當瘧疾在北越軍隊中肆虐時，毛澤東命令中國科學家采取行動。
自從奎寧在幾個世紀前被發現之後，中藥青蒿素被廣泛推崇為治療熱帶疾病瘧疾的最偉大進步。
諾貝爾醫學獎正在考慮把青蒿素的發現列為候選名單之一。每年，美國納稅人數百萬美元的錢都通過這種藥物的方式流向非洲。
但是幾乎沒有人知道其背後真實的曆史，這種藥物的發現要感謝毛澤東，當越南人在熱帶叢林中反抗美國人時，他挺身而出采取了行動。而它在中國默默無聞地存在了30年，是因為中國與世隔絕的政策，和西方捐獻者、醫療機構和製藥公司對它漠不關心的態度。
現在，這段曆史浮出了水麵。科學界依然像往常一樣，多名與此有關的人士拚命爭奪這項桂冠。9月份，紛爭達到白熱化程度，一名拉斯克獎----又稱“美國的諾貝爾獎”----獲獎者試圖在數百位參與研製藥物的中國科學家中選取一名。
毛的角色是顯而易見的。
60年代，他收到了越南的求救信息：當地的瘧疾似乎可以抵抗任何藥物的療效，軍隊士大批死亡。他於是命令頂級科學家伸出援手。在接下來的14年裏，來自60個軍方和民用機構的500名科學家致力於這項研究。
與此同時，數千名陷入越南戰爭的美國士兵也感染了瘧疾，沃爾特瑞德研究所也開始了新藥的探索。最終，他們生產出美爾奎寧，進入市場後改名為甲氟喹。
這種藥盡管有強大的效果，但也有嚴重的副作用，包括噩夢和妄想。2003年，幾十名美國海軍陸戰隊士兵在利比亞寧可感染瘧疾也不服用這種藥物，因為有傳言說，幾名2002年從阿富汗回國的特種部隊士兵殺死了自己的妻子，就是這種藥物導致的。
中國的探索之旅開始於1967年5月23日的一次會議，後來根據日期被命名為“523項目”。
研究人士兵分兩路。一組人在已知的4萬類化學品中篩選；另一組人研究傳統的醫學文獻，派人到農村地區，向當地中醫詢問治療發熱的秘方。
中國在幾十年前發現，晚花期、帶有清香味的蒿尾植物中含有青蒿素。
公元前168年的一塊墓碑上提到了一種草藥----青蒿，在後來幾個世紀的古代文獻中都有提到，包括1798年的《季節性發熱之書》。農村的中醫大夫發現了青蒿，也就是西方所謂的黃花蒿，一種葉子細小、開黃花、帶有清香味的蒿尾植物。
在50年代，中國部分農村地區飲用青蒿茶來抵抗瘧疾，但是從科學角度進行研究還從未有過。社會上還至少存在9種具有抵抗瘧疾效果的傳統藥物，包括胡椒。
在實驗室中，從青蒿裏提取出來的物質殺死了白鼠感染的瘧疾病毒。研究人員試圖找到是哪種化學物質起的作用，哪種植物裏含量最多，是否可以跨越血腦屏障對抗腦型瘧疾，以及是否可以製成口服、靜脈注射和栓劑藥物。
老舊的設備拖慢了研究的速度，但是到了70年代，一種核心化學物質已經被人們找到。青蒿素具有一種自然界從未出現過的化學結構，用術語來說，它是具有一個過氧橋的倍半萜烯內酯。在2,000名病人身上的試驗表明它可以迅速殺死寄生蟲。
然而，人體對青蒿素的代謝過快，沒有被殺死的寄生蟲很快又會繁殖。於是科學家把它與更持久的藥物混合，發明出蒿素組合療法（最新的混合型藥物是甲氟喹）。
原523辦公室副主任張劍方在2006年主編的一本曆史資料中，包含了一些引人關注的細節：派別之間的紛爭；文化大革命的街頭武鬥被迫讓試驗轉入地下；醫生在中國南部熱帶山區中進行臨床試驗時，隻能以糙米和蔬菜果腹；其它醫生步行進入胡誌明市治療越共病患。
毛在1976年去世，523項目在1981年正式解散，但臨床工作仍在繼續。
1979年，在香港幫助美軍研究甲氟喹的Keith Arnold博士輾轉來到中國，希望在那裏測試他的藥物。他遇到了正在測試青蒿素變異體的李國橋博士，他們決定進行平行對照研究，結果這種神秘的中國藥物擊敗了Arnold博士的藥物。
很快，國際衛生組織的科學家們紛紛索取中國醫學雜誌上的文章，第一篇文章發表於1977年，回應了一份有關南斯拉夫化學家試驗苦艾的報道。
1941年出版的醫藥曆史中的一張插圖，描繪出奎寧源於金雞納樹，以一位秘魯的女伯爵而命名。
1982年，Lancet發表了一篇中國研究人員的文章。這篇文章獲得了一個獎項，但英鎊支票在中國無法兌現。
Arnold博士說，很快，沃爾特瑞德研究所的科學家就發現波托馬克河岸邊生長的苦艾可以提取蒿素，但是藥物的研究進展極為緩慢。世界衛生組織直到2000年才批準這種藥物，2006年才在市場中大量投放。
多種原因造成了這種延遲----中國當時的政治混亂；中國和海外的研究室都在研究派生產品。共產主義製度下沒有專利法，中國也無法獲取西方專利，因此沒有一家處於壟斷位置的大型醫藥公司可以因此獲利。瘧疾是窮人的疾病，直到今天仍然沒有一家專門以此為目的的基金會。
沒有WHO的批準，救援機構就無法買到藥物。Arnold博士說，多年來，他一直幫助中國的研究人員試圖獲得在泰國和越南進行臨床試驗的批準，但WHO遲遲沒有決定。（作為一家聯合國機構，它從不大膽行事，但在90年代那十年裏，它的辦事效率最低，內訌最激烈。）
當非洲一年死去了100萬兒童之後，Arnold博士公開譴責WHO，說它的猶豫不決是“種族屠殺”。
盡管使用甲氟喹的代價昂貴，但美國軍方依然不為所動。直到2002年，當無國界組織為青蒿素大聲抗議時，一位美國國際發展機構的顧問在接受《紐約時報》的采訪時，依然說“現在不是最好的時候”。在各界抗議聲此起彼伏的時候，他依然為氯喹和其它古老、廉價的藥物辯護。
一家瑞士公司諾華最終打破了僵局。它購買了一個中國的新專利，是蒿甲醚、蒿素的派生物、本芴醇、和一味中藥的混合物，並獲得了西方專利，起名為Riamet，計劃以高價向旅遊者和軍方出售。2001年，它同意以成本價向WHO出售，藥品的名字是Coartem。
2002年國際對抗艾滋、瘧疾和結核病基金會的成立，加上布什政府的總統抗瘧項目在2005年的啟動，讓國際機構有足夠的錢來采購這些藥物。現在，每年有1.5億劑各類藥物發放給貧窮國家。
隨著藥物的成功，523項目中尚未謝世的科學家和外部人員開始爭奪榮譽。1996年，一家香港科學基金會表彰了10位項目領導人。2009年，周義清以Coartem獲得了歐洲專利局“年度發明家”大獎。
9月，25萬美元的拉斯克獎金被授予進行臨床醫學研究的屠呦呦博士，她是前北京中藥研究所主任。拉斯克評委會稱她是“青蒿素的發明人”。
一些中國和西方瘧疾學家被激怒了。
著名的牛津瘧疾學家Nicholas J. White博士說：“把這項發明歸功於某個人是不公平的。”他提到了其他幾位做出同樣貢獻的人士，包括臨川研究領頭人李博士和化學家李穎。
Arnold博士同李博士的研究也在拉斯克授獎儀式中得到表彰，他讚同這種說法。香港科技大學的瘧疾學家和曆史學家Richard K. Haynes說指明一個發明者是“荒唐的”。
拉斯克基金會拒絕給予評論，隻是說屠博士在論文中提到，523項目是集體努力的成果。
在頒獎儀式前的采訪中，81歲的屠博士說她的獲獎是實至名歸，因為她的團隊最早從青蒿中分離出活性成分，而其他團隊關注了錯誤的研究對象。
而且，四世紀的一位醫學家葛洪流傳下來的草稿中提到，浸泡在冷水中的青蒿可以治療發熱。她由此而意識到傳統的加熱提取方式會破壞其中的活性成分，她於是轉而使用乙醚，青蒿因此成為第一種可以100％提取有效殺死老鼠瘧疾病菌的植物。
屠博士說，在進行人體實驗之前，有兩位同事已經服用了藥物，確保沒有毒性。
她說，在西方聽說這個藥物之前，她就是1977年論文的4位匿名撰寫人之一，她還在1978年接受了中國政府頒發的523項目獎勵。
盡管對曆史功績的篩選是極為複雜的，但諾貝爾評委會無論如何都要做出決定。諾貝爾的規則是每個獎項不超過三名獲獎者，而且候選人必須在世----毛鐵定沒有機會獲獎了。
