FRON­TIER

Chi­nese sci­en­tists of­fer fresh hope in the long quest to erad­i­cate malar­i­a千年抗疟史的新篇章:青蒿素在非洲

The World of Chinese - - Contents - BY LIU JUE (刘珏)

When Tu Youyou was awarded a No­bel prize in 2015 for her work on the an­ti­malar­ial drug artemisinin, she cred­ited a 1,500-year-old Daoist with her find.

Ge Hong (葛洪) , a fourth-cen­tury physi­cian, was search­ing for alchemy in­gre­di­ents when he un­wit­tingly found an al­ter­na­tive path to im­mor­tal­ity. Trav­el­ing through Guang­dong, Ge was in­vited to stay at Luofu Moun­tain by the lo­cal gover­nor, where he started prac­tic­ing and study­ing lo­cal medicine, even­tu­ally com­pil­ing The Hand­book of Pre­scrip­tions for Emer­gen­cies《肘后备急方》( ).

Cen­turies later, a key pas­sage in this an­cient tome in­spired the 2015 No­bel lau­re­ate Tu to study the sweet worm­wood plant for the treat­ment of malaria. Her ef­forts even­tu­ally led to artemisinin, a drug that’s saved hun­dreds of thou­sands of lives.

Now Chi­nese sci­en­tists are hop­ing to use artemisinin-based drugs in co­or­di­na­tion with new meth­ods of tack­ling the dis­ease, in­volv­ing mass drug ad­min­is­tra­tion and source erad­i­ca­tion, in a bid to wipe out the dis­ease en­tirely. It has been a mil­lenia­long bat­tle. A mos­quito-borne trop­i­cal dis­ease that still in­fects nearly 200 mil­lion peo­ple ev­ery year, malaria causes fever, ane­mia, chills, and

headaches, and can lead to or­gan fail­ure and death if not treated prop­erly. Artemisinin—a key in­gre­di­ent of the com­pound drug Arte­quick—is a highly ef­fec­tive com­pound with a close to 100 per­cent re­sponse rate for treat­ing malaria.

Ge’s orig­i­nal pre­scrip­tion in­volv­ing the worm­wood plant, known as qing­hao (青蒿), was picked up from com­mon folk reme­dies and in­cor­po­rated into Tra­di­tional Chi­nese Medicine, be­fore Tu be­gan ap­ply­ing mod­ern sci­en­tific meth­ods to study its ef­fi­cacy and de­velop a drug that could be pro­duced in use­ful quan­ti­ties to tackle malaria’s spread.

But this break­through was still a long way off when Tu and her team be­gan study­ing the dis­ease as part of a top-se­cret mil­i­tary re­search project as­sem­bled dur­ing the Viet­nam War. Sol­diers on both sides had built up re­sis­tance to ex­ist­ing reme­dies like qui­nine and chloro­quine. While the United States was test­ing a new series of syn­thetic drugs, Viet­nam turned to its Com­mu­nist ally China for help.

The year 1967 was hardly the best time for clin­i­cal re­search in China—quite the op­po­site, in fact. Re­search in­sti­tutes across China were in paral­y­sis, and the Cul­tural Rev­o­lu­tion was in full swing. But a di­rect or­der from Chair­man Mao led to the as­sem­bly of a se­cret lead­ing com­mit­tee. Their first con­fer­ence took place on May 23, 1967, in Bei­jing (hence the mis­sion’s co­de­name, “523 Project”). Dur­ing the next 13 years, over 60 sci­en­tific re­search in­sti­tutes, up to 3,000 sci­en­tists, and count­less lo­cal staff and per­son­nel were mo­bi­lized to as­sist the 523 Project—a col­lec­tive ef­fort on a pre­vi­ously unimag­in­able scale. It led to some of the most dis­tin­guished break­throughs in an­ti­malar­ial re­search ever, while pro­vok­ing con­tro­versy over the credit for decades to come.

