artemisinin , derived from sweet wormwood , artemisia annua , is the spearhead of anti - malarial chemotherapy . in 2004 , the world health organization ( who ) recommendation that artemisinin - based combination therapy ( act ) should be the norm for the treatment of falciparum malaria in most endemic countries came into effect . financial backing for this treatment from the global fund for aids , tuberculosis and malaria and other international sponsors has led to a massive increase in the demand for artemisinin , but with an estimated 1214 months lead - time from planting of a. annua to artemisinin extraction , stepping - up production ( or adjusting to fluctuations in demand ) from the plant is not simple , and alternative means of producing the raw material by complete chemical synthesis or recombinant technologies are being explored . it would , however , be naive to believe that the cost of the raw material is the main determinant of the cost of a drug . this article looks at issues surrounding the production of artemisinins , particularly in the light of a recent paper by jay keasling and colleagues ( ro et al . ) in bmc biotechnology , which describes a way of improving the yield of the precursor , artemisinic acid , in genetically engineered yeast . artemisinin ( qinghaosu ) was discovered in 1971 by chinese scientists looking at the anti - malarial properties of herbs in the traditional chinese pharmacopeia : a. annua had been used as an antipyretic tea for more than 2,000 years . although no longer used as a drug itself , artemisinin is the starting compound for a class of highly active anti - malarials , which are produced by chemical modification of artemisinin . these ' artemisinins ' include dihydroartemisinin , artemether and artesunate , the latter being a particularly interesting derivative because it is water - soluble and can be given intravenously . artemisinin is a sesquiterpene lactone containing an endoperoxide bridge that is considered essential to its anti - malarial action : haem - catalyzed cleavage of the peroxide generates unstable free radicals to which malaria parasites are particularly sensitive . although the peroxide activity is necessary , it may not be sufficient to explain the mechanism of action of artemisin , and alternative hypotheses might need to be considered . specific interactions of artemisinin with parasite proteins , such as the translationally controlled tumor protein ( tctp ) and the parasite ortholog of sarcoplasmic / endoplasmic - reticulum ca - atpase ( pfatp6 ) , have been reported , but the interaction with haem within the parasite - containing vacuole inside the host cell is of special interest . the conversion of toxic haem into non - toxic hemozoin , or malarial pigment , is crucial for parasite survival , and the inhibition of hemozoin formation is a major mechanism of action of many existing anti - malarials , including chloroquine . kannan et al .   have shown that there is a potent interaction between protein - bound haem in hemoglobin and artemisinin , with the formation of ' hemarts ' , which bind to pfhrp2 ( plasmodium falciparum histidine - rich protein-2 ) and inhibit hemozoin formation . artemisinins have broad stage specificity in their anti - malarial action , killing all asexual stages , as well as gametocytes , but have no effect on the exo - erythrocytic stages . where artemisinins differ from other anti - malarials is that they kill young trophozoites ( ' ring ' stage ) ; ( figure 1 ) . as a result , artemisins are rapidly effective and reduce the number of late trophozoites in the capillaries . there is a rapid clinical improvement in patients and reduction of the risk of severe complications . the effect on gametocytes means less efficient transmission of the parasite to the mosquito vector , which potentially contributes to an interruption of transmission to humans and also reduces the risk of dispersion of any drug - resistant mutants . recent field studies have shown that artemisinin treatment significantly reduced gametocyte carriage compared with other drugs , an effect that was variable from one geographical area to another , depending on the level of malaria endemicity and access to treatment . artemisinins kill parasites more effectively and at an earlier stage in the erythrocytic part of its life cycle than most of the other anti - malarial currently in use . they do not work on the exo - erythrocytic forms , hence do not prevent relapses in p. vivax or p. ovale . monotherapy with artemisinins has now mostly been abandoned . who finally agreed , after years of lobbying , to recommend the use of a three - day regimen of combination therapy  that is , artemisinin together with a partner drug  for the treatment of uncomplicated malaria . because of their different kinetics of action , not only does one drug protect the other from provoking resistance , but as artemisinins effectively kill most of the parasites in the first few hours of treatment , the partner drug has a better chance of being effective against the remaining few . two fixed - dose drug combinations are available , artemether - lumefantrine ( coartem or riamet ) and artesunate - amodiaquine ( coarsucam or asaq ) : these have broadly comparable efficacy and the fixed dose has many advantages over other presentations , such as blister - packs . intravenous artesunate acts significatively faster than intravenous quinine , in terms of both parasite clearance and clinical improvement , and there is now a strong case for recommending parenteral artesunate instead of quinine for the treatment for severe malaria . as well as their anti - malarial activity , artemisinins are effective against a number of other parasitic diseases , particularly schistosomiasis , and there is now growing experimental evidence that they may potentially be useful against cancer , especially as their mechanism of action is so different from that of other anti - cancer drugs . this question can be rephrased as ' how many cases of malaria need to be treated with act every year ? ' and is difficult to answer . estimates of the true prevalence of malaria worldwide vary greatly because they are not based on accurate reporting at the country level . in most endemic countries , treatment is given on a presumptive diagnosis , sometimes using a clinical algorithm with the presence of fever as a key factor but generally without laboratory confirmation . at best this approach is only 50% reliable ( and less than 5% reliable in areas of low endemicity ) . in africa alone , various estimates suggest that there are 215 to 375 million malaria episodes per year , and , on the basis of usage of the ' old anti - malarials ' , kindermans et al .   calculated projected drug consumption to be between 113 and 314 million adult - equivalent treatment courses per year . in 2004 , the forecast was for 60 million treatment courses in 2005 and 130 million in 2006 . although these figures already underestimated actual medical need , the amount of act delivered in africa in 2006 was even lower ( less than 100 million treatment courses ) . underproduction leads to shortages and inflated prices , whereas overproduction leads to rapid expiry of the drugs and potential losses by suppliers , as outlined by cohen and colleagues , who looked at forecasting issues from a funding agency angle . a. annua is an annual plant , growing to 150 cm tall and found wild in many countries ( figure 2 ) . production of a. annua is dominated by china and vietnam , but it is also now grown in the highlands of tanzania , south africa , india and madagascar . the active pharmaceutical ingredient ( api ) or ' raw artemisinin ' is extracted from the leaves , just before the plant flowers , and from planting to extraction takes more than 12 months . soil , climate , altitude and grower 's know - how can affect the content of artemisinin substantially . early problems with scaling - up production have , to a large extent , been solved by selection of plants for high artemisinin content and adaptation to the environment in which they are to be grown . further improvement in yield and quality may be possible by further selection , like that being undertaken by artemisinin enterprise at the university of york , in collaboration with the swiss not - for - profit organization mdiplant , using fast - track genetic breeding technologies . hydroponics and in vitro plant culture are other interesting options , which have not yet confirmed their potential . there are claims that the plant simply infused in water could provide a ' home - grown ' malaria treatment in rural areas in the tropics . although trials of such a tea yielded higher than expected amounts of artemisinin , and the plasma concentration achieved by consumption of the tea was compatible with an effective anti - malarial activity ( reviewed in ) , the same trials showed considerable variation in artemisinin content from one batch of plants to another and a high rate of malaria recrudescence . it would be wrong to promote the use of wormwood tea as a ' cheap ' alternative to drug treatment . this use would certainly increase the risk of resistance emerging and a. annua does not grow in the tropical environment where malaria is endemic and can not , therefore , be ' home - grown ' where it would be most needed . raw artemisinin is extracted with solvents , such as hexane , followed by chromatography to improve purity . the extracts usually contain both artemisinin and its precursor , artemisinic acid , which can later be transformed into artemisinin . on average , 40 hectares ( ha ) of land produce a tonne of dried leaves , which can yield 6 kg of artemisinin . the production of 100 million adult treatment courses would require about 10,000 ha of a. annua plantations . despite the relatively low yield , the exploitation of a. annua is commercially viable as long as the price of api is sufficiently stable . in reality , there have been massive fluctuations since 2004 , with prices varying between us$1,600/kg , when there was a world shortage following the who recommendation , to as low as $ 150 at the end of 2007 , when there was a glut . this see - saw effect , which is a direct result of the problems in forecasting demand , is not sustainable in the long term and efforts are being made to stabilize the market . even more than cost , the difficulty in coping with fluctuations in the supply of raw artemisinin of plant origin is the major pressure for a switch to alternative sources . it is considerably easier to cope with ups and downs in demand by switching on a chemical synthesis or a fermentation process than by dealing with the long lead - time of plantations . the drugs currently used as components of act are no longer ' natural ' artemisinins , as extraction from the plant is followed by a semi - synthetic