For Intrigue, Malaria Drug Gets the Prize MADE TO ORDER Mao Zedong, center, demanded that Chinese scientists act when a malaria strain felled North Vietnamese troops. The Chinese drug artemisinin has been hailed as one of the greatest advances in fighting malaria, the scourge of the tropics, since the discovery of quinine centuries ago. LATE BLOOMER Sweet wormwood provides artemisinin, discovered decades ago in China. EARLY CURE An illustration from the 1941 Bulletin of the History of Medicine depicted the idea that quinine’s source, the cinchona tree, was named for a countess in Peru Artemisinin’s discovery is being talked about as a candidate for a Nobel Prize in Medicine. Millions of American taxpayer dollars are spent on it for Africa every year. But few people realize that in one of the paradoxes of history, the drug was discovered thanks to Mao Zedong, who was acting to help the North Vietnamese in their jungle war against the Americans. Or that it languished for 30 years thanks to China’s isolation and the indifference of Western donors, health agencies and drug companies. Now that story is coming out. But as happens so often in science, versions vary, and multiple contributors are fighting over the laurels. That became particularly clear in September, when one of the Lasker Awards — sometimes called the “American Nobels” — went to a single one of the hundreds of Chinese scientists once engaged in the development of the drug. Mao’s role was simple. In the 1960s, he got an appeal from North Vietnam: Its fighters were dying because local malaria had become resistant to all known drugs. He ordered his top scientists to help. But it wasn’t easy. The Cultural Revolution was reeling out of control, and intellectuals, including scientists, were being publicly humiliated, forced to labor on collective farms or even driven to suicide. However, because the order came from Mao himself and he put the army in charge, the project was sheltered. Over the next 14 years, 500 scientists from 60 military and civilian institutes flocked to it. Meanwhile, thousands of American soldiers in Vietnam were also getting malaria, and the Walter Reed Army Institute of Research began its own drug hunt. That effort ultimately produced mefloquine, later sold under the brand name Lariam. While powerful, mefloquine has serious drawbacks, including nightmares and paranoia. In 2003, dozens of American Marines in Liberia got malaria after refusing to take pills because of military scuttlebutt that several Special Forces soldiers who killed their wives after returning home from Afghanistan in 2002 had been driven insane by the drug. China’s effort formally began at a meeting on May 23, 1967, and was code-named Project 523, for the date. Researchers pursued two paths. One group screened 40,000 known chemicals. The second searched the traditional medicine literature and sent envoys into rural villages to ask herbal healers for their secret fever cures. One herb, qinghao, was mentioned on tomb carvings as far back as 168 B.C. and praised on medical scrolls through the centuries, up to the 1798 Book of Seasonal Fevers. Rural healers identified qinghao as what the West calls Artemisia annua, or sweet wormwood, a spiky-leafed weed with yellow flowers. In the 1950s, officials in parts of rural China had fought malaria outbreaks with qinghao tea, but investigating it scientifically was new. It also had at least nine rivals from traditional medicine with some