Science - March 10, 2005

How a plant makes malaria medicine

Wageningen researchers have worked out how the plant wormwood makes artemisinin. This is not just any old substance, but a medicine against malaria. It is also one of the few anti-malarials to which the malaria parasite has not yet become resistant.

According to a Chinese document that dates from around 2,000 years ago, healers in ancient China already used extracts of wormwood (Artemisia annua) to treat malaria. Scientists forgot the old remedy until a herbal researcher came across the ancient document in the 1970s. Since then the active ingredient, artemisinin, has undergone a big revival. As the larvae of the malaria parasite became increasingly resistant to the conventional malaria medicines such as chloroquine and sulfadoxine-pyrimethamine, mixtures containing the rediscovered plant extract are still effective in fighting the parasite.

‘The problem is the price,’ says Dr Harro Bouwmeester of Plant Research International. ‘The plant only makes a small amount of artemisinin, and anything that increases the production would be welcome.’ At present a three-day artemisinin cure costs about three euros, but that is far more than most of the million people who die each year from malaria can afford.

Bouwmeester and his colleagues recently published a biosynthesis route in Planta Medica, which indicates how the precious substance is formed. ‘When we started this project six years ago we knew that farnesyl-diphosphate was a precursor of the medicinal compound, but that was all,’ says Bouwmeester. The only clue that Bouwmeester had to go on was a metabolite that a researcher in the 1990s had identified as being a substance that should occur somewhere half along the route from farnesyl-diphosphate to artemisinin. ‘But in the end this turned out not to be the case. It is difficult research,’ adds Bouwmeester. ‘We collaborated for a long time with Organic Chemistry, and lots of students wrote their dissertations on the subject, which is why twelve authors are mentioned in the paper.’

Although breeders should be able to use the new knowledge to breed more productive plants, Bouwmeester fears that this will not happen just yet. ‘I suggested the idea to the Medicines for Malaria Venture, but there was little enthusiasm. There is more interest in synthesising artemisinin in the conventional chemical way, the argument being is that this process is easy to up-scale. I think it’s also psychological. If you can make a substance chemically you are not dependent on nature.’

Nevertheless the work of the Wageningen researchers has not been in vain. The Bill Gates Foundation has invested millions of dollars in a biotech project in which bacteria will manufacture artemisinin. ‘The knowledge we have developed is of great importance to this project,’ says Bouwmeester. / WK