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Profile of William C. Campbell, Satoshi�Omura, and Youyou Tu, 2015 NobelLaureates in Physiology or MedicineWhere new drugs come from: A Nobel tale of ancient Chinese texts and aJapanese golf course

Wesley C. Van Voorhisa,b,c,1, Rob Hooft van Huijsduijnend,and Timothy N. C. WellsdaCenter for Emerging and Re-emerging Infectious Diseases, Division of Allergy and InfectiousDiseases, Department of Medicine, University of Washington, Seattle, WA 98195-6423;bDepartment of Global Health, University of Washington, Seattle, WA 98195-6423;cDepartment of Microbiology, University of Washington, Seattle, WA 98195-6423; anddMedicines for Malaria Venture, 1215 Geneva, Switzerland

Nobel Prizes are intended for “those who (...)shall have conferred the greatest benefit to man-kind,” as stated in Alfred Nobel’s will. The 2015Prize in Medicine, for William C. Campbelland Satoshi �Omura for one half and YouyouTu for the other half, for novel therapies againstroundworm infections and malaria, respec-tively, fulfils this criterion particularly well.

Miracle Worm Drug from the Rough ofthe Golf CourseNobel Prize winner Satoshi �Omura says thatalong with a picture of his wife and daughter,

he always carries a small plastic specimen bagwherever he goes. This habit of collectingenvironmental samples led him in 1970 tocollect NRRL 8165, the mold later namedStreptomyces avermectinius, from the woodsclose to a Japanese golf course. Extracts fromit and other tens of thousands microbescollected by �Omura and his colleagues at theKitasato Institute in Japan were sent to theMerck Institute for Therapeutic Research inthe United States for testing in the laboratoryrun by his co-Nobel Prize winner, William C.Campbell. There, the extract of S. avermectinius

was found to have remarkable effects oneliminating a Nematospiroides dubius nema-tode infection in mice, in an antihelminthicscreening test. The extract was fractionated,and macrocyclic lactones were found tobe responsible for the activity, with theAvermectin B1a component having theleading activity (1). Campbell’s group showedthat Avermectin B1 had potency and safetysuperior to all known antihelminthic thera-pies at the time, capable of resolving a widevariety of animal nematode (roundworm)infections (2). Merck chemists made a minorchemical modification to Avermectin B1 tocreate ivermectin, which was marketed in1981 for animal use. Beyond infections withnematodes, such as heartworm in dogs, anddozens of other worm species in commerciallivestock, ivermectin has potent effects onkilling ectoparasitic insects, such as fleas andticks. Ivermectin was and is a “blockbusterdrug” in animal medicine, and remains oneof the most effective, potent, and safe anti-parasite drugs for animal use.

Human Side of Ivermectin: Merck’s RoyVagelos Pledges to Do the Right Thing.In addition, ivermectin had great potential forhuman helminthic infection. After Campbell’sgroup found ivermectin had great activityagainst Onchocerca infection in horses, hehypothesized the compound could also beuseful in treating river blindness in humans,caused byOnchocerca volvulus.Onchocerciasis,or river blindness, is the second most commoncause of blindness, after trachoma. It alsocauses a debilitating, chronic skin diseasedue to inflammation caused by microfilariareleased from adult worms. Mohammed Azizof Merck led the clinical trials that con-firmed Campbell’s hypothesis that ivermectinwould be effective for onchocerciasis, andremarkably so. A single dose of ivermectin led

William C. Campbell. Image courtesy of Corbis Images, copyright Brian Snyder/Reuters/Corbis.

Author contributions: W.C.V.V., R.H.v.H., and T.N.C.W. wrote the paper.

The authors declare no conflict of interest.

1To whom correspondence should be addressed. Email: Wesley@uw.edu.

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to a dramatic reduction in microfilaria burdenin humans, with amelioration of disease. Onedrawback was that ivermectin did not killadult worms, which would resume microfi-laria production after about six months; thus,about six to eight repeated doses at six-monthintervals are necessary. Nonetheless, no drugcame close to ivermectin’s safety and efficacyfor river blindness. In October of 1987, RoyVagelos, Merck’s Chief Executive Office,made the unprecedented decision to donateas much Mectizan, alias ivermectin, as wasneeded, for as long as it was needed, to any-one who needs it. Merck still stands behindthis decision today, providing ∼300 milliondoses annually of ivermectin for the controland eventual eradication of river blindnessand, more recently, for lymphatic filariasis(elephantiasis), another human helminthicdisease that ivermectin treats effectively.

