by Sonia Shah
Which begs the question as to malaria’s tenacity and continuing malevolence. Malaria has been plaguing humans in Africa for some five hundred thousand years, with the first encounters between human, mosquito, and malaria parasite probably occurring around the time our ancestors discovered fire. Malaria existed in Africa before then, too, feeding on the birds, chimps, and monkeys that lived in the canopy.6 We’ve had plenty of time—our entire evolutionary history, in fact—to adapt to malaria, and it to us. Or, at least, to devise tools and strategies to blunt its appetite. And yet, despite the millennia-long battles between us, malaria still manages to infect at least three hundred million of us—that is one out of twenty-one human beings on the planet—and kills nearly one million, year after year. As an extinguisher of human lives, write the malariologists Richard Carter and Kamini Mendis, malaria historically and to this day “has few rivals.”7 It remains essentially wild and untamed, despite its great antiquity.
And experts such as Terrie Taylor have spent lifetimes trying to figure out why.
One simple reason for malaria’s ferocity is that the protozoan creature that causes the disease is, by definition, a cheater at the game of life. It is a parasite, a creature that can eke out its livelihood only by depleting others of theirs. The rest of us all do our obscure little part in the drama of life, weaving ourselves deeper into local ecology and strengthening its fabric, the bees pollinating the flowers, predators culling the herds of their weakest members. Parasites don’t help anyone. They’re degenerates.
Take the parasitic barnacle, Sacculina carcini. It is born with a head, mouth, segmented body, and legs, just like any respectable barnacle. But then, because it is a parasite, it stops developing into an independent creature. It burrows into the shells of the crabs off of which it will spend its life feeding. There it loses its segments, its legs, its tail, and even its mouth, devolving into a pulsing plantlike form, little more than a blob with tendrils sucking food from the forlorn crab’s body.8 It’s the very definition of repellent. In 1883, Scottish lecturer Henry Drummond called parasitism “one of the gravest crimes of nature” and a “breach of the law of Evolution.” Who can blame him?9
And yet parasites such as Plasmodium are not anomalous on this earth. According to the science writer Carl Zimmer, one third of all described species practice the parasitic lifestyle.10 To be fair, for Plasmodium, parasitism arose as an accommodation to newfound opportunities, not because of any intrinsic quality or irreversible mechanism within it. Plasmodium did not start out life hardwired to steal. This killer first emerged on the planet as a plantlike creature, most likely some kind of aquatic algae. We know this because 10 percent of the proteins in modern-day Plasmodium parasites contain vestiges of the machinery of photosynthesis.11
Plasmodium’s ancestors probably rubbed shoulders with the eggs and larvae of mosquitoes, similarly floating on sun-dappled waters.12 When the mosquitoes took wing, malaria’s ancestors likely went quietly along with them.13 It must have happened, then and again, that when a mosquito pierced a bird or chimp or some other blood-filled creature, malaria’s algae ancestors fell into the wound. Most probably died. But through the blind ticking clock of evolution, one day some subset of the interlopers found themselves thriving in those crimson seas, and a vampiric parasite was born.
Such are the ironies of surviving on this protean planet. A creature at the very bottom of the zoological scale, a humble being beneficently converting sunlight into living tissue (and thereby providing the basis for the planet’s entire food chain), turns into one of the most ruthlessly successful parasites ever known, commanding two separate spheres of the living world, human and entomological.14
Henry Drummond would have been appalled.
Delve into even the most rudimentary scientific literature on malaria and you will soon be confronted with a dizzying range of unpronounceable words. There is exflagellation, erythrocytic schizogony, and exo-erythrocytic schizogony. There are gametocytes and trophozoites and sporozoites. These are not obscure terms for little-discussed facets of the parasite whispered over cluttered lab benches by a few old-school malaria nerds, but rather basic stages in the parasite’s life cycle bandied about by nearly everyone in the malaria world, from ponytailed Harvard undergrads to queenly Cameroonian researchers and grizzled Italian vaccine makers. It is as if scientists had to come up with a whole new language just to talk about malaria.
