The Fever: How Malaria Has Ruled Humankind for 500,000 Years (15 page)

Meanwhile, in Bolivia, a cinchona harvester named Manuel Incra Mamani trekked to the hills to collect seeds from a rare stand of cinchona rumored to produce copious quantities of quinine. It took
five years to gather the tiny pips. Under threat of death, in 1865 he surreptitiously gave them to a British trader named Charles Ledger, who spirited them out of the country.

The pirated seeds eventually landed in the hands of, among others, the Dutch, who lovingly prepared a bed for them in the rich fertile soil of Java, in present-day Indonesia. The Dutch lavished their horticultural finesse upon the plundered cinchona,
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clearing thousands of acres of mountainous jungles for the seedlings.
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But cinchona proved a recalcitrant guest. It preferred the conditions of its Andean home, in areas between three thousand and seven thousand feet above sea level. Closer to the sea, the trees perished; at higher altitudes, they withered to the size of shrubs. Steep mountainsides wouldn’t do, either, but only the loose, rich soil of the foothills. Their delicate leaves demanded a constant sprinkle of moisture. Heat greater than eighty-six degrees or cold below forty degrees was intolerable, and a single frost spelled instant death for a young cinchona sapling. The trees would produce not a drop of quinine until they were at least five years old, and they wouldn’t countenance the harvesting of their bark until they were at least fifteen years old.
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It didn’t help that wandering Javanese rhinos kept trampling the sprouts.
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The Dutch meticulously fulfilled each of these exacting conditions, even as critics condemned the cinchona plantations as “expensive folly.”
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If all went well, the cinchona harvest would be complete within a decade. By the time the trees were age six, their bark coursed with 5 percent quinine,
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and by age ten, the trees bloomed, their fragrant feathery flowers turning into small fruits teeming with the seeds that would secure the next generation of cinchona trees. Unfortunately, as dedicated as the Dutch were, they hadn’t taken into account the miscegenating bees that introduced pollen from worthless cinchona scattered across Java—remnants of earlier attempts at cinchona cultivation—to Ledger’s superior, quinine-rich strain.
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The Dutch had to laboriously deflower thousands of non-Ledger cinchonas around their plantations, forbid farmers from cultivating them ever again,
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and maintain a rigorously pure seed line, from the original seeds, on
the government’s estate, for safekeeping.
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“No tree, not even rubber,” mused American horticulturalist Norman Taylor, had “ever had such a long history of patient, intelligent care bestowed upon it.”
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Establishing cinchona in Java took thirty years.

Overcoming the horticultural barriers to cinchona cultivation proved to be just the first of a series of barriers to widespread quinine use. By 1900, the Dutch produced over five million kilograms of quinine a year.
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But quinine still did not flow to the masses.

At first the Dutch shared the quinine trade with the Germans, who dominated the factories that processed cinchona bark into quinine. But after World War I, the Allied victors forced the Dutch to stop selling cinchona to the Central Powers and, on the wrong side of the war, the German quinine industry collapsed.
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If growing cinchona had been a tad easier, rival powers and enterprising entrepreneurs might have established their own cinchona plantations to compete with Dutch quinine. Cinchona culture being what it was, however, the Dutch lock on the quinine market proved as ironclad as any brand-name patent. And they defended their monopoly with zeal.

To be fair, the Spanish had tried to keep cinchona (and the natural wealth of South America more generally) to themselves, too. During their reign, no one could even go to South America without the permission of the king of Spain, and “nothing on South America could be published,” writes the quinine historian Fiammetta Rocco, “without it first being submitted for censorship.”
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(Thus the malaria-plagued Scots in Darién, in 1698, drank whiskey instead of chewing cinchona, despite their dangerous proximity to the bark. They had no idea.) Peru, which gained independence from Spain in 1824, was no more forthcoming. They slapped cinchona on their national emblem and banned the export of cinchona seeds.
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When Mamani spirited those pirated cinchona seeds out of the Andes, government authorities detained and tortured him for twenty days.
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The Dutch were happy to sell the world quinine, but given the economics of cinchona farming, they’d do it only at a suitably high price. After all, if the price of quinine fell, their cinchona farmers in Java would rip up the unprofitable trees and plant tea instead, they said.
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They set up an agency in Amsterdam called the Kina Bureau, which dictated the terms on which the malarious masses would get their meds.
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If the price of quinine fell, the Kina Bureau would order cinchona plantations destroyed, quinine held off the market, or bans on the export of planting material.
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There wasn’t much that national governments could do about this, let alone the average fever patient. In 1927, the U.S. Department of Justice prosecuted the Kina Bureau for violating U.S. antitrust laws,
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and staged a dramatic raid on a New York warehouse holding five tons of Kina Bureau’s quinine, which the authorities seized and locked away at an army base in Brooklyn. A federal grand jury convened to consider the charges against the Bureau
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and indicted several Dutch leaders.
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But it was all just so much empty bluster. None of the alleged criminals of the Kina Bureau showed up for any of the proceedings, nor did they attend a showdown meeting U.S. authorities organized at the American embassy in Paris.
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“Representatives of the Kina Bureau, whose presence was essential to the gayety of the party,” a 1934 issue of
Fortune
magazine snarkily noted, “politely declined to eat cake at the American Embassy.” The meeting disbanded in humiliation, and the Justice Department agreed to file a “consent decree” with the Kina Bureau, although, as
Fortune
pointed out, “just who did the consenting, and to what, meant very little to anyone.”
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The Kina Bureau remained, as quinine historian M. L. Duran-Reynals wrote, “in absolute command of the situation.”
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While the Dutch cinchona planters enjoyed 36 percent profit margins, according to a 1934 investigative report in
Fortune
magazine,
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nine out of ten malaria victims fevered and chilled oblivious to the bitter taste of quinine, their coffers too modest to pay the Kina Bureau’s price.
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•    •    •

