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本帖最后由 woikuraki 于 2012-3-31 15:51 编辑
【中文标题】毛泽东会获得诺贝尔医学奖吗？
【原文标题】For Intrigue, Malaria Drug Gets the Prize
【登载媒体】纽约时报
【原文作者】DONALD G. McNEIL Jr.
【原文链接】http://www.nytimes.com/2012/01/17/health/for-intrigue-malaria-drug-artemisinin-gets-the-prize.html?_r=1&ref=china
当疟疾在北越军队中肆虐时，毛泽东命令中国科学家采取行动。
自从奎宁在几个世纪前被发现之后，中药青蒿素被广泛推崇为治疗热带疾病疟疾的最伟大进步。
诺贝尔医学奖正在考虑把青蒿素的发现列为候选名单之一。每年，美国纳税人数百万美元的钱都通过这种药物的方式流向非洲。
但是几乎没有人知道其背后真实的历史，这种药物的发现要感谢毛泽东，当越南人在热带丛林中反抗美国人时，他挺身而出采取了行动。而它在中国默默无闻地存在了30年，是因为中国与世隔绝的政策，和西方捐献者、医疗机构和制药公司对它漠不关心的态度。
现在，这段历史浮出了水面。科学界依然像往常一样，多名与此有关的人士拼命争夺这项桂冠。9月份，纷争达到白热化程度，一名拉斯克奖——又称“美国的诺贝尔奖”——获奖者试图在数百位参与研制药物的中国科学家中选取一名。
毛的角色是显而易见的。
60年代，他收到了越南的求救信息：当地的疟疾似乎可以抵抗任何药物的疗效，军队士大批死亡。他于是命令顶级科学家伸出援手。
但事情并非一帆风顺。文化大革命正在以无法控制的趋势蔓延，知识分子和科学家被当众羞辱、送到集体农场改造，甚至被逼自杀。但由于这个命令直接来自毛本人，而且由军方负责，因此免受冲击。在接下来的14年里，来自60个军方和民用机构的500名科学家致力于这项研究。
与此同时，数千名陷入越南战争的美国士兵也感染了疟疾，沃尔特瑞德研究所也开始了新药的探索。最终，他们生产出美尔奎宁，进入市场后改名为甲氟喹。
这种药尽管有强大的效果，但也有严重的副作用，包括噩梦和妄想。2003年，几十名美国海军陆战队士兵在利比亚宁可感染疟疾也不服用这种药物，因为有传言说，几名2002年从阿富汗回国的特种部队士兵杀死了自己的妻子，就是这种药物导致的。
中国的探索之旅开始于1967年5月23日的一次会议，后来根据日期被命名为“523项目”。
研究人士兵分两路。一组人在已知的4万类化学品中筛选；另一组人研究传统的医学文献，派人到农村地区，向当地中医询问治疗发热的秘方。
中国在几十年前发现，晚花期、带有清香味的蒿尾植物中含有青蒿素。
公元前168年的一块墓碑上提到了一种草药——青蒿，在后来几个世纪的古代文献中都有提到，包括1798年的《季节性发热之书》。农村的中医大夫发现了青蒿，也就是西方所谓的黄花蒿，一种叶子细小、开黄花、带有清香味的蒿尾植物。
在50年代，中国部分农村地区饮用青蒿茶来抵抗疟疾，但是从科学角度进行研究还从未有过。社会上还至少存在9种具有抵抗疟疾效果的传统药物，包括胡椒。
在实验室中，从青蒿里提取出来的物质杀死了白鼠感染的疟疾病毒。研究人员试图找到是哪种化学物质起的作用，哪种植物里含量最多，是否可以跨越血脑屏障对抗脑型疟疾，以及是否可以制成口服、静脉注射和栓剂药物。
老旧的设备拖慢了研究的速度，但是到了70年代，一种核心化学物质已经被人们找到。青蒿素具有一种自然界从未出现过的化学结构，用术语来说，它是具有一个过氧桥的倍半萜烯内酯。在2000名病人身上的试验表明它可以迅速杀死寄生虫。
然而，人体对青蒿素的代谢过快，没有被杀死的寄生虫很快又会繁殖。于是科学家把它与更持久的药物混合，发明出蒿素组合疗法（最新的混合型药物是甲氟喹）。
原523办公室副主任张剑方在2006年主编的一本历史资料中（译者注：书名为《迟到的报告》，由羊城晚报出版社出版），包含了一些引人关注的细节：派别之间的纷争；文化大革命的街头武斗被迫让试验转入地下；医生在中国南部热带山区中进行临床试验时，只能以糙米和蔬菜果腹；其它医生步行进入胡志明市治疗越共病患。
毛在1976年去世，523项目在1981年正式解散，但临床工作仍在继续。
1979年，在香港帮助美军研究甲氟喹的Keith Arnold博士辗转来到中国，希望在那里测试他的药物。他遇到了正在测试青蒿素变异体的李国桥博士，他们决定进行平行对照研究，结果这种神秘的中国药物击败了Arnold博士的药物。
很快，国际卫生组织的科学家们纷纷索取中国医学杂志上的文章，第一篇文章发表于1977年，回应了一份有关南斯拉夫化学家试验苦艾的报道。
1941年出版的医药历史中的一张插图，描绘出奎宁源于金鸡纳树，以一位秘鲁的女伯爵而命名。
