Artemisinin 青蒿素

This first scientific paper is a real bombshell. The drug was not discovered in China at all, but by a Yugoslav chemist called Milutin Stefanovic. His name has been in the frame for a few years, but no one seems to have bothered chasing him up, so that's what I did. He's now a very old man in his 80s who lives in retirement in Belgrade, and unfortunately I couldn't speak to him in person.

But a former student of his, Bogdan Solaja, who is now a Professor of Chemistry at the University of Belgrade, kindly sent me an original scientific abstract, published in 1972, which I think confirms that Stefanovic discovered the drug before the Chinese. Stefanovic didn't know it could cure malaria, and I think he probably studied it because of Soviet claims about the antibacterial properties of a herb called Artemisia annua. A. annua contains artemisinin in quite large amounts.

But that's not the point here, so I give you a scanned version of the original abstract, presented at the Eighth International Symposium on the Chemistry of Natural Products, held in New Delhi, India, 6-12 February 1972.

Stefanovic got the chemical structure a little wrong, but in my opinion he's describing artemisinin. How this relates to the Chinese discovery of the drug, well that's something I'll be discussing over the coming months.

Milutin Stefanovic and Artemisinin 青蒿素

The next artemisinin reference I've found came out in 1975. In a short note submitted to the journal Phytochemistry on 6 February 1975 and published later that year, Stefanovic mentions a chemical he calls "arteannuin A". The note itself is, unfortunately, not about arteannuin A, but another, unrelated, chemical found in Artemisia annua.

But what's interesting is the reference attached to the arteannuin A, which I've scanned here. The first part cites the New Delhi abstract. The second part is more tantalizing: "full experimental data will be published soon." Alas, Stefanovic never published that data. In my view, a mistake of historic proportions because of course "arteannuin A" is artemisinin.

Into China in search of Artemisinin 青蒿素

We finally reach China, after beginning our journey in Belgrade. This is the first scientific article to report on Chinese artemisinin research. It appeared in the journal Ke Xue Tong Bao 科學通報 in 1977. According to a footnote printed at the bottom of the article itself, it was received at the journal on 20 February 1976.

It's a one page article and I reproduce a picture of the page here. The title reads: "A new type of sesquiterpene lactone - qinghaosu". The body texts starts with the words: "We isolated a type of crystal from Artemisia annua. It was given the name qinghaosu." Then we get a mass of technical details about melting points and infrared, proton and C-13 spectra, that, frankly, would only be comprehensible to a physical chemist and certainly aren't comprehensible to me.

But I think a few things are still worth noting. First, the Chinese refer to the molecule as qinghaosu 青蒿素. They abandon Stefanovic's "arteannuin A" terminology, and they also don't cite Stefanovic, or anyone else, because the paper lacks references.

Second, the paper goes out under an anoymous authorship, namely: "Coordinating Group for Research on the Structure of Qinghaosu". There's no information whatsoever about who might be part of this group, or even how many members there are.

Third, unlike Stefanovic, I think the Chinese get the chemical structure correct. I would, however, appreciate the views of a proper organic chemist on this conclusion.

But there is something more. Unbelievably, they don't mention malaria! Essentially, they avoid telling us just about the most interesting feature of the molecule: that it can cure malaria. This is such a curious omission that it raises all sorts of interesting questions that I will discuss in future posts.

Artemisinin, 1979

This is the big year - 1979 - when the Chinese announce their artemisinin discovery in detail, two years after the first brief report. And it starts in May 1979, exactly 29 years ago this month, with a paper in the journal Hua Xue Xue Bao 化學學報. It's quite a long paper, 10+ pages, so I only reproduce the first page.

There's a lot to discuss here, but I first want to point out that the authors submitted the article to the journal on 3 April 1978, a full year before it was actually published.

For the first time we have some actual Chinese names. They are: Liu Jing-ming, Ni Mu-yun, Fan Ju-fen and Tu You-you, at the Institute of Chinese Materia Medica, Academy of Chinese Traditional Medicine, Peking; and Wu Zhao-hua, Wu Yu-lin and Chou Wei-shan, at the Institute of Organic Chemistry, Academia Sinica, Shanghai. Here I'm using the original English transliterations that accompanied the paper back in 1979 (it was before the widespread use of pinyin).

So we can clearly say who the key players were. According to the standard format, where the leaders of the research go last in the lists of authors, they are: Tu You-you 屠呦呦 and Chou Wei-shan 周維善. Mark those names well, because it gets more complicated. I'm going to discuss these complications in later posts.

A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin)

I've been meaning to post this up for some time, so it's a bit out of date. This is the book published in 2006 that gives a historical overview of the artemisinin discovery, from the Chinese perspective.

Here's the citation:
張劍方. 遲到的報告五二三項目與青蒿素研發紀實. 羊城晚報出版社, 2006.
Zhang Jianfang. A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin). Yangcheng Evening News Publisher, 2006.

