The blockbuster antimalarial drug artemisinin was discovered in mysterious circumstances in China in the 1970s.
Many of the original scientific papers have been lost to public record.
This blog is an effort to find these papers so we can seek truth from facts.
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?
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.
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.
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.
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...
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.
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 Naturesupplement
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).
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 ofqinghaosu. 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 disease, mental 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.
Conclusion
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.
