by Sonia Shah
Not for inconsequential reasons. At the appropriate dosage, quinine is not a benign drug. Unpleasant side effects are so common that physicians early on gave them a name: cinchonism. Cinchonism included tinnitus, deafness, headache, nausea, and even visual disturbances. And those were just the expected side effects. (Livingstone recommended taking quinine “until the ears ring.”) Quinine could also, albeit rarely, cause severe bleeding, a dramatic decline in white blood cells, abnormal blood clotting, and renal failure, all of which could kill.67
There was also the matter of blackwater fever, a mysterious and fatal illness associated with quinine therapy, in which quinine-imbibing patients suffered diarrhea, vomiting, abdominal pain, and finally a jet-black urine and death.68 Blackwater fever was “perhaps the most important disease, medically and economically, affecting Europeans in the more malarious regions of the tropics,” noted the early twentieth-century British malariologist John William Watson Stephens.69 Although scientists have never established a clear link between quinine and blackwater fever, it’s probably not unfair to blame quinine for it—the syndrome died out after long-term prophylactic quinine therapy fell out of favor in the 1950s.70
But malaria is no picnic, either. For someone sick with the disease, the side effects of the drug may seem if not trivial then at least tolerable. Still, try as they might, military officers throughout the twentieth century rarely persuaded many of their troops to take the prophylactic quinine as prescribed. In fact, during World War I, soldiers failed to take their prescribed prophylactic doses of quinine so often that the higher-ups began to suspect the men wanted to be sick so they could be evacuated. They called it “malarial defeatism.”71
A similar reluctance to down the required dose thwarted Italy’s ambitious state-run program of free quinine distribution. The idea behind the program, which started in 1902 and continued until World War I, was to douse the populace with such quantities of quinine that the survival of the parasite itself became untenable. The famed German bacteriologist Robert Koch figured the method could knock out malaria in as little as nine months.72
But the “divine medicine” didn’t seem so exalted to the locals.73 For too long, quinine had been a rich man’s luxury, and Italian villagers mistrusted the seeming ease with which they could suddenly acquire the drug. “The countryside teemed with dark rumors of a diabolical plot,” the historian Frank Snowden writes in his history of malaria in Italy. The government wanted “to rid the nation of its surplus population,” some figured; it was a trick to collect more taxes, others speculated.74
Despite the huge toll of malaria in Italy and quinine’s great promise in fighting it, the majority of Italy’s free quinine was never consumed.75 At least not by Homo sapiens. Frightened and skeptical, many peasants fed it to their pigs.76
Badly used, misunderstood, and poorly distributed, quinine still prevailed as the world’s sole malaria drug (save for traditional remedies used locally) until the 1940s. And so it might have stayed, too, had it not been for the catastrophic quinine disasters of World War II.
At first, malaria was the least of the concerns of American generals prosecuting the war in the Pacific, even as scores of nonimmune troops pushed deep into the malarial jungles and swamps in New Guinea, the Philippines, and elsewhere. The malariologist Paul Russell, envisaging multiple bloody malaria epidemics, visited with American military leaders in New Guinea to plead for greater attention to malaria prevention. They dismissed his concerns out of hand. “If you want to play with mosquitoes in wartime,” one told him, “go back to Washington and stop bothering me. I’m busy getting ready to fight the Japs.”77
Back in Washington, the U.S. government felt prepared. By the time the country entered the war, six million ounces of quinine sulphate had been stockpiled and plans were in place to fortify the U.S. quinine supply with new shipments of tablets from both the Kina Bureau and cinchona plantations outside the cartel, such as a new one in the U.S.-controlled Philippines. In 1921, the governor-general of the Philippines paid the Dutch four thousand dollars for a bottle of cinchona seeds from their quinine-rich Ledgeriana trees, which he then planted in the southern Philippines, on the island of Mindanao.78 By 1941, the Mindanao plantations produced around two thousand pounds of quinine a year.79
But then, war being war, Germany invaded the Netherlands. One of their first orders of business: hijack Amsterdam’s stores of quinine and send them to Berlin.80 The crushing of quinine’s queen bee was ominous enough. Then, in 1942, Japan invaded Indonesia and took control of Java’s cinchona plantations (along with its tin, rubber, and other tropical riches).81 Within a matter of months, 95 percent of the world’s quinine had fallen into enemy hands.82
As the flow of quinine ebbed, Plasmodium flourished among the nonimmune troops. In Papua New Guinea, malaria laid claim to four times more casualties than the ferocious battles themselves, with more than 70 percent of Australian soldiers down with malaria.83 Every single soldier of the U.S. Americal Division, sent to Guadalcanal in the Solomon Islands in late 1942, came down with malaria, some more than once. According to what General MacArthur told Paul Russell, “one-third of his fighting men were in the throes of malaria, one-third were recovering, and only the final third were truly fit for combat.”84 Overall, malaria sickened 60 percent of Allied troops in Southeast Asia.