Ivermectin and Elimination Campaigns.The deployment of ivermectin, coordinatedby the Carter Center and Pan AmericanHealth Organization, has led to river blind-ness being eliminated from three of sixcountries in the Americas as certified by theWHO, whereas transmission was halted ina fourth. Today transmission has been re-stricted to the Amazonas region of Braziland to Venezuela.* In Africa, where thedisease was much more prevalent, rates ofinfection are down fivefold, and in 2014,most African countries with endemic in-fection decided to move from river blindness

control with annual doses of ivermectinto elimination campaigns with twice-annualdosing (3). Moreover ivermectin has re-cently been used in elimination campaignsfor lymphatic filariasis, greatly reducing thenumbers of human cases as well (4).

Beyond Ivermectin. Fortunately, human hel-minthic resistance to ivermectin has not (yet)emerged despite the large-scale campaignsundertaken, and it remains effective for riverblindness and lymphatic filariasis. However,ivermectin resistance has emerged in someanimal helminths, prompting agencies suchas the Bill & Melinda Gates Foundation,Drugs for Neglected Diseases Initiative, andpartners to seek new drugs for river blindnessactively. In addition, a drug that kills adults(macrofilaricidal) is actively sought because itwould simplify elimination campaigns, whichnow require twice-annual mass administra-tion of ivermectin for at least several years toeliminate infection and transmission.

Rediscovery of a 1,700-Year-Old Long-Forgotten Malaria CureOn May 23, 1967, China set up secret militaryProject 523 to identify new medicines thatcould be used against malaria. This strategicobjective was important, not only for theeradication of malaria but also to supporttroops during the Vietnamese war, who diedmore frequently from mosquito bites thanfrom bullets. It is noteworthy that many of theother antimalarial medications come from thisperiod, with both the Chinese and the Amer-ican military investing significantly to protecttroops in Southeast Asia. The project startedfrom over 2,000 Chinese herb preparations,

which were tested against infected erythro-cytes: Continuous culture of parasites did notcome until a decade later (5). One of the plantextracts was taken from an ancient text calledEmergency Prescriptions Kept Up One’s Sleeve,from Ge Hong (A.D. 284–346), who recom-mended to take a handful of qinghao (the“blue-green herb,” which refers to Artemisiaspecies, including A. annua or sweet worm-wood) immersed in 2 L of water for patients todrink. The initial results were difficult to re-produce, but Tu discovered that cold, not hot,water was to be used for extraction (laterreplaced by ether). With this extractionmethod, the team obtained good, reproducible,biological activity. The first (modern) humansubject to test qinghao in 1971 was Youyou Tuherself, with preclinical safety testing not beingpractical during the Chinese cultural revolu-tion. With the safety of the drug shown, itsefficacy was proved on patients in Hainanprovince. Spurred on by this success, the teamthen went on to purify the active ingredient,known as qinghaosu, or artemisinin, andcharacterized its surprising structure as asesquiterpene lactone in 1975.

Road to a Medicine. The work was onlypublished in 1977, by the “CollaborationResearch Group for Qinghaosu” (listing noindividual contributors) in Chinese (6); how-ever, by 1981, it was presented at the WHOworking group meeting on chemotherapy andentered the mainstream literature in 1982 (7).By then, the conflict in Vietnam was over, andthe control of malaria in Hainan province hadalso been mainly achieved using older medi-cines that were based on quinine. Herbalmedicine from Pre-Columbian Peru had de-livered quinine, but medicinal chemistry im-proved on quinine to make chloroquine andits followers. The path was long from thescientific breakthrough discovery of artemisi-nin to a new medicine that would save thelives of millions of children, whereas olderantimalarials were lost one by one to re-sistance (8). New variants of artemisininwere developed, such as the methyl etherartemether, which is soluble in oils. Later,the hemisuccinate ester prodrug of arte-misinin, artesunate, was developed. Thisderivative more easily produces stable for-mulations, and it is also more soluble thanartemether. In 1994, Novartis signed anagreement with the Beijing Academyof Military Medical Sciences to developartemether-lumefantrine. This process en-tailed many early clinical trials, and demon-strated that moving from a two-day regimen toa three-day regimen increased efficacy from83% to well above the 95% seen today. Muchwork was needed to develop an appropriateformulation; these combinations had to bestable under conditions of high temperature

Satoshi �Omura. Image courtesy of Satoshi �Omura.