Zhang Jianfang, who edited the volume, directed the artermisinin project back in the 1960s, and the book is a good start on mapping the details of the discovery. But I think it's vital the Chinese make even greater efforts to record the oral history of the discovery - and do it now, rather than waiting. If I understand it right, one of the leading project workers from the 1960s/70s, Professor Zhou Keding 周克鼎, sadly died of old age a few months ago.

Another unfortunate problem is that the book isn't available online, and of course it's in Chinese. There is an English translation, but a Chinese publisher apparently backed out of printing it because he couldn't read English and worried the translation might say something that would upset the censor.

Dr Keith Arnold - the first Western scientist to hear about artemisinin when he visited Guangzhou in 1979 - kindly gave me the unpublished English version of the first two chapters back in 2007, but as far as I know the full translation hasn't yet found a publisher. Arnold's wife, Dr Muoi Arnold, did the translation.

There was talk at the time of posting the English version online, but I don't think this has happened. The British Medical Journal commissioned me to write an article on the book, but in the end they didn't publish it, so the story sank without trace.

For those wanting to know more, the only online information I can find on the book is the publisher's site, Yangcheng Evening News. I do wonder if you can order the book from Chinese Amazon, or similar (I haven't checked because I already own a copy).

Further progress along the road to integrating Chinese and Western medicine...

Here's a paper from January 1979 reporting on the qinghaosu discovery. It was published in the Journal of New Medicine and Pharmacology. The headline reads:


In other words:

Further progress along the road to integrating Chinese and Western medicine - Report of a meeting to appraise scientific research on qinghaosu as a cure for malaria

In fact this is an editorial introducing a series of articles on qinghaosu. It's the earliest mention I can find of qinghaosu as a cure for malaria (as I've discussed before, the 1977 paper doesn't mention the malaria part).

The Chinese Medical Journal paper, 1979

This must be about the most famous artemisinin paper ever. It really brought the artemisinin discovery to the world's attention, not least because it was written in English.

Professor Nick White, who pioneered the clinical use of artemisinin in Thailand, waxes lyrical about when he first saw the paper.

The Chinese published it in the December 1979 issue of the Chinese Medical Journal - again under an anonymous authorship, so we have no idea who wrote it.

I'm not going to reproduce the paper here; what interests me most are the paper's references, published in Chinese. So before I get on with any more discussion, I want to post up a translation.

1. Ma Wang Dui Han Tomb Study Group. Ma Wang Dui Han Tomb Excavation Medical Book Translation [Explanation?] (2nd). Wu Shi Er Bing Fang [Fifty-two Prescriptions]. Report 9:42, 1975.

2. Wei Dynasty. Wu Pu. Shen Nong Ben Cao Jing [The Divine Farmer's Materia Medica]. Volume 3. Page 103. Shang Wu Publisher, 1955.

3. Jin Dynasty. Ge Hong. Zhou Hou Bei Ji Fang [Handy Therapies for Emergencies]. Volume 3. Page 44. Ren Min Wei Sheng Publisher, 1956.

4. Sheng Ji Zong Lu [General Record Commissioned by Sagely Benefaction]. Volume 36. Page 724. Ren Min Wei Sheng Publisher, 1962.

5. Yuan Dynasty. Zhu Zhen Xiang. Dan Xi Xin Fa [The Heart and Essence of Dan-Xi's Methods of Treatment?]. Volume 4. Page 47. Shanghai Science and Technology Publisher, [1955?].

6. Ming Dynasty. Zhu Su. Pu Ji Fang [Prescriptions for Universal Benefaction]. Volume 197. Page 2755. Ren Min Wei Sheng Publisher, 1955.

7. Ming Dynasty. Li Shizhen. Ben Cao Gang Mu [The Great Pharmacopoeia]. Volume 15. Page 13. Shang Wu Book Publisher, 1955.

8. Qing Dynasty. Wu Ju Tong. Wen Bing Tiao Bian [Systematic Discourse on Warm Diseases?]. Volume 2. Page 169. Chinese Medicine [Publisher?], 1955.

9. Coordinating Group for Research on the Structure of Qinghaosu. A new type of sesquiterpene lactone - qinghaosu. Ke Xue Tong Bao 22:142, 1977.

10. China Science Biophysics Institute, Qinghao Structure Group. Absolute crystal structure of qinghaosu. Waiting to be published.

Discussion of the 1979 paper in the Chinese Medical Journal

Here I'm continuing my discussion of the famous 1979 Chinese Medical Journal paper, in particular the references on the paper.

The first thing that strikes me: although the paper is entirely in English, the authors decided to keep the reference list in Chinese. To my mind, a very strange decision as the paper's intended audience, the international scientific community, can't (as a general rule) read Chinese.

The second thing to note is that references 1-8 are 1950s reprints of old Chinese medical books, or materia medica.

At the time, Chairman Mao made a big show of promoting Chinese medicine, so Chinese publishers made a big effort to revive the old books by reprinting them. This, by the way, is an interesting story in itself, and it's been documented by the historian Kim Taylor in her book Chinese Medicine in Early Communist China, 1945-63.