Quinine stocks in American shops dried up entirely. “If you require quinine, you must now have a doctor’s prescription,” Harper’s magazine complained, “and even with that you will probably get only the ground-bark solution.”85 Malaria cases in India rose precipitously, up to one hundred million by the end of 1942, The New York Times reported that year.86
But the most notorious epidemic occurred on the island of Bataan, in the Philippines, where American and Filipino troops had fled from a Japanese invasion. With 85 percent of the troops sick with malaria, there wasn’t enough quinine for the sick to finish their courses, let alone take the drug prophylactically.87 Under fire, the weakened, emaciated troops—they’d been eating their own horses by then—surrendered to the Japanese. It was the largest surrender in American and Filipino military history. The Japanese took more than fifteen thousand American and sixty thousand Filipino soldiers as prisoners, forcing them to march one hundred miserable kilometers to prison camps.88
It was an outrage, fumed American legislators in Congress.89 Bataan had been lost “not because the ammunition was gone,” as The New York Times pointed out, “but because the quinine tablets gave out.”90 The years of reliance on a single highly controlled source for a lifesaving medicine now appeared recklessly foolish. The Kina Bureau had “ruthlessly stifled” competition in the quinine market, a California legislator railed, with “preclusive purchasing, subterranean political activity and indirect economic pressure.”91 Meanwhile, the Japanese, by controlling the Dutch monopoly, “ could have all the bark [they] wanted,” quinine historian Duran-Reynals pointed out, allowing them to conquer mosquito-ridden China unworried by malaria.92 To add to their antimalarial superiority, the Japanese army employed elderly women to perform the job of “net tucker-in” to secure the mosquito nets after the soldiers got in their beds.93
Allied governments quickly ramped up their efforts to stanch malaria by other means. General MacArthur appointed Paul Russell as chief malariologist for the U.S. military,94 and Russell assigned malaria control and survey teams to every combat force present in malarious regions—all in all, more than two hundred units, each of about a dozen people. Their supplies and officers leapt from tenth priority in overseas shipment to first.95 The U.S. Army newspaper reminded troops to keep their sleeves rolled down to avoid mosquito bites. The Armed Forces Radio broadcast so many antimalaria messages that troops called it the Mosquito Network.96 Even the famed author Theodor Seuss Geisel, aka Dr. Seuss, brought his talents to bear on the malaria problem, producing a cartoon distributed by the U.S. Army in 1943. “This is Ann,” Seuss wrote, under a comic rendering of an Anopheles mosquito.
&nb
sp; She drinks blood! Ann moves around at night (a real party gal) and she’s got a thirst. No whiskey, gin, beer or rum coke for Ann . . . she drinks G.I. blood . . . Never give her a break. She can make you feel like a combination of a forest fire, a January blizzard, and an old dish mop. She will leave you with about as much pep as a sack of wet sand and now and then she can knock you flat for keeps . . . Bathing and swimming at night where Ann hangs out really is asking for trouble. Head nets, rolled-down sleeves, leggings and gloves may seem like sissy stuff and not so comfortable—BUT, a guy out cold from MALARIA is just as stiff as the one who stopped a hunk of steel. Now IF you really are looking for trouble and you don’t want to miss [out]—just drop down to the nearest native village some evening. The places are lousy with fat little Anns sitting around waiting for you with their bellies full of germs. They stock up on MALARIA bugs from the home-town boys and gals and when they find a nice new sucker they give him the works.97
As the troops digested these morsels of wisdom, scientists back home rushed to screen tens of thousands of compounds in search of a drug that might replace the divine remedy they’d lost. This massive effort at long last ushered in a new chapter in humankind’s fight against malaria, with the development of powerful, easy-to-manufacture synthetic chemicals that could lay waste to malarial mosquitoes and the parasites they harbored.
