Zika: Of Virus, Vector, Victim, Drought, Deforestation, the World Cup, the Epigenome & Evolution (updated 2|2|2016)
Among the daily mix of outrageous mayhem and unfathomable disaster of the Evening News, Zika stands out as a nightmare apart: a virus that targets the unborn with catastrophic and irreversible brain damage. Victims can be diagnosed at a glance at birth: their heads are small and brains shrunken, a condition known as microcephaly. Lives are stunted before they begin and families left devastated and heartbroken.
Since 2014, the incidence of microcephaly in Brazil has risen more than 10-fold, from fewer than 200 annually to more than 3,500 suspected cases—and counting. Early lab tests point to Zika, a mosquito-borne virus new to Brazil, though conclusive evidence is still being pieced together. Yet with a risk so dire, the government is taking no chances, cautioning women, particularly those living in the northeast region of the country where there has been a high density of cases, to avoid getting pregnant if at all possible. Colombia, Ecuador, El Salvador and Jamaica have also issued warning as Zika spreads through South and Central America and the Caribbean. In January, 2016, the US Centers for Disease Control (CDC) issued a warning to pregnant travelers—or those considering it—to stay clear of 14 countries in the region (a list that has since nearly doubled to include several countries in Asia and Africa). The warning came too late for an American woman who spent the last year living in Brazil. Her baby, born in Hawaii, was diagnosed with with Zika-linked microcephaly.
Cases of Zika are starting to turn up from Texas to the UK. It is only a matter of time until Zika itself is established along the southern tier of the US. Although the use of screens, air-conditioning, insect repellents, larvicides and pesticides can significantly reduce infection rates, already stretched budgets have to be stretched further to pay for them on an ongoing basis.
As bad as it is, the situation may actually be worse. There is evidence that Zika, unlike other mosquito-borne viruses, can also be transmitted through sex (infected semen) and orally (through saliva). In 2008, two male US scientists, were infected while working in Senegal. Neither showed symptoms until several days after their return home to Colorado. In the interim, it is thought one of the scientists infected his wife through sex. Among other things, this suggests that a travel ban aimed only at women of child-bearing age isn’t enough: Their partners could bring the plague home, an insidious invisible souvenir. (2/5/16: CDC announces news Guidelines for Prevention of Sexual Transmission of Zika Virus.) Also of concern is the possibility that Zika can be transmitted via blood transfusion.
That said, when half the women in a Colombian prison come down with the virus, it is clear that mosquitoes are the primary threat.
Diagnosing Zika is unusually tricky. Viral particles can only be found in blood while the infection is active. Testing for antibodies that develop later is difficult because of cross-reactions with two-related viruses: dengue and yellow fever. Millions of people have either been exposed to former or vaccinated against the latter. Better tests will be developed, but will require both time and money. As many as 1.5 million people have been infected with Zika so far, according to Brazilian health officials, though most won’t show any signs of illness. In fact, they will likely gain a natural immunity—a rare plus in an otherwise grim story.
Although most people infected—an estimated 80%—do not develop symptoms (subclinical), new research on dengue, a related virus, suggests that they can still infect mosquitoes that bite them as long as viral particles are circulating in their blood. In fact, these silent carriers may be more adept at transmitting the virus than patients with full blown cases, possibly due to immune system interactions.
From a viral perspective, a healthier host is a better host. For example, during the first wave of West Nile in the US, crows played a key role in amplifying and spreading the disease. The virus replicated at such an astounding rate in the birds, they died off and were no longer available to be hosts. Robins, on the other hand, for whom the virus is not fatal, are the birds sustaining it: infected mosquito bites robin, virus replicates in robin, another mosquito bites robin, virus replicates in mosquito, and around and around it goes. If the research for dengue proves true for Zika, then primates—primarily humans—are the robins in this outbreak.
Ironically, the very people presenting the greatest threat to controlling the spread of Zika will develop immunity. When enough of a population has immunity, a “herd immunity” kicks in, slowing down the transmission cycle, at least for a while. This has been observed in the spread of dengue, where epidemics tend to peak every three to five years, then recede. Add unprotected populations into the mix—for example, a large influx of tourists—and even a virus lurking in the background at the low ebb of its cycle can spark a new outbreak.
Those that do become ill can suffer through a range of symptoms described as a milder version of dengue. Considering that dengue is also known as “break bone fever” for the severe pain it causes, “mild” is a relative term. The aches, pains, swelling and rash usually clear up within a week, however, so cases can easily fly under the public health radar, especially those in poor areas where people are less likely to see a doctor.
