The Malaria Thesis, Part 1

In February I attained my Ph.D completion letter from the Universities of Melbourne and Edinburgh for my thesis titled ‘Biochemical and Biophysical Investigations Into Key Malaria Parasite Proteins’. I have since decided to turn parts of the thesis into a series of articles on malaria that are accessible to a non-expert. If you want to read the full, technical thesis, then it has been published and available for download here. This first article will give some historical background on malaria.

Malaria is an ancient disease poetically known as “the scourge of humanity”, and for good reason- since the first confirmed human case of the disease dating back to 450 A.D, it is estimated that half of all people who have ever lived have succumbed to this pathogen. With this ancient disease comes a rich and fascinating history, from mankind originally thinking the disease originated from so-called miasmas (malaria as a word comes from the medieval Italian “mal’aria”, meaning “bad air”), to famous world-changers that are thought to have fallen prey to this parasitic infection such as Alaric I, King of the Visigoths who sacked Rome from 401 A.D. Obviously, it is beyond the scope of this article to examine the full history of malaria (interested parties are directed to the CDC link and the wiki page), however a brief look into two of the major discoveries in the history of malaria should be warranted so as to set the tone for later articles.
Pertaining to the idea that malaria was caused by some form of toxic air, it was not until the 19th century that the paradigm around the aetiology was shifted thanks to the heroic efforts of two military doctors Charles Alphonse Laveran and Ronald Ross. During the early days of medical microscopy, Laveran made the discovery that blood of malarious patients contained parasites. Initially, he observed small, spherical bodies complete with flagella amongst the blood cells obtained from an infected patient’s blood sample (like those in the image above, from ‘Malaria (Ed. I. Sherman) ASM Press, Wash. D.C. 1998’). Laveran notes “I was still hesitating whether these elements were parasites, when on November 6th, 1880, on examining the pigmented spherical bodies mentioned above, I observed, on the edge of several of these elements, moveable filaments or flagella, whose extremely rapid and varied movements left no doubt as to their nature”. This was of course what we know now to be the gametocyte form of the Plasmodium parasite, but Laveran would go on to document various morphological forms. Ronald Ross was the first to demonstrate definitively that mosquitoes were infecting people with malaria, a feat accomplished by two years of microscopically examining thousands of mosquitoes fed with infected patient blood. Upon examination of the mosquitoes fed with infected blood (in contrast to the control group), Ross could observe the characteristic pigment that we now know today to be haemozoin, a metabolic by-product generated from Plasmodium parasites conversion of the haem encountered in erythrocytes. Due to the lack of pigment observed in the control mosquitoes, it was in 1897 that Ross correctly deduced that mosquitoes must be the agent responsible for the transmission of malaria parasites.
Both Laveran and Ross went on to be awarded the Nobel Prize in Medicine or Physiology (1907 and 1902, respectively) for their paradigm-shifting work. Furthermore, these discoveries are of great importance from both a historical and philosophical stand-point. Inductively, it makes sense that people had thought “bad air” around swamps and marshes led to malaria (or “paludisme” as Laveran preferred, which is from the Latin root for swamp); swamps, of course are breeding grounds for mosquitoes and those in swamp-dense areas can be at a higher risk of contracting malaria. However, this is the central philosophical problem with inductive reasoning. Just because swampy areas gave rise to more suffering from malaria, it does not mean the swamp air was the cause; this is a form of post hoc ergo propter hoc fallacy in logic and reasoning (for more on logical fallacies refer to our previous articles). What Laveran and Ross were able to do was to take a more scientifically rigorous deductive approach that possessed falsifiable hypotheses and methodologies open to independent verification. This was indeed the case when the world was initially skeptical over the claims made by Laveran; however, once other researchers were also able to observe and report on finding parasitic microorganisms in patient blood the skepticism subsided. Interested readers in the philosophy of science, particularly in the superiority of deductive means of reasoning over inductive ones, and paradigm shifts are referred here.
The rich history of malaria also encompasses a vast variety of disciplines, from epidemiology to economics, from basic biology to biochemistry, drug/vaccine development and structural biophysical chemistry. It is these fields that shall be examined in more depth with respect to malaria in the subsequent parts of this article series to provide the reader with an integrated understanding of the field of malariology, before embarking on an in-depth biophysical and biochemical analysis of key P. falciparum invasion ligands that are of interest to anti-malaria vaccine development, a development researchers hope will lead to some freedom from parasite-related pain, a truly positive element in any life.