1982年，《Lancet》发表了一篇中国研究人员的文章。这篇文章获得了一个奖项，但英镑支票在中国无法兑现。
Arnold博士说，很快，沃尔特瑞德研究所的科学家就发现波托马克河岸边生长的苦艾可以提取蒿素，但是药物的研究进展极为缓慢。世界卫生组织直到2000年才批准这种药物，2006年才在市场中大量投放。
多种原因造成了这种延迟——中国当时的政治混乱；中国和海外的研究室都在研究派生产品。共产主义制度下没有专利法，中国也无法获取西方专利，因此没有一家处于垄断位置的大型医药公司可以因此获利。疟疾是穷人的疾病，直到今天仍然没有一家专门以此为目的的基金会。
没有WHO的批准，救援机构就无法买到药物。Arnold博士说，多年来，他一直帮助中国的研究人员试图获得在泰国和越南进行临床试验的批准，但WHO迟迟没有决定。（作为一家联合国机构，它从不大胆行事，但在90年代那十年里，它的办事效率最低，内讧最激烈。）
当非洲一年死去了100万儿童之后，Arnold博士公开谴责WHO，说它的犹豫不决是“种族屠杀”。
尽管使用甲氟喹的代价昂贵，但美国军方依然不为所动。直到2002年，当无国界组织为青蒿素大声抗议时，一位美国国际发展机构的顾问在接受《纽约时报》的采访时，依然说“现在不是最好的时候”。在各界抗议声此起彼伏的时候，他依然为氯喹和其它古老、廉价的药物辩护。
一家瑞士公司诺华最终打破了僵局。它购买了一个中国的新专利，是蒿甲醚、蒿素的派生物、本芴醇、和一味中药的混合物，并获得了西方专利，起名为Riamet，计划以高价向旅游者和军方出售。2001年，它同意以成本价向WHO出售，药品的名字是Coartem。
2002年国际对抗艾滋、疟疾和结核病基金会的成立，加上布什政府的总统抗疟项目在2005年的启动，让国际机构有足够的钱来采购这些药物。现在，每年有1.5亿剂各类药物发放给贫穷国家。
随着药物的成功，523项目中尚未谢世的科学家和外部人员开始争夺荣誉。1996年，一家香港科学基金会表彰了10位项目领导人。2009年，周义清以Coartem获得了欧洲专利局“年度发明家”大奖。
9月，25万美元的拉斯克奖金被授予进行临床医学研究的屠呦呦博士，她是前北京中药研究所主任。拉斯克评委会称她是“青蒿素的发明人”。
一些中国和西方疟疾学家被激怒了。
著名的牛津疟疾学家Nicholas J. White博士说：“把这项发明归功于某个人是不公平的。”他提到了其他几位做出同样贡献的人士，包括临川研究领头人李博士和化学家李颖。
Arnold博士同李博士的研究也在拉斯克授奖仪式中得到表彰，他赞同这种说法。香港科技大学的疟疾学家和历史学家Richard K. Haynes说指明一个发明者是“荒唐的”。
拉斯克基金会拒绝给予评论，只是说屠博士在论文中提到，523项目是集体努力的成果。
在颁奖仪式前的采访中，81岁的屠博士说她的获奖是实至名归，因为她的团队最早从青蒿中分离出活性成分，而其他团队关注了错误的研究对象。
而且，四世纪的一位医学家葛洪流传下来的草稿中提到，浸泡在冷水中的青蒿可以治疗发热。她由此而意识到传统的加热提取方式会破坏其中的活性成分，她于是转而使用乙醚，青蒿因此成为第一种可以100％提取有效杀死老鼠疟疾病菌的植物。
屠博士说，在进行人体实验之前，有两位同事已经服用了药物，确保没有毒性。
她说，在西方听说这个药物之前，她就是1977年论文的4位匿名撰写人之一，她还在1978年接受了中国政府颁发的523项目奖励。
尽管对历史功绩的筛选是极为复杂的，但诺贝尔评委会无论如何都要做出决定。诺贝尔的规则是每个奖项不超过三名获奖者，而且候选人必须在世——毛铁定没有机会获奖了。
原文：
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.
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.
LATE BLOOMER Sweet wormwood provides artemisinin, discovered decades ago in China.
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 disbanded 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.
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
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.
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发表于 2012-1-29 12:04