Adding yet another level of complication, the same mosquitoes that carry Zika can also carry several other diseases, including dengue, West Nile, chikungunya and yellow fever. There is also the possibility of co-infection, either from a single bite or from a series of bites from mosquitoes each carrying different viruses. This becomes an even deeper dive down the rabbit hole with prenatal infection, the mechanics of which are poorly understood. Could fetuses exposed to several viruses over a short span of time be at greater risk?
Serial infection is another a possibility. For example, in an adult, a second bout of dengue can be much worse than the first, depending on the variety of the pathogen (there are four serotypes and some subtypes, too). Antibodies primed by the first infection can be co-opted by a second infection caused by a different serotype. The antibodies actually help the virus become more effective, potentially leading to dengue hemorrhagic fever or dengue shock syndrome. Is it possible that a similar dance involving repeated exposures to Zika, or perhaps a combination of viruses, in utero helps the stage for disaster?
Microcephaly could be the extreme on a spectrum of neurological impairments. In an interview broadcast on NPR, University of Michigan fetal medicine physician Marcie Treadwell speculated that “...since many people who get infected with Zika don't get sick at all, there may be a whole host of women who have had the virus while pregnant who have kids who are completely normal, or appear completely normal (but) develop mental issues as (they) get older. We just don't know.”
In adults, Zika has now also been linked to Guillain-Barré syndrome, another example of the body's immune system being co-opted, in this case to attack parts of the peripheral nervous system. An unrelated virus, poliomyletis, also destroys motor neurons—although the pathogenic mechanism is different. Still, might it be possible that a survivor could live long enough to develop a condition similar to Post-Polio Syndrome (PPM), with muscle atrophy and skeletal deformities? In PPM, nerve cells that survived infection begin dying off at an accelerated rate decades later, worn out from doing double-duty to make up for the neurons that were lost. Diseases can have long very shadows indeed.
All in all, a dizzying, horrifying, lifespan-arcing epidemiological tangle.
BRAZIL: EVERYTHING THAT COULD GO WRONG...
Why Brazil and why now? In Uganda, where the virus was first identified nearly 70 years ago in a rhesus monkey chained to tree stand as part of a yellow fever “live bait” monitoring system in the Zika forest, the virus doesn’t appear to be a serious threat to people. There are many possible reasons: Non-human primates may be the mosquitoes’ preferred meal, keeping humans out of harm’s way. Or humans may be exposed as children so that by the time a woman is of child-bearing age, she would have acquired natural immunity. Or it is possible that the strain of the virus—there are at least three—isn’t as severe.
By contrast, humans in the New World have had absolutely no exposure to this virus. Zika, like any successful invasive organism has an outsider’s advantage: no natural predators to keep its spread in check (think smallpox and Native Americans or the emerald ash borer and devastated forests).
The tragedy unfolding in Brazil has actually been centuries in the making, beginning with the introduction of two invasive species of mosquitoes: Aedes aegypti and its cousin, Aedes albopictus. The former, infamous as a carrier of yellow fever, is a native of sub-Saharan African that traveled to Europe through trade routes and was brought to the Americas first by European explorers in the 17th century and then by merchants plying the African slave trade. Albopictus, a.k.a. the Asian Tiger Mosquito, likely first made the trek west during the 1980s, hidden in puddles of water collected tires shipped to Texas—and has also been to stowaway in shipments of that perennial office decor favorite, “lucky” bamboo.
In the wild, both species lay eggs in shallow pools of water, such as those found in tree holes. But buckets, pots, gutters and garbage dumps are more than satisfactory substitutes. As an added bonus, living in close proximity to humans makes it super convenient for breeding females to snag an easy blood meal.
Aegypti was actually eradicated in Brazil during the 1950s, but global trade provided ample opportunity for the mosquitoes to come buzzing right back. Now entrenched, they have evolved to better adapt to their new home:
“... The mosquito has acquired the ability to replicate in increasingly smaller volumes of water, which does not have to be clean anymore. It has developed resistance to some insecticides and shifted eating habits and now attacks at night...”
— Brazilian Society for Tropical Medicine, January, 2016
Deforestation has played a more subtle role: Lose the rainforest and you also lose the rain it transports via “aerial rivers.” These form when water evaporates from a forest, forming clouds that are blown “down stream” by the wind. When the clouds cannot hold any more moisture, it rains, and the cycle repeats. Slash, burn and cut the forest and the aerial river dries up. Brazil’s record drought has many exacerbating factors, including a strong El Niño and climate change, but reckless deforestation almost guarantees that the severe water crisis shriveling up the country won’t be broken any time soon.