References 1-8 give me an excuse to wander off into an incense-filled world of temples, scholars and Daoists, but before I do that, I want to tackle the more prosaic issues brought up by references 9-10.

The question here is: why don't the authors cite the 1979 article by 屠呦呦 and 周維善? Could it be they were not aware of this article - or did they deliberately avoid citing it?

Reference 9 is, of course, the 1977 paper in 科學通報.

Reference 10 I think must refer to a paper submitted to the journal Scientia Sinica 中國科學 on 9 May 1978 and published in English in March 1980. I reproduce the original title and abstract of that paper here, but I'll discuss it at a later date because I'm trying to keep a roughly chronological order to these blog entries, at least in the first instance.

Chinese scientists and Western journals

Why didn't the Chinese scientists publish the first qinghaosu report in a Western journal?

Well, Western journals aren't the be all and end all, but I think the reason here must be that to publish in a foreign journal in the 1970s would have been viewed as treason. Anyone who did it would have been labeled a capitalist-roader or some such and dealt with very harshly.

So it wasn't until March 1982 that Tu Youyou 屠呦呦 published a report on the discovery in a foreign (German) journal, Planta Medica.

Now, of course, there's no such reticence and Chinese scientists are positively encouraged to publish in high-impact foreign journals. Shows how times have changed.

Changshan 常山

Haven't posted here for ages, too busy watching the Olympics.

Well, here's an article that's been in the pipeline for ages but finally came out this month, on 8 August no less. It's about Dichroa febrifuga, or changshan 常山.

The article's DOI is: 10.1016/j.endeavour.2008.07.001. I'm afraid you'll need a subscription to read it in full.

Publishing delays

Back to the Kremlinology...if the Chinese discovered qinghaosu in 1972, why didn't they publish anything until 1977?

The usual explanation is that this was the time of Chairman Mao's reign of terror, so there was no place to publish because the scientific journals had been closed down. In historical research, of course, just because things happen at the same time doesn't make one the cause of the other.

Go in a little closer and it gets more interesting. While the reason not to publish must surely have been the reign of terror, the reason they eventually did publish seems to have been good old academic rivalry. It's nice to know that survived in spite of everything.

According to Zhang Jianfang's account, the Chinese saw the suggestive footnote in Milutin Stefanovic's 1975 paper, and rushed to the presses.

If we fast forward a bit, the other question that bugs me is the long lead times between the early papers being sent to the journals and the papers actually getting published:

1. Structure and reactions of arteannuin. Submitted: 3 April 1978. Published May 1979.
2. Crystal structure and absolute configuration of qinghaosu. Submitted: 9 May 1978. Published: March 1980

Perhaps there was a long backlog of papers because the journals had been closed down for a bit? The editor might therefore have worked through, methodically publishing submissions in chronological order, according to when they had been received.

Scrupulously fair no doubt, but surely any journal editor worth his or her salt would have realized the qinghaosu papers were dynamite, and rushed them to the presses?

Qinghaosu heads West

I'm going to fast forward to the early 1980s and the first reports about qinghaosu published in Western scientific journals. For the moment I'm ignoring the large numbers of scientific papers published in Chinese journals that came out at the same time, which you can easily find by searching PubMed (don't worry, I'll return to these later).

To begin, here are some highlights:

March 1982
Tu Youyou 屠呦呦 is the first Chinese scientist to publish a qinghaosu article in a Western scientific journal.
Tu You-you, Ni Mu-yun, Zhong Yu-rong, Li Lan-na, Cui Shu-lian, Zhang Mu-qun, Wang Xiu-zhen, Ji Zheng and Liang Xiao-tian. (1982) Studies on the constituents of Artemisia annua Part II*. Planta Medica 44:143-145.
(*Part I is Structure and reactions of arteannuin, published May 1979.)

13 March 1982
Veteran malariologist Leonard Bruce-Chwatt publishes a short letter describing qinghaosu.
Bruce-Chwatt, L.J. (1982) Qinghaosu: a new antimalarial. British Medical Journal (Clinical Research Edition) 284:767-768.

7 August 1982
Keith Arnold is the first Western scientist to publish a primary research paper on qinghaosu (in collaboration with Li Guoqiao 李國橋).
Jiang, J.B., Li, G.Q., Guo, X.B., Kong, Y.C. and Arnold, K. (1982) Antimalarial activity of mefloquine and qinghaosu. Lancet 2:285-288.

Publication of two papers from a collaboration between Gu Haoming 顧浩明 (Shanghai Institute of Materia Medica); Li Zelin 李澤琳 (Institute of Chinese Materia Medica, Beijing); and David Warhurst and Wallace Peters (London School of Hygiene and Tropical Medicine).
Gu, H.M., Warhurst, D.C. and Peters, W. (1983) Rapid action of qinghaosu and related drugs on incorporation of [3H]isoleucine by Plasmodium falciparum in vitro. Biochemical Pharmacology 32:2463-2466.
Li, Z.L., Gu, H.M., Warhurst, D.C. and Peters, W. (1983) Effects of qinghaosu and related compounds on incorporation of [G-3H] hypoxanthine by Plasmodium falciparum in vitro. Transactions of the Royal Society of Tropical Medicine and Hygiene 77:522-523.

