Whack-a-Bug: Vectors, Victors and Vanquished in the Age of Zika

MOSQUITO PLANET

Mosquitoes were on Pangaea. The little buzzkills were annoying fellow species 225 million years ago (possibly longer), back in the days when every land-living creature on planet Earth shared a single continent. Think about that. The distinctive whine of a female on the prowl for a blood meal is older than the Himalayas.

They sailed through the End Triassic extinction that killed off an estimated 80% of species 200 million years ago — including many, no doubt, that had been part of their daily diet. They made do with the leftovers. They survived the giant asteroid impact that did in the dinosaurs 65 million years ago, too. Mosquitoes, with more than 3,000 species spread across every conceivable nook and literal cranny across the planet (except for Antarctica unless, of course, it warms up), will likely make it three for three, with better odds of surviving the current Sixth Great Extinction than the hominids which have been whittled down to one species: ours.

There are mosquitoes that can survive freezing, going into a hibernation state called diapause — along with any viruses they may be harboring. Others manage to hang on just this side of life in a dried out state. Eggs can be even tougher than the bugs, waiting months and even years for a little water to set the machinery of life in motion. Since many mosquito viruses can be passed “vertically” infecting eggs, they, too, can remain dormant until conditions are right.

Still, except for mosquitoes that attack in such boggling numbers that their victims risk death by a thousand sips (see “Horrifying Alaskan Mosquito Swarm Engulfs Scientists Who Record ‘God-Awful’ Phenomenon w. video”), they are themselves comparatively harmless. The threat is in the pathogens and parasites inside. Jurassic Park got it wrong: The scariest recipes for prehistoric monsters preserved in the blood-engorged bellies of mosquitoes encased in ancient amber would not have been velociraptors or T. Rex’s, but the pathogens that plagued them. (Fortunately, in real life, DNA in the blood of such entombed bugs long ago disintegrated, saving us from the half-baked dreams of theme park hustlers.)

How did the dinosaurs deal with the hoards of airborne bloodsuckers that must have enveloped them in clouds of irritating buzz? It’s an interesting question the filmmakers conveniently ignored. Could dinosaurs selectively twitch groups of muscles as horses do to keep flies away? Did they ooze some kind of special dinosaur mucous making it harder for bugs to insert feeding tubes? Did they wallow in mud? Or seek out plants full of volatile compounds in an attempt to make themselves less tasty? Whatever they did, the detente between the mighty and the meek lasted for tens of millions of years, until a stray space rock, 10 km wide, slammed into the planet, leaving a 180 km crater in its wake. So great was the heat generated by the impact, new research suggests it “briefly boiled the Earth’s atmosphere.” Nonetheless, mosquitoes managed to survive to bite another day.

It should come as no surprise, then, that a nuclear catastrophe such as Chernobyl would be but a blip in the mosquito story. Post melt-down, researchers focused primarily on how radiation affected people, plants and larger animals living in the zone. A few, including Cornelia Hesse-Honegger, a scientific illustrator from Switzerland, were curious about the impact on insects. Long before the term “citizen science” was coined, she began a personal project to look for “morphologically disturbed” insects (specifically, “true bugs” — Heteroptera — a sub-order that molt as they grow, suck on plant juices and, most important for the study, spend their lives within a confined geographic area). For decades, Hesse-Honegger has visited nuclear sites all over the world, collecting bugs and studying patterns of deformity:

In 1992, I decided to start a systematic study of the effects of nuclear power, traveling to nuclear plants around the world and gathering true bugs living around them. By the end of 2012, I had visited over 25 locations, from Chernobyl to Three Mile Island to Cape de la Hague, and gathered close to 16,500 insects. I painted at least 250 insects or insect parts. What I found was that around nuclear power plants, even ones that hadn’t suffered any accidents, the insects exhibited a consistently higher rate of deformations. I also found that wind direction and frequency of direction change were important predictors of deformation, sometimes more important than distance alone. Today, wind frequency and direction are commonly taken into account when considering environmental impacts.
— Cornelia Hesse-Hornegger,

Although mosquitoes (order: Diptera) were not included in her surveys, clearly they have survived. Like their Heteroptera cousins, some may have ended up with a few extra limbs, uneven wings, missing antennae or altered color schemes. No one really knows. Neither does anyone know what may have happened to the pathogens inside, though they, too, have prevailed.

