From Bad Air to Mosquito-Borne Disease: How folks found out malaria was transmitted by mosquitoes Published by on

Given how frequently public health alarms are sounded around mosquito-borne diseases in the United States (Zika and West Nile come to mind), I’m certain all of us have heard of at least one mosquito-transmitted disease. Indeed, mosquito-borne diseases are a big threat to our health and every year cause significant death globally. At the Johns Hopkins Bloomberg School of Public Health, we have a large insectary (the largest in the country) where we breed and study mosquitoes – some of which I use for my own research on malaria vaccines. Before I began working at Johns Hopkins, I never thought I’d be breeding my own mosquitoes. But working with them made me curious. I wondered how mosquitoes were first discovered as the causative agents or “vectors” of these diseases — specifically for malaria (since that’s what I’ve been working on for the past few years). And that’s the story I’d like to share.

Our story starts all the way back in the 1800s, because before we can understand the paradigm (a lens through which we filter things) of mosquito-based transmission, we need to understand the prevailing theories at the time as well as other scientific developments and discoveries, without which the discovery of mosquito-borne transmission would likely have not been possible. This prevailing paradigm that I’m referring to is the miasmatic theory of disease transmission. It was the belief that disease was caused by miasma, which is basically toxic air. In fact, this idea that miasma caused disease, particularly malaria, had been around since the time of Hippocrates 2000 years ago. The word “malaria” itself means “bad air.” However, there were many variations to this paradigm: that the disease was caused by ingestion of stagnant water, or alternatively could be contracted from the soil, which possessed some poisonous vapors that somehow caused fevers in people if the soil was disturbed.

The miasmatic paradigm was first challenged in 1854 by John Snow, the Broad Street pump guy that most public health folks simultaneously regard as legendary, but are also tired of hearing about. John Snow narrowed down the cause of the cholera epidemic in central London to a water pump on Broad Street, and suggested that the cause of the disease wasn’t noxious air, but something in the water.

In the 1860’s, the miasmatic paradigm was again challenged, even more seriously, when a scientist named Louis Pasteur was investigating Puerperal fever, which is a bacterial infection of the female reproductive tract usually following child birth. Pasteur showed that the fever was actually caused by a specific bacterium — and provided the foundation for what we now know as the germ theory of disease (the idea that microscopic organisms are what cause disease). Another scientist named Robert Koch, a few years later in 1876, built on Pasteur’s work and showed that anthrax was also a disease caused by a specific bacterium. Some years later, Koch would show that both cholera and tuberculosis were also diseases of bacterial origin. So you can imagine how the germ theory of disease was becoming both pervasive and accepted, and the miasmatic theory was just beginning to lose ground. It was within these two paradigms — the miasmatic theory and the emerging germ theory — that scientists at that time were trying to explain away the etiology of malaria.

A great example of how these two paradigms were prevailing in the scientific thinking of the time was experiments done in rabbits – injecting them with stagnant water to see how many developed malarial fevers. But the essential problem that these experiments kept running into was the issue of reproducibility. No one could seem to consistently reproduce malaria infection in the rabbits. Others tried the same thing with birds, and even with human volunteers (fodder for another interesting article: the beginning of bioethics), but the result was disappointingly the same. Thomas Kuhn, in his The Structure of Scientific Revolutions would have called this a crisis in normal science — which builds upon the prevailing paradigms of the time, and is an anomaly that just doesn’t seem to make sense. And Kuhn argues that this precedes revolutionary discoveries (which as we’ll see, it did).

So now that we have a better idea of the context within which the discovery that mosquito were vectors of the causative agent of malaria was made, I’d like to introduce some of the specific people and findings that led to the discovery. By understanding the perspective of these scientists through their letters to each other, I learned the circumstances under which they were working.

The first character I want to introduce is Sir Patrick Manson, a Scottish physician who is widely regarded as the founder of tropical medicine. His call to fame was his discovery in 1876, while he was working in China, that the filarial worm that causes Elephantiasis (super swollen limbs that look elephant-like, affecting many poor people around the world – it’s pretty terrible, google it), was taken from human blood by female mosquitoes of the Culex species and continues its growth within the mosquito’s abdomen. He conducted these experiments on his gardener, Hin Lo, who was infected with the worm. He would have mosquitoes feed on Hin Lo, and then dissect the mosquitoes. Aside from the ethics of such work, this discovery was considered to be the beginning of the mosquito-malaria hypothesis! What is extremely interesting to note here is that Manson, in line with the paradigms of the time, thought that malaria was transmitted to humans through drinking water that was polluted by infected mosquitoes (which of course is bs).