July 1984
The first entirely Western study of qinghaosu, conducted by Daniel Klayman at the Walter Reed Army Institute of Research in the USA.
Klayman, D.L., Lin, A.J., Acton, N., Scovill, J.P., Hoch, J.M., Milhous, W.K., Theoharides, A.D. and Dobek, A.S. (1984) Isolation of artemisinin (qinghaosu) from Artemisia annua growing in the United States. Journal of Natural Products 47:715-717.

31 May 1985
Daniel Klayman finally brings the discovery out of the shadows and into the scientific mainstream when he publishes his famous qinghaosu review in Science.
Klayman, D.L. (1985) Qinghaosu (artemisinin): an antimalarial drug from China. Science 228:1049-1055.

Citations in the early scientific papers

Now we are in the realms of Kremlinology, but lets proceed anyway to analyse the citations in the early Chinese papers.

What puzzles me is the inconsistency of citation in the following papers (papers that I've already mentioned on this blog):

1. Structure and reactions of arteannuin, published May 1979
2. Antimalaria studies on qinghaosu, published December 1979
3. Crystal structure and absolute configuration of qinghaosu, pubished March 1980

What's curious is that the 1980 paper doesn't cite the 1979 papers (see picture for list of references in the 1980 paper), nor does the December 1979 paper cite the May 1979 paper. Most obviously, why doesn't the 1980 paper cite the May 1979 paper, as both are on similar topics?

What could be the explanation for these inconsistencies? It seems to me there are two possibilities.

First possibility: the authors of the 1980 paper - and we don't know their names because the paper went out under an anonymous byline of the Institute of Biophysics - didn't know about Tu Youyou 屠呦呦 and Zhou Weishan 周維善 and the other authors of the May 1979 paper.

Second possibility: we are in much darker waters, where the authors of the 1980 paper did know about Tu and Zhou but deliberately avoided citing them.

Either way, it would tend to suggest that, far from being a highly coordinated project (as it is often thought to have been), it was a bit disorganized, with different (rival?) groups publishing their results pretty much independently.


A very interesting blog called 青蒿情黃花香, in other words, "Qinghao - news and views on the yellow flower", referred to me. (For those who don't know, Artemisia annua sports rather pretty yellow blooms.)

It's nice to know a Chinese person is reading my blog, and what's more, is interested in the history of qinghaosu and what people outside China think about the discovery.

青蒿情黃花香 says that my blog is "a mixture of fact and speculation", so lets get on with the facts and speculation...

Who should get the Nobel Prize?

I thought I'd wrap up today's discussion with this provocative question, which I'll discuss in more detail in later posts.

My citation would be: For their analytical work leading to the discovery of artemisinin.

Based on the record of published scientific works, two Chinese scientists should get the prize. They are: Tu Youyou 屠呦呦 and Zhou Weishan 周維善.

But, as a Nobel can go to three people, I'd give the final third of the prize to Milutin Stefanovic. He may not have known the chemical could cure malaria, but he beat the Chinese to the printing press.

There's a precedent for this: Jerome Horwitz gets the credit for developing the anti-HIV drug AZT, even though he synthesized the chemical long before HIV came on the scene. Like Stefanovic, he could never have dreamed his chemical would later help millions of people.

Now let's pull these conclusions apart again and see where we get...

Ge Hong 葛洪

My next stop is Ge Hong 葛洪, or reference number three in the Chinese Medical Journal paper.

While the Ma Wang Dui manuscript is merely a historical curiosity, this reference is said to be directly related to the discovery.

I've scanned an excerpt from an article in the magazine China Reconstructs - now known as China Today - that was published in August 1979 and throws a little light on this part of the story.

The sweet wormwood mentioned must be qinghao. In other words: Artemisia annua.

In those days China Reconstructs was the main English-language organ of the Chinese Communist Party, and it was edited by a Western journalist called Israel Epstein who had defected to China in the 1950s and was actually a Chinese citizen.

Incidentally, the paragraph excerpted here comes from an article written by Ximen Lusha. It doesn't sound like a Chinese name, but Hubert Wang from the English Department at China Today told me that Ximen Lusha was a Chinese woman. I don't have the characters for her name, so it's really difficult to find out anything about her, or even if she's still alive. I wonder if there's anyone out there on the Web who could tell us more?

Ge Hong and Mount Luofu 羅浮山

The story goes that in the year 331, Ge Hong retired to Mount Luofu 羅浮山 where he lived until his death.

In my ongoing quest to track down every place even remotely connected with qinghaosu, I made a stop at Mount Luofu last year.

