World War II was a global conflict on an unparalleled scale with soldiers deployed all over the world. While the immense death toll is no secret, the role of disease in the war is often underappreciated. The Pacific Theater of the War in particular was host to an insidious and debilitating killer, a disease known for millennia – malaria. During WWII, malaria reached epidemic proportions, infecting about half a million men and leading to a significant investment of resources to curb its spread. Pamphlets were created to educate soldiers, like the one by Dr Seuss warning soldiers about ‘Ann’, the female Anopheles mosquito that acts as the malaria vector1. The Centers for Disease Control and Prevention (CDC), was founded to drive the development of new therapeutic agents. While the anti-malarial research was focused on optimising the war efforts, it led scientists to the path of personalised medicine. 

 

Historically, malaria has been treated by a variety of herbs. The first modern breakthrough was the isolation of quinine from the cinchona tree in South America. Disruptions in the supply of quinine in WWI and WWII prompted research in Germany and the USA for the development of new, synthetic treatments for malaria. The first promising agent was pamaquine, a drug soon proven to be too toxic to be used clinically. This was soon followed by mepacrine which was later used by WWII troops. However, multiple side effects, such as toxic psychosis, made the drug unpopular among soldiers and the low compliance undermined the efforts to reduce the impact of malaria. In order to find a safe drug, anti-malarial research continued throughout the war, but it was only near the end of it that primaquine and chloroquine, anti-malarial drugs with much fewer side effects, were finally discovered2.

 

Even after WWII was finished, chloroquine and primaquine were significant landmarks in the development of anti-malarial drugs. Chloroquine was adopted by WHO in their global malaria eradication scheme and was used prophylactically by American troops in the Korean war. The treatment was so successful, that it was only when the American troops were returning from Korea that symptoms due to relapsing malaria appeared. The soldiers were then effectively treated by primaquine, however, a proportion of them suffered from a severe side effect – acute haemolytic anaemia. In this condition, red blood cells break down faster than they are produced. This observation restricted the use of the drug but was a critical finding that paved the way towards a modern understanding of personalised medicine.

 

In 1956, Carson et al. made a significant discovery that revealed the cause of primaquine-induced acute haemolytic anaemia: those that suffered from this side effect had a deficiency in glucose-6-phosphate dehydrogenase (G6PD), an enzyme crucial for red blood cell function3. G6PD is a component of a metabolic pathway that is responsible for the production of glutathione (GSH), which protects red blood cells from oxidative stress. Primaquine induces oxidative stress in red blood cells, resulting in their destruction in individuals with G6PD deficiencies. This was a milestone in the development of personalised medicine as it revealed how the treatment of patients can vary between individuals according to their genetic makeup. However, in the 1950’s the identification of patients with a G6PD deficiency was difficult, resulting in primaquine only being used in low doses to prevent haemolysis. 

Primaquine is still used in clinical settings for the treatment of malaria, as the advent of modern genetic testing has enabled the prior screening of patients for G6PD deficiency to ensure their safety. According to the NICE guidelines, primaquine is used to treat non-falciparum malaria in conjunction with chloroquine and is the only effective drug for the eradication of latent malaria caused by Plasmodium vivax and Plasmodium ovale. A study from 2009 revealed that G6PD deficiency is one of the most common enzyme deficiencies in humans, which illustrates the significance of the early observation of the phenomeno5. Nowadays the stratification of patients with and without G6PD deficiency is simple, but this early example of personalised medicine encapsulates a key tenet of the field: the understanding of a patient’s genetic context is critical to optimising their treatment. In other scenarios, an individual’s genetic makeup can also be crucial for predicting how likely they are to develop a disease, or what their prognosis may be. Further understanding of the interactions between individuals, diseases, and therapeutics will continue to push personalised medicine forward, enhancing patient care.

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References 

1. Cornell University – PJ Mode Collection of Persuasive Cartography. 

2. Institute of Medicine (US) Committee on the Economics of Antimalarial Drugs; Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington (DC): National Academies Press (US); 2004. 

3. Alving AS, Carson PE, Flanagan CL, Ickes CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science. 1956 Sep 14;124(3220):484-5. 

4. Pinna A, Carru C, Solinas G, Zinellu A, Carta F. Glucose-6-phosphate dehydrogenase deficiency in retinal vein occlusion. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2747-52

5. Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of  glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis.  Blood Cells Mol Dis. 2009 May-Jun;42(3):267-78.