A closeup of the Ebola virus, isolated in a patient’s blood sample.
When you consider them individually, viruses don’t seem like much to fear — each a little more than a handful of genes wrapped in a protein coat. While humans carry in their genomes the recipes to produce thousands of proteins, influenza viruses have but eight gene segments encoding no more than a dozen proteins. The dreaded and deadly Ebola? Just seven protein-coding genes in a single segment that together make a measly eight proteins. Even in comparison to single-celled bacteria, viruses are puny by any measure.
Technically speaking, viruses aren’t even alive exactly, existing in a kind of gray area between biological life and biochemistry. They’re parasitic hijackers unable to reproduce on their own. Before they can do anything at all, they must find their way inside the cells of another organism, be it plant, animal, human, or bacteria. Once there, viruses transform those cells — much larger and seemingly more complex than themselves — into factories producing more viruses, which infect more cells and more individuals.
Genetic counselor and science writer Ricki Lewis captured it rather well in a post to her PLOS blog written in the midst of the most recent Ebola outbreak. “The irony of it all is stunning. Genetics and genomics journals overflow with data. Always more exomes, more genomes, meta-analyses of meta-analyses that search for meaning among the nearly limitless combinations of variants of our 20,000 or so genes. And yet a 7-gene ‘infectious particle,’ so streamlined it isn’t even a cell, isn’t even alive, can reduce a human body to a puddle, inner barriers dissolving into nothingness, within days.
“How,” she asked, “does Ebola virus, so much simpler than influenza, than HIV, do it?”
No other viruses in recent memory have stoked our imaginations and fears in quite the way Ebola and Zika have. At the same time, it’s worth considering the power of even the most run-of-the-mill cold and flu bugs. Those viruses take over our bodies regularly, spoiling our best-laid plans with painfully familiar aches, coughs, and sniffles. In most of these everyday instances, our immune systems are adept in fighting back. Recovery comes quickly, and life goes on. But that’s not to say we won’t get sick all over again the next year or even the next month. As for HIV, treatments can now make it possible for infected people to live long and relatively healthy lives, but, despite decades of research, there’s still no vaccine or cure.
So how, then, do viruses in general do it?
A paper co-authored by prominent biochemist and virus expert Joseph DeRisi of the University of California, San Francisco, points to the ease with which viruses evolve and change as the underlying root of “many of the problems they cause.” Viruses might not have many genes, but those that do can often shift at a rapid pace.
Different viruses mutate in different ways. While our own cells work tirelessly to reproduce our genomes as faithfully as possible from one generation to the next, by comparison the enzymes that copy viral genomes seem built to make mistakes, which is how the Ebola virus mutates.
The genomes of other viruses, such as certain types of flu and HIV, tend to leave bits behind or pick up new ones, sometimes from the very organisms they infect. In some cases, when different strains of the same virus or two totally different viruses end up in the same cell, they can swap sequences to produce shuffled mixtures of their former selves.
All of that genetic diversity gives viruses plenty of opportunity to land on combinations with new abilities. As DeRisi and his colleagues explain, viruses’ rapid evolution is the reason we need a new flu vaccine every year. It’s how HIV and other viruses resist our best attempts to treat them. It’s also part of how viruses like HIV and influenza can sometimes jump from animals to humans (or vice versa) to cause new diseases.
The ability of some viruses to morph and change, coupled, in some cases, with the convenience of modern transportation, helps to explain how once obscure viral contagions can suddenly explode into full-blown pandemics, sweeping from one person to the next and across borders, causing dangerous, sometimes deadly disease and, in many cases, an equally contagious fear. Many other features of modern life are also at play: deforestation, a rapidly expanding human population, and just plain old bad luck.
In 2002, it was the SARS-associated coronavirus, which showed up first in Asia. Over the next year, the mysterious and severe respiratory illness would sicken people in more than two dozen countries in North America, South America, Europe, and Asia, causing hundreds of deaths. Then, just as quickly, it has seemed to disappear. Since 2004, there hasn’t been a single case of SARS reported anywhere in the world.
In 2009, we had the “swine flu” pandemic. At the time, experts had geared up for the threat of avian influenza, a virus that primarily infects wild birds and poultry, with occasional spillover into humans. But, unpredictable as viruses often are, what popped up instead was H1N1. Most closely related to a strain of virus described in pigs, the 2009 H1N1 virus consisted of a unique combination of genes that had never been seen before in people or animals. Although the U.S. public health emergency over the new virus was called off in the summer of 2010, the new breed of H1N1 never went away. It’s now considered a “regular human flu virus,” causing seasonal illness in countries around the world.
In 2014, almost 20 years after the publication of Richard Preston’s best-selling, Ebola-inspired book, The Hot Zone, the world watched in horror as the biggest Ebola outbreak in history unfolded in West Africa. (Read on for more about Ebola). And, today, the eyes of the world are on Zika.