It's a couple of hours drive from Guangzhou 廣州, deep in the countryside. When I visited there was a temple, a few souvenir stalls, a fairground-style shooting range - and a stand of Artemisia annua.

The artemisinin maker Artepharm has even sponsored a few plaques and information boards that record Ge Hong's legendary connection with the drug. They are clustered around the A. annua plants.

I took this photo when I visited. The banner reads: 青蒿抗瘧尋源羅浮山. This means
something like: Mount Luofu - the birthplace of antimalarial qinghao.

Zhou Hou Bei Ji Fang 肘後備急方

This is Ge Hong's book, Zhou Hou Bei Ji Fang 肘後備急方. The title is usually translated as Handy Therapies for Emergencies.

I reproduce the critical page from my edition of the book, published by Tianjin Science and Technology Press 天津科學技術出版社. Unfortunately I don't think this book has ever been translated into English.

The page starts:

Volume three.
Number 16. Prescriptions for treating various types of nüe with chill and fever.
Prescriptions to treat nüe disease.

Then we get a list of about 20 or so prescriptions. Prescription number two reads, in Elisabeth Hsu's translation:

Another recipe. Take a bunch of qing hao and two sheng of water for soaking it, wring it out to obtain the juice and ingest it in its entirety.

In the first instance, I think there are two points worth making.

First, the recipes are to treat nüe 瘧. In modern Chinese this character simply means malaria, but in Ge Hong's time, it must have been a less precise term. That said, the mention of chill and fever pins it down more precisely as these are typical malaria symptoms we know today.

The second point is more trivial: according to Elisabeth Hsu, two sheng was about 400 mL - about a cup of water - not one litre as is usually stated.

I followed Ge Hong's recipe using a handful of fresh Artemisia annua leaves from a plant I grew in my back garden. Squeezing, or wringing out, the leaves in the water produced a pale green-coloured liquid that had a very subtle herbal flavour (a bit like camphor, but not unpleasant). But it was so weak I can't believe it would have any effect against a serious malaria infection.

Ma Wang Dui 馬王堆

Well, time for a detour into the very ancient past, and reference number one in the Chinese Medical Journal paper. This refers to the medical manuscripts excavated from Ma Wang Dui 馬王堆 at Changsha 長沙 in southern China.

I used to have a copy of the manuscripts, or rather Donald Harper's English translation in his book Early Chinese Medical Literature, but I seem to have lost it somewhere.

If I remember rightly, there was a lot of discussion about herbs that could improve a man's sexual performance, and the best sexual positions for "approaching the inner chamber". All in all it was a rather racy read for something that's nearly two thousand years old.

But the point here is that it mentions a herb called qinghao 青蒿, not as a sex aid, but to treat hemorrhoids - the manuscript advises the reader to expose his bum over a steaming concoction of the herb.

It's the first mention of qinghao in history, and a rather undignified one at that. But the herb is said to have been Artemisia annua. A stretch of the imagination perhaps, but not completely implausible.

Curious about the tomb itself, I visited 長沙. The first must-see is the Hunan Provincial Museum, which houses the artefacts from the tomb.

The second, more obscure, tourist attraction is of course the site of the tomb itself, ironically in the grounds of a hospital. Here's a picture I took of the hospital's entrance. The sign reads: 湖南省老年醫院, 湖南省馬王堆療醫院. In other words: Hunan Geriatric Hospital, Hunan Ma Wang Dui Hospital.

The Chinese discovered the tomb in 1971 during construction of underground wards, although having now been to the hospital myself, there weren't any underground wards that I could see.

The name Ma Wang Dui literally means King Ma's Mound, but actually the tomb contained a Chinese nobleman, his wife and son and a thousand-and-one perfectly preserved artefacts. They were all sealed in giant wooden coffins that protected them from the elements.

Among the artefacts, which included musical instruments, clothes, statues and furniture, the archeologists found manuscripts written in black ink on strips of bamboo and on sheets of silk, and that is where the characters 青蒿 appear for the first time.

Medical manuscripts from Ma Wang Dui 馬王堆

I just stumbled across Donald Harper's translation of the medical manuscripts, so here is his rendering of the entry on qinghao. It doesn't make for pretty reading:

Female Hemorrhoid

Recipe for (female hemorrhoids) that are one cun inside the anus, are shaped like a cow louse, burst and ooze blood when defecating, and face upward when not defecating.

Take five dou of urine. Use it to boil two large handfuls of qinghao, seven fuyu (golden carp) the size of a hand, a six cun piece of smithed gui (cinnamon), and two nodules of dried jiang (ginger).

Let it bubble ten times. Remove (the liquid) and put it in a water jar. Bury (the jar) under a sitting mat, make an opening in it, and fumigate the hemorrhoids. Stop when the medicine becomes cold. Fumigate thrice a day...

Li Shizhen 李時珍

My final stop on this tour of references in the 1979 Chinese Medical Journal paper is Li Shizhen 李時珍, author of the famous Ben Cao Gang Mu. He lived in Qizhou 蘄州, about 60 miles from Wuhan. I visited the town last year to see the Li Shizhen museum.