In crowded cities such as São Paulo, people who are now desperate for water store it in whatever containers they can find, unwittingly providing yet more places for mosquitoes to breed.
Everything was in place for a perfect viral storm: a virus-naive population, mosquitoes capable of transmitting a terrifying plague and loads of mosquito-friendly habitat. There have been several such storms in the last few years. The first was dengue, followed by chikungunya, another scourge making the global rounds. Yet as dreadful as those diseases are, they pale in comparison to one that takes aim at the future, maiming babies with a kind of lottery-like random abandon. Every mosquito bite throughout the long months of pregnancy triggers a cascade of frightening thoughts of “What if?...”
What if, for example, Brazil hadn’t hosted the World Cup soccer championship two years ago? Millions of fans from dozens of countries traveled to Brazil to cheer on their teams. Some suspect that Zika tagged along for the ride, possibly hidden in the bodies of stowaway mosquitoes; possibly in mosquito eggs (vertical transmission happens in related viruses such as West Nile); and possibly in the bodies of infected humans who then spread it to local mosquitoes.
The babies of women who were in the early stages of pregnancy during the month-long tournament would have been born starting in early 2015. It would take several more months, however, for public health officials to be able to chart a spike in the number of microcephalic babies. It is worth noting that since Zika’s symptoms can be similar to those of dengue and Zika was not yet on the health system’s radar, identifying the date of the index case—the first human case—is at best a guess.
“...Zika virus was probably introduced in Brazil during the World Soccer Cup, in 2014, when many tourists visited the Natal and other Brazilian capitals, possibly contributing to the infection of Aedes (Stegomyia) mosquitoes. Because dengue fever occurred in several cities where the games were played, tourists could also have acquired the viruses, possibly carrying them to their respective homes...” (emphasis added)
—Zika virus in Brazil and the dangers of infestation by Aedes (Stegomyia) mosquitoes, December, 2015
Infected tourists would explain the quick spread of both dengue and Zika across the continent. Now there is concern that next summer’s Olympic games in Rio could spread these diseases across the globe.
Trade, travel, vector, victim—that much of the story is clear. Less clear is how Zika causes microcephaly in a fetus. As a neurotropic disease—meaning it affects the nervous system—it might directly attack nerve cells, which develop at an astonishing rate of 250,000 per minute starting in the first trimester. This is the time also when the basic layout of the nervous system is set, so it may be the virus impedes development another way. Anything that goes wrong at this stage has amplifying implications down the line. If the neural tube fails to close, for example, the forebrain and skull cap won’t form causing anencephaly; or the spine may split causing spina bifida.
Microcephaly has been linked to everything from genetic glitches and maternal malnutrition to exposure to drugs, alcohol and to several viruses, including rubella, toxoplasmosis, chickenpox, cytemegolavirus and now zika.
By what mechanism(s) do these very different causes lead to such catastrophic damage? Toxins and some viruses—including several that cause cancer—have been shown to affect the epigenome, a system of chemical tags that control how individual genes function. If genes don’t send the correct instructions at the right moment and in just the right sequence, a brain will not be properly built.
THE EPIGENOME: WHERE NURTURE BECOMES NATURE
Thirteen years ago, the map of the human genome was published. It was remarkable achievement that took well over a decade at a cost $2.7 billion. Scientists celebrated that finally it would be possible “to read nature's complete genetic blueprint for building a human being.” The genome, however, turned out to be more of a starting point.
Genes, to follow the analogy in the excellent “explainer” video below, are like notes in a musical score. It is the epigenome that determines how those notes are played.
Each cell in our bodies, with the exception of eggs and sperm, have the same identical suite of genes. The epigenome adds the necessary tweaks to differentiate a skin cell from a bone cell from a brain cell—hundreds of cell types in all. This remarkable feat is accomplished through chemical tags called methyl groups that bind to genes, turning off the ones that aren’t needed. In addition, there are proteins called histones, around which long strands of double-helixed DNA wrap, that also affect how genes function.
In 2005, just two years after the Human Genome Project was completed, Washington State University biologist Michael Skinner threw a wrench in the works when his lab discovered that exposure to an agricultural pesticide not only changed the epigenome of mice, but that the changes were passed down through several generations of progeny. The long-discredited theory of acquired characteristics put forth by pioneering French zoologist Jean-Batiste Lamarck more than two centuries ago, seemed to be true at a micro level. The implications were immense: The battle scars of life experienced by your grandparents, great-grandparents or even beyond could be hardwired into your programming, too, courtesy of the epigenome.