In 1881, Alphonse Laveran, a French physician, Key Figure #2 (not pictured), noticed the presence of a dark pigment in the blood of all of his patients who had malaria. And after careful observation, he noticed what appeared to be parasitic forms that had the ability to actively move around… which it later turned out had been the sex cells of the Plasmodium parasite (if you haven’t already, I suggest reading my article on the parasite that causes malaria here) . The way these organisms were moving around in the belly of the mosquito convinced him that he had found the parasite that causes malaria. He went on to win a Nobel Prize for this in 1907. In the picture below, you can see the motile forms that he drew (I’m always in awe of how good scientists, back in the day, were at drawing things – if you see the drawing I drew above, I’m sure you can make the comparison…)!

But until 1890, no one wanted to accept this idea, because proponents of the germ theory of disease were married to the idea that a bacterium caused malaria — not a parasite. It’s likely that the technological advancements in microscopy at the time may have been directly related to Laveran’s discovery. It turns out it was also in the 1880s that oil immersion light microscopy was revealed, which uses oil instead of air between the sample and the objective of the lens. This increases the resolution of the microscopy, and allows things to be viewed in more detail.

Let’s get back to Manson (key player #1) though: Manson was convinced that malaria was originally taken up by a mosquito, where the parasite develops some more, and then the mosquito then lays infected eggs in water, where it dies, and releases the parasite into the water. This water is then ingested by a human. That’s how he thought malaria was transmitted. He badly wanted to do these experiments but didn’t want to go to regions where malaria was endemic. So he needed to find someone who would. He found Sir Ronald Ross (key player #3) — who is now credited with the discovery of malaria transmission.

Sir Ronald Ross was an English medical doctor and actually not all that interested in science. He was more interested in literature, poetry, and drama, and had apparently seriously considered becoming a poet. But his dad didn’t let him, so he went off to India as part of the Indian medical service. Manson found Ronald Ross when the latter was visiting London, and apparently inspired him to solve the age-long puzzle of malaria transmission. In 1895, Ross began his work, and then over the next four years toiled laboriously under the distant guidance of Manson, conducting experiment, collecting mosquitoes, and basically struggling to establish new methods for breeding them so he could then feed mosquitoes on people with malaria. The goal was to infect mosquitoes and then study parasite development inside mosquitoes. He faced a ton of obstacles. For example, some of the mosquitoes didn’t breed, some didn’t feed on the patients, or the patients refused to get bit (I mean….I would also refuse). When mosquitoes did bite the patients, the mosquitoes didn’t always get infected with the parasite. During this time, Ross relied on Laveran’s drawings for identifying the parasites inside the mosquito. But due to the simple microscopes that Ross was using, identifying parasitic forms was challenging.

In one of his letters, Ross wrote: Manson had been able to follow the migrations of the filarial embryos with comparative ease, because they are large organisms readily distinguishable from the fluids or tissues which surround them. But the motile filaments [of Plasmodium] are exceedingly delicate bodies, the movements of which are very difficult to follow even with the highest powers of a good microscope, and in the clear spaces of an ordinary preparation of blood.” The main problem was that Ross was using the wrong species of mosquito for about two years. He was using Culex mosquitoes in which human malaria just doesn’t develop (I suggest reading my article that touches on which mosquitoes can transmit malaria).

On March 2nd, 1898, Ross wrote to Manson from Calcutta: “I have also bought some sparrows, and will examine their blood tomorrow; will try mosquitoes on them. In the same letter, Ross wrote about the considerable difficulty of finding human cases: “I hunt in the native hospital for new cases every morning”. The sparrows were, in fact, where the breakthrough came. It turns out that Culex mosquitoes CAN transmit BIRD malaria, and it is within this model that Ross was finally able to track the complete development of the bird malaria parasite, and was able to infect healthy birds by the bites of infected female mosquitoes. Apparently, upon this discovery, Ross cried and wrote the following poem:

This day relenting God hath placed within my hand,

A wondrous thing; and God be praised.

At his command, Seeking His secret deeds,

With tears and toiling breath,

I find thy cunning seeds, O million-murdering Death.

I know this little thing, a myriad men will save.

O Death, where is thy sting? Thy victory, O Grave

Ronald Ross was very much aware of the implications of his discovery, and said: Ignorant of the route of entry, we could rest our prophylaxis only upon an unsatisfactory empirical basis; cognizant of it, we might hope to stamp out the plague even in its most redoubtable haunts!” I like this quote. And indeed, this discovery was a result of many years of careful observation (and luck!) in finding the right combination of mosquito and host. And though attributed to Ronald Ross, couldn’t have been possible without a whole community of scientists, especially Manson and Laveran. So now you know how malaria transmission got linked to mosquitoes.

Author Bio: Gibbs Nasir is a former malaria researcher in the Sinnis Lab at the Department of Molecular Microbiology & Immunology – Johns Hopkins Bloomberg School of Public Health (Baltimore, Maryland). He recently joined Neon Therapeutics as a Sr. Research Associate to work on translational immuno-oncology. Find him on LinkedIn

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