Qizhou is very much China B, to use China-watcher Nicholas Bequelin's terminology. The old town was razed to the ground by Red Guards during the Cultural Revolution - and what replaced it isn't pretty. The streets aren't paved and there's rubbish everywhere.

There's a run-down looking Li Shizhen hospital built in a pastiche Ming dynasty style. When new, it must have been quite something. But when I visited it was deserted and very grubby. It was a travesty of what a hospital should be - all the more ironic given the Li Shizhen connection. Next door there was an overgrown football stadium that hosted a forlorn medicinal herb market.

On a dismal December day it was extraordinarily depressing even for a casual day-tripper like me.

There obviously had been some investment once, but it had dried up. These days I doubt China's metropolitan central government is going to lift a finger to help. But I think the companies making money out of artemisinin should be able to chip in a dollar or two to help the town of Qizhou.

There is always beauty, no matter how bleak. Around the town there are reed-lined lakes. Men and women wade around in the water grubbing for lotus roots that they boil with pork to make a wholesome stew. Their feet must be frozen in the icy water and their hands swollen and chapped, but I tasted some of the stew in what seemed to be the town's only functioning restaurant and it tasted good.

I digress: there is large museum dedicated to the town's most famous son, Li Shizhen. It was built on the outskirts in the 1980s.

Biomedical traditional Chinese medicine

Artemisia annua. Source: Jorge Ferreira.
In this final post I want to suggest some connections between Chinese herbal medicine and biomedicine, and highlight the existence of a hybrid discipline that one might call 'biomedical traditional Chinese medicine' (BTCM, I think more narrow in my meaning than Elisabeth Hsu's 'Chinese medicine and pharmacotherapy', but please c.f.).

Let's begin with the conventional arguments on Chinese herbal medicine and its relationship to science. The first is East vs. West - polar opposites. The cultural critique of this dichotomy follows, i.e., the idea that both East and West are essentialist constructs, faulty to the core, one, by analogy to Edward Said, the product of Orientalism (one might call its opposite 'Occidentalism', pace Chen Xiaomei). Scholars such as Sean Hsiang-lin Lei and Vincanne Adams move around the edges of this subject.

Another line of commentary, developed out of the work of Kim Taylor and Elisabeth Hsu, runs along historiographical tracks laid down by Eric Hobsbawm, namely, that Chinese Traditional Medicine (TCM) was 'invented' in Maoist China and therefore is not 'traditional' at all. This revelation is taken several steps further in the writing of the polemicist Edzard Ernst, who condemns TCM as a sham and draws a parallel to the Nazis' fixation  with homeopathy in the 1930s.

All great analyses produced by others who know far more than me - and represented rather briefly and crudely in the above summary (and apologies for that). I want to take a different approach . What I am interested in describing is the modern interpenetration of ('Western') biomedicine and Chinese herbal medicine to the extent that the two have become indistinguishable components of a new form of biomedicine we see today.

Hsu makes a point about the indivisibility of the 'two medicines' in a material sense, describing how Chinese medical cures sold in East Africa combine ostensibly Western preparations such as paracetamol with ostensibly Chinese cures based around herbs - in the same pill (here, pay wall). This represents a material form of alternative modernity.

What of this interpenetration, cast in institutional and scientific terms, beyond the materiality of the cure itself? After all, modern biomedical research is not about cures per se, but the evocation of future medical utility in the basic biological sciences.

Let's tackle this problem in two parts. In the first, I want to map out what contemporary biomedical TCM (BTCM) might be. Characteristics thus established, I will then describe how it might have arisen in conjunction with contemporary biomedicine.

Biomedical Traditional Chinese Medicine (BTCM)
Let us consider the ways in which BTCM is promoted, studied and described, using as our starting point a Nature supplement dedicated to the subject. (The WHO has more recently published a similar piece, available here.)

The first point is the tendency in this new discipline to describe 'modern medicine' as highly reductionist. Thus we learn that 'modern medicine, imported [into China] from the West, consists of chemically purified compounds that have been discovered through scientific investigation and tested in controlled clinical trials' and that 'for decades, European and US regulatory agencies held the view that a drug must be either a highly purified or synthetic agent.'

The Nature commentary probably sounds a little simplistic for anyone with a passing acquaintance with medical history - a history in which American, European and Chinese scientists reveal themselves to be (actually) rather sophisticated thinkers about the nature of health, medicines and healing. The point is that we have a biomedical straw-man (of weirdly simplistic orthodoxy) against which the more sophisticated forces of BTCM can react.

The second hallmark of BTCM is technological boosterism - in other words, that herbal medicine is a 'treasure house' of (now) lucrative cures waiting to be uncovered (to subvert Chairman Mao's comment on the matter, but not in the sense he meant it).

