The Fever Page 10
Good drugs—some half as effective, twice as expensive, three times harder to get—have vanquished countless other scourges, from leprosy to rheumatic fever. But despite the range of effective parasite-killing drugs in our arsenal, despite the world being awash in antimalarial medications, malaria flourishes. In the battle between Homo sapiens and Plasmodium, the parasite is winning. It has eluded attempts to capture it by drug every time.
Our use of medicines to treat malaria dates back to the beginning of human history. Long before the first mosquito bit a human, plants waged a silent, slow-motion war against insects, microbes, and rival plants by producing toxic chemicals.4 They produce them in their leaves, stems, roots, and barks, and exude them when cut, or attacked from within. The liquid drips and chemical pongs of these silent, primeval green battles play out all around us.
Since the earliest times, we’ve consumed plants to harness the pharmacological potency of their chemicals (called secondary compounds to distinguish them from those primary compounds that do the work of brute survival). The secondary compounds of plants such as belladonna, poppy, and foxglove—aka atropine, opium, and digitalin—captivate human biochemistry in powerful ways, too.
In the normal course of things, malaria parasites that live inside insects, mammals, and birds don’t encounter these botanical bio-weapons. But some of those compounds dripping down leaves and branches can do serious damage to malaria parasites. Perhaps it’s just a side effect. Then again, 10 percent of the parasite’s five thousand proteins retain their algaelike chemistry and remnant chloroplasts. In an earlier life, Plasmodium photosynthesized, too.
The shrub mululuza is one of many plants with secondary compounds that provide relief from malaria. Chimpanzees chew on its bitter leaves, as did our African ancestors, suggesting the curious idea that our knowledge of botanical malaria medicines—like malaria itself—may have survived the evolutionary hop from ape to human.5 Clove, nutmeg, cinnamon, basil, and onion similarly all assuage Plasmodium’s appetite, making the body’s repair of damage from free radicals—oxygen molecules untethered to hemoglobin—more difficult. This, paradoxically, can help destroy malaria parasites by exposing infected cells to the armies of free radicals that malaria infection unleashes, and may explain why for millennia people sought out and added these nutritionally empty products to their diets.6
One of the very best drugs for malaria can be found thousands of miles away from malaria’s African cradle, in the bark of the cinchona, a tree that clings to the slopes of the Andes. Like mululuza and basil, cinchona bark started out as a traditional medicine used by the locals for myriad ailments involving fever and chills.7 The bark teems with complex alkaloids, most likely used by the tree to defend itself against pathogens and herbivores.8 One of them, quinine, has a striking effect on the Plasmodium parasite, interfering with its digestion of hemoglobin. The result: the feasting parasite is poisoned with the undigested toxic residue of its own meal.9 While it can’t prevent malaria infection, quinine circulating in the body can prevent and mitigate illness.
Quinine dropped upon a world beset by malaria like rain on a dry sponge. “Had our bread failed, our wells and the river dried up, we could have endured it,” wrote one typical nineteenth-century quinine enthusiast from Michigan. “But to be without cathartic pills and quinine . . . was worse than a bread and water famine.”10 The drug was considered a “sovereign remedy,”11 a “divine medicine.”12 And when, finally, in the nineteenth century, quinine was made widely available, the Brits were at last able to penetrate malarious Africa. Historians credit the drug, along with filtered water, for Britain’s successful 1874 offensive against the Asante Empire in Ghana,13 ushering in a brief but long-awaited period of European colonization of the African continent.14
But despite being a wonder drug for malaria and nearly a half-millennium of usage, quinine barely made a dent in the global burden of malaria.
Jesuit missionaries who’d noticed the bark’s effect against the disease in South America introduced it into malaria-plagued European society in the 1630s.15 Malaria ran rampant in Europe, and cinchona bark was quite possibly the best and most effective medicine ever known. Most of the other medicants then available, such as opium, had a vague, generalized effect on illness. In contrast, cinchona bark could cure malaria effectively and with surgical precision.16
It took fifty years for it to gain its rightful stature. Having been introduced by the Jesuits, cinchona fell under a cloud of anti-Catholic sentiment. The Protestant English scoffed at the bark, deriding it as “Jesuit’s powder.” Elites such as Oliver Cromwell, who successfully led the bloody overthrow of the British monarchy, pointedly eschewed the bark. He died of malaria in 1658, twenty years after the Jesuits brought cinchona to Europe.17 European elites did, however, approve of a remedy called “Talbor’s Wonderful Secret,” which everyone, from the son of Louis XIV to the Queen of Spain, extolled. Word got out that the secret remedy got its kick from cinchona, aka the reviled Jesuit’s powder, in 1682.18
The trouble was, only the tiniest trickle of the stuff could be had. Up until the late nineteenth century, worldwide demand for cinchona mostly had to make do with whatever bark could be stripped off the wild cinchona forests in the far-off and perilous Andes.19 Political rulers in the region considered the cinchona tree to be their exclusive property. Nevertheless, European entrepreneurs and explorers eager to produce their own lucrative stands of cinchona repeatedly attempted to pirate the seeds out of the Andes, with a nearly comic chain of calamities.20 The tree and its seedlings, accustomed to steep, forested mountainsides, proved too delicate for long, dank sea voyages across the Atlantic. If it wasn’t the heat, piracy, and theft, fires and storms foiled their attempts.