anti-malarial effects, including a pepper. In the lab, qinghao extracts killed malaria parasites in mice. Researchers tried to find exactly which chemical worked, which plants had the most, whether it could cross the blood-brain barrier to fight cerebral malaria, and whether it worked in oral, intravenous and suppository forms. Outmoded equipment slowed research. But by the 1970s it was known that the lethal chemical, first called qinghaosu and now artemisinin, had a structure never seen before in nature: In chemical terms, it is a sesquiterpene lactone with a peroxide bridge. Trials in 2,000 patients showed that it killed parasites remarkably rapidly. However, the body eliminated it so fast that any parasites it missed made a comeback. So scientists began mixing it with slower but more persistent drugs, creating what is now called artemisinin combination therapy. (One new combination includes mefloquine.) A 2006 history of the project by Zhang Jianfang, its former deputy director, contains some gripping details: petty disputes between rivals, Cultural Revolution street fighting that forced one laboratory into a basement, project doctors’ living on brown rice and vegetables as they did clinical trials in remote villages in China’s tropical southern mountains, and other doctors’ hiking the Ho Chi Minh Trail with the Vietcong. Mao died in 1976; Project 523 was officially di*****anded in 1981, though clinical work continued. In 1979, Dr. Keith Arnold, a malaria researcher in Hong Kong who had helped the Army develop mefloquine, wangled his way into China, hoping to test his drug there. He met Dr. Li Guoqiao, who was testing artemisinin variants. They decided to try head-to-head trials, and the Chinese mystery drug beat his, Dr. Arnold said. Soon, World Health Organization scientists asked for articles from China’s medical journals, the first of which had been published in 1977, in response to reports that a Yugoslav chemist was experimenting with wormwood. In 1982, The Lancet had an article by Chinese researchers. It won a prize, but the check, in British pounds, could not be cashed in China. Shortly thereafter, Dr. Arnold said, Walter Reed scientists found wormwood growing on the banks of the Potomac and extracted artemisinin. Nonetheless, the drug languished. The W.H.O. did not endorse it until 2000, and it was not widely available until 2006. The reasons for that delay are disputed. China was in political disarray. Different labs in and outside China were working on derivatives. Patent law had vanished under communism, and China never took out Western patents, so there was no way a major drug company could get a monopoly and make big profits. Malaria was a disease of the poor, and today’s big donor funds did not exist. Aid agencies could not buy drugs that were not W.H.O.-approved. For years, Dr. Arnold said, he tried to get permission for his Chinese collaborators to do clinical trials in Thailand and Vietnam, but the W.H.O. stalled. (As a United Nations agency, it is rarely bold, but the 1990s were a decade of particularly low morale and constant infighting.) As nearly one million African children a year died, Dr. Arnold denounced its indecisiveness as “genocidal.” The American military stuck with mefloquine, despite its expense. As late as 2002, as Doctors Without Borders