Not one or two but the efforts of many over centuries led to the deciphering of the Plasmodium life cycle. Malaria histories point to, , , , , , , , , , and as the most notable of these scientists.
This answer summarizes key discoveries related to the Plasmodium life cycle,
- How focus shifted from bad air to mosquitoes.
- How the Malaria causing organism was identified to be a protozoan, not bacterium.
- How the protozoan parasite gets into human blood in the first place.
- The role of the insect vector, mosquito, in transmitting Malaria between people.
What causes Malaria, Bad Air or?
Combining two Latin words, mal (bad) and aria (air), and originally written as ‘mal’aria’, obviously Malaria was associated with marsh air so much so that simply breathing it was for long thought sufficient to cause the disease. Ague, Cattivara, Intermittent fever, Paludism, Periodic Fever, Swamp miasmata, the various names used through history to describe this disease thus allude to two of its cardinal features, fever and proximity to swamps.
While speculating on the connection between swamps and Malaria epidemics in his 1717 treatise, De Noxiis Palodum Effloriis (On the Noxious Emanations of Swamps), the 17th century Italian physician, Giovanni Maria Lancisi, theorized that swamps produced two types of emanations, animate and inanimate, both potentially capable of causing Malaria. Africans and Indians had long recognized the link between Malaria and mosquitoes (2). Lancisi thus theorized animate emanations were mosquitoes that could carry Malaria-causing animalcules (1). Did such animalcules actually exist?
Are there Malaria causing organisms, and if yes, what are they? Bacteria or Protozoa?
Long before the discovery of the Malaria parasite, Plasmodium, careful observers had already discerned something different about the blood and often also the spleen and liver of Malaria patients. Specifically, autopsies showed some type of heavy pigmentation in these cells and organs. For example, Professor Joseph Jones of the University of Louisiana testified in an 1876 court case that (see below from 2)
‘certain stains on the coat and shirt of an accused prisoner were not paint, as had been affirmed, but were the blood ‘of a human being who had suffered and was probably suffering at the moment when the blood was abstracted, with malaria or paroxysmal fever…many of the particles of melanic pigment were spherical, others irregular and angular, some entirely free, others encased in a hyaline mass’
Today we know this pigment to be, a product of Malaria parasite metabolism inside red blood cells.
Having already observed such pigmented cells in the autopsied tissues of Malaria patients as well as in fresh blood drawn from those known to have the disease, Charles Louis Alphonse Laveran, a French army physician posted to Constantine, Algeria, in 1878, was already determined to in his own words ‘follow the pigment‘ (). Looking for pigment in fresh Malaria patient blood with the additional advantage of using a microscope objective with a maximum magnification of 400X, Laveran meticulously examined blood smears of 200 patients, and found in 148 not just the characteristic pigment associated with Malaria blood but also crescent-shaped ‘spherical motionless bodies with pigment, spherical moving bodies with pigment and bodies that extruded flagella-like structures‘ ( ), reporting his breakthrough on 6 November 1880 thus (see below from 2),
‘I had suspected for a long time the parasitic nature of these bodies when on November 6th, 1880, while examining one of the spherical pigmented elements in a preparation of fresh blood, I noticed with joy at the periphery motile filaments [probably exflagellation] of the animated nature of which there was no room for doubt’
Laveran obviously (see below from 1)
‘was astonished to observe, [in a soldier’s blood specimen] . . . a series of fine, transparent filaments that moved very actively and beyond question were alive’
Laveran‘s key findings were ()
- Crescent-shaped bodies present in blood smears of 148 Malaria patients but never in those without Malaria, and
- That Quinine removed these stages from the blood.
Realizing he’d found a parasitic protozoan, Laveran called it Oscillaria malariae and presented his findings to the French Academy of Medical Sciences in December 1880 (4). Though Laveran did win the Nobel Prize in 1907 for identifying the Malaria parasite as a protozoan, his discovery was without precedent since no protozoan had ever been reported inside a human blood cell and thus his findings were initially greeted with skepticism. After all this was the heyday of the bacterium and scientific luminaries such asand ruled the roost with their discovery of important disease causing bacteria.