That’s because during the course of its life, Plasmodium transmogrifies into no fewer than seven different forms, which vary in both morphology and physiology. Its parasitic modus operandi demands such shape-shifting wiliness. After all, in order to survive, the malaria parasite must extort from two different species: the animal whose blood it feeds upon, and the insect who deposits it into that animal’s blood. It’s sort of like robbing a bank while stealing a car. Things get complicated.
The mosquito’s immune system instinctively attacks the parasite, encapsulating the intruder in scabs and bombarding it with toxic chemicals.15 To survive, the parasite must unleash armies of progeny in such massive numbers that fighting it off becomes more trouble than it’s worth.16 Male and female forms of the parasite, called gametocytes, then fuse, and the resulting parasites create cysts that cling to the walls of the bug’s gut. (The spasmodic waving of the male gametocyte’s long tail, which precedes the act of fusing with the female—yes, this microbe reproduces sexually as well as asexually—is called exflagellation.) Tens of thousands of slithering threads explode from the cysts and swarm up to the mosquito’s salivary gland. This is the form the parasite must take to infect human beings. Malariologists call it the sporozoite. When the mosquito starts a blood feed, some two dozen slivery sporozoites will escape into their next host.
The parasite’s shtick fails in most of the world’s 3,200 species of mosquito. It works only in a single genus, called Anopheles (rhymes with “enough of peas”), most likely because of that mosquito’s strangely tepid defenses. This restriction doesn’t hinder the parasite terribly, though: there are some 430 known species of Anopheles, distributed in every corner of the planet except for Polynesia, east of Vanuatu. At least 70 species are known to carry malaria.17
Outwitting the human body’s defenses, though, requires orders of magnitude more cunning. The parasite must conceal its appetite and indeed its very presence inside the body. The object of its desire—the hemoglobin inside red blood cells, which it feasts upon—is particularly precious. Produced from iron in bone marrow, hemoglobin makes it possible for blood cells to attach to oxygen molecules, and thus ferry life-giving oxygen to the body’s tissues. Without hemoglobin, lone oxygen molecules maraud unattached, degrading cells, proteins, and DNA as surely as they brown sliced apples and rust metal, and the body weakens, becomes anemic, and ultimately perishes.
The parasite must hide. First, the sporozoites retreat to the liver, where they spend a few surreptitious days shifting, regenerating, dividing, and generating again, secretly transforming into an army of fifty thousand parasites in a new form capable of infecting red blood cells: the merozoite. In the next stage of the invasion, the merozoites pour into the bloodstream. They are cleverly disguised inside the liver cells they’ve gagged and murdered,18 but an epic battle ensues nevertheless, and the body’s immune fighters slaughter thousands. It isn’t a perfect victory. If a few stragglers in this marauding horde manage to escape, they latch onto red blood cells, and within moments penetrate the cells’ interior. There, they quietly feast on hemoglobin, and a new round of shifting, regenerating, dividing, and generating ensues. Some transform from tiny ring-shaped beings into fat, rounded creatures and unleash a wave of progeny. When nothing is left of the former oxygen-carrying cell besides a stream of waste and a bulge of fattened parasites, the parasites burst out of the cell and rush out to invade and consume a fresh crop of cells. Others quietly shape-shift into the male and female forms called gametocytes and lie in wait inside their hijacked blood cells. With any luck, they will be picked up
by another bloodthirsty Anopheles mosquito.19
A creature this protean and multifarious defies easy challenge.
Nor is there any simple way for humans or mosquitoes to foil the parasite by avoiding the behaviors it so ably exploits.