The Zika virus isn’t new to humans. It’s an old virus, first described in 1947 in Uganda and previously most common in Southeast Asia, tropical Africa, and the Pacific Islands. It is an arbovirus and primarily transmitted via mosquitoes, but we now know that it can also be spread from a pregnant mother to her fetus and through sexual contact with an infected person. The virus comes with deceptively mild or even nonexistent symptoms. The world is now on high alert over Zika nonetheless, both because of its apparent links to thousands of babies born in Brazil with unusually small heads, a condition known as microcephaly, and because of its incredibly rapid spread through the Americas.
Unique as each of these viral outbreaks and the specific questions they raise may be, the basic approaches to tackling them are, by and large, the same. If scientists are to understand and anticipate where these viruses might go next or how we might ever stop them, they need to know where the viruses came from, how the viral genes they carry adapt and change, and how they (typically) don’t. They need to know the stories that are written in their genomes.
Martha Nelson, now at the National Institutes of Health Fogarty International Center in Bethesda, Maryland, started tracking viruses as a graduate student at Penn State. Her focus initially was on seasonal influenza A, your basic flu. As familiar as seasonal influenza is and was, no one really knew even just a few years ago why it was that the virus tended to resurface as a new epidemic each winter in temperate regions of the world, only to disappear again as the temperatures warmed. Were the viruses lying in wait like seeds until conditions favored them again? Or did they head south for the winter?
To find out, Nelson and her colleagues analyzed the genomes of 900 influenza A samples collected from people in New Zealand, Australia, and New York from 1998 to 2005. The analyses showed that the viruses in New York each winter were most closely related to those circulating in New Zealand and Australia during the colder months of the year in that hemisphere. The analyses suggested that the annual flu season is driven by what researchers describe as widespread viral traffic, as flu viruses crossed the equator each season and later returned.
The discovery highlighted an important role for modern transportation, even in today’s most predictable, seasonal flu epidemics. Nelson’s later work also revealed tremendous changes in seasonal flu strains over time, as distinct human influenza viruses sometimes exchanged genetic material with one another. Those shifts could explain complete, historic failures of flu vaccines in certain years, she and her colleagues found.
Nelson was immersed in the study of the flu, but she says the April 2009 emergence of the H1N1 “swine flu” pandemic still came as a “major wake-up call.” The 2009 virus, a new strain of human H1N1 influenza A, was first detected in Mexico. By the middle of June 2009, it had been reported in 74 countries, with 30,000 confirmed cases. The emergence and rapid spread of the virus revealed the important and underappreciated role of pigs as reservoirs for diverse strains of viral influenza with the potential to cause serious illness in humans. For Nelson, the H1N1 pandemic “exposed major gaps in our knowledge of the global and spatial ecology and evolution of influenza A viruses in swine.” It showed just how much she and other scientists still had to learn.
“To me, it was striking in an age of increased technology, molecular biology, and sequencing that we still had no idea where this pandemic virus came from,” she says. “That’s been my quest since 2009 — to figure out where and how that virus evolved.”
The Zika virus, shown in a transmission electron microscope image.
Nelson notes that the genetic information can only be as good as global surveillance of viruses will allow and, at the time swine flu emerged, there were huge gaps in the data. Those gaps included not only parts of the U.S., Canada, Asia, and Europe, but also whole continents or countries, including Mexico. She began building partnerships with people in agriculture and the swine business specifically, to convince them it was in their best interest to understand the viruses that were making their pigs sick, not just for the health of the public but for the health of their pigs and businesses, too.
By looking at data going back to the 1960s, Nelson has found that the global trade in live pigs strongly predicts the distribution of influenza A viruses in the animals. Generally speaking, Europe and North America have been exporting viruses in infected pigs to countries in Asia. While more pigs live in China than any other country, few of them travel internationally. As a result, China’s pigs don’t make a habit of sickening pigs in other places.
Nelson says this clearer picture of swine influenza can help to predict places where the next pandemic might occur, even if information in that specific location may be lacking. She also found something else unexpected: It’s not so much that pigs are making people sick; it’s the other way around.
“As I dug into the data, it became clear that humans are transmitting far more influenza to pigs than pigs ever transmit to humans,” she says. “We have a huge bias in thinking of animals as sources of disease.”
The value of genomic surveillance has also been demonstrated in the latest epidemic of Ebola, a disease with a fatality rate of 78 percent. In 2014, in the midst of the outbreak, a long list of researchers, including Kristian Andersen of the Scripps Research Institute in La Jolla, California, applied deep sequencing to viral genomes as they searched, almost in real time, for insights into the pathogen’s origin almost. They had a long list of questions: When had the Ebola virus entered the West African population this time around? Was the outbreak being fed by new transmissions of virus from animals to humans? How had the virus evolved over time, both before and just after its leap into human patients?
As the virus was spreading through Guinea, Liberia, and Sierra Leone at an exponential rate, Andersen and his colleagues sequenced 99 Ebola genomes from 78 patients in Sierra Leone, representing more than 70 percent of those diagnosed with the virus in that country from late May to mid-June. To get an accurate picture, the researchers read each of those 99 viral sequences about 2,000 times. As Andersen explains, the genome sequences showed a pattern very different from that he’s seen in Lassa fever, another hemorrhagic fever affecting the people of West Africa.