Even the eminence grise of physicians,, was skeptical at first and only became convinced by looking at blood smears of Malaria patients himself over several weeks (see below from 2).
‘When I first read Laveran’s papers nothing excited my incredulity more than his description of the ciliated bodies. It seemed so improbable and so contrary to all past experience, that flagellate organisms should occur in the blood…The work of the past six months has taught me a lesson on the folly of skepticism based on theoretical conceptions, and of pre-conceived notions drawn on limited experience’
Unknown to Laveran, the Russian physiologist, Vasily Danilewsky, had already discovered a number of parasites in the blood of birds and reptiles (). Calling them ‘pseudovacules’, by 1885, Danilewsky had identified , and . Since most of his work was published in Russian, only the French publication of his 3-volume book, La Parasitologie Comparée du Sang, in 1889, made his discoveries widely known.
How the protozoan Malaria parasites get into patients’ blood in the first place: Discovery of the insect-to-human cycle
Laveran‘s discovery connected Malaria to a microscopic protozoan organism. However, how did the protozoan parasite get into Malaria patients’ blood in the first place?
A key figure in parasitic diseases, Scottish parasitologist Patrick Manson was born in Aberdeenshire, Scotland, in 1844, and practiced medicine in Formosa (now Taiwan), where he saw many cases of. While on leave in London in 1874, Manson searched the medical literature and found several reports of microfilariae in blood of filarial patients. While wondering how such parasites could spread from one person to another, Manson hit upon the notion of a bloodsucking insect. Back in Formosa, Manson researched and cross-referenced the distribution of bloodsucking insects with filariasis cases. He found mosquitoes to be the best fit. Manson then tried to carefully reconstruct the human-to-insect transmission cycle. First, he fed mosquitoes on active filarial patients and then dissected the mosquitoes at varying lengths of time. This way Manson was able to
- Identify filariae in mosquito gut post-human feeding.
- Observe filarial development and migration into mosquito thoracic muscle where they continued growing.
However, Manson erred in his final conclusion, thinking infected mosquitoes returned to die in water and that humans got accidentally infected after drinking infected water. Shortly afterward,in Australia and in England (in Patrick Manson‘s lab) independently proved that infected mosquitoes transmitted filaria into humans when they bit them to take their blood meal.
Following in Manson’s footsteps, in the final decade of the 19th century, studies of various tropical diseases were leading scientists to a common notion, that of an insect-to-human cycle (1, 2).
- While local Texas ranchers had long believed ticks were somehow responsible for spreading Texas cattle fever, and F.L. Kilbourne finally proved that the local ‘hard tick’, , transmitted the parasite, .
- Working in then-Zululand, showed that transmitted nagana or . However, Bruce made a mistake, correct about how insects became infected from taking blood meal on an infected person/animal but incorrect in being unable to decipher that infected insect biting uninfected host could transmit disease back.
- While the Cuban epidemiologist, , had suggested mosquitoes might spread , there was no proof yet. Already back in 1804, observing that doctors and nurses who cared for yellow fever patients seemed to not get the disease, had subjected himself to some remarkable self-experiments by exposing himself to the ‘hemorrhagic vomitus, other excretions, and blood of patients dying of yellow fever‘ (1). Unable to transmit infections through these methods, Ffirth had concluded that yellow fever was not directly transmitted from person to person. During the 1898 , a yellow fever commission led by was tasked to investigate. Using human volunteers, the commission found yellow fever could be transmitted to humans by Stegomyia fasciata (now called Aedes aegypti) mosquitoes, with one volunteer Jesse W. Lazear (1866-1900) succumbing to yellow fever from a mosquito bite ( ).