With lim­ited ex­pe­ri­ence in sci­en­tific re­search and phar­ma­ceu­ti­cal devel­op­ment, the project was later com­pared to find­ing a nee­dle in a haystack. The team was di­vided into sev­eral groups that stud­ied chem­i­cal syn­the­sis, clin­i­cal tri­als, trans­mis­sion, im­mu­nity, TCM, and more. The Guangzhou Univer­sity of Chi­nese Medicine (CUCM) was one of the first in­sti­tutes to join. Led by Pro­fes­sor Li Guo­qiao, the CUCM team was ini­tially as­signed to study acupunc­ture, which turned out to have lit­tle ef­fect on treat­ing malaria. But Li de­vel­oped a deep un­der­stand­ing of the devel­op­ment of malar­ial par­a­sites, and when Tu and her team later suc­cess­fully ex­tracted a pure form of artemisinin, Li was as­signed to study its clin­i­cal tri­als. In 1974, he was able to con­firm artemisinin’s rapid ef­fi­cacy and min­i­mal side ef­fects.

Iden­ti­fy­ing the ex­tract was just the first step. De­vel­op­ing an ef­fec­tive drug that could be pro­duced in use­ful quan­ti­ties was the CUCM team’s next goal— one that turned out to be far more com­pli­cated than pre­vi­ously imag­ined.

Artemisinin and its de­riv­a­tives were mainly in­ef­fec­tive be­cause the seven-day course of oral treat­ment was too long. Most malar­ial epi­demic ar­eas are poor, which means pa­tients usually stop tak­ing med­i­ca­tion once symp­toms fade, to avoid fur­ther costs. Many also share drugs with fam­ily mem­bers to save money, fur­ther un­der­min­ing their use­ful­ness in fully erad­i­cat­ing the dis­ease from the body.

In the 1980s, CUCM be­gan de­vel­op­ing com­pound drugs to shorten the treat­ment to three days. Li’s team pro­duced four gen­er­a­tions of ef­fec­tive artemisinin com­pounds over the next two decades. In 2004, they part­nered with Guang­dong New South Group to found Artepharm, a phar­ma­ceu­ti­cal com­pany de­vel­op­ing and man­u­fac­tur­ing artemisinin-based med­i­ca­tion for the in­ter­na­tional mar­ket. Their prod­ucts in­clude Arte­quick, a com­pound of artemisinin and piper­aquine able to cure malaria with a once-daily, two-day course.

But the over­all goal is pre­ven­tion, rather than cure. Tra­di­tional meth­ods to con­trol malaria—spray pes­ti­cides, re­pel­lent, win­dow screens—heav­ily fo­cus on erad­i­cat­ing or stymieing its vec­tor, the mos­quito. In 1955, en­cour­aged by early re­sults of the pes­ti­cide DDT, the World Health Or­ga­ni­za­tion (WHO) started the Global Malaria Erad­i­ca­tion Pro­gram (GMEP). But GMEP was aban­doned 14 years later, hav­ing achieved no ma­jor suc­cess in Sub-sa­ha­ran Africa, which ac­counts for 80 per­cent of malar­ial in­fec­tions.

For Song Jian­ping, a key CUCM pro­fes­sor who has led sev­eral over­seas an­ti­malar­ial pro­grams in

South­east Asia and Africa, the ef­fi­ciency of projects like GMEP are lim­ited in many trop­i­cal ar­eas. “Lots of the lo­cal houses are not fully en­closed from the out­side,” ex­plained Song, “so not even a screen or re­pel­lent at their en­trances can pro­tect the res­i­dents in­side.” Even if they could, mos­qui­tos in the wild would still pose a threat.

“The in­fec­tion is fluid: When one per­son gets in­fected, even if they are treated dur­ing that pe­riod, they may have al­ready passed it on to some­one else, and that per­son would be­come a new ori­gin of in­fec­tion,” Song told TWOC. “In heav­ily in­fected ar­eas, if the dis­ease can­not be con­trolled quickly and ef­fec­tively, peo­ple will con­tinue to get sick and even die.”

