MERS At One: The Deadly Virus Drizzle

We have the dubious privilege of observing a new disease in the midst of being born. The disease could go on to spread around the world, stall out as a minor, local blight, or disappear altogether. Scientists have been observing its emergence for a year now, and while they know more than they did in 2012, they still can’t predict quite what will happen. Part of their uncertainty stems from the fact that they still don’t know much about its past.

The disease I speak of is Middle Eastern Respiratory Syndrome–MERS for short. Last fall, doctors began recognizing this pneumonia-like disease in people who either lived in or passed through Saudi Arabia. Virologists soon isolated a virus common to them all, which they named MERS-CoV. Now, a year after its discovery, people are still getting infected with MERS, and many of the infected are dying. The World Health Organization reported on Friday that, from September 2012 to date, they’ve been notified of 130 people with laboratory-confirmed MERS-CoV infections, the vast majority of whom are in Saudi Arabia. Out of those 130 people, 58 have died.

Some scientists are scrambling to test out MERS vaccines and anti-viral drugs that can fight the pathogen. Others are acting as the virus’s historians, trying to figure out where it came from. Back in March, I wrote about the preliminary investigations into the origins of MERS. Now, six months later, researchers have looked at some of the viruses from newer cases, using powerful methods for statistically comparing the genes in the viruses. They’ve carried out the biggest genetic study of MERS so far.

The new study, from a team of Saudi and British scientists, appears in the journal The Lancet. (It’s free if you register. Or get it free without registering here.) The researchers isolated genetic material from viruses taken from 21 people sick with MERS. Many of them had become ill during a hospital outbreak in May 2013 in eastern Saudi Arabia. The scientists sequenced the full genome of 13 of the viruses, and got a third or more of the genetic material of the other eight. They compared the viruses to one another, as well as to other viruses that have been found earlier.

The differences between virus genes can tell scientists how the viruses spread to their victims. Each time a virus replicates inside a host, there’s a chance that its genes will mutate. Its descendants will inherit that mutation, and as more mutations stack up, they can create a fingerprint-like identifier for different lineages.

Reading these viral fingerprints isn’t easy, however, in part because viruses mutate fast. It’s possible for the same mutation to arise in two different lineages, or for a second mutation to reverse an earlier one, erasing a virus’s genealogical tracks. Scientists take on this challenge with statistics. Based on what they know about how viruses mutate–which mutations are more common and which less, for example–they can calculate the most likely evolutionary tree to explain the genetic diversity in a group of viruses.

Scientists can then overlay other kinds of information on this tree to probe the virus’s history. They can estimate how long ago the viruses all split from a common ancestor by adding up their mutations and comparing that figure to the rate at which the viruses mutate.

They can also trace the spread by looking at the geography of infection, noting where different lineages of the virus infected people. It’s even possible in some cases to get clues about how an outbreak spreads from person to person by tracking the mutations carried the viruses in each patient. (In January described this new method in this feature for Wiredthis feature for Wired about a deadly bacterial outbreak.)

What’s striking about the new results is the difference between different groups of the MERS viruses. The scientists found that the viruses fell into distinct genetic clusters, suggesting that they’ve been diverging from other clusters for a long time. One virus isolated from a patient from Riyadh on October 23, 2012 was on a separate branch from another virus isolated from another Riyadh patient a week later. That suggests that two virus strains were circulating in the city at that time.

That’s not to say that all of the viruses were distantly related to each other. Some of the viruses in the May 2013 hospital outbreak were very similar, genetically speaking–so similar, in fact, that the scientists could track their spread from one patient to another. Nevertheless, even in the hospital outbreak, some of the viruses were distantly related to the others.

When the scientists looked at all the genetic diversity of the viruses in their study, they concluded that their common ancestor emerged in July 2011, over a year before MERS was identified. There are a couple possible scenarios in which MERS viruses could have evolved this way.

Hypothetically, MERS might have leaped from an animal to a human over two years ago and then spread from one person to another, splitting into genetically distinct branches. The researchers find this unlikely. If that were true, you’d expect that doctors would have encountered a lot more sick people along the virus’s path.

The alternative is that the virus has been jumping again and again from animals. They’ve been circulating in some animal host for the past couple years, splitting into different lineages. Those different lineages have independently infected humans. Once the viruses cross over, people may bring them to cities, such as Riyadh, and from there to other parts of the country. Along the way they sometimes spread the virus to other people–especially in hospitals, where the virus encounters sick people with weakened immune systems.

Back in March, I noted that MERS closely resembles viruses in bats on other continents. Researchers at Columbia University identified short fragments of MERS virus in Saudi bats, but a number of virologists find the results far from conclusive. Even if MERS did get its start in bats (which happened with other human diseases like SARS and Nipah virus), people may not be getting sick from direct contact with them. One possibility scientists are investigating is that camels or other livestock have picked up MERS from bats, and are now passing it on to people.

These results got me wondering. Should we feel comforted by these results, or freaked out, or warily mindful? We might take comfort from the fact that all of the people sick with MERS do not seem to form a single human-to-human chain of infection. Instead, they form many chains, most of which may have few human links. That pattern might mean that MERS is lousy at spreading among people and a poor candidate for a new scourge.

On the other hand, perhaps we should feel a chill up our spines when we consider that MERS is peppering our species boundary, implying that there’s a big supply of the viruses in close contact with us in some unknown species, and one of them may manage to get through and evolve into a fast-spreading human scourge.

Hoping for a little clarity, I got in touch with Andrew Rambaut of the University of Edinburgh, one of the co-authors of the new paper. Rambaut has studied a number of these boundary-crossing viruses, including influenza, SARS, and HIV.

To Rambaut, success for a cross-over virus is largely a matter of luck. “It is down to a virus with the right properties getting into an adequately connected network to allow sustained transmission,” he told me.

HIV, for example, probably infected a lot of people in rural west central Africa over many years without reaching sustained transmission. Only when it happened to get from the bush into the city of Kinshasa in the mid-1900s did it take off. SARS, likewise, exploded once it got into the urban regions of southern China.

The research Rambaut and his colleagues have carried out on MERS shows that the virus is indeed mutating. But even in the hospital outbreaks, they haven’t seen any clear evidence that those mutations are favored by natural selection for spreading among humans. And Rambaut sees little opportunity for MERS to undergo that transformation.

“Natural selection requires time and numbers,” says Rambaut. “It can’t pull a rabbit out of a hat.”

In other words, a virus needs a big population and many generations for natural selection to allow a mutation to rise to dominance. Rambaut estimates that MERS has infected hundreds of people at most. If one virus inside a person gains a mutation that increases its spread among humans, the odds that it will be the one that gets the chance to infect another human is tiny.

For now, in Rambaut’s view, MERS is a virus that relies on chronically ill people to spread. In hospitals, it can find lots of new hosts, and so it can sustain its population. Outside of hospitals, it fares poorly and will be unlikely to do better.

Of course, Rambaut warns that this conclusion is based on what he calls “wildly inadequate information.” This recent article by Helen Branswell provides an excellent survey of what scientists have learned after a year of studying MERS, and it’s a small fraction of what was learned after a year of studying SARS. Basic epidemiology has yet to be carried out on MERS, according to Branswell’s sources, and we don’t even know what animals are hosting the virus yet. The latest study on the history of MERS brings it into sharper focus, but a lot of blurriness remains.