Ironically, given the greater urgency of the Allied nations’ search for a quinine replacement, German researchers at I.G. Farben were the first to discover the antimalarial drugs quinacrine and chloroquine, which were only later stumbled upon and developed further by American scientists.
Quinacrine persisted in the blood for a week, which could be useful, but it yellowed the skin and could sometimes trigger psychotic reactions. It also wasn’t nearly as effective against vivax malaria as quinine. Quinine-deprived American troops forced to take it during the tail end of the war hated it.98
Chloroquine was another matter. Like quinine, it killed malaria parasites by interfering with their ability to metabolize the iron compounds in red blood cells known as heme.99 But chloroquine departed from its pharmacodynamic cousin in every other way. Where quinine failed, chloroquine excelled. It lasted longer. Its side effects were insignificant. And best of all, it could be churned out in factories as reliably as widgets.
Produced cheaply by drugmakers all over the world, chloroquine exploded into the postwar global marketplace. Elites positioned their bottles of chloroquine prominently on their dinner tables, next to the condiments.100 Troops assembled for “chloroquine parades.”101 The American drug company that started promoting chloroquine in 1947 claimed it was eight to thirty-two times more effective than quinine,102 and people, it seems, took them at their word. In Africa, chloroquine overtook aspirin as the drug of choice for fevers, and even aches and pains. This was encouraged by top malaria experts, remembers WHO’s José Nájera. “Chloroquine, it was said, should be treated as a commodity, not a drug.”103 Why bother even trying to diagnose malaria before taking chloroquine? The pill, experts advised, should be simply taken as soon as a fever comes on, as “presumptive treatment,” by sufferers in their own homes.104
The divine medicine quinine, with its quaint botanical heritage, fell into obscurity. The cinchona plantations in Java were left to wither after the war.105 The German military knocked down the imposing statue erected in Paris commemorating Pelletier and Caventou for their heroic extraction of quinine, melting it down for metal to turn into weapons.106
Under siege, the Kina Bureau’s tactics grew increasingly unhinged. They secretly paid syndicated newspaper writers to propagandize for quinine. Their collaborators “would not dare write more than eight or nine articles in any one year,” however, “in case the syndicate should become suspicious of their featuring quinine too regularly.”107 The bureau promoted risky self-medication with quinine, even though “this might lay us open to attack by the medical authorities,” as one Kina Bureau promoter put it.108 They also tried to engineer criticism of anti-quinine medical authorities. “The best method of attack . . . must appear on the surface to be a spontaneous protest by some outstanding man in this country,” one noted, “while it is true that I would supply such a man with all the material.” They even toyed, pitiably, with the idea of raising money to rebuild the statue of quinine chemists Pelletier and Caventou.109 But for nought. In the giddy celebration of chloroquine, the world’s hunger for quinine steadily declined.
Plasmodium did not survive for millennia by virtue of some unerring killer instinct, unfailingly homing in on the immunological loopholes and secret hiding places in its prey. It survived by being more adaptable than its hosts. Each species of malaria parasite boasts scores of genetically distinct strains, each with a unique set of strengths and weaknesses. Some parasites may be especially adept at, say, quick reproduction inside the mosquito. Others might be skilled at avoiding capture by immune cells. And the various species hang out together, playing out their rivalries and alliances inside our infected bodies. The human host can, albeit painstakingly, devise a defensive maneuver or two to fight them. But we are single individuals, relatively fixed in our capacities. The parasites infesting us, on the other hand, comprise a rapidly regenerating mini-civilization. Even if some fall prey to our defenses, there will be others who won’t—and whose progeny will rapidly conquer the body.
The parasite’s tremendous adaptability most likely escaped observers during the quinine era, when the drug’s strikes against the parasite remained weak, sparsely distributed, and sporadic. It probably remained hidden during the 1950s, too, as chloroquine consumption took off. But inside drug-dosed bodies all over the world, parasite populations found themselves under assault. Under those conditions, the few hardy individual parasites that could withstand the toll were suddenly plucked from obscurity.
