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Desperately seeking manufacturers without taking royalty fees. s As a result, Atabrine was soon produced by The threat drove the Allies’ WWII other pharmaceutical companies, includ- “Cinchona Mission”. ing Abbott, Lilly, Merck, and Frederick Stearns. Intermediates that were no longer BY VASSILIKI BETTY SMOCOVITIS available from Germany were supplied by The outbreak of the Second World War Commerce Jesse Jones thought the price chemical companies such as Harmon Color saw Allied troops ill-prepared to deal with of quinine was too high. He refused to Works, Hilton Davis, the National Aniline war in malarial zones. By 1942, as with secure enough of the drug even though the Division of the Allied Chemical and Dye its famous cinchona plantations—and the Office of Foreign Economic Administration Corporation, and the Pharma Chemical largest quinine factory in the world, the had ordered him to stockpile strategic mil- Company. As a result of the concerted Banfoengsche Kininefabriek—fell to Japan, itary materiel, including medicines like qui- effort, the U.S. wartime production of the Allies found themselves cut off from the nine, along with rubber, nitrates, and tin. Atabrine in 1944 reached 3.5 billion tablets. world’s largest producer of quinine. The Caught largely unprepared, the United But the troops refused to take it. German Army had already taken over Drastic conservation measures for the world’s main supplier and repository quinine were adopted at home. The War of processed quinine run by the Dutch Production Board restricted the use of Kina Bureau, the cartel that monopolized quinine and other antimalarials to the quinine distillation, when it took over treatment of malaria. But it was clear that Amsterdam in 1940. such actions were not enough. As World War II spread to the Pacific In response to the crisis, the United theater, more Allied troops fell to malaria States began a massive effort to provide than to Japanese bullets. By December quinine to American troops. The best 1942, more than 8500 U.S. soldiers were option appeared to be to procure species hospitalized with malaria. In one hospi- native to Andean and tal, as many as 8 of every 10 soldiers had then to cultivate plantations of the high- malaria, not war-related injuries. An est-yielding crops. In April 1942, qui- Army Air Corps count of hospital admis- nine procurement was placed under the sions made between November 1942 control of the Board of Economic and February 1943 made a disturbing Warfare, a U.S. government wartime projection: If left unabated, in just one agency that had charge of the accumu- year as many as 4 out of every 10 soldiers lation of strategic materials. Shortly would be hospitalized for malaria alone. thereafter, what became known as the Synthetic antimalarials such as those Cinchona Mission was established under that would eventually be trademarked the Board of Economic Warfare with “Atabrine” were available during the the cooperation of the Department of war. Atabrine had originally been manu- States entered the Pacific theater without Agriculture and the National Arboretum. factured by the German industrial giant an adequate amount of the best antimalar- William C. Steere, a botanist from the I. G. Farben from coal tar in the early 1930s. ial agent available. University of Michigan, and F. Raymond But Atabrine lacked the efficacy of quinine In the United States, significant amounts Fosberg, a botanist with the Department and caused horrible side effects like nau- of the less desirable Atabrine became avail- of Agriculture, were enrolled to help organ- sea, diarrhea, headaches, and yellow-tinged able through Winthrop Chemical Company. ize the procurement process. skin; if that weren’t bad enough, Japanese Winthrop had been a partner with I. G. The principal cinchona-producing coun- propaganda spread the rumor that it caused Farben but severed its ties to the German tries of the 19th century were approached, impotence. U.S. troops would go to great giant through the Alien Properties Act just and “cinchona agreements” were drafted. lengths to avoid taking the bitter pill. The before the bombing of Pearl Harbor. Using The countries agreed to “sole buying priv- lack of an adequate and stable supply of a intermediate chemicals imported from ileges” for all cinchona if it had a fixed usable antimalarial agent thus became a vital Germany, it was producing some minimum total crystallizable con- national security issue. The United States 5 million tablets of Atabrine at the outbreak tent, which varied from 2 to 3% minimum. had failed to stockpile adequate amounts of of war. Winthrop increased production and The countries agreed to give technical aid

ILLUSTRATION: HUNT INSTITUTE FOR BOTANICAL DOCUMENTATION, CARNEGIE MELLON UNIVERSITY quinine when it should have. Secretary of then licensed the production process to in the exploration and procurement of cin-

