The deadly viruses that vanished without trace

twitter sharefacebook share2020 Oct 01 - 2020-10-01

Scientists are only just starting to unravel why some viruses disappear, while others can linger and cause disease for centuries.

It was the year 1002. The English king Ethelred II – not-so-fondly remembered as “Æthelred the unready” – was at war. For over a century, Viking armies had been scoping out the land as a potential new home, under the command of leaders with well-groomed facial hair and evocative names, such as Swein Forkbeard.

So far, the Vikings had found the English resistance enticingly weak. But Ethelred had decided to make a stand. On 13 November, he ordered for every Danish man in the country to be rounded up and killed. Hundreds perished, and the incident went down in history as the St Brice's Day massacre. Ethelred’s brutal act proved to be in vain, and eventually most of England was ruled by Forkbeard’s son.

But what was a bad day to be a Viking in England was a gift for modern archaeologists. Over a thousand years later, 37 skeletons – thought to belong to some of the executed victims – were discovered on the grounds of St John’s College in Oxford. Buried with them was a secret.

When scientists analysed DNA from the remains earlier this year, they found that one of the men had been doubly unfortunate. Not only was he violently murdered – at the time, he had been suffering from smallpox.

And there was another surprise. This wasn’t the smallpox virus that we’re familiar with from recent history – the kind that was famously driven to extinction in the 1970s by a determined vaccination programme. Instead, it belonged to a remarkably different strain, one which was previously unknown, and silently disappeared centuries ago. It seems that smallpox went extinct twice.

By now the story of how new viral threats emerge should be familiar – the close contact with infected animals, the virus leaping between species, the “patient zero” who catches it first, the super-spreaders who carry it across the globe. But what occurs at the end of a virus’s existence is only just starting to gather interest. Why do some viruses disappear? And what happens to them?

As the threat posed by these tiny, primitive life forms grows ever stronger, scientists are racing to find out.

One of the most recent viruses to vanish was Sars. The world first became aware of its existence on 10 February 2003, after the Beijing office of the World Health Organization (WHO) received an email describing “a strange contagious disease” which had killed 100 people in the space of a week.

The earliest cases occurred in Guangdong, a coastal province in southeast China known for its many restaurants serving exotic meats. At the time, local wet markets bustled with racoons, badgers, palm civets, doves, rabbits, pheasants, deer and snakes, which were often dispatched on the spot, mere metres from where people ate. It was common to find beheaded and disembowelled animals just lying around. Even in the earliest days of the epidemic, it was clear how Sars had emerged.

Fast-forward two years, and the virus had infected at least 8,096 people, 774 of whom died. But it could have been so much worse.

Like its close relative Covid-19, Sars had many of the necessary qualities for world domination – it was an RNA virus, meaning it was able to evolve rapidly, and it was spread through droplets expelled when breathing, which are hard to avoid. At the time, many experts were concerned that the virus could cause devastation on the same level as the HIV crisis, or even the 1918 flu pandemic, which infected a third of the world’s population and killed 50 million.

Instead, Sars disappeared as abruptly as it arrived. By January 2004, there were just a handful of cases – and by the end of month, the last suspected natural infection was announced. Oddly, while “patient zero” describes the first known person to be infected with a virus, there is no equivalent label for the last ever person to catch it in the wild. But this would arguably apply to a 40-year-old man with the family name of “Liu” from the southern city of Guangzhou. (There was another outbreak a couple of months later, when it is thought to have escaped from a Beijing research lab – twice).

So what happened?

In a nutshell, we got lucky. According to Sarah Cobey, an epidemiologist at the University of Chicago, Sars was driven to extinction by a combination of sophisticated contact-tracing and the quirks of the virus itself.

When patients with Sars got sick, they got very sick. The virus had a staggeringly high fatality rate –almost one in five patients died – but this meant that it was relatively easy to identify those who were infected, and quarantine them. There was no extra spread from people without symptoms, and as a bonus, Sars took a relatively long time to incubate before it became contagious, which gave contact-tracers extra time to find anyone who might be infected before they could pass it on.

“But also governments and institutions acted really fast,” says Cobey.

The case of Liu Jianlun, who caught the virus before it had been properly identified, shows just how differently the Sars pandemic could have played out. The 64-year-old specialist in respiratory medicine became infected after treating a patient at the hospital where he worked in Guangdong Province. On 21 February 2003, Jianlun travelled to Hong Kong to attend a wedding, and checked into a room on the ninth floor of the Metropole Hotel. Although he had been suffering a slight fever and mild respiratory symptoms for five days, he was well enough to do some sightseeing with a relative. But the following day his symptoms had worsened, so he walked to a nearby hospital and asked to be put into isolation. By then, he had already unwittingly infected 23 people, including guests from Canada, Singapore and Vietnam, who then carried the virus back to their own countries, where they spawned further outbreaks.