Though never awarded the Nobel prize, Manson‘s groundbreaking insight has led to him being labeled the ‘father’ of tropical medicine. Most importantly, Manson‘s observations of Malaria patients in London had shown him that flagellated forms of the Malaria parasite only appeared after blood taken from Malaria patients cooled, i.e., at a temperature far below that of human body temperature. From this he concluded other stages of parasite development occurred outside the human body, perhaps in mosquitoes. Thus, by the time British medical doctor Ronald Ross entered the picture, the time was ripe for connecting all the dots in the Malaria transmission cycle.
Meantime, by 1884 Laveran had convinced the leading Italian malariologists Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Giovanni Battista Grassi, Camillo Golgi, Ettore Marchiafava, as well as the ‘more cynical’ microbiologists Louis Pasteur, Charles Eouard Chamberland and Pierre Paul Emile Roux that Malaria was caused by a protozoan, not a bacterium (). Only Robert Koch, perhaps the pre-eminent microbiologist of the time, still remained a holdout against the protozoa-Malaria idea.
Moving full speed ahead on their independent studies to decipher the role of mosquitoes in Malaria transmission set the British and Italians on a famous collision course where the rightful recognition for discovery became a casualty of politics.
Deciphering the role of the insect vector in Malaria transmission: Independent discovery by British and Italians
The British side of the Malaria story
Meeting Manson for the first time in 1894 when he was home in London on leave, Ross, then a low ranking physician in the Indian Medical Service, became his student. Convinced Malaria was spread by mosquitos and that India was the ideal place to finally crack the case, Manson taught Ross the basics, showing him human blood smears containing Malaria parasites.
With Manson supervising his studies long-distance, and heeding his dictate to ‘follow the flagellum‘ () over the next four years, Ross tried to connect the dots between Plasmodium, mosquitoes and Malaria. First, Ross fed different types of mosquitoes on Malaria patients. Ross had three different types of mosquitoes to choose from, common grey or barred-back, less common ‘brindled’, and much rarer ‘dappled-winged’ ( ).
On two consecutive days in August 1897, Ross was fortunate to have supply of the rarer ‘mosquitoes whose wings were dappled and had four dark spots‘ (2). Today, we call such mosquitoes anopheline. After feeding such mosquitoes on a Malarial patient with crescent-shaped bodies in their red blood cells, Ross observed cysts growing on the mosquitoes’ stomachs, and that when these cysts ruptured, they released ‘rods’ that invaded the mosquitoes’ salivary glands. Indeed he found mosquito salivary glands to be packed with Plasmodium rods, a discovery he marked by calling August 20, 1897, ‘mosquito day’, a date that’s been commemorated as such ever since,.
Unfortunately, before Ross could pursue the next logical step in the discovery process and experimentally show Malaria transmission from diseased to healthy people through the bite of Malaria-infected mosquito, he was transferred to Calcutta, a city with little human Malaria, to instead work on kala-azar,. Luckily, Manson had suggested to Ross the possibility of studying Malaria in birds as well. Thus, in Calcutta, Ross began work on Proteosoma relictum (now called Plasmodium relictum), a common Malaria parasite in crows and sparrows.
Here he found that rather than ‘dappled-winged’, the more common ‘grey’ (now called culicine) mosquitoes did the trick. Specifically, he found that 178 of 242 ‘grey’ mosquitoes fed on infected birds developed ‘pigmented spores’ (). Ross was then able to follow all of the parasite’s developmental steps within the mosquito, from exflagellation and fertilization in its gut to oocyst formation and sporogony to final migration of sporozoites in its salivary glands (2). The final proof came when Ross could infect healthy sparrows by inoculating them with sporozoites isolated from experimentally infected mosquitoes.