 2003 AMERICAN CHEMICAL SOCIETY MAY 2003 MODERN DRUG DISCOVERY 57 dthetimeline

chona, and in return the United States was so that the bark could be airlifted. Detailed were soon harvested, and botanists expected to establish a permanent cinchona reports were produced, which included had to survey more and more remote areas. plantation program in the host country. geographical data of the cinchona areas The botanists experienced altitude sick- The first procurement team left in the fall where plantation development was desirable ness at collecting sites as high as 11,000 ft of 1942 for , which had been the and feasible, and other commercial infor- and suffered from the high humidity, which chief provider of quinine in the 19th cen- mation valuable in addressing the immedi- rotted their clothes and damaged their tury. Cinchona missions were then estab- ate problem of harvesting and transportation. instruments. They also suffered from mal- lished in and , but , the Collection was more difficult than any- nutrition, amoebic dysentery, and even first source of quinine-rich bark, never rat- one had realized. Cinchona frequently malarial fevers. One botanist, Arthur ified the agreement. It had agreed to send hybridized with diverse strains and with Feathersonhaugh, died of a heart attack its cinchona bark to the Dutch Kina Bureau numerous varieties that contained vary- induced by the high altitude. His body was instead. Nevertheless, the Board of ing amounts of . Chemical tests carried on a stretcher in a dangerous trek Economic Warfare established agents in La soon determined that there were varia- down a precipitous slope. Paz to arrange for the purchase of surplus tions in type and amount of the alkaloid in The botanists hunted for two years. quinine and quinine bark. Besides the Then, in 1944, synthetic quinine (in a non- agreements with those countries in which Cinchona, the source stereoselective mixture) was synthesized cinchona trees are native, agreements were of quinine and other from precursors by two American scientists, made with Costa Rica and Guatemala. antimalarial alkaloids, is William E. Doering of Columbia University Cinchona plantation programs had been ini- an and Robert B. Woodward of Harvard tiated as early as 1934 by the pharmaceu- ( Cinchona) native to University. Although it was not made avail- tical company Merck, which had explored mountainous areas of South able for commercial purposes, it eventually the cultivation of cinchona plantations in and . The tree led to more synthetic drugs that, although Guatemala in an attempt to gain control of was named for the Spanish lacking the ability to cure malaria, were able the Dutch monopoly in Java. Its nurseries Countess of Chinchón, said to control various stages of the disease. As and laboratory became enrolled in the to have been cured of a fever a result of the improvement of such syn- wartime procurement effort. in 1638 by a preparation thetic antimalarial agents, the U.S. cin- The work of the cinchona missions of the bark. chona missions returned home at the end involved hunting for the quinine-rich strains of 1944, after having shipped back some 12.5 first found in the Andes. The survey teams individual based on their location. million lb of cinchona bark. In November consisted of a botanist, a forester, and local Barks were classified into good bark and 1945, all agreements with the South Latin assistants who were to be trained in bad bark, depending on their usefulness, American governments for the collection the collection of cinchona. At their peak, the but quick and easy tests based on color or of bark were terminated. Overall, the cin- cinchona missions involved as many as 30 taste quickly proved unreliable. Many of the chona missions met with mixed success. American botanists. For more than two botanists, too, had never seen tropical They provided a significant quantity of cin- years, beginning in 1942, these teams tra- plants in situ, let alone been trained to chona for the Allied war effort, but they versed known cinchona regions of the quickly identify such a complex genus. were never able to locate the high-quinine- Andes, finding, in addition, several previ- The American foresters were equally baf- yield species Cinchona ledgeriana. ously unknown bark areas. fled; they could easily recognize their own Botanists on the team were expected to native trees but initially had a hard time rec- Editors’ note: Gilbert Stork and co-workers completed the first total stereoselective syn- identify and collect cinchona. They also col- ognizing and working with cinchona. Nor thesis of quinine in 2001. lected related Rubiaceous genera that might could the local people easily recognize the prove useful in breeding programs. The plants. Despite some residual harvesting of Sources task of the foresters was procurement, esti- bark in Colombia and Ecuador before the Hodge, W. H. Econ. Bot. 1947, 1–2, 229–257. Howard, R. A. Bot. Rev. 1994, 69, April–June, mation of bark volume, and determination wartime need, the local people lacked spe- 197–257. of best harvesting procedure. Once pro- cial skills at stripping or shipping the bark. Rosengarten, F. History of the Cinchona Project of cured, the bark was transported back to one To prepare the botanists, foresters, and Merck and Co., Inc. and Experimental Plantations, 1934–1949; Merck: Rahway, NJ, of the field laboratories in Bogotá, Colombia; local collectors and to help train a perma- 1944. , Ecuador; , Peru; or La Paz, nent staff, Department of Agriculture Wor then, D. B. Pharmacy in History 1996, 38, Bolivia. The work was arduous. Indian pack- botanist Fosberg wrote The Cinchona 143–147. men or bark-cutters called cascarilleros Manual and translated it into Spanish. This article is adapted from Today’s Chemist were hired to transport 40–80 lb of the bark Other problems ensued. The survey at Work, 2000, 1, 69–72. on their backs along narrow trails. teams encountered hostile local peoples. Vassiliki Betty Smocovitis is an associate pro- Occasionally, mules were used to transport Rivalries soon broke out among the local fessor in the department of history at the University of Florida. Send your comments or bark to the nearest rivers for further trans- collectors, the landowners, and govern- questions about this article to [email protected] port. Landing strips were sometimes built ment collecting agencies. Easily accessible or to the Editorial Office listed on page 3. o

58 MODERN DRUG DISCOVERY MAY 2003