In the end, the WHO estimated that around 4,000 cases could be traced back to Jianlun, who himself succumbed to the virus. Without the global effort to eliminate Sars, and the virus’s built-in features that made this easier, there’s little doubt the pandemic could have spiralled out of control.

Unfortunately this situation is extremely unusual. Other than Sars, only two other viruses have ever been driven to extinction on purpose – smallpox and rinderpest, which affects cattle. “It’s not trivial. It’s really very difficult when you have a virus that’s well adapted,” says Stanley Perlman, a microbiologist at the University of Iowa.

The war against these two viruses was won using vaccines, which are also set to eliminate polio – cases have decreased by 99% since the 1980s – and possibly eventually measles, though recently these efforts have been set back by war, the anti-vaxxer movement and Covid-19.

So, what about the other viruses that have plagued humanity in recent years? Will Ebola disappear? And where did swine flu go?

Unfortunately, some viruses are unlikely to ever go extinct, because we aren’t their only host.

In humans, outbreaks of Ebola end all the time. There have been at least 26 across Africa since the virus was discovered in 1976, and these are just the ones that caused enough cases to be picked up by health authorities. They tend to occur when the virus hops from an animal – usually a bat – to a human, who then infects other humans. As long as there are bats, it may always be with us, regardless of whether there is a single person infected anywhere on the planet.

In the West African country of Guinea, one analysis by Emma Glennon and colleagues at the University of Cambridge found that subtly different types of Ebola are likely to have jumped from an animal to a person roughly 118 separate times, often without anyone noticing. Indeed, the amount of genetic variation between the strains responsible for different outbreaks suggests that these “spillover” events are alarmingly common.

Though the 10th Ebola outbreak to have plagued the Democratic Republic of the Congo was declared officially over on 25 June this year – and there’s no evidence the strain that caused it has lingered on in humans – by then another had already begun. The 11th outbreak is currently confined to the north-west of the country, and is thought to be caused by a brand new type of Ebola, which was acquired from an animal entirely independent of all the others.

Local health authorities and the WHO face several other challenges when it comes to fighting Ebola. A lack of funding has made surveillance of Ebola cases difficult, while the presence of armed groups in the affected areas is making it unsafe for health workers. There is also reluctance among some to seek treatment for Ebola, with people preferring instead to stay in their communities. Of the six species of Ebola, there is only a vaccine for one of them – the type that killed 11,000 people in West Africa between 2013 and 2016.

Even with a Herculean effort to eradicate the virus from human populations, it will still remain circulating in its original host – bats.

This means the only way to drive the virus to extinction is to eliminate it in the wild, which is a near-impossible task.

Similarly Mers, which hit global headlines in 2012 when it first emerged after infecting humans from camels, is thought to have crossed over to people on hundreds of separate occasions since then.

“Sars went away because there's no other obvious host,” says Perlman. Sars is thought to have made the leap to humans via a palm civet, a tree-dwelling jungle mammal that’s considered a delicacy in China. Perlman points out that the virus couldn’t just retreat back to this species, because they aren’t commonly infected – the individual animal that gave it to a human was probably one of very few which were infected, and may have caught it directly from a bat.

The same cannot be said for Covid-19, which again, is thought to have originally belonged to bats, before briefly being passed on to another animal – possibly pangolins – and eventually humans. “With Covid-19, the reservoir is now us,” says Perlman. In fact, it’s become so much of a human virus that scientists have begun to wonder if it will spread the other way around – from humans to wildlife, in a kind of “reverse spillover”, if you will. This would make it even harder to stamp out.

This brings us to another possible scenario, which involves viruses that exist continuously in people. While they may well be with our species forever, it turns out individual lineages of virus vanish remarkably regularly.

Take the flu, of which there are two main types.

Firstly there’s influenza A, which infects many other animals as well as humans – mostly aquatic birds, from ducks and geese to rare Antarctic wildlife, such as the Giant Petrel – but is always with us in one form or another. This kind is responsible for the majority of cases of seasonal flu– and it also causes pandemics.

Then there’s influenza B, which only infects humans and – oddly – seals, and never causes pandemics.

For years, it was thought that the influenza A strains we live with are constantly evolving to be better able to infect us. But the latest scientific research shows that this is not the case.

