Lunch with the Captain

These days I’m having trouble finding time to write, especially to blog.

My colleagues and I are busy building a team and a large network of collaborators for a series of related malaria elimination projects.  Our initial goal in this project is to wipe malaria out in very specific populations.  If this works, and from our initial work at a smaller scale it appears as though it can, it will be vastly scaled up – reaching throughout Southeast Asia.

The impetus for this work is the so-called evolutionary arms race.  This part of the world has a very long history of popping out drug and multi-drug resistant strains of falciparum malaria (C Wongsrichanalai et al., 2001; Chansuda Wongsrichanalai, Pickard, Wernsdorfer, & Meshnick, 2002).  We (malaria workers) roll out a new line of defense (antimalarials) against our chosen adversary, and our adversary quickly develops a defense strategy against us.  These strains can subsequently move from this part of the world to others, parts of sub-Saharan Africa for example, where the malaria burden is much heavier and the results would be much more devastating (Payne, 1987).

Occasionally there are deaths from malaria infections here along the Thailand-Myanmar border (though usually the major toll the illness takes here is in time spent ill and therefore unable to work.)  Not that long ago, a 15 year old boy died from malaria.  He was not far from health care clinics that would have treated him.  The story I hear is that he was without close family members, he lived alone and worked in the agricultural fields, and that he essentially lay in those fields dying from the disease through an apparent gap in his and his community’s social network.  Everyone was devastated.  If complete drug resistance were to reach Africa, this story would be magnified in both space and time.  Even where the social networks were strong, the health clinics wouldn’t be able to adequately treat people with malaria.  The geographic reach would be huge and the numbers of death would likely dramatically increase.  This can’t happen.

Today our last, best tool against malaria is artemisinin and its derivatives.  But already throughout Southeast Asia researchers and health care workers are seeing parasites survive much longer in the human hosts after being treated with artemisinin (Ashley et al., 2014).  How much longer will it work at all?  And should we really wait to find out?  It often feels as though everyone around here has been doing the same “malaria control” game for a very long period of time, regardless of the fact that the outcome is always the same.  Our drugs stop working and we have to start over again.  Sometimes this problem is exacerbated by a lack of information and/or the dissemination of scientific knowledge.  Many of my Thai colleagues who actually work in direct malaria care in this area just learned last year (2013) that resistance to artemisinins might be occurring or even growing and spreading in their region.  A major scientific paper on this (that I’m aware of) came out 5 years ago (Dondorp, Nosten, & Yi, 2009), with rumors of it almost 10 years ago (Noedl et al., 2008)!  Shouldn’t the people who live in the war zone know that a war is happening!?  What a failure of science – and of our strategy over the long term.  It is time for a change.

So what we’re working on is a tool that we’re calling “targeted chemo-elimination.”  Essentially this is a form of mass drug administration.  That is, everyone in a targeted community would take drugs (antimalarials) regardless of whether or not they felt sick (some recent thoughts on this here, here, and here).  It is much more complicated than this though, in that it isn’t a single strong dose of the antimalarials, we’ll be using a cocktail of drugs so that we can hope to avoid further driving resistance, and since the administration will occur over time, over several stages, we’ll be able to vary this cocktail if necessary.

Logistically this is extremely difficult to pull off.  It is hard enough to get people in easy to reach populations in places like the U.S. to take medicine when they feel sick, let alone to take a vaccine that would prevent them from being sick.  How do we go about convincing people in extremely remote populations, frequently in the middle of old or continuing conflict zones, to take medicine, over a long period of time, regardless of whether or not they are currently feeling sick?  It isn’t easy.

But it can be done and the way to do it is through community engagement – drawing on notions and principles well-known in anthropology and other social sciences.  It can happen when there is understanding, trust, and social cohesion.  Sometimes these things are lacking in our target communities between members of the community, and/or between us and members of the community, and it is therefore important to build them up.  Sometimes we need to plant a seed, water it, foster it, and help it to grow.

This is exhausting work, physically, psychologically, and emotionally.

A little while back I made a trip to one of the communities in our target area, to visit local people and share some of what our project is about.  I wound up eating lunch at a table full of “freedom fighters”, some dressed in fatigues and drinking whisky out of small coffee cups.  A captain who was sitting at the table gave me a history lesson, translated to English through one of my colleagues who speaks both my tongue and the local language.  I heard stories about being betrayed by colonialists who promised these people their own land but never followed through and of people who were willing to die for that land, many of whom did in fact pay that price.

Among the things he said to me was that he admired two major things about Americans.  One is that their time is their money (time is extremely valuable).  And the other is that they realize they have a burden, to help others, that is bigger than a mountain (we were sitting at the base of a relatively large one).

I don’t know if this generalization is true of all Americans and I don’t care to go into that.  But I do know that time is of the essence and that I feel a burden.  There is a lot of work to do, and not so much time in which to do it.

*** As always, my opinions are my own.  This post and my opinions do not necessarily reflect those of Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit, or the Wellcome Trust. 