Lest one suspect the Dutch of some special craftiness, the British failed to adequately distribute the quinine they grew, too.

The Raj grew their own pirated cinchona in colonial India’s Nilgiri Hills. Having acquired seeds of relatively quinine-poor cinchona, their plantations never produced much.
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What little they made, the Brits deposited into small packets and sold to local street vendors and retailers, for resale to the malarious masses.
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And there, too, needs were not being fulfilled. In 1907, researchers at the Calcutta Medical School found that up to 25 percent of the government-sourced quinine doses available for sale were understrength, most likely adulterated by retailers.
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Caveat emptor.

In the end, no province in the British Raj ever provided more than 650 milligrams of quinine per person per year, about one third the quantity necessary to treat a single bout of malaria
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; some, such as the Northwest Province of Punjab, provided just 70 milligrams per person per year. The similarly desiccated private quinine market in India sold about 100 milligrams a year per capita.
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To take on
Plasmodium
, which killed roughly two million a year in India alone, they’d need a whole lot more quinine than that.
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Price, supply, distribution: these weren’t the sole obstacles to effective deployment of quinine against malaria. Effective dosing of quinine eluded doctors and patients for centuries. Before the French chemists Pelletier and Caventou figured out how to extract quinine from cinchona bark, people simply consumed the bark itself, scraped off the tree, pulverized, and (sometimes) dissolved in liquid. This practice ensured a highly variable quantity of quinine in the treatment. If it was the right species of cinchona tree, at the right age, there might be some quinine inside the powder. But if it was the wrong species, or the right species but the wrong age, there could be none at all. Unsurprisingly, sometimes the bark worked, sometimes—
as in the case of Britain’s Charles II, who died of malaria in 1685, despite taking cinchona—it didn’t.
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Even after doses with relatively standard quantities of quinine became available, problems with effective dosing lingered. Some clinicians in Europe and the United States felt quinine should be reserved until late in the disease; others argued for tiny doses; still others for bloodletting instead.
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The recommended prophylactic dose of quinine during the 1850s—based, perhaps, more on economics than on pharmacology—hovered around a measly 2 grains a day, or about 120 milligrams.
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That’s perhaps a third of the dose later proven effective for malaria prevention.
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The missionary doctor David Livingstone traveled through Central Africa between 1850 and the 1870s. Not surprisingly, Livingstone found that despite taking the low dose religiously, some of his party fell ill with fever. When Livingstone encountered a comatose Portuguese officer in what is now southern Mozambique, he rakishly tried something different: massive doses of 30 grains, or 1.8 grams. One can only imagine how this might have appeared to his medical colleagues. Reckless, perhaps. In fact, this is roughly the quantity of quinine considered necessary to treat an adult falciparum case today. Livingstone knew he was onto something.

A national celebrity for his exploits in Africa—people followed him around London asking for his autograph—Livingstone had the kind of panache that could grab the attention of the sclerotic medical establishment.
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Even after heroic quantities of quinine failed to revive his beloved wife, Mary, dying of malaria in a tent pitched along the Zambezi River, he brokenheartedly continued his advocacy for higher doses of the drug.
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In time, both the British and the U.S. military came to adopt high-dose quinine therapy as standard treatment for their troops.
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If the distributors of quinine failed to disseminate enough of the drug, and the scientists and doctors often failed to expertly administer
it, it’s only fair to point out that the patients failed, too. Too often, people would simply refuse to take the drug, even when it was given freely and at effective doses.

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.
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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.
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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.
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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.
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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.”
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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.
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But the “divine medicine” didn’t seem so exalted to the locals.
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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.
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