Malaria: The Disease That Shaped History
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Malaria is one of the oldest known infectious diseases, with a history spanning thousands of years. It shaped human civilization, influenced wars, and driven scientific advancements in medicine and public health. However, humanity has been making strides against this ancient disease over the last 250 years. We've learned what caused it, how it's transmitted, and we might be close to eradicating it completely.

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Malaria is one of a small handful of diseases that have majorly impacted humanity throughout history. Some diseases like smallpox have been completely eradicated. Others, such as bubonic plague and cholera, still exist but can easily be treated with modern medicine.

Malaria, however, has a unique history. It's been around probably longer than any other disease that has impacted humanity, and it's still around today. While we're making strides in eradicating the disease, it hasn't been totally tamed, and it still takes the lives of hundreds of thousands of people every year.

For most of you listening to this, malaria isn't something you've probably suffered from and not something you probably worry too much about. Nonetheless, it does affect an enormous number of people all over the globe. Malaria is caused by parasites of the Plasmodium genus of Protus, which are transmitted to humans through the bite of an infected female Anopheles mosquitoes.

Protists are single-cell eukaryotes, meaning that they have a nucleus in their cell. So they're not bacteria, but they're also not plants, animals, or fungi. Malaria has a history that goes back further than any other disease that we know of. Fossilized mosquitoes trapped in amber dating back around 100 million years actually contain malaria-like parasites.

DNA studies suggest that malaria-causing parasites have co-evolved with humans and primates for at least 30 million years. Many of the worst diseases that have affected humanity have come from contact with domestic animals or were passed from person to person. Many of those diseases, like smallpox, were probably seldom seen or were non-existent before the rise of agriculture.

However, because mosquitoes transmit malaria, it's basically been around forever. It didn't require a large population for it to spread. As soon as humans began recording information, there were reports of malaria. Ancient Sumerian and Egyptian texts describe periodic fevers and enlarged spleens, symptoms characteristic of malaria.

Egyptian mummies from the New Kingdom about 3,500 years ago have shown traces of Plasmodium falciparum, the most deadly malaria parasite. The Atharva Veda, an ancient Hindu scripture, refers to fevers and diseases linked to mosquito-infested swamps. In China, the Ni Qing, aka the canner of medicine from around 2700 BC, describes febrile illnesses similar to malaria.

Malaria likely migrated from Egypt to Rome through trade, military campaigns, and human migration, facilitated by the extensive network of the Roman Republic and the Roman Empire. The Nile River Valley in Egypt was a known hotspot for malaria, particularly due to its warm climate and abundant mosquito breeding grounds. As Rome expanded its influence into North Africa, soldiers, merchants, and slaves carried the parasite with them across the Mediterranean.

The disease found a suitable environment in the marshy areas of Italy, particularly around Rome, where stagnant water provided an ideal breeding ground for Anopheles mosquitoes. Over time, malaria spread northward into Europe aided by Roman roads, trade routes, and urbanization, weakening populations and contributing to the decline of the Roman Empire. During the Middle Ages to the Renaissance, malaria remained endemic across Europe, the Middle East, and Asia.

The disease was known as Roman fever due to its association with the marshy areas around Rome. The term malaria derives from the Italian phrase mal aria, which means bad air, based on the mistaken belief that the miasmas or foul air from swamps caused the disease. When Europeans went to the Americas, they probably brought malaria with them. I say probably because some mummies found in the New World had malaria antibodies.

So it could be that there was a strain of malaria in the New World, and other more deadly strains came over in the Columbian Exchange. Oddly enough, it was in the New World that one of the first major breakthroughs in treating malaria was made. In the 17th century, Jesuit missionaries in South America observed that indigenous people used cinchona bark to treat fevers. An extraction made from the cinchona tree became the first effective treatment for malaria.

and the extraction was known as quinine. Quinine works by interfering with the Plasmodium parasite's ability to digest hemoglobin inside red blood cells. The malaria parasite consumes hemoglobin as a food source, producing a toxic byproduct called heme, which it normally detoxifies by converting it into an insoluble form called hemozoin.

Quinine disrupts this detoxification process, causing toxic heme to accumulate within the parasite, ultimately leading to its death. Quinine is particularly effective against Plasmodium falchiparum, the deadliest malaria strain, and it's been used since the 17th century. However, it can cause side effects like tinnitus, nausea, and headaches, and most modern treatments have largely replaced quinine in most cases.

Malaria was one of the biggest reasons why most of Africa wasn't colonized until the 19th century. Europeans who went into the interior of Africa suffered high rates of malaria, which prevented colonization. Quinine was one of the things that made the colonization of Africa possible. The reason why Europeans had a unique disadvantage was that they didn't have the genetic adaptations to resist malaria.

Over thousands of years, natural selection has led to the development of several genetic adaptations that provide resistance to malaria, particularly in regions where the disease is endemic, such as sub-Saharan Africa. These adaptations affect red blood cells, which the Plasmodium parasite infects, making it harder for the parasite to survive and reproduce. One of the most common genetic resistances is the sickle cell trait.

People with one copy of the sickle cell gene have partial protection against Plasmodium falchiparum. Sickle-shaped red blood cells are less hospitable to the parasite, making it harder for malaria to thrive. However, inheriting two copies of the gene leads to sickle cell disease, a severe blood disorder. The late 19th century saw huge advancements in the understanding of malaria and its transition.

In 1880, Alphonse Laveron, a French army doctor, identified malaria parasites in the blood of infected patients. He won the Nobel Prize in Medicine in 1907 for this discovery. In 1897, British physician Sir Ronald Ross demonstrated that anopheles mosquitoes transmitted the malaria parasite. This discovery revolutionized malaria control efforts, leading to mosquito eradication campaigns.