The first signs that malaria parasites could resist synthetic drugs cropped up during the tail end of World War II, as the Allies dosed their troops with the hated quinacrine.
With widespread distrust and dislike of the drug, General MacArthur had instructed the director of medicine for the Australian army, Neil Hamilton Fairley, to provide solid evidence of quinacrine’s effectiveness, especially under the wartime conditions in which the drug would be used.
This Fairley did, conducting a series of wrenching human experiments in the unlikely locale of the lush Australian highlands west of Cairns.110 He rounded up hundreds of volunteers—Jewish refugees and injured soldiers among them—to be purposely infected with malaria and then rigorously dosed with quinacrine, to show how well the drug worked to prevent illness. But he didn’t stop there. He exposed the volunteers to hundreds of bites from infected mosquitoes, made them march more than two hundred kilometers in a matter of a few days, with minimal breaks for rest and food, injected them with adrenaline and insulin, and herded them into the freezing chamber of the local meat works. Still, quinacrine quelled their experimentally induced malarias. The drug, in other words, worked.111 (“They never told us anything,” recalls one subject who survived the trials. “At first I didn’t realize it was dangerous . . . I thought it would be an adventure and that is why I went,” remembered another.112)
In 1944, Fairley announced the results at a high-level military conference, in Atherton, Queensland. “It has now been amply demonstrated to you that the control of this disease is in your own hands,” announced the director general of Australia’s Army Health Services. “It is purely a matter of training and discipline in all antimalarial measures, particularly the taking of Atebrin [the brand name for quinacrine] . . . I have no hesitation in saying, most emphatically, Gentlemen—the ball is now in your court.”113
A few months later, more than seventeen thousand Australian soldiers landed along the northern coast of New Guinea. There was no ambiguity about what they were to do to avoid malaria. Quinacrine had the stamp of approval from the very highest authorities. It is hard to imagine, given the known malariousness of New Guinea and the weight of
confidence in quinacrine, that the troops did not take it religiously. But just to make sure, if they didn’t, their platoon commanders were under threat of removal. And it worked. For months, the troops stayed healthful despite the swarms of malarial mosquitoes around them.
But then, about three months into the campaign, the troops started to advance alone the coast. Inexplicably, their antimalarial armor of quinacrine seemed to falter. Three hundred and fifty soldiers fell ill with malaria.114
News of this must have jolted the troops like a bolt of lightning. Nobody particularly liked taking quinacrine, and these infections could only have been seen as an utter betrayal. The hated drug had failed them! But the leadership, Fairley’s faith fresh in their minds, suspected just the opposite. Having worked so hard to implement the distribution of quinacrine, how could they think otherwise? For them it couldn’t be the drug that had failed. Rather, the troops had failed to take their medicine.
Amid the controversy over the three hundred and fifty fevered bodies, the troops’ commander, Major General J.E.S. Stevens, urged greater compliance. “Brigadier Fairley . . . is the most eminent malariologist in the world,” he announced.
He has devoted his whole life to this disease. He carried out the most extensive investigations and experiments made in the history of mankind and from that made a definite pronouncement that 1 tablet of Atebrin per day will suppress malaria. It would be presumptuous for us to suggest that this authority is not absolutely correct. There must be no weakening of our faith in his doctrine, otherwise the whole structure of antimalarial measures will collapse.115
To restore the drug’s reputation and the protection he believed it provided, Stevens cracked down even more heavily on the wilting troops. Not only did the troops have to line up to receive their tablet, he declared, but the commanding officer was to place the tablet in each mouth himself. After the soldiers drank some water and swallowed, they would be required to call out their names “in a loud voice,” and finally, to prove beyond a shadow of a doubt that the pill had in fact gone down their throats, they were to open their mouths for a thorough inspection.116 In addition, the soldiers were banned from taking off their long-sleeve shirts, trousers, and boots, even “for the purposes of ablutions.” Every two hours from dusk to nightfall, whistles were blown, signaling the troops to coat another layer of mosquito repellent onto their unwashed clothes and bodies.117
