven’t been any natural infections since it was eradicated, the virus took its last victim a year after it was declared extinct, when a medical photographer contracted the disease at a lab in Birmingham in 1978. And it could happen again. To this day, smallpox stores exist at labs in Atlanta, Georgia, and in the scientific city of Koltsovo in central Russia.
Back in the 1970s, most people had been vaccinated in childhood. But today state vaccination programs for the virus have been discontinued, and the only people with any immunity are middle aged or older. The United States and many other countries have stockpiles of the vaccine, just in case. Even so, an outbreak of such a contagious disease could easily rip across the globe and kill millions.
Then there’s the risk of bioterrorism. It’s now possible to build viruses from scratch, using nothing more than their genetic sequence for instructions, so you don’t need to be a government scientist to have access to the world’s most lethal pathogen. If it’s ever released, the virus could change the world forever. As Bill Gates put it last year “With nuclear weapons, you’d think you would probably stop after killing 100 million. Smallpox won’t stop. Because the population is naïve, and there are no real preparations. That, if it got out and spread, would be a larger number.”
It may have been centuries since the dreaded sweating sickness of 1485, but we can still learn from the past. The flu is seen as a likely candidate for the next pandemic – not the only candidate. And if the scientists have got it right, failing to take D-list viruses seriously could be a catastrophic mistake.