*Sauerbrey M, Progress Toward Onchocerciasis Elimination WithEmphasis in the Americas, IDWeek 2015, October 7–1, 2015,San Diego, abstr 681.

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and humidity for over two years. This workled to the medicine becoming available, andanother landmark agreement with the WHOin 2001, which resulted in over 250 milliontreatments being delivered over the followingseven years. Clearly artemisinin derivativeswere a powerful ally, but knowing how readilyother treatments had succumbed to re-sistance, the WHO decided to advise againstthe use of artemisinin monotherapy, withWHOmember states adopting World HealthAssembly resolution WHA60.18 in 2007.Artemisinin was to be used in fixed-dosecombinations, for its own protection, withother existing medicines, such as lumefantrineand amodiaquine, and, later, mefloquine,piperaquine, and pyronaridine. These medi-cines have now been developed by the phar-maceutical industry in product developmentpartnerships with the Medicines for MalariaVenture (MMV) and Drugs for NeglectedDiseases Initiative (reviewed in 9). All theseproducts have now been approved by astringent regulatory authority and are avail-able at low prices to developing countries, withtheir quality underscored by the WHO’s pre-qualification program (apps.who.int/prequal/query/ProductRegistry.aspx). A reasonable es-timate is that a billion treatments have beenproduced, and these treatments have hada massive impact on malaria disease-endemiccountries. The latest efforts aim at developingmore child-friendly formulations, with taste-masking and sweetening to mask the bittertaste of both artemisinin and the partner drug.Even though the cost of a medicine to treat

a child is between $0.25 and $0.60, this costis still far higher than the cost of earliergeneration medicines, such as chloroquine.Two directions have been taken to reducethe bulk price below its long-term averageof $400 per kilogram. First is the generationof semisynthetic artemisinin: although denovo synthesis is still too complex to becompetitive, despite progress in this area(10), the precursor, artemisinic acid, can bemade in genetically engineered yeast cells(11) and converted into artesunate. Althoughthis process is not cheaper than producing thedrug from cultured Artemisia plants, it meansthat the lead time to generate large batches ofmaterial can now be measured in weeks ratherthan the usual 18 months. This drug avail-ability should lead to the end of the wild priceswings in raw material costs over the pastdecade. An alternative approach was to designand synthesize new synthetic endoperoxides,originally pioneered at Roche in the 1990s(12), leading to the development of OZ277and OZ439 in an academic collaboration co-ordinated by the MMV (13). OZ277 has beenlaunched in India as part of Synriam byRanbaxy; OZ439 is in clinical trials (14).

Severe Malaria, Chinese Medicine fromChina. Artemisinin has an extremely rapidmode of action, and so it clearly also hadpotential for treating severe malaria, wherethe blockade of brain capillaries with infectederythrocytes may result in coma and death.Two major clinical studies showed that i.v.artesunate was superior to i.v. quinine interms of lives saved, both in Africa and Asia(15, 16). The challenge back in 2009 was toensure a high-quality producer of artesunatefor injection. Guilin Pharmaceuticals took onthe challenge, and for the past five years, ithas been the world’s sole producer of arte-sunate for injection for the treatment of se-vere malaria. With over 30 million vialsdelivered over the past four years, poten-tially saving almost 200,000 lives, Chinesemanufacturing has therefore come to the aidof a Chinese product, completing the cycle.