In the 20th century, malaria was still a major problem in North America, Europe, Asia, South America, and Africa. The war on malaria was fought on two fronts. One was the development of treatments for malaria, and the other was the eradication of malaria-carrying mosquitoes. One of the biggest advances in the treatment of malaria was the discovery of chloroquine.

Chloroquine was first synthesized in 1934 by German scientist Hans Andersag and his team while working for the Bayer Corporation. Initially, it was dismissed as too toxic and remained largely unutilized. However, during World War II, the search for anti-malarial drugs intensified due to quinine shortages, prompting researchers to re-examine chloroquine.

By the 1940s, it was found to be both effective and safe for malaria treatment, leading to its widespread use as the primary anti-malarial drug for decades. Unfortunately, by the 1950s through the 1970s, Plasmodium falchiparum developed resistances to chloroquine. Several other treatments were developed, but they too suffered from resistance strains, which quickly developed. One of the biggest advances was artemisinin, which was discovered in the 1970s.

Derived from the sweet wormwood plant, it was discovered by Chinese scientist Tu Yu Yu. She won the Nobel Prize in Medicine for her discoveries in 2015. This became the foundation for artemisinin-based combination therapies, which remain the gold standard for malaria treatment today. On the mosquito front, the biggest development was the creation of dichlorodiphenyltrichloroethane, or DDT, in 1939.

It became a revolutionary insecticide in the fight against malaria. During World War II, DDT was used to protect troops from malaria in the South Pacific. Post-war, DDT spraying campaigns were launched globally to eliminate Anopheles mosquito populations. These efforts were largely disjointed and unorganized until 1955, when the World Health Organization launched the Global Malaria Eradication Program, or GMEP.

The program's goal was nothing less than to eliminate malaria worldwide through massive mosquito control and anti-malarial treatment efforts. The program relied heavily on indoor residual spraying with DDT, draining mosquito breeding sites, and widespread distribution of anti-malarial drugs like chloroquine. The GME-P saw significant success in North America, Europe, the Caribbean, and parts of Asia and Latin America, where malaria was largely eliminated.

However, it failed in Sub-Saharan Africa, where logistical, financial, and environmental challenges, DDT-resistant mosquitoes, and drug-resistant parasites made eradication infeasible. Despite its successes, the program was ended in 1969 due to funding shortages.

Starting in the 1970s, the overuse of DDT led to mosquito resistance. Also, environmental concerns about DDT's effect on wildlife led to DDT bans in many countries and a shift to alternate pesticides. Slowly but surely, more and more countries were able to eliminate malaria. In the late 20th and 21st centuries, strategies started to change. The remaining countries where malaria was still prevalent were the ones where it was the hardest to eradicate.

One of the biggest modern techniques to fight malaria has been the adoption of insecticide-treated bed nets. Bed nets seem like a rather low-tech solution, and it is in some ways, but it's also highly effective. Insecticide-treated bed nets are one of the most effective tools for malaria prevention, designed to protect people from mosquito bites while they're sleeping.

These nets are impregnated with long-lasting insecticides which not only act as a physical barrier, but also kill or repel mosquitoes that come into contact with them. Bed nets have shown to reduce malaria transmissions by over 50% and lower child morality rates in endemic regions. They are especially crucial in sub-Saharan Africa where malaria transmission is the highest. Perhaps the most promising development in the war on malaria, however, has been the development of malaria vaccines.

The development of malaria vaccines has been a long and challenging process due to the complex life cycle of the Plasmodium parasite, which allows it to evade the human immune system. The Mosquerix vaccine was developed over several decades with research beginning in the 1980s. It was created by GlaxoSmithKline in collaboration with the PATH Malaria Vaccine Initiative. The first successful clinical trials were conducted in the early 2000s, and large-scale Phase III trials took place between 2009 and 2014.

demonstrating partial efficacy against Plasmodium falciparum. After years of evaluation, the World Health Organization officially endorsed Mesquirex in October of 2021, making it the first malaria vaccine approved for widespread use. Mesquirex has an efficacy of only 40%, which is good, but not great. A more effective alternative emerged with the R21 Matrix M vaccine developed by Oxford University and the Serum Institute of India.

Approved by the WHO in October 2023, this vaccine demonstrated a higher efficacy of around 75% in clinical trials. Like muscarix, it targets the liver stage of the malaria parasite, but appears to provide longer-lasting protection. With a production capacity expected to reach 100 million doses per year, R21 is seen as a more scalable and cost-effective solution, and its rollout began in early 2024 in Burkina Faso, Ghana, and Nigeria.

Malaria is still a significant problem in the world. Currently, malaria causes approximately 600 to 620,000 deaths per year, with the vast majority occurring in sub-Saharan Africa, particularly among children under the age of five. There is a belt around the equator where malaria still exists. This includes Southeast Asia, South America, India, the Middle East, and sub-Saharan Africa. However, progress is slowly being made.

In 2024, two more countries, Cape Verde and Egypt, were declared malaria-free. And that means that there were three consecutive years of zero cases in each country. With those two additions, there are now 44 countries that have been declared malaria-free. Malaria has shaped human history for millennia, influencing civilizations, wars, and scientific advancements. While major progress has been made, the battle against malaria is far from over.

but new vaccines and global eradication programs finally offer a hope for a future that is malaria-free. The executive producer of Everything Everywhere Daily is Charles Daniel. The associate producers are Benji Long and Cameron Kiefer.

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