Thursday, November 8, 2012

Even after all these years

For anthropologists, perhaps the most studied types of human adaptation to malaria are those that are biological in nature (I may return to this in the future).  But we also have socio-cultural adaptations.  For example, when I’m doing field work in the tropics I typically wear long sleeves and pants, regardless of the heat, in order to avoid being successfully bitten by mosquitoes.  Architectural design can also prevent malaria transmission.  Window screens and air-conditioning both mean that fewer mosquitoes are likely to enter your home.  And while we may not be alone in this ability, humans are also capable of finding chemicals, or rather organisms containing chemicals, that alleviate our ills when ingested.  Today the pharmaceutical business is a massive entity and one could argue that it provides some of us (at a cost, of course) with the ability to live longer, healthier lives.  But the curious thing about many of these socio-cultural adaptations is that their original function wasn’t always as a protection against diseases, let alone a single disease.   

Frequently we think of pharmaceutical science as being a razor sharp, laser specific approach to tackling the world’s worst problems.  For example, perhaps we’ll find weak spots in the genome of some parasite and develop a vaccine that somehow targets that weakness.[1]  The tricky thing, perhaps especially when dealing with multicellular, relatively complex organisms like Plasmodium parasites, is that the things that kill them or even make them feel a little icky are likely to do the same thing to us.  Rather than an exact, narrowly focused approach to finding medications to cure our ills, what frequently happens is much more clumsy and sometimes borderlines on luck.  Sometimes what happens is a relatively savvy individual has some knowledge of a chemical or compound, is thinking about some disease that needs to be cured, and that individual begins with a “I wonder what would happen if…” kind of approach.   

Antimalarials are an excellent example from which to draw.  I’ll focus on two: quinine and artemisinin.  Both are important for treating severe malaria.  Furthermore, Plasmodium falciparum populations have shown widespread resistance to all other antimalarials, making these two drugs crucial for treating drug and multi-drug resistant malaria.      

There is a lot of lore surrounding quinine, but apparently during the 17th century, Jesuit priests in South America noticed that Quechua Indians would chew on the bark of the Cinchona tree for medicinal purposes.  The exact reason the natives were using it is lost in history, but it may have had something to do with its ability to calm shakes.  Knowing that people suffering with ‘the ague’ (which was probably malaria) also suffered from shaking spells, the Jesuits reckoned that it might work as a cure.  And for many of the people who began using quinine (from the Quechua quina-quina), it did in fact work.  Quinine quickly spread to Europe and elsewhere (it was particularly useful for colonialists that weren’t doing so well in malarious regions). 

Artemisinin has an even longer history (at least in writing) than does quinine, and so far appears to have less severe side effects.  Referred to as Qin Hao, the plant’s use in medicine was described in 168 B.C. in China and was likely used prior to this date.[2]  It was mentioned several subsequent times in ancient texts and appears to have largely been used to treat inflammation, arthritis, fevers and probably several other ills. 

During the late 1960s a group of scientists in China, under the command of Mao Zedong, came together in order to find a new antimalarial (apparently their North Vietnamese friends were plagued by drug resistant parasites).  The effort, named Project 523, took a scientific approach to finding valid antimalarials.  Scientists working on Project 523 tested thousands of potential antimalarials and happened across Artemesia annua.  It showed some promise in halting parasite growth but early attempts, based on extraction through heat, were inconsistent in the laboratory.  After an extensive literature search, some of the researchers working with A. annua came across a reference that suggested the curative agent in the plant might be destroyed when exposed to heat.  Indeed, subsequent efforts at extraction with light heat proved quite fruitful.[3]  

Today artemisinin is an extremely potent antimalarial and is sometimes considered the last hope against drug and multi-drug resistant malaria.  (They are now finding artemisinin resistant malaria on the Thai-Cambodia and Thai-Myanmar borders now.[4])  It is used in most, if not all, places that have malaria and drug resistant malaria though it is frequently used in combination with another drug (or drugs) in an effort to prevent widespread resistance.      