clamored for artemisinin, an adviser to the United States Agency for International Development dismissed it in an interview with The New York Times as “not ready for prime time” and defended chloroquine and other old, cheap drugs even though resistance to them was widespread. A Swiss company, Novartis, finally broke the logjam. It bought a new Chinese patent on a mix of artemether, an artemisinin derivative, and lumefantrine, another Chinese drug, and took out Western patents, planning to sell it under the name Riamet at high prices to tourists and militaries; in 2001, it agreed to sell it nearly at cost to the W.H.O. under the name Coartem. The money to buy the drug on a large scale became available with the creation of the Global Fund to Fight AIDS, Tuberculosis and Malaria in 2002 and the Bush administration’s introduction of the President’s Malaria Initiative in 2005. Now, about 150 million doses of several combinations are bought for poor countries each year. With that victory, surviving Project 523 scientists and some outsiders began vying for credit. In 1996, a Hong Kong science foundation recognized 10 team leaders. In 2009, Zhou Yiqing got the European Patent Office’s “Inventors of the Year” award for Coartem. In September, the $250,000 Lasker Award for clinical medical research was given to Dr. Tu Youyou, former chief of the Institute of Chinese Materia Medica in Beijing. The Lasker committee named her “the discoverer of artemisinin.” Some Chinese and Western malariologists were outraged. Dr. Nicholas J. White, a prominent Oxford malaria researcher, said it was “not fair to credit this discovery to one individual”; he named others he considered equally deserving, including the clinical trial leader, Dr. Li, and a chemist, Li Ying. Dr. Arnold, whose work with Dr. Li was mentioned in the Lasker citation, agreed. Richard K. Haynes, a malaria researcher and historian at the University of Science and Technology in Hong Kong, called naming one inventor “a travesty.” The Lasker Foundation declined to comment, other than to note that Dr. Tu’s citation mentioned that Project 523 was a large collaborative effort. In an interview before the ceremony, Dr. Tu, 81, argued that she deserved it because her team had been the first to isolate qinghao’s active ingredient while other teams worked on the wrong plants. Also, after rereading a manuscript by Ge Hong, a fourth-century healer, prescribing qinghao steeped in cold water for fever, she realized that boiling, the typical extraction method, was destroying the active ingredient. She switched to ether, and qinghao became the first plant extract 100 percent effective at killing malaria in mice. And before human testing began, Dr. Tu said, she and two colleagues took it themselves to make sure it was not toxic. Before the West even heard of the drug, she said, she was one of the four anonymous authors of the initial 1977 paper, and in 1978, she was chosen to accept the Chinese government’s overall award to Project 523. However difficult winnowing the field would prove, the Nobel Prize committee would be forced to do it anyway. The Nobel rules specify no more than three winners. And no posthumous prizes, either — meaning Mao would be out of the question.
Published: January 16, 2012
Related
Health Guide: Malaria
Luigi Rignanese