The blood-feeding of mosquitoes, for example, is probably the most important thing a mosquito ever does—so crucial, in fact, that it risks its very life to do it. Piercing the skin of some creature many times larger than yourself is not for the fainthearted, particularly when your body can be pulverized with a simple wave of the hand or swish of the tail. Plus, blood is thick and therefore crushingly heavy for the average mosquito, which weighs significantly less than, say, a drop of water. Swollen with bloody bounty, a mosquito can barely fly, which is a mortal debility.20
But because velvety blood, rich with life-giving protein, is pure cream compared to the nectar they generally dine on, mosquitoes have devised clever strategies to circumvent each of these challenges. For one, they reserve blood-feeding to just a few precious moments in life, when it really counts. Emboldened by the promise of impregnation, only the female dares do it, using the rich meal to nurture her eggs. She finds her victim by following a trail of lactic acid and carbon dioxide in its exhalations. Then she numbs her chosen spot with a drop of saliva, which is spiked with compounds that deaden pain and retard clotting. Once sated with a volume of blood several times heavier than her own body, she departs immediately for the nearest vertical surface, where she spends forty-five death-defying minutes excreting all the water from her feast until, unburdened, she’s once again light enough to flap her tiny wings and sail away.21
Malarial sporozoites that spilled into the wound with her drop of saliva, meanwhile, have by then already infected her victim’s liver. But what else can the mosquito doff? The survival of her progeny depends on her blood-feed.
Plasmodium’s wiles similarly thwart overt human challenge, mostly because in the vast majority of cases, victims are completely oblivious to the fact of infection until it is far too late to do anything to impede the parasite’s progress—even if they knew how. Almost all of Plasmodium’s manuevers inside the body occur in utter secrecy. When it slips into the body, while it hides in the liver, and even after it emerges into the bloodstream and attacks blood cells, there is no itch, no rash, no sweaty forehead that belies the infestation roiling within. It is only after malaria parasites rupture out of their hijacked cells, well into the parasitic invasion, that the infected person feels sick. The waste from the parasite’s hemoglobin feast leaks out of the destroyed cells, and that tiny spike of poison triggers a round of detoxification, throwing the victim into a high fever, followed by chills and shivering. When the waste disperses, the fever passes, and for several days there might be no symptoms at all—until the parasite finishes gobbling up its next batch of hemoglobin and explodes again in search of more, triggering another attack of fever and chills.22
The parasite’s steady consumption of its victim’s blood drains him of vitality, making him easy pickings for other pathogens of various ilk. But while the parasite grows inside, aside from an enlarged abdomen—the spleen of the malaria-infected can swell to twenty times its normal weight while clearing the body of dead cells23—its passage remains obscure. All the while, mosquitoes will bite, and imbibe the parasite roosting in the blood, and the cycle continues.
Just in case all this proves insufficient to secure malaria’s safe passage, Plasmodium manipulates its unwitting hosts to more pliantly succumb to its will. While gestating inside the mosquito, the malaria parasite somehow manipulates the mosquito to become more cautious, seeking less of the life-giving blood it needs for its young, thus reducing the insect’s risk of getting smashed or eaten and destroying the parasite developing within.24 Once fully developed inside an infected mosquito, though, the parasite shifts its calculus, manipulating the host insect to bite more often, and more persistently,25 by depressing the anti-clotting compound in her saliva, apyrase, so the mosquito can barely get enough. Unsated, she is more likely to seek out yet another victim, whom she can infect with yet more parasites.26 Genetically engineering mosquitoes to resist malaria infection weakens them. Could there be something about malaria infection that helps mosquitoes stay alive, despite the parasite’s selfish intentions?27
Not very much is known about how malaria infection manipulates human behavior to its own ends. Obviously, it leaves human victims passive, despondent, supine: in other words, more vulnerable to the bites of mosquitoes. Human attractiveness to mosquitoes depends on various factors—the smell of their feet, the chemicals on their breath, and the temperature around them—but according to studies of how mosquitoes behave around infected and uninfected people, being infected with malaria parasites alters human chemistry in some subtle way that mosquitoes find especially attractive.28
Certainly, malaria has left a deep fingerprint on our genomes. Today, one out of every fourteen human beings carries genetic mutations that first evolved to defend the body from malaria’s onslaught.29 This legacy has resulted in myriad conditions, reverbs of malarial destruction, some more debilitating than others.