Ashley, E. a., Dhorda, M., Fairhurst, R. M., Amaratunga, C., Lim, P., Suon, S., … White, N. J. (2014). Spread of Artemisinin Resistance in Plasmodium falciparum Malaria. New England Journal of Medicine, 371(5), 411–423. doi:10.1056/NEJMoa1314981

Dondorp, A., Nosten, F., & Yi, P. (2009). Artemisinin resistance in Plasmodium falciparum malaria. The New England Journal of MedicineEngland Journal of …, 455–467. Retrieved from http://www.nejm.org/doi/full/10.1056/nejmoa0808859

Noedl, H., Se, Y., Schaecher, K., Smith, B., Socheat, D., & Fukuda, M. (2008). Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med, 359(24), 2619–2620.

Payne, D. (1987). Spread of chloroquine resistance in Plasmodium falciparum. Parasitology Today (Personal Ed.), 3(8), 241–6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15463062

Wongsrichanalai, C., Pickard, A. L., Wernsdorfer, W. H., & Meshnick, S. R. (2002). Epidemiology of drug-resistant malaria. Lancet Infectious Diseases, 2, 209–218.

Wongsrichanalai, C., Sirichaisinthop, J., Karwacki, J. J., Congpuong, K., Miller, R. S., Pang, L., & Thimasarn, K. (2001). Drug resistant malaria on the Thai-Myanmar and Thai-Cambodian borders. Southeast Asian J Trop Med Public Health, 32(1), 41–49.

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.  

REFERENCES

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. 

The next challenge in malaria control - artemisinin resistant parasites

Anopheles mosquito, Wikimedia Commons

Sometimes the news about malaria is good, as recently when deaths from malaria were reported to be decreasing, even if inexplicably, and sometimes it's not so good.  Last week saw two not-so-good stories -- one in The Lancet and one in Science -- about the increase in anti-malarial resistance in the Plasmodium falciparum parasite.  The Lancet paper documents this on the border between Thailand and Burma, and the Science paper reports the identification of the genome region in the parasite that is responsible for this newly developing resistance.  Because the parasites are becoming resistant to the best anti-malarial in use today, arteminisin, this is a serious issue.

The Science paper sets the stage:

Artemisinin-based combination therapies (ACTs) are the first-line treatment in nearly all malaria-endemic countries and are central to the current success of global efforts to control and eliminate Plasmodium falciparum malaria. Resistance to artemisinin (ART) in P. falciparum has been confirmed in Southeast Asia, raising concerns that it will spread to sub-Saharan Africa, following the path of chloroquine and anti-folate resistance. ART resistance results in reduced parasite clearance rates (CRs) after treatment...

As the BBC piece about this story says, "In 2009 researchers found that the most deadly species of malaria parasites, spread by mosquitoes, were becoming more resistant to these drugs in parts of western Cambodia."  This will make it much harder to control the disease in this area, never mind eradicate it.

Most malaria deaths occur in sub-Saharan Africa, and the spread of resistance to this part of the world would have disastrous public health consequences.  There is no therapy waiting in the wings to replace ACTs.  Whether the newly identified resistance is because infected mosquitoes have moved the 500 miles from the initial sites where resistance was found toward the border or because the parasites spontaneously developed resistance on their own is not known.  If the latter, this suggests that resistance is likely to arise de novo anywhere that artemisinin is in use -- and that's everywhere malaria is found, as ACTs are the most effective treatment currently in use.

This is, of course, evolution in action, artificial selection in favor of resistant parasites.  It's artificial because we're controlling 'nature' and how it screens.  Normally, selection that's too strong for the reproductive power of the selected species can mean doom -- extinction.  Blasting the species with a lethal selective factor can do that.  In this case, we'd like to extinctify the parasite.  But selection in a rapidly reproducing species is difficult because if any resistance mutations exist, the organisms bearing them have a relative smorgasbord of food -- hosts not hosting other parasite individuals, and this can give them an emormous selective advantage.  So the artificial selection against susceptibility is also similarly strong selection for resistance.

Unfortunately the development of resistance is inevitable when a strong selective force such as a drug against an infectious agent is in widespread use against a prolific target.  And it shows why the idea that Rachel Carson was personally responsible for millions of deaths from malaria because she pointed out in her 1962 book, Silent Spring, the harmful environment effects of DDT, an insecticide that effectively kills non-resistant mosquitoes, is short-sighted.  If its use against mosquitoes had been widespread and sustained, it would have long ago lost its efficacy.

The inevitable rise of resistance to treatment is why prevention or, even better, eradication are the preferred approaches.  Unfortunately developing a vaccine against malaria is proving to be a scientific challenge, and similarly evolutionary considerations will apply; and eradication, while doable in theory, is a political and economic challenge, and could involve the same resistance phenomenon if not done right.  So, the documented rise of drug resistant P. falciparum on the Thai Burma border is a severe blow.

We don't happen to know what, if any, intermediate strategies are being considered or tried.  Multiple moderate attacks, with different pesticides or against various aspects of the ecology or life-cycle might not wipe individuals out so quickly, but may 'confuse' them so that no resistance mechanism can arise because those bearing the new mutation protecting from agent X would be vulnerable to agent Y.  A complex ecology of modest selective factors, could possibly reduce the parasite population to a point where it really did become lethally vulnerable to some wholesale assault.

Or would it be necessary to accept some low level, but not zero, rate of infection to prevent major resistance?   Small pox and polio would seem to suggest that real eradication is possible, but how typical that can be expected to be, is unknown (to us).