KILL THE MESSENGER

Viruses are even more ancient than mosquitoes, going back billions of years to origins of life itself. They have easily weathered all five of Earth’s extinction events through a combination of genetic diversity, geographic spread and sheer numbers. There are viruses in, on and infused through everything and everybody. Bacteria have viruses (bacteriophage). Even genomes have viruses. Most viruses are, in fact, benign or irrelevant to our day-to-day lives. Only a comparative handful cause disease.

Given a virus such as Zika, however, whose favorite mammalian host is a primate and whose main mode of human transmission is through mosquitoes equipped with special sense receptors to sniff us out, the most sure-fire way to keep the pathogen at bay is to kill the messenger, Aedes aegypti. These mosquitoes can also carry dengue, chikungunya, yellow fever and West Nile, among other diseases — potentially a medley of viruses in one bite — qualifying for them for a spot at the top of the public health list of vector villains.

It is a numbers game. Even if eradication is futile, reducing mosquito numbers can make a huge difference. A Zika-infected human, even a subclinical case (no symptoms), can generate enough virus to infect mosquitoes for several days. Each infected mosquito, in turn, can potentially spread the disease to several people (sometimes it take multiple “sips” to get enough blood to incubate eggs). At some point, when enough people develop natural immunity, a “herd immunity” kicks in, slowing down transmission and reducing the number of new cases. But that’s a long way off, especially as Zika is poised to spread into Brazil’s sprawling mega-cities. The quickest way to short out the transmission cycle, then, is to whack the bugs before they bite.

With Zika’s association to microcephaly in infants and Guillain-Barré paralysis in adults, it is all hands on deck to stomp out Aedes mosquitoes. Researchers are testing to see whether Culex mosquitoes, common throughout North America, can also effectively vector Zika. If so, the challenge becomes immeasurably more difficult, but one battle at a time…

GENE WARFARE

There are a number of ways to muck around with a bug’s genes:

  • Radiation: “It’s family planning for insects,” says Jorge Hendrichs of the International Atomic Energy Association. Zap male mosquitoes with X and/or Gamma rays to make them sterile, then plant vast numbers of them in affected areas. Irradiated males must outnumber the locals by a factor 10, or even 20 to 1, to ensure the odds that females will mate with them. Sterile Insect Technology (SIT) has been around for quite a while, with a long history for battling agricultural pests. While effective — field tests have shown reduction in mosquito populations of 80% and higher — it takes millions of lab-raised mosquitoes to make a dent, so may not be a popular approach in a large city such as Rio. Also, as mosquito populations increase, new batches of zapped insects would be required.
  • Traditional GMO: Slightly sneakier is British biotech Oxitec’s approach (recently acquired by US-based Intrexon for $160 million), which tweaks a gene in lab-raised male mosquitoes so that offspring die before they’re old enough to mate. Like radiation, local mosquito populations have been cut by more than 80% in the field, but whether the approach is feasible within the crowded confines of sprawling cities remains a question. Also, repeated introductions of modified bugs is required to keep the numbers down. It would take billions, if not trillions, of Oxitec mosquitoes to protect a country the size of Brazil at a cost that could quickly ramp up to hundreds of millions of dollars.
“…Oxitec has not said how much the mosquitoes cost, but officials in Piracicaba said they expected to eventually pay about 30 Brazilian reals, or $7.50 a year, per person protected. The bill for the city of 390,000 would come to about $2.7 million a year. That is approximately what the health department currently spends on sprays, larvicides, and costs like sick leave….”
Inside the Mosquito Factory That Could Stop Dengue and Zika, Technology Review
  • Gene Drives: CRISPR/Cas9 literally cuts to the chase, making it possible to introduce an altered gene that could spread throughout an entire mosquito population within a few generations. It bypasses natural selection by making sure that both paternal and maternal copies of a gene are identical. MIT researcher Kevin Esvelt calls it “sculpting evolution.” It is conceivable that if a “kill switch” gene were inserted, an entire species could be annihilated. One possibility being discussed involves the aptly named “Nix” gene that would turn female embryos into males. Even for a species as troublesome as Aedes aegypti, engineering its extinction is a heavy responsibility. Perhaps more worrisome is the potential for the technique to be used as a bioterror weapon.
  • RNAi Sprays: Although low on the radar of those on the frontlines of the Great Mosquito War and rarely mentioned by the media, RNA interference (RNAi), like CRISPR, is a technique that can target specific genes with great precision. Its discovery was important enough to merit a Nobel prize in 2006.
“…The mechanism is a natural one: it appears to have evolved as a defense system against viruses. It is triggered when a cell encounters double-stranded RNA, or two strands zipped together — the kind viruses create as they try to copy their genetic material. To defend itself, the cell chops the double-stranded RNA molecule into bits and uses the pieces to seek out and destroy any matching RNA messages….”
— The Next Great GMO Debate (RNAi), Technology Review