process to transform the molecule first into dihydroartemisinin , then into artemether or artesunate . another alternative , which is , surprisingly , not used industrially outside china , is to focus the extraction process entirely on artemisinic acid , which being 810 times more abundant in the plant gives much better yields , and then to use one of the conversion processes described to transform it into artemisinin . the full chemical synthesis of artemisinin was achieved in 1983 , but is too complex and expensive for commercialization . these molecules have similarities with artemisinin , including the key endoperoxide bridge , but their mode of action is different in many ways . of the many peroxides tested , one trioxolane showed promise ( oz277/rbx11160 or arterolane ) : it was highly potent against p. falciparum in vitro and its synthesis was sufficiently simple for industrial scale - up . the drug proved too unstable in vivo , however , and clinical trials were stopped before phase iii . more stable molecules are in development and a hybrid trioxane - aminoquinoline ( trioxaquine )   may achieve the looked - for objective of a fully synthetic anti - malarial peroxide . artemisinic acid can be produced in escherichia coli and , even more effectively , in saccharomyces cerevisiae , following pioneering work by keasling and colleagues , who transferred 10 a. annua genes into e. coli to create an almost ' plant - like ' environment in the bacteria . their approach circumvents some of the previous problems of engineering the precursors ( amorphadiene or artemisinic acid ) or enzymes ( amorphadiene oxidase ) involved in the artemisinin biosynthetic pathway . expression levels in yeast are still insufficient for industrialized scale - up , but the new publication by the group   describes a further improvement in production in yeast ( with a 10 times higher yield ) by using a high - copy plasmid system . this opens the way for a production process that would completely bypass the need for plantations of a. annua , and in which the yeast - produced precursor would be chemically converted to artemisinin as indicated above . there are still a few hurdles to clear , including confirmation of structural and functional identity between the natural and engineered molecules . we know from past experience that , once emerged , resistance of the malaria parasite to a drug spreads fast : chloroquine resistance emerged in the late 1950s in south - east asia , was reported for the first time in east africa in the 1970s , and has since invaded the entire african continent . it is probably inevitable that mutants resistant to artemisinins will eventually emerge and , if they do , this will probably happen in south - east asia , where artemisinins have been used extensively as monotherapy for nearly 20 years . studies from the thai - cambodian border , and more recently from south cambodia , have already shown reduced susceptibility , as well as treatment failure rates with act exceeding 10% , which is higher than anywhere else . this area is now carefully observed by the scientific community , but monitoring is difficult in the absence of reliable molecular markers for artemisinin resistance , and relies on in vivo and in vitro sensitivity testing , which is cumbersome . as long as there is no resistance to the partner drug , it is usually assumed that the risk of resistance spreading will remain low . it is important that malaria treatment be most carefully controlled in south - east asia , banning monotherapy ( which is still frequent ) , ensuring access to prompt act treatment with good - quality drugs and , whenever possible , treating asymptomatic carriers , who contribute to the spread of resistance . in conclusion , even when synthetic or recombinant artemisinin - like molecules have gone through preliminary tests to confirm their worth , there will still be a long way to go  at least five to six years and millions of dollars  before they will be available as drugs . it is , therefore , likely that a. annua will continue to be the main source of artemisinin for the foreseable future . it is true that the effectiveness of increasing worldwide utilization of act relies on a sustainable supply of artemisinin , preferably at an affordable price . it is also true that limited access to act , as is still the case in many african countries , is not necessarily due to a shortage of raw material , or insufficient production , or even the high cost of the drug . major funding organizations , including the global fund , have begun to understand that , in order to be effective , they not only have to deal with the cost of the drug , but must also strengthen health - system infrastructure and improve provision for diagnosis and treatment in the field . keeping the cost of the drug down means not only ensuring a sustainable supply of the raw material , but also putting pressure on manufacturers to keep the price of the final drug reasonable ; both of which could be achieved by using subsidies to pre - order drugs years in advance . this , however , assumes that forecasting need becomes much better than is currently feasible . the recent endorsement by the 2008 roll back malaria action plan of the affordable medicines facility for malaria ( amfm ) initiative , a proposed $ 1.9 billion financial resource , is likely to have a major role in improving access to the drug at all levels .