Shortages reigned. Even the most richly endowed enterprises—the American war effort against Britain, the British drive to end the African slave trade—had to ration their quinine. During the American Revolution, the Continental Congress managed to acquire a paltry three hundred pounds of the bark. George Washington’s bout of malaria got eight doses of bark, but the regiments of soldiers—including New Milford’s Elijah Boardman—had to make do with days of treatment with bowel-purging antimony and mind-dulling opium before their bosses would tap the precious cinchona supply (another reason why Boardman and others sickened on the battlefield and on the trek back home, broadcasting the parasite throughout the land).21
The abolitionist British parliamentarian Thomas Fowell Buxton took “ every precaution which human ingenuity could suggest” to keep healthy on his 1841 expedition up the Niger River to press African leaders to stanch the slave trade.22 But his party, too, had to ration quinine. To prevent malaria, they relied mostly on copious volumes of coffee, reserving their quinine supply for a few shots in their wine.23 (Physicians long suspected that coffee had antimalarial properties, which seemed to explain why coffee-drinking French colonists suffered less malaria than tea-drinking English ones, and may have helped inspire a nation of American tea drinkers to switch allegiances.24) Coffee having failed them, disease and death ran so rampant that the expedition was called back home.
A single day’s worth of quinine, which French chemists Joseph Caventou and Pierre Pelletier had figured out how to extract from cinchona in 1820,25 cost about three dollars between 1830 and 1884, which translates to more than sixty 2006 dollars.26 The moneyed and powerful could at least hoard a few precious grains, but everyday folks had to make do with the cheap knock-offs that littered the market: quinine-spiked pills and potions and chill tonics, which claimed curative powers at a fraction of the price of the real thing. Many of these contained insignificant quantities of quinine, dissolved in copious quantities of alcohol. While not particularly effective at treating malaria, at least they provided plebes with an otherwise verboten drink or two.27
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,28 clearing thousands of acres of mountainous jungles for the seedlings.29 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.30 It didn’t help that wandering Javanese rhinos kept trampling the sprouts.31
The Dutch meticulously fulfilled each of these exacting conditions, even as critics condemned the cinchona plantations as “expensive folly.”32 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,33 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.34 The Dutch had to laboriously deflower thousands of non-Ledger cinchonas around their plantations, forbid farmers from cultivating them ever again,35 and maintain a rigorously pure seed line, from the original seeds, on the government’s estate, for safekeeping.36 “No tree, not even rubber,” mused American horticulturalist Norman Taylor, had “ever had such a long history of patient, intelligent care bestowed upon it.”37
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.38 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.39
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.”40 (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.41 When Mamani spirited those pirated cinchona seeds out of the Andes, government authorities detained and tortured him for twenty days.42
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.43 They set up an agency in Amsterdam called the Kina Bureau, which dictated the terms on which the malarious masses would get their meds.44 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.45
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,46 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 Bureau47 and indicted several Dutch leaders.48 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.49 “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.”50 The Kina Bureau remained, as quinine historian M. L. Duran-Reynals wrote, “in absolute command of the situation.”51
While the Dutch cinchona planters enjoyed 36 percent profit margins, according to a 1934 investigative report in Fortune magazine,52 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.53
• • •
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.54 What little they made, the Brits deposited into small packets and sold to local street vendors and retailers, for resale to the malarious masses.55 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.56 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 malaria57; 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.58 To take on Plasmodium, which killed roughly two million a year in India alone, they’d need a whole lot more quinine than that.59
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.60
Even after doses with relatively standard quantities of quinine beca
me 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.61 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.62 That’s perhaps a third of the dose later proven effective for malaria prevention.63
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.64 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.65 In time, both the British and the U.S. military came to adopt high-dose quinine therapy as standard treatment for their troops.66
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.