What is BTCM, as a laboratory practice? In an interesting article on South Korean research on herbal medicines, Jongyoung Kim described how herbal screening work was boring, creativity-sapping and ultimately soul-destroying. Junior investigators had to plow through organic extractions and bio-assays on different herbs, producing identikit data and dull, identikit papers.

This picture of labor practice will hardly surprise anyone who has visited a biomedical laboratory recently. It is the kind of repetitive work that requires no brain input and therefore can (when funds and technology allow) be readily outsourced or automated, or both.

There is a synergy between the practices of BTCM and those most biomedical/neo-liberal constructs, 'systems biology' and 'personalized medicine' - but let's leave that for another day.

Co-construction of herbal medicine and biomedical science
In any discussion on BTCM, attention invariably alights on qinghaosu/artemisinin as proof of concept. The drug, a sequiterpene lactone, was extracted from a herb traditionally used in Chinese medicine to treat fever. The special significance of the drug may not be that it works as a biomedicine (anti-malarial drugs are, after all, ten-a-penny), but because it articulates a larger project of biomedical reform, a story in which China plays a central part.

Typically, the artemisinin story is told along the lines of conventional pharmacognosy. Accordingly, credit for the work of discovering the drug falls to Tu Youyou, the Chinese scientist who isolated the active principle. However, this telling of the story - of pharmacognosy sui generis - misses out the broader significance of the drug in framing the post-1980 construction of BTCM - and the parallel story of its interpenetration with biomedicine.

It's worth noting in passing the coincidence between the contemporary globalization of Chinese medicine and equivalent changes in the practice of biological research (re-configured as 'biomedicine') that occured in the late 1970s and afterwards.This is probably nothing more than a coincidence.

Two points. The first as follows. Even casual acquaintance with the story of artemisinin reveals the importance of intellectual property issues in negotiations between the Chinese government on one side, and the World Health Organization on the other. The Chinese, by their own admission, were obsessed with safeguarding the intellectual property around what was actually a rather run-of-the-mill medical discovery.

Indeed, the post-1980 history of the drug was shaped by disputes over who owned what and who had the right to make the drug. Looking back, this seems all perfectly understandable, but in the context of the time, it is rather curious. Here was what amounted to government-backed research, conducted in academic centers, being pushed into a commercial context.

Of course, as it turned out, there was no way for the Chinese scientists to protect their IP, simply because such a legal concept did not exist in China in the years when the discovery was made (private property of any sort being anathema in a Communist regime). The important thing is that the Chinese wanted to protect their IP, even if such a move was deemed legally impossible.

What is interesting is that this is a time when, even in America, the various instruments of contemporary biomedical IP, such as routine patenting of unproven or non-commercial discoveries, the use of material transfer agreements, etc., were still in their infancy. Thus, I want to suggest that the evolving connections between academic research and intellectual property were made in important ways through the medium of artemisinin - ways of which we have zero understanding.

A second point. Chinese qinghaosu factories, which were designed to make the drug, notably the Guilin and Kunming plants, were deemed to be producing below GMP standards and therefore the drugs they made were not suitable to export, according to inspectors from the US Food and Drug Administration. By September 1982, Chinese manufacture for export had been effectively thwarted. But the point for the Chinese, at least in the only account we have of the process, was to learn how to implement GMP standards in Chinese pharmaceutical factories (see the Project 523 account, Zhang, et al., pp. 78-79).

The willing transfer of knowledge from American experts to China is a familiar scenario from that era - but a possibly critical role of artemisinin in the reform of the Chinese pharmaceutical trade needs to be investigated. In other words, what was the role of artemisinin in the broader story of the Chinese drug trade?

I want to suggest that, while also a medicine derived from traditional practices, artemisinin was one of the means by which the Chinese pharmaceutical trade modernized (and perhaps, also, American standards were revised and qualified). In this case, the supposed opposites of herbal medicine and biomedicine were constitutionally inseparable.

Source: Dartford Town Archive
Pharmaceutical industry as herbal hybrid
Synthetics were not the be-all-and-end-all of the modern drug trade, even in the West. Investigation (and production) of herbal medicines was in fact stock-in-trade of at least the British pharmaceutical industry. Wellcome, for example, operated a materia medica farm at Dartford in Kent in the 1930s, where the company grew foxgloves for the production of the heart drug digitalis (see the picture to side - and note the factory in the background).

We can take the story into the post-WWII period, to the 1950s - the chemical conglomerate Fisons set up a plantation in Nicaragua to grow Ipecacuanha root (source of emetine) [see: 'The End of a Chapter', a printed history of Whiffen and Sons, Ltd., by Rupert S. Law, B/WHF/245, 1972].

My point here is that these fragments of a yet-to-be-written history show that herbal extracts continued to have commercial value in the pharmaceutical industry in the mid-twentieth century. Furthermore, while herbal medicines probably declined in value as a source of revenue for firms after the 1950s (it was cheaper to make drugs from coal tar and petroleum, rather than exotic herbs), the trade did not give up on them entirely.