It turns out that anyone who died before 1893 will never have been infected with any of the influenza A strains that exist today. That’s because every flu virus that existed in humans until about 120 years ago has gone extinct. The strain that caused the 1918 pandemic has also disappeared, as has the one that led to the 1957 avian flu outbreak, which killed up to 116,000 people in the US, and the type of flu that was circulating in 2009, before swine flu emerged.

Established flu strains tend to continue evolving down many different paths – then the vast majority will abruptly go extinct. Every few decades, a new type of flu will evolve to replace them, usually made from a combination of old flu viruses and new ones, fresh from animals.

“It’s really interesting because if you're focused on any particular strain – or more like, any particular genetic sequence that is replicating itself – there is a very, very high extinction rate,” says Cobey. “Strains are dying out every couple years now. It’s complicated, but we are seeing a very high turnover.”

Intriguingly, rather than adapting to humans over time, it seems that H1N1 – the type that caused the 1918 flu pandemic and swine flu, and has now disappeared – had been quietly accumulating mutations which were useless or even actively harmful to its own survival.

Now some scientists are suggesting that speeding this process up might allow us to use the rapid evolution of endemic human viruses to our advantage. The idea has been around for a while as a way to rid ourselves of the flu and colds – but recently it was also suggested as a method of combating Covid-19.

At the heart of the plan is the biology of “RNA viruses” – a group that includes many of humanity’s most intractable pathogens, including HIV, the flu, coronaviruses, and Ebola. Their genetic material is made of RNA as opposed to DNA, which means that when they hijack their host’s machinery to copy themselves, they don’t include a “proofreading” step where they check for mistakes.

This is usually thought of as a bad thing for humans, because these mutations mean that there’s an extraordinary amount of genetic diversity among RNA viruses, allowing them to evolve rapidly – so any vaccines or drugs that target them quickly become obsolete.

“Although we like to think of flu strains as a unitary sequence, in fact, what they represent is a whole swarm of different genetic sequences,” says Lipton. In the short term, this quirk makes it harder to eradicate the flu, because among this “swarm” might be viruses that our immune systems do not recognise and are therefore able to sneak around our bodies unnoticed.

But this staggering rate of mutation is a double-edged sword. Above a certain rate, mutations become harmful, leading to virus strains which are burdened with genetic faults that hinder their spread. Eventually, this can lead to their extinction.

Speeding up viral evolution artificially with drugs that encourage them to mutate at an even higher rate than usual could bring some benefits. First, it might weaken the virus enough to reduce the amount circulating within individual patients. This could make it easier to treat in those with severe illness. There's already some evidence that this can work – clinical trials in the US and Japan have found that the mutation-inducing drug "favipiravir" is effective against the flu strain H1N1. Virologist Elena Govorkova at St Jude Children’s Hospital in Memphis, Tennessee, and her team have shown that the drug appears to make the flu virus less infectious.

Secondly, certain virus strains, like the types of Covid-19 – of which there are already at least six – might amass enough mutations that are harmful to themselves so that they disappear altogether. In India, there’s already evidence that this could be happening naturally. The virus is mutating at a staggering pace, and it’s been suggested that it might be heading for an evolutionary cliff all on its own.

However, regardless of how hard we try, some scientists are sceptical that we will ever be able to say that any virus is gone forever.

“The term extinct is maybe misleading,” says Ian Lipkin, an epidemiologist at Columbia University, New York. “Viruses can be present in many locations – they can lurk in people, they can lurk in materials that are stored in freezers, they can lurk in wildlife and domestic animals – it’s really impossible to say if a virus has gone extinct.” He points out that vials of smallpox still exist in freezers in at least two locations – and there’s an ongoing debate about whether to drive it to extinction more definitively.

Since most vaccination programmes ended in the 1970s, many are concerned that these rare stashes of smallpox might have the potential to spark another major global pandemic. That’s not to mention the latent threat of synthetic viruses – in 2017, a team of Canadian scientists stitched together a horsepox virus, which is a close relative of smallpox and may or may not be extinct. As with many other viruses, no one knows for sure if it has died out, but the scientists were able to recreate it using records of its genetic code and scraps of DNA they ordered over the internet.

Of course, this doesn’t mean our eradication efforts are pointless. In fact, Cobey thinks now more than ever we should be focused on whittling down the pool of human pathogens. “I hope this is a period in which we can reflect on, you know, what sort of illnesses we want to work toward eradicating,” she says. “There are lots of pathogens out there – most people don't appreciate just how many.”

Who knows, perhaps Covid-19 will inspire a new scientific revolution, and the concept of catching several colds or the flu each year will become as alien as having to worry about smallpox.