Curing Malaria - a Chinese triumph
By Tony Butler
Malaria has been with us since the dawn of civilisation. The Greeks described it, and it was also widespread in Italy until the Pontine Marshes were drained. In the Middle Ages it was common in England, where it was known as the ague, but was absent from Scotland because of the colder climate. Other parts of the world suffered as much as Europe and there is plenty of written evidence that it occurred in China, particularly in the south.
The older Chinese term for malaria is yaozi. Many commentators in different parts of the world noted that it was most prevalent in marshy areas, hence the name malaria (bad air). The symptoms are principally an intermittent fever, anaemia and lethargy, with the first being the most characteristic. It is caused by a blood parasite (Plasmodium) that enters red blood cells, reproduces asexually, and then bursts out, each new parasite entering another red blood cell. The parasite is transmitted from person to person by the female mosquito (Anopheles), which likes to feed on human blood.
In the West, until the 17th century, there was no cure for malaria although many nostrums were tried and promoted. Then Spanish missionaries returning from South America brought back the bark of a tree, the cinchona tree, that South American Indians used to treat fevers, but, as it was generally known as Jesuits bark, there was prejudice against its use in Protestant Britain. However, a Cambridge quack, Robert Talbor, included the bark in a secret concoction that was used successful for curing malaria in many prominent people all over Europe and brought him great financial success. The Chinese emperor Kangxi was treated with cinchona bark taken to China by Jesuits.
One problem in the use of cinchona bark was quality control, as adulteration, which is difficult to detect, was widespread. In the early 19th century two French chemists, Joseph Pelletier and Joseph Caventou, extracted from cinchona bark the component of the bark responsible for killing the malarial parasite p and called it quinine. Quinine proved to be even better than the bark in curing malaria, and it was much easier to check the purity of the sample.
As European nations tried to colonise tropical and subtropical parts of the world where malaria was widespread, the demand for quinine, and hence cinchona bark, exhausted that available from trees growing wild in South America and plantations of cinchona trees were established in Java. Here the bark was removed in a controlled way so that the trees were not killed. However, there was still not enough, and in the 1920s the Germans developed a purely synthetic alternative to quinine, mepacrine. Quinine and mepacrine are chemically related but the latter can be made in a pharmaceutical factory.
During World War II supplies of both quinine and mepacrine were denied to the Allies after Japan over-ran Java and German exports ceased. The absence of a good antimalarial drug had serious consequences for the war in the Pacific, but the Americans quickly found a way to make their own mepacrine. However, the drug had a major drawback - the recipient's skin became yellow. The Japanese propagandist Tokyo Rose broadcast to American troops and told them that mepacrine not only turned skin yellow (true) but also made them infertile (untrue). Such was the alarm of the troops that they stopped taking the drug, and so many fell ill with malaria that the tide of the fighting could have turned against the Americans. The response was to make a better antimalarial drug that did not affect the recipient's skin, and this is the origin of chloroquine, for many years the bedrock of antimalarial medicine. When the World Health Organisation initiated an unsuccessful campaign to eradicate malaria in the 1950s, chloroquine therapy was a major component.
In the 1960s there were two major developments in the fight against malaria. The use of the insecticide DDT, which had been so successful in reducing the number of mosquitoes, was banned because of human toxicity, and the malarial parasite developed resistance to chloroquine. By the1970s malaria was again rampant in many parts of the world where previously it had been under control, and today the situation is even worse. Worldwide there are probably about 400 million cases of malaria and in Africa alone over one million children die of the disease every year. The burden for Africa is not just AIDS and tuberculosis but also malaria. Of these malaria is the biggest killer.
As chloroquine's effectiveness declined, doctors decided that a new drug, working in an entirely different way from chloroquine or mepacrine, was required, and this is where the Chinese enter the story.
The People's Liberation Army wanted a new antimalarial drug specifically so they could fight in the jungles of Vietnam. The Chinese government set over 100 of the country's leading scientists to test all the herbs mentioned in Chinese herbals (called bencao) as cures for intermittent fever. The scientists who worked on the project were excused hard labour in the fields, which was the fate of most intellectuals. After many false starts one herb emerged as a serious candidate for the treatment of malaria. It was a plant growing wild in southern China, called in Chinese qinghao and in English sweet wormwood (Artemisia annua). The Chinese alchemist of the 4th century Ge Hong noted its use in treating fevers, and in the great herbal of the 16th century, the Bencao Gangmu, its properties are described in detail. For modern investigators the situation was confused by claims, made in some bencao, that qinghao cured a whole range of diseases. It is unlikely that all the claims are true, but that concerning malarial fever is correct. Chinese chemists then extracted from qinghao the active principle for killing the malarial parasite and named it qinghaosu (extract of qinghao) or artemisinin. In a brilliant piece of science, with limited equipment, they determined the chemical structure of qinghaosu and concluded that it contained a peroxide bridge, a most unusual structure. A molecule of qinghaosu consists of a tricyclic framework of carbon atoms - the unusual feature is the -O-O- group spanning one of the rings.
It was tested as an antimalarial drug in China and found to be highly effective, particularly against the most deadly form of malaria, cerebral malaria. Moreover, its mode of action was completely different from that of chloroquinine and so, initially, resistance was not a problem.
When this work was being done, China was a closed country and news of it did not reach the West. However, two western scientists, David Warrell and Nick White, working in Vietnam, came across a tatty copy of the Chinese Medical Journal describing the work on qinghaosu. They were astonished at the claims made but doubted the truth of what they read as so little was known, at that time, about Chinese science.; After many twists and turns to the story, the work was taken up by the World Health Organisation, the Wellcome Trust and western pharmaceutical companies and almost every claim made by the Chinese authenticated.
The Chinese have a near monopoly in the production of qinghaosu from the plant and it is in short supply because of the great demand, particularly in Africa. Consequently the price is rising. The unsupervised use of qinghaosu in Asia is a cause for concern, as these circumstances may lead to the emergence of resistant strains of the malarial parasite. In Africa the situation is better as it is used in combination with other antimalarial drugs in the hope that this will prevent resistance arising. If malaria is ever defeated it is probable that the Chinese discovery of qinghaosu will have played a major part in that defeat.