Writing to Manson on July 6, 1898, Ross memorialized his discovery thus (see below from 1, emphasis mine),
‘I think that this, after further elaboration, will close at least one cycle of proteosoma, and I feel that I am almost entitled to lay down the law by direct observation and tracking the parasite step by step—Malaria is conveyed from a diseased person or bird to a healthy one by the proper species of mosquito and is inoculated by its bite. Remember, however, that there is virtue in the “almost.” I don’t announce the law yet. Even when the microscope has done its utmost, healthy birds must be infected with all due precaution. . . . In all probability it is these glands which secrete the stinging fluid which the mosquito injects into the bite. The germinal rods . . . pass into the ducts . . . and are thus poured out in vast numbers under the skin of the man or bird. Arrived there, numbers of them are probably instantly swept away by the circulation of the blood, in which they immediately begin to develop into malaria parasites, thus completing the cycle. No time to write more’
Manson presented these results to the British Medical Association in Edinburgh in July 1898 (1).
The Italian side of the Malaria story
In the 1890s, Italian scientists such as Bastianelli, Bignami, Golgi, Marchiafeva reported how the protozoan parasite invaded blood cells, grew within them, and produced daughter cells that invaded other blood cells (). By 1898, Bignami and Grassi had access to Malaria sites in Rome and Siciliy. Over the next two years, the Italians methodically filled in the blanks (6, 7),
- Showed only female Anopheles mosquitoes could transmit Malaria.
- Described the entire lifecycle of Plasmodium vivax, P. falciparum and P. malariae. Feeding local Anopheles claviger mosquitoes on infected patients transmitted infection to uninfected individuals via the bite of such infected mosquitoes.
- In a classic experiment, Grassi sent 112 volunteers to a malarious region in the Capaccio Plains, protecting them from mosquito bites between dusk and dawn. Only 5 of these volunteers succumbed to Malaria compared to 415 unprotected volunteers, all of whom contracted it.
Thus, by 1898, Grassi, Bastianelli and Bignami had not only resolved the entire life cycle of the human Malaria parasite, Plasmodium falciparum, but also demonstrated that Malaria could not exist without Anopheles mosquito. Yet, only Ross was awarded the Nobel Prize for this discovery in 1902. Why this discrepancy? Politics, which is never pure nor simple ().
This is when Robert Koch enters the picture, ostensibly at the invitation of the Italian government to ‘solve the malaria problem‘ (8). Apparently this is when the Italians rushed to publish their results, with Grassi first publishing his initial report on the P. falciparum lifecycle in November 1898, citing Ross‘ work only at the very end, and then publishing a fuller report a month later not citing Ross at all (2). Thus ensued a battle royale between Ross and Grassi with Koch apparently eagerly adding the kindling. Rich irony there that of all the world famous microbiologists of his time, Koch was perhaps the last to begrudgingly acknowledge only by 1887 that Malaria was caused not by a bacterium but by a protozoan. When the committee considered splitting the 1902 Nobel Prize between Ross and Grassi, it was apparently Koch‘s vehement opposition that led to the prize going to Ross alone (1), more proof, not that we need more, that human society rewards aren’t merit-based as a matter of course, even though we or at least some of us fervently wish they were.
1. Nelson, Kenrad E., et al. “Infectious disease epidemiology theory & practice.” (2001): 205.
2. Esch, Gerald. Parasites and Infectious disease: discovery by serendipity and otherwise. Cambridge University Press, 2007.
3. Cox, Francis EG. “History of the discovery of the malaria parasites and their vectors.” Parasites & vectors 3.1 (2010): 5.
4. Laveran, Alphonse. Un nouveau parasite trouvé dans le sang des malades atteints de fièvre palustre: origine parasitaire des accidents de l’impaludisme. 1881.
5. Reed, Walter, and James Carroll. “The prevention of yellow fever.” Public health papers and reports 27 (1901): 113.
6. Grassi, Battista, Amico Bignami, and Giuseppe Bastianelli. Ulteriori ricerche sul ciclo dei parassiti malarici umani nel corpo del zanzarone. tip. della R. Accademia dei Lincei, 1898.
7. Grassi, Giovanni Battista. Studio di uno zoologo sulla malaria. Vol. 3. R. Accademia dei lincei, 1900.
8. Harrison, Gordon. “Mosquitoes, malaria and man: a history of the hostilities since 1880.” Mosquitoes, malaria and man: a history of the hostilities since 1880. (1978).