The sensitivity of the epigenome provides a real-time flexibility that the genome itself cannot. The downside: toxic exposures such as smoking cigarettes or inhaling massive amounts of smog (see Delhi and Beijing) can impact methylation (the attachment of methyl groups to genes) in ways that lead to disease. Similarly, drinking heavily during pregnancy impedes healthy fetal methylation, potentially leading to fetal alcohol syndrome. On the plus side, mothers who take nutritional supplements during pregnancy can improve the methylation in their babies, making them healthier.
The ability to change how genes function has the potential to revolutionize medicine. Therapeutic epigenetics—a field that didn’t exist just a few years ago—takes aim at everything from cancer to obesity by isolating epigenetic targets. According to some analysts, therapeutic epigenetics could become a $12 billion medical market segment by 2018.
If there is any good to come from the tragedy of Zika, it may be that it helps pull back the curtain a bit on some of the more subtle mechanics of evolution.
If maternal exposure to a virus at a critical juncture in fetal development can lead to microcephaly, could exposure to a “good virus”—one that perhaps slides by unnoticed under radar of the immune system—lead to something advantageous, a change that would make a baby smarter or stronger? What if the acquired improvement could be be passed down through generations? Would the rules of natural selection kick in, favoring the “fitter” babies?
Only a tiny handful of microbes cause disease and for that very reason are the ones that get all the attention. Most of the trillions of microbes in constant swirl around and within us are either harmless or beneficial.
Over the last decade, the study of the microbiome—microbial ecosystems in our guts and on our skin—has completely changed our understanding of health. “...We're not just eating for ourselves. We're eating for the trillions of microbes that inhabit us,” notes writer and food industry critic Michael Pollan. In an astonishing example of the wonders of nature, breast milk turns out to contain a compound specifically formulated to nourish microbes that keep an infant’s delicate colon protected against pathogens. Researchers are now on the hunt to uncover evidence that there are “good viruses” working on our behalf.
Our relationship with viruses has been a long and complicated one. It began with a gene of viral origin called syncitin, without which a human placenta could not implant within a uterus. We literally owe not just our lives, but our species to the virus that provided that gene way back when in our evolutionary history.
Our genomes are riddled with viruses: As much as eight percent of our DNA is viral. Over the eons, several viruses managed to insert themselves directly into egg and sperm cells and have thus traveled through the generations as part of us. Known as HERVs (Human Endogenous RetroViruses), given the right trigger, they can break out and behave like regular viruses, replicating within cells and causing disease. Among other maladies, HERVs may play a role in HIV and ALS. It is certainly possible that at least some are beneficial. What they are all not is “junk DNA” as was once thought.
MEET THE FAMILY: OF HOMINIMS, CHIMPS, BONOBOS, GORILLAS & ORANGUTANS
An individual’s combination of genome and epigenome is not only unique, but also unique to the moment. Even identical twins—natural clones who share a common genome—develop very different epigenomes shaped by diverging life experiences.
At the same time, each genome is also a fossil record of all that came before. If you are of European descent, you are part Neaderthal, with a genome sprinkled with genetic souvenirs of when our two species last walked the Earth together over 40,000 years ago.
More astonishing, perhaps, is that roughly 99% percent of the chimp, bonobo and human genomes are identical. The overlap is 98% with gorillas and 97% for orangutans. Much of what makes each species different are the differences in their epigenomes.
In a paper published in PLOS: Genetics in 2013, a team of researchers from the Institute of Evolutionary Biology in Barcelona compared epigenomes of humans and great apes:
“...Our analysis identified ∼800 genes with significantly altered methylation patterns among the great apes, including ∼170 genes with a methylation pattern unique to human. Some of these are known to be involved in developmental and neurological features, suggesting that epigenetic changes have been frequent during recent human and primate evolution...” (note: emphasis added)
Is it possible that a prenatal exposure, possibly to a virus, might have had something to do with these changes, triggering the process of speciation? It is clear that we share a common ancestor with great apes, but when, why and how exactly did hominims cleave off to develop their own branch of the primate family tree? What gave rise to all the different versions of hominims? And how did sapiens sapiens wind up with a brain so much larger (macrocephaly) than those of everybody else?
The new field of evolutionary comparative genomics sorts through the molecular fossil record for clues. The answer, remarkably and poetically, lies within us, in each and every one of our cells.