“Lassa is a result of spillover almost every time you see new patients,” he says.
It’s estimated that 98 percent of the time that a person in West Africa gets sick with Lassa fever, he or she has contracted the illness directly through contact with the urine and droppings of an infected African soft-furred rat. The pattern in the case of the 2014 Ebola epidemic showed something quite different. The researchers saw one spillover infection, meaning one case in which the infection jumped from animal to human. After the first patient became sick, all additional infections were the result of transmission from one person to the next.
Andersen says that those insights offered some immediate health benefits, in the form of clues about where to focus public health efforts to curb the virus. People had been talking about banning bushmeat, which refers to meat hunted in the forest. “There was, at the time, a sense that people got Ebola from bushmeat and that people wouldn’t get Ebola if people didn’t eat bushmeat,” Andersen says.
As a result, not only did some people believe they could protect themselves by avoiding bushmeat, but people without other means to obtain healthy food were being pressured not to hunt. But the data showed, in the 2014 outbreak at least, the Ebola virus wasn’t coming from animals but from other people with Ebola. If the outbreak was to be contained, it was time to stop talking about banning bushmeat and focus instead on breaking the human-to-human transmission chain.
In the middle of an Ebola outbreak, when containment of the virus is everything, Andersen still thinks the most important insight to come from the sequencing work was a very immediate and practical take on what was happening on the ground. In the longer term, those first genome sequences and others they continue to produce are essential for understanding where it might be most useful to target vaccines, drugs, and diagnostics.
“It’s important to get a good picture of where the changes are, how fast they change, and regions that change more or less,” Andersen says.
Sequences of the Ebola virus in 2014 produced a catalog of 395 mutations, including 50 that led to changes in the way particular viral proteins were put together. It still isn’t clear whether some of those changes might explain the severity of the outbreak or the ease of its spread from one person to the next.
“The question is,” says Andersen, “do we have any reason to believe that any of those changes might have anything to do with the size of the outbreak? My answer to that would be a categorical no. Human and ecological factors are fully sufficient and much more likely to explain why it got so big.”
Still, the genomic data was a starting point for more experimentation aimed at better understanding the virus and how it might best be stopped. There was some reassuring news, too. Despite the mutations researchers had uncovered, the sequencing data and careful mapping of the genomic data provided by Jim Kent and his colleagues at the University of California, Santa Cruz, showed that Ebola seemed to have changed little between the first outbreak, in 1976, and the one in 2014. So, a vaccine developed to protect against the much older virus would likely protect against the Ebola circulating in 2014.
Best known for his role in assembling the first human genome, Kent got drawn into working on Ebola after learning about the outbreak early on from his sister, who works at the Centers for Disease Control and Prevention. For him, the confirmation that the Ebola virus genome had been well conserved over the years, together with its eventual containment by people working tirelessly on the ground, came as a huge relief. Despite the virus’s slow evolution, it was crucial to keep Ebola from spreading to large urban areas.
“We were really afraid that if it got loose in Lagos [Nigeria], which it almost did, or any place without good sanitation, it would be devastating,” Kent recalls. “I was afraid it could knock out half the world, honestly.”
Fortunately, it didn’t. While limited cases of Ebola continue to pop up, in March 2016 the World Health Organization has officially ended the world public health emergency.
Everybody really wants the ability not only to reconstruct past and present viruses, but also to “predict the next pandemic, whether it’s a coronavirus or influenza or an arbovirus [like Zika],” Nelson says. “But it’s hard to predict what exactly it’s going to be. We’re continually presented with new diseases — a lot of them coming from animal reservoirs — and there are huge gaps in our understanding of pathogen dynamics.”
Filling those gaps won’t be easy in the case of influenza, when one considers that particular strains of the virus can infect horses, dogs, and seals, in addition to humans, birds, and pigs. For Andersen, the future of Ebola is much easier to foresee, however. At a talk he delivered recently to fellow scientists, he closed by raising a question about the likelihood that an Ebola outbreak would happen again.
“The chance of [another outbreak] I’m going to put at 100 percent,” he said. “We know that Ebola is in the environment. There’s absolutely no chance that we won’t see further cases of Ebola.” When those cases do arise, “we need to detect it faster. We need to be able to know that it’s there and need to be able to do something about it,” he says.
“Early detection,” Andersen adds, “and having the capacity in affected countries is critical. If we can detect it immediately, the outbreak will stop with those first cases.”
As for Zika, scientists are busily studying the virus and its genome in search of clues to explain its sudden explosion and unusual potential to influence the developing brain. While trials of Zika vaccines have begun, it will take much longer to find out if they work. In the meantime, women who are pregnant or who may become pregnant have been advised to take precautions when traveling to a growing list of areas where the virus is being transmitted.