Chinese culture has long treated ailments using herbal extracts in intricate combinations. This oeuvre of herbal experimentation gave rise to purified forms more recognisable as medicines, of which Artemisinin is one success story.
Chinese writings as far back as the Han dynasty (around the same era as the Roman Empire) refer to wormwood-tree infusions as a cure for malaria. Preparations for wormwood remedies to treat malaria persist in Chinese writing, through good times and bad, to the modern era.
The 523 Project
Armed with more modern methods, Chinese scientists in the 20th Century looked to isolate anti-malarial compounds from traditional Chinese medicine. With patience, persistence and precision, Tu Youyou isolated Artemisinin from the wormwood tree in 1971 .
Since then, Artemisinin has become the lynchpin in anti-malarial therapy. It has been crucial in treating the drug-resistant malaria emerging in southeast Asia, saving millions of lives. In 2015, Tu Youyou was awarded the Noble Prize in Physiology or Medicine for her discovery.
Heading
Artemisinin is an unlikely candidate for so-called ‘rational’ drug design. It features a strained ‘double oxygen’ peroxide bond above a carbon ring – a structure so unstable that in most other chemicals, it is only glimpsed as a fleeting intermediary in chemical transformations.
For reasons unknown, the peroxide bond in Artemisinin is kinetically stable enough for the chemical to be isolated. Tu Youyou attributes the success of her cold-water extraction scheme to a wormwood-tree-extraction discussion by Chinese scholars in 340 AD. In a ‘rational’ paradigm, Artemisinin’s chemical structure would never be considered stable enough to form a viable compound for a medicine. Nevertheless, numerous clinical trials have shown its efficacy against malaria.
Yes but how?
Understanding how exactly small molecules work in the body appears to be a bit of a luxury. The mechanism of Artemisinin, like Aspirin, still eludes us.
Most people favour the idea that Artemisinin’s unstable peroxide bond is broken, perhaps by the haem in haemoglobin (in red blood cells), which is also the cellular host for the malaria parasite. The active, radical chemicals released when the bond breaks would wreak havoc on the parasite – much more than on the red blood cells (which are disposable anyway).
This is a good hypothesis, but we still do not understand the details. What we do know is that people treated with Artemisinin recover from Malaria far more than those treated with the sham medicine (placebo).
Wrestling with malaria
Humans have been wrestling with malaria ever since mosquitos discovered people and a variety of malaria parasites started to specialise on specifically humans as a host. It is rare for anyone to find a ‘new’ mechanism that can be interrupted to stop malaria. Infecting bipedal apes is such a successful strategy for the parasite that it has become a truly formidable enemy.
Humans have adapted in different ways: huge chunks of our genome are optimised to resist or mitigate malaria infection. Sometimes, as in the case of sickle-cell disease and thalassemias (which offer some protection against infection when only present from one parent’s chromosome, but also cause bad blood diseases when someone inherits an affected copy from each parent ), this comes at the expense of our overall health as a population in regions without malaria.
Synthetic biology
Making Artemisinin is not easy, and for a long time this still required wormwood to provide the source chemical. It is also one of the earliest examples of ‘synthetic biology’: Artemisinin was one of the first molecules to be made by deliberately engineering yeast, successfully introducing components of wormwood metabolism into a more amenable fungus.
However, human chemists have conquered the effective synthesis of Artemisinin, so we are able to produce large amounts of this life-saving chemical on short order. It is interesting to ponder how many other beneficial drugs may lie in the extracts of plants, perhaps already discovered by generations long past.
Preventing resistance
You can definitely have too much of a good thing. Delivering Artemisinin across the board, too efficiently, actively encourages the development of resistance in the malaria parasite. This is a serious concern in areas that are constantly threatened by reinfection by mosquito vectors, like southeast Asia, and where healthcare delivery is becoming increasingly consistent. In 2006, the World Health Organisation called for a ban on single Artemisinin therapies to prevent widespread resistance from emerging.
Artemisinin in EMBL-EBI data resources
Have a look at Artemisinin in EMBL-EBI‘s public data resources
You might also enjoy the write-up of Artemisin as a ChEBI Entity of the Month (February 2012).