Its application in a spray is essentially a biomimicked hack. Monsanto, Bayer and Syngenta (the latter soon to be acquired by China National Chemical Corporation in a $43 billion deal), have all been working on RNAi bio-pesticides that would either coat or be soaked up by plants to defend themselves against insects. Synthesizing RNA has become so cheap, such an approach is now feasible, although it will likely be another decade before there are any products on the market. In the meantime, the USDA, working with Monsanto, is experimenting with an RNAi spray to kill the insect behind the spread of a devastating citrus disease leveling orange and grapefruit orchards in Florida at an alarming rate. So far, no one has brought up the potential to weaponize the technology, but like CRISPR, the risk is there.

THE ENEMY OF MY ENEMY…

  • Fish: Mosquito larva-gobbling sambo fish tossed into water storage barrels and tanks have been used in small scale efforts to keep mosquito populations in check. It’s a cheap, easy, direct and effective fix, reducing the transmission of a variety of diseases. Whether it can be scaled remains a question, along with general issues of water filtration.
  • Bacteria: First identified over 90 years ago, Wolbachia is a bacterium that specializes in infecting insects, including some mosquito species. Typically, it doesn’t kill the insects, but at least in the case of Aedes aegypti, it impedes their ability to pass along pathogens dangerous to humans: It makes them just sick enough not to make us sick. It can spread though a population quickly: When infected males mate with healthy females, her eggs won’t hatch. When infected females mate with healthy males, the offspring are born infected. When infected males and females mate, their offspring are infected, too. The infection is self-sustaining so while the annoyance of biting mosquitoes would remain, the disease threat would be quashed. If a field test of a distributed deployment in city of 170,000 in Queensland, Australia, proves effective, then Wolbachia will rank among the cheapest, easiest ways to keep Aedes aegypti in check.
  • Virus: For the last dozen years, a handful of researchers scattered around the world have been studying Mosquito Densoviruses (MDV) that naturally target mosquitoes. There is a densovirus for Aedes aegypti, another for Aedes albopictus and both can also infect Culex mosquitoes. They show promise as a larvicide and shorten the lives of those bugs that manage to hatch: They die before they can transmit human pathogens. Although most of the work has been in the lab, there is promise, along with a certain satisfying poetic justice, in vanquishing the threat of a virus with another virus.

CHEMICAL ATTACK

Chemical pesticides and larvicides have by far been the most popular go-to solution in response to Zika. News accounts are filled with images of men cocooned in moon-suits, breathing through respirators while fogging the heck out of homes and streets in neighborhoods afflicted by the virus. Almost invariably they are surrounded by residents not sealed in moon-suits and not wearing respirators, including pregnant women and children.

Pesticide manufacturers are legally bound to put warnings on their products: “safe if used as directed.” But are they being used as directed? What happens if a toddler crawls around a room shortly after its been sprayed and little hand goes into little mouth? How much exposure is safe for a pregnant mother? Is there any risk to her slathering on repellent several times each day for months on end? It is worth noting that the discovery that epigenetic changes — alterations to the molecular groups that regulate genes — can, in some cases, be inherited emerged from an experiment involving pesticide exposure. Are governments keeping tabs of what’s been sprayed where and how often?

VENN DIAGRAM OF DISASTERS

Some have questioned whether Brazil’s rampant use of pesticides may be driving the spike in microcephaly cases. It is possible there may be overlapping tragedies in play: chemical poisoning and the spread of a series of mosquito-borne diseases in recent years (dengue, chikungunya and now Zika). The picture should become clearer in the coming months with the birth more than 5,000 babies in Colombia whose mothers who were diagnosed with Zika during pregnancy. If there is not a similar increase in the incidence of microcephaly, then there is more to the story in Brazil.