Two achievements of post-WWII commercial research attributable in part to herbal medicines were the development of 'The Pill' by the firm Syntex (story told here); and lesser-known, Fisons' work on the anti-asthmatic drug sodium cromoglycate, or Intal.

As this intriguing film shows (above), in the 1960s, a scientist called Roger Altounyan initiated research on khella tea, a traditional middle-eastern herbal remedy for spasm. By experimenting on himself, he found that khella derivatives were anti-allergenic (they stopped his asthma attacks from developing).

The fact that Fisons would commit to such a long-term development project on the drug - eight years - implies that herbal medicines were taken seriously within the management of the company.

Roche and artemisinin
That brings me back to artemisinin, which like Intal, must be one of the major triumphs of post-war  pharmacognosy. In a study of herbal medicine research at the London School of Hygeine and Tropical Medicine, Taylor and Berridge make the point that researchers at the school were always receptive to herbal drugs - and indeed, when qinghaosu was announced to the world in 1979, the school commenced research on the drug without any qualms. In other words, herbal medicines were not a conceptual leap for the leading academic experts of the time.

In this final section I want to flesh out the artemisinin story by examining the work of the Swiss drug maker, Roche.

The Roche Far East Research Foundation, an organization that operated between 1970 and 1999 (in 1987 it seems to have been re-christened the 'Roche Asian Research Foundation'), is a little-known player in the emergence of qinghaosu. Working out what this organization actually did is rather difficult  - Swiss drug company Roche's official history says nothing of it. Accordingly, I have gathered the following data through Google. Based in Hong Kong; its registered address was a mysterious post office box (no. 98595) in Tsim Sha Tsui - there is also reference to an office at 1332 Prince's Building (a tower block on Hong Kong Island); notable staff and collaborators included Dr. Keith Arnold, Dr. R. Laserre and Dr. T. Harinasuta.

Publications associated with the institution give us clues as to its work: apparently lacking its own laboratory facilities, it funded and organized conferences, helped Asian scientists publish their work in English-language journals and provided grants for scientific research and medical training in countries like Thailand, Indonesia, Singapore, Burma and China. Areas of interest included, at a minimum, infectious diseasemental health and 'psychotropic drugs'.

We can deduce that the foundation's aim was to tap medical expertise in Asia, look around for ideas, and  perform a hearts and minds function among governments, academics and medical doctors. It was effectively an intelligence-gathering organization, appropriately based in Hong Kong, which, as a British colony adjacent to Communist China, served as a wider intelligence hub throughout the Cold War.

The big coup for the foundation, if one can call it that, occurred in 1979, when Keith Arnold found out about qinghaosu. How he actually obtained this information, we can only speculate, but the significance of it was that Roche established a relationship with a Chinese researcher, Li Guoqiao, at the Malaria Research Unit, Guangzhou College of Traditional Chinese Medicine (just across the border from Hong Kong, in Mainland China).

The extent to which these contacts benefited Roche financially is hard to gauge (anti-malarial drugs are not major profit centers), but the company certainly made some of the early running when G. Schmid and W. Hofheinz of the company's pharmaceutical research department in Basel succeeded in the first total synthesis of the drug, publishing their work in 1983 (here, pay wall). Roche also secured a contract as principal maker of the drug for the World Health Organization (WHO).

What is interesting is the way Roche moved the drug from a bit player in the anti-malarial game to the leading treatment for the disease, often in combination with another Roche product, mefloquine. Indeed, did Roche actively push the use of qinghaosu in Thailand and Vietnam? Certainly, the Roche Far East Foundation's already-established network of academic collaborators, notably Professors Nick White and François Nosten in Thailand are closely implicated in the story. In Vietnam, Keith Arnold directly recruited Professor Tran Tinh Hien to the program of study and promotion of the drug.

To move one step further, the apparent opposition of the WHO to the artemisinin program, typically read as an ideological bias against 'the East' or herbal medicine, might also be seen as an uneasiness about Roche's commercial projects. Ultimately, it seems to have been academic collaborators, not Roche directly, who conducted extensive clinical trials on qinghaosu, and vociferously argued for its use. The WHO eventually dropped its opposition and embraced the drug.

What I think we can say is that in the 1980s and 90s, 'biomedical' drug companies like Roche seem to have been receptive to the idea of herbal drugs - and were prepared to develop them and promote their use.

We know practically nothing about the actual relationship between 'traditional' knowledge and biological science in the production of drugs - but the cursory grab-bag of factoids I have assembled here suggests a rich history in which the two forms of knowledge have been thoroughly co-constructed.

To talk in terms of binary opposition is clearly fallacious and probably always was. If anything, science's supposed hostility to traditional knowledge is a manufacture of very recent vintage and has more to do with the epistemic practices of contemporary biomedicine (inflected as they are by the US Food & Drug Administration's very particular scientific culture as the key regulator of innovation in the pharmaceutical trade) - rather than some essentialist conflict over the 'truth' of traditional knowledge.

BTCM appears to thrive as a scientific practice in China and elsewhere.