There may also be clues about what—or who—could be next. There are very few taxonomic genera with only one species, making modern humans a rare exception. By contrast there are 260 species of monkey, though just two species and several sub-species of gorilla, and two species each of chimpanzees and orangutans. As sapiens sapiens, we are the last of our kind. Unless, of course, something happens and a new species emerges: a “sapier” sapiens.
It is not out the question. For hundreds of thousands of years, Neanderthals and Denisovans dominated. Then our ancestors showed up on the plains of Africa, began migrating and took over. It it always comes down to the survival of the fittest. On a planet with a rapidly changing climate and increasingly polluted air and water, that might not be us for much longer. A few tweaks to the epigenome and enough time and, well, you never know. There just might be a virus involved...
Back to the present and Zika’s unrelenting march toward world domination continues. As the casualties mount, the grim implications have become more apparent. At the very least, economies heavily dependent on tourist dollars will be blighted. At the very worst, the future itself hangs in the balance. When nations advise citizens not to have babies, demographic ripples will be felt far into the future. El Salavador has suggested waiting until 2018, a full two years away. Yet what seems to be an abundance of caution is based more on hope than substance. It will be several years before there is an effective vaccine.
It is a matter of when (soon), not if Zika will arrive in the US and, making a bad situation worse, vast colonies of North American bats that provide natural mosquito abatement by collectively devouring bugs by the billions, have themselves fallen prey to an invasive disease. Whether bat populations reduced by 90% or more should legally be considered merely threatened or altogether endangered has become a matter of bureaucratic politics. In the meantime, the mosquitoes have one less hurdle to hurdle. It is all of a piece.
That leaves massive spraying of insecticides (the toxic residues of which likely have human epigenetic implications) and gene warfare. Transgenic male Aedes aegypti mosquitoes designed to produce offspring that die before maturity have been experimentally released in Brazil with encouraging results. Soon, perhaps, scientists will take aim at the virus using CRISPR/Cas 9, a gene editing tool that has already been used to short circuit the parasite that causes malaria by creating malaria-resistant mosquitoes. A vector-borne pathogen without a vector literally has nowhere to go.
Zika is just the latest in what has been a steady parade of headline-grabbing, incredibly frightening global disease outbreaks over the last decade, from SARS to Ebola to Nipah to dengue to Mad Cow to bird flu. The focus, understandably, is always the victims and heroic efforts of doctors to heal and researchers to find a cure. Once the crisis passes, the spotlight turns to the next global disaster.
Lost in the shadows of shifted attention is an opportunity to connect the dots. These diseases are often referred to as “emerging,” implying that they are in some way new. They are new to us. Almost all of these modern plagues are ancient pathogens that have either escaped infection cycles evolved over millennia and/or have adapted to make the most of new opportunities. Some may not even cause any illness in their traditional hosts, but a new host is a whole new ballgame.
All of these recent outbreaks are in some way human-mediated and often years in the making. Deforestation, pollution, shredded biodiversity, chemically-soaked monoculture food production, an exploding human population, an accelerating rate extinction for everything else, climate change, increased global trade and travel have all played roles.
The bottom line is that there can be no public—or economic—health without environmental health. Although the recent announcement at Davos of a $5 million deal to develop an Ebola vaccine is laudable, money must also be allocated to stop the kinds of rampant deforestation that made last year’s outbreak in West Africa all but inevitable.
Similarly, while the glow of the COP21 agreements to cut carbon pollution has given way to the hard work of making them real, it only one part of a much larger environmental crisis. We need to do better. We need to get this right.
Lives depend on it. Our future depends on it.
• Zika virus in Brazil and the danger of infestation by Aedes (Stegomyia) mosquitoes, Revista da Sociedade Brasileira de Medicina Tropical, December 2015
• Asymptomatic humans transmit dengue virus to mosquitoes, PNAS, October, 2015
• Scott Weaver, Director, Institute for Human Infections and Immunity, University of Texas Medical Branch, on lab’s Zika research, January, 2016 (video)
• The Zika virus foreshadows our dystopian climate future, by Bill McKibben, The Guardian, January, 2016
• Spread of Zika virus a challenge to Latin America abortion bans, by Christina Cauterucci, New Scientist, January, 2016
• Human Epigenome Project (website)
• The Epigenome Roadmap (website)
• Technology helps personalized medicine, enabling epigenomic analysis with a mere 100 cells, Phys.org, July, 2015
• Skinner Laboratory, Washington State University (website)