At best, pesticides kill about half the mosquitoes targeted. The rest stay safe tucked into nooks and crannies, or having developed resistance, buzz on impervious to the poisons swirling around them. Larvicides work, but when a single mosquito can lay as many as 100 eggs in a capful of water and every plastic bottle and puddle has the potential to serve as a nursery, there is a limit to what can be done.

Still, spraying seems better than doing nothing. Fifty percent fewer mosquitoes is a move in the right direction. For decades, pesticides and larvicides, along with screens and air-conditioning, have kept us well-protected against mosquito-borne plagues here in the US. Less than a century ago in 1922, there was an outbreak with tens of thousands of cases of dengue in the Gulf Coast states. The use of DDT, fraught though it may have been, paved the way for the post-WWII boom years. Today, Texas and Florida rank two and three in the nation as the most populous states with a combined population approaching 48 million people. That’s more than 40% of the entire US population in 1922. Tens of millions more flock to the Gulf states as tourists each year. If the mosquitoes and the diseases they carry stage a comeback, everyone is at risk. Local, state, national and global economies are at risk.

The cost to families and individuals is a devastating plague of its own, one that in the US can all too easily lead to “co-infections” of medical bankruptcy and insurmountable poverty. Caring for a microcephalic child for years on end is a full-time job. A case of Guillain-Barré syndrome, a paralysis that primarily affects adults and has also been linked to several related mosquito-borne viruses, including dengue and West Nile, requires several days of expensive treatment in a hospital.

PERSPECTIVE

Over the eons, mosquitoes have seen animals of every shape, size and description — meals on the hoof, wing, and foot, furred, feathered and scaled — come and go from the planet. Our likelihood of defeating them is slim. In 1947, the newly formed CDC’s anti-mosquito program was given $4.6 million dollars by Congress — the equivalent of about $50 billion in today’s money — to eradicate malaria in five years. Armed with ecosystem-shredding chemicals, and supported by the widespread use of screens and air-conditioning, they made good headway in the US. Globally — mostly in Africa — the epidemic rages on. According to the CDC, there were an estimated 207 million clinical episodes, and 627,000 deaths in 2012.

It turns out that North America is not, however, free of malaria. Researchers have just announced the discovery that estimated 25% of white tail deer have malaria. It doesn’t appear to make the deer terribly sick and presents little threat to humans, but the fact that researchers had missed it speaks to the need to better fund field research.

“You never know what you’re going to find when you’re out in nature–and you look,” says Martinsen, a research associate at the Smithsonian’s Conservation Biology Institute and adjunct faculty in the University of Vermont’s biology department. “It’s a parasite that has been hidden in the most iconic game animal in the United States. I just stumbled across it.”
”Many white-tailed deer have malaria: First-ever native malaria in the Americas,” Science Daily

Zika, too, it is worth noting, was an accidental discovery by scientists studying yellow fever in Africa during the 1940s.

A BETTER WAY FORWARD

The combination of a virus and a vector tailored to attack humans is a worst case scenario. Although Zika’s link to birth defects has yet to be confirmed (it is technically an association), the threat to the unborn is a direct assault on the future. The apparent randomness of Gullian-Barré syndrome (also an association) adds a chilling sense of Russian roulette to the crisis. The stakes couldn’t be higher.

A new approach to disease prevention is needed, one that provides both a big picture environmental perspective and an incentive to be proactive. In the short-term, though, the mission is strategic containment: whack-a-bug!

Also needed as soon as possible is a fast, inexpensive and accurate test. If statistics hold true and 80% of cases are subclinical (no symptoms) and there are four million cases in the Americas this year, then 3.2 million people will have been naturally vaccinated, but with no way to know it. A woman with natural immunity to Zika who became pregnant would know that her baby was safe from developing microcephaly due to the virus.

Lost in the urgency of the moment is an understanding that these seemingly endless waves of headline-grabbing outbreaks are part of a larger pattern. Vector-borne diseases, whether the vector is a mosquito or a tick, are on the rise fueled by trade, travel, deforestation and urban sprawl. A fast-warming climate has extended both the range of vectors and the length of the seasons in which they present a danger. It will take a sustained and substantial financial commitment to fund the level of field surveillance, basic research and vector control to keep an ever-expanding array of risks as low as possible. Tropical diseases aren’t just for the tropics any more.

The next epidemic is waiting in the wings. Wouldn’t it be great if we knew enough about what it might be to keep it there?

— J.A. Ginsburg | @TrackerNews

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