So HowDoes It Work?Using MS, Meshnicket al. (17) discovered that artemisinin generatesheme adducts, which may interfere with themalaria parasite’s detoxification/polymerizationof heme following hemoglobin digestion.Several other molecular targets have beenproposed, including PfATP6 (18), and it islikely that artemisinins have multiple modesof action associated with their free radical-generating capabilities. This pleiotropic ac-tivity likely contributes toward the drug’sresilience against the emergence of resistance.Nevertheless, in 2008, the first reports ofresistance to artemisinin came in from theThai-Cambodian border region (19, 20),although later longitudinal studies showthat resistant Plasmodium strains alreadyexisted almost a decade earlier (21). It tookseveral years before genetic markers couldbe found that correlate with resistance, allof which, so far, occur in one genetic locus,Kelch13 (22). The phenotype of resistance isstill subtle, resulting in a twofold increase inthe time artemisinin takes to clear the para-site in patients. This fact makes the task oflinking the genetics to the molecular mech-anism of resistance a considerable task, andone that is still to be completely solved (23).In addition to its activity against malaria,

artesunate and dihydroartemisinin may haveanticancer activities. An effect on tumor cellshas been described by many authors (24),although only a few have followed thisreported effect up with clinical trials (25).Two researches, Krishna and Kumar ofSt. George’s University in London, haverecently initiated a crowd-sourcing cam-paign to test artesunate in bowel cancer.The path to the discovery of artemisinin il-

lustrates several important points. It empha-sizes the importance of early testing ofdecoctions for their activity in patients. Thisconcept was suggested in 1952 by Chen

Guofu, labeled dao-xing-ni-shi, or “acting inthe reversed order”; namely, clinical and thenanimal studies, structure elucidation, resyn-thesis, and retesting, followed by structureoptimization (26). The idea that a simpleactive ingredient could be identified fromtraditional Chinese medicine required beingable to see the world from both the traditionalChinese perspective and a Western approach,and holding those two ideas in tension.Linking both discoveries, the “wonder

drug” ivermectin, incredibly, is a double-edged sword that also kills malaria-trans-mitting mosquitoes that feed on individualswho have taken the medicine, preventingtransmission of the disease (27, 28). Due tothis activity as an endectocide, the drug hasbeen proposed for use in vector control andmalaria elimination (29).The omitted text in the earlier citation

from Nobel’s will adds “...during the pre-ceding year. . .,” a clause that is wisely ignoredby Nobel Committees. Even with 40–50 yearsof hindsight since the discovery of these twodrug classes, it is difficult to quantify theirimpact precisely in terms of millions livessaved, and cases of blindness and othermisery averted. A recent analysis estimatedthat in Africa alone, artemisinin combinationtherapies have averted 146 million malariacases since 2000 (30). Nobel Prizes are rarelyscored by impact, but were there ever to be apopular vote, this year’s Prize in Medicinewould be outranked by few others.

Youyou Tu. Image courtesy of Han Haidan/CNSPHOTO/ChinaFotoPress via Getty Images.

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21 Phyo AP, et al. (2012) Emergence of artemisinin-resistant malariaon the western border of Thailand: A longitudinal study. Lancet379(9830):1960–1966.22 Ariey F, et al. (2014) A molecular marker of artemisinin-resistantPlasmodium falciparum malaria. Nature 505(7481):50–55.23 Mbengue A, et al. (2015) A molecular mechanism of artemisininresistance in Plasmodium falciparum malaria. Nature 520(7549):683–687.24 Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR(2001) The anti-malarial artesunate is also active against cancer. Int JOncol 18(4):767–773.25 Krishna S, Bustamante L, Haynes RK, Staines HM (2008)Artemisinins: Their growing importance in medicine. TrendsPharmacol Sci 29(10):520–527.26 Lei SH-l (2014) Neither Donkey nor Horse: Medicine in theStruggle over China’s Modernity (Studies of the Weatherhead EastAsian Institute), (Univ of Chicago Press, Chicago).27 Chaccour C, Lines J, Whitty CJ (2010) Effect of ivermectin onAnopheles gambiae mosquitoes fed on humans: the potential of oralinsecticides in malaria control. J Infect Dis 202(1):113–116.28 Kobylinski KC, et al. (2010) The effect of oral anthelmintics onthe survivorship and re-feeding frequency of anthropophilic mosquitodisease vectors. Acta Trop 116(2):119–126.29 Chaccour CJ, et al. (2013) Ivermectin to reduce malariatransmission: A research agenda for a promising new tool forelimination. Malar J 12:153.30 Bhatt S, et al. (2015) The effect of malaria control onPlasmodium falciparum in Africa between 2000 and 2015. Nature526(7572):207–211.

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