Returning to my previous point, both of these antimalarials (as well as several others) were not discovered through calculated efforts designed to attack a single metabolic process or some other potential weak spot in the malaria parasite.  They also weren’t discovered through a process of invention, that is, they weren’t designed in a laboratory with the specific aim being to treat malaria infection (though derivatives and some antimalarials, such as chloroquine, were).  In fact quinine was successfully used to treat malaria in the absence of any knowledge about the microbial basis of malaria and both were used as medicine prior to the advent of germ theory.  Furthermore, there continues to be debate over how they actually work.  Sometimes these wonderful things that keep many people alive seem to come along by sheer accident.  

I frequently wonder at how such medicinal herbs were ever discovered by humans in the absence of modern science.  On the other hand, one only has to consider that they are probably the rare exception rather than the rule when it comes to attempts at curing ills over the many centuries.  Probably many adventurous proto-medics, or even worse their patients, died in their experiments.  Furthermore, many of these types of adaptations to nasty environments aren’t unlike other forms of socio-cultural adaptations in that they may be helpful for things other than their original intended use.  The long sleeved shirts that I wear in the field probably weren’t invented for protecting against insects (though I suppose the origin of clothing isn’t fully understood, meaning it is one possibility).  

But how far have we now come?  That is, will our new technologies prove to be the next great leap forward when it comes to treating or even eliminating malaria or other similar diseases?  I suppose I’m pretty pessimistic about that.  And even after all these years we still don’t really know how these antimalarials work.  That makes me think that designing new ones isn’t quite likely and that instead we will wind up returning to processes of discovery, where we will hopefully stumble across something that is different enough from what we already have so that the parasites don’t already have resistance to it.  

Furthermore, it makes me worry that in a world with finite resources, we might be diverting too much money towards some very specific approaches that haven’t yet been overly fruitful.  I remain hopeful, but it has now been 10 years since we’ve had genome sequences for both Plasmodium falciparum and Anopheles gambiae (and humans too).  Has it helped us, from a public health perspective, yet?  Has it just not been long enough for it to be a public health benefit and if so, how long is long enough?  From my own perspective, this process seems a little like unwrapping an onion.  There are turtles all the way down.  The more that we know, the more we know that we don’t know so much.  And to some extent we knew that a long time ago.    

Finally, I think taking a historical look at how science has (and hasn’t) worked is valuable.  If we only focus on laser specific inventions then we might be neglecting time well spent discovering.  And for some of us, our passion for science lies in discovery.  Malaria and other persistent human plagues will probably always need to be addressed in multiple, collaborative ways, including but not only relying on antimalarials.  That means that there is room at the table for people from many different approaches, but we need to be careful to not neglect approaches that aren’t necessarily sexy and new.  

After all, it’s been thousands of years at least since we first had to deal with malaria, and here we are, still clinging to antimalarials that we had hundreds of years ago.  


1. Seib KL, Dougan G, Rappuoli R (2009) The key role of genomics in modern vaccine and drug design for emerging infectious diseases. PLoS genetics 5: e1000612. 
2. Willcox M, Bodeker G, Bourdy G, Dhingra V, Falquet J, et al. (2004) Artemisia annua as a traditional herbal antimalarial. Traditional Medicinal Plants and Malaria. pp. 43–60.
3. Tu Y (2011) The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nature medicine 17: 1217–1220. 
4. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, et al. (2012) Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. The Lancet 12.
5. Krishna S, Uhlemann AC, Haynes RK (2004) Artemisinins: mechanisms of action and potential for resistance. Drug resistance updates 7: 233–244.
6. Brown G (2006) Artemisnin and a new generation of antimalarial drugs. Education in Chemistry 43: 97 – 99. 
7. Brown GD, Liang G-Y, Sy L-K (2003) Terpenoids from the seeds of Artemisia annua. Phytochemistry 64: 303–323. 

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