China had gone down the same path, spend­ing vast re­sources on con­trol­ling malaria us­ing tra­di­tional meth­ods, tak­ing decades to pro­duce re­sults in ar­eas along the Yangtze River, Hainan, and Yun­nan prov­inces. The in­ef­fi­ciency spurred GUCM to switch their fo­cus from mos­qui­tos to hu­man hosts, cur­ing the dis­ease while block­ing fur­ther in­fec­tion. This new scheme, named “Fast Elim­i­na­tion of Malaria by Source Erad­i­ca­tion” (FEMSE), costs less than 100 RMB per pa­tient and is con­sid­ered by many to be ideal for heav­ily in­fected ar­eas.

Be­tween 2004 and 2006, Song worked with Cam­bo­dia’s State Min­istry of Health and Cen­ter for Dis­ease Con­trol to pro­mote FEMSE among 28,000 vil­lagers in highly in­fected ar­eas in Kam­pong Speu prov­ince and its pe­riph­eral area, curb­ing mor­tal­ity rates by more than 90 per­cent in area where 95 per­cent of res­i­dents took Arte­quick once a month, for two months.

The big­gest vic­tory so far has been on the is­land na­tion of Co­moros, in the In­dian Ocean, where malaria was the ar­chi­pel­ago’s big­gest pub­lic health prob­lem and cause of death by dis­ease. With the ap­proval of the Na­tional Min­istry of Health and Ethics Com­mit­tee, FEMSE was de­ployed be­tween 2007 and 2013 us­ing mass drug ad­min­is­tra­tion (MDA) on all three ma­jor Co­moros is­lands, slash­ing mor­tal­ity by 98 per­cent. In 2014, there was not a sin­gle death from malaria on Co­moros.

Though sim­i­lar in method to a vac­cine, MDA treat­ment is not with­out crit­ics. “Peo­ple who ask ‘Why give drugs to peo­ple with no symp­toms’ have no idea how malaria works,” Pro­fes­sor Li told Guangzhou Daily, responding to com­plaints that one Ja­panese re­searcher had made to the WHO over Li’s method­ol­ogy in Cam­bo­dia. He be­lieves there are min­i­mal side ef­fects to drugs like Arte­quick. “With the trans­mis­sion model of the dis­ease, hu­man vec­tors are also in a dy­namic sta­tus. To­day there could be 50 peo­ple in­fected and to­mor­row, an­other 50…Only MDA can en­sure the break of the in­fec­tion cy­cle.”

Hav­ing been at the fore­front of both the Cam­bo­dia and Co­moros projects, Song em­pha­sizes the im­por­tance of work­ing with lo­cal groups to fight malaria, who can keep a close watch on the spread of the in­fec­tion. His team trained over 4,000 vol­un­teers on to work with the FEMSE pro­gram who were key to its suc­cess. “Build­ing on decades of solid work, we now have this low-cost, safe, and ef­fec­tive scheme to erad­i­cate malaria,” said Song. “The rest is be­yond sci­ence.”

“WE NOW HAVE THIS LOW-COST, SAFE, AND EF­FEC­TIVE SCHEME TO ERAD­I­CATE MALARIA; THE REST IS BE­YOND SCI­ENCE”

A field of Artemisi­aan­nua in Guangxi helps pro­vide the world with artemisinin, the raw in­gre­di­ent for the lat­est an­ti­malar­ial medicine

Pro­fes­sor Song Jian­ping started his re­search into trop­i­cal dis­ease in 1998, and has since led sev­eral over­seas an­ti­malar­ial pro­grams

Lo­cal vol­un­teers in Co­moros as­sist with the dis­tri­bu­tion of Arte­quick

The di­rec­tor of Dis­ease Con­trol and Pre­ven­tion ex­plains the an­ti­malar­ial scheme to lo­cal vol­un­teers in Co­moros in 2013

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