Malaria is not just a human problem. During its long reign, Plasmodium has been able to spread its tentacles into a wide range of furry, fanged, and scaled bodies. More than one hundred different species of Plasmodium parasites specialize in infecting a veritable Noah’s ark of creatures. There are malarias in chimps, gorillas, and orangutans; in thicket rats, porcupines, and flying squirrels; in pheasant and jungle fowl. Malaria parasitizes lizards and occasionally snakes. As I write this, malaria parasites teem with purpose inside the veins of the house sparrows skittering outside my window.30
Malaria’s relentless pursuit of every available ecological niche from which it might suck sustenance includes a wide range of human habitats, from the deepest tropics of Asia to the deserts of Africa and the cool climes of northern Eurasia. In some, human-mosquito intimacy is intense; in others, distant. In some places it is sporadic; in others, continuous. At times, human defenses have been able to repel parasitic invasion; at others, we’ve fallen like sand castles in the tide. Throughout it all, Plasmodium has successfully maintained its contagion of humankind, a long pillage that has left us with no fewer than four different species of malaria parasites stalking the human race.
The first human malarias probably made a fairly marginal living. The bite of a mosquito was a relatively rare thing millions of years ago when early humans roved the savannah in search of game. If the parasite managed to get deposited into them, it probably never got out: early humans might not be bitten again for years, even decades. Stuck in dead-end hosts, the malaria parasite inside them thus would have fed for a while, reproduced, and then perished, waiting for a ride that never came. That early proto-Plasmodium parasite could probably have infected only about 1 percent of the thirty trillion or so red blood cells that gushed through human veins.31
Despite the difficult circumstances, Plasmodium found ways to hang on with the emergence of a species of malaria parasite called Plasmodium malariae, which preceded the familiar microbes that exploited the filth and population density of early farm life—measles, smallpox, cholera—by several hundred thousand years. Once it finds its way into a human body, P. malariae can persist in a kind of suspended animation for as long as seven decades, waiting for that fateful day when its victim might chance to be pierced by another mosquito.32
This was an advantage, but along with developing slowly inside the human, malariae also developed slowly inside the mosquito, which was a serious liability, especially given Africa’s much cooler climate in pre-agrarian times. Even though they never live free in the outside environment, malaria parasites are still highly vulnerable to it, subject to the fluctuating temperature inside the cold-blooded mosquito. If the mosquito’s body is warmed by summery weather, the malariae parasite can mate and produce the necessary slivery sporozoite forms in about two weeks. But in temperate weather—say, sixty-eight degrees
Fahrenheit—P. malariae’s development inside the mosquito gets sluggish. It needs a month or more to mate and produce sporozoites. Its mosquito, by then, is long dead.33
P. malariae’s prospects, therefore, were never that great. For thousands of years, it probably just barely hung on, perennially at risk of extinction given the uncertainty in its transmission cycle. Such is the fate of the pioneer.
Adjustments continued. Most likely there were dead ends, of which we know nothing. We do know that, in time, a new strain of malaria parasite emerged: intense, furious, awkward. Plasmodium vivax parasites use proteins studded along red blood cells to attach themselves to the cell before invasion. P. vivax could foil human defenses better than P. malariae, allowing it to multiply much faster within its human victims, a huge step forward from its slow-developing cousins. P. vivax could perform its cycle within the human host—reproducing an army of parasites, feasting on hemoglobin, and producing gametocytes, the form that is able to infect mosquitoes—in just three days.34 So long as the mosquitoes were biting, early human communities would have found themselves at its mercy.
But P. vivax could not sustain a constant contagion upon early peoples, either. Mosquito carriers in human communities were still too few and far between, and the parasite still dangerously vulnerable to the cool climate of Ice Age Africa. P. vivax’s transmission cycle remained uncertain. For the humans, this made it much more dangerous. For when P. vivax did emerge, it did so suddenly and with epidemic force, burning through entire tribes like an erupting volcano, only to vanish suddenly, leaving behind piles of bodies as carrion.35
We know that P. vivax must have exerted a powerful blow because of the way early peoples responded to it, with genetic mutations that stopped the parasite dead in its tracks. The stakes for anyone with an edge against P. vivax must have skyrocketed. With each assault, our ancestors’ immune system primed itself against the parasite, honing its ability to foil it. Its scrambling genes trotted out different permutations, holding out the possibility that one might outmaneuver the enemy.
