Ever since the early days of human civilization, people have sought to combat malaria around the world. From ancient remedies to modern pharmaceutical agents (and their noteworthy discoverers), the history of malaria and its treatment is a rich one.
History of Antimalarial Treatments
Malaria has afflicted humans for thousands of years. The “Father of Medicine,” Hippocrates, described the disease in a medical text in the 4th or 5th Century BC. Even great warriors were no match for the tiny parasites as Alexander the Great may have died of a malaria infection at age 305. However, it was not until 1718 that the term malaria (from Italian malaria, or “bad air”) was coined by Italian physician Francisco Torti, a title stemming from the belief perpetuated by Roman physicians that the disease was called by malignancies in the swamp air6-8.
The Beginnings of a Mosquito-Transmitted Malaria
For centuries after the Romans initially proposed the idea, it was widely believed that malaria was caused by something in the air rising from swamplands, and that contact with these fumes was a risk factor for the disease8. Though the notion of swamp-gas infecting travelers with malaria seems preposterous now, it was not immediately discounted by 18th century Italian physician Giovanni Maria Lancisi who gained great acclaim by observing black pigmentation in the organs of malaria victims8.
The swamp-gas theory deteriorated over time, particularly once scientists correctly identified an animal culprit for infection8.The concept of a mosquito-born illness was endorsed during an 1882 meeting of the Philosophical Society of Washington. Though the speaker’s suggestion that a giant net be placed over the city to control the mosquito population was met with ridicule, the fact remained that many prominent scientists, including Robert Koch and Alphonse Laveran (see below), suspected that the bloodsucking insects were the root cause of infection8.
Laveran Discovers the Malaria Parasite
Even into the 19th Century, the means by which malaria was transmitted were still unclear. The tiny world of microorganisms and the role these life forms played in the spread of disease remained mysterious. The transmission of malaria was unraveled in 1880 by the French surgeon Alphonse Laveran, who, while stationed at a hospital in Algiers as a military surgeon, observed a parasite moving within a red blood cell from a malarial patient. For his discovery, Laveran was awarded the Nobel Prize in Medicine in 19078.
Identification and Naming of the Malarial Parasites
Italian neurophysiologist Camillo Golgi was the first to describe different species of malarial parasite (based on the frequency of attacks they caused and the number of parasites released once the red blood cells containing them ruptured), work for which he was awarded a Nobel Prize in 19068. Italian researchers Giovanni Grassi and Raimondo Filetti first put a name to these, classifying P. vivax and P. malariae8. Americans William Welch and John Stephens later contributed, respectively, the names P. falciparum and P. ovale8.
Discovering Malarial Transmission
The description of how malarial parasites move among different organisms was accomplished in two major steps. The first was English physician Sir Ronald Ross’ painstaking efforts to show the complex life cycle of the malarial parasite. In his Nobel Prize acceptance speech from 1902, Ross describes his search for both the species of mosquito responsible for transmission and the location of the parasites within the insect’s tissue9. While initially using many subjects from the native Indian population in his experiments (allowing him to show that mosquitoes feeding on malaria victims contained parasites in their tissues), his later breakthrough came when lack of human participants forced Ross to employ birds9. He was ultimately able to observe not only the female and male versions of the malarial parasite in avian hosts but also the transmission of fertilized parasites from birds to the mosquitoes that fed upon them9. Interestingly, Ross was not a trained scientist, but received considerable guidance from another prominent malaria researcher9.
The second revelation that mosquitoes could also pass the disease between human hosts was shown by Giovanni Grassi and his team of Italian investigators in the late 19th Century8. This was done by shuttling willing hospital patients in a room with Anopheles and observing the development and progression of malaria in the subject, a protocol many of Grassi’s contemporaries found exploitative8.
The History of Antimalarials
Unrefined natural products served as the first antimalarial agents. In the 2nd century BCE, Chinese physicians identified the wormwood plant as an effective treatment8. The knowledge of this remedy was lost for thousands of years, while the Western world, coping with the seemingly insoluble problem of malaria, relied mainly on strategies such as DDT spraying into the 1950s8. With a shift in politics in the East came medical innovations. Following the Cultural Revolution, Chairman Mao’s distrust of Western medicine led to a search for effective remedies documented in China’s ancient medicinal texts8. One of these compounds was artemisinin, which soon gained great popularity worldwide10.
In a similar scenario in early Latin America, native Peruvians recognized the beneficial properties of the cinchona tree long before quinine was identified in its bark. With the discovery of the Americas by Europe, an increasing flood of Spanish missionaries entered Latin America at the end of the 15th Century. In the early 1600s, these newcomers learned of the medicinal properties of the cinchona tree, which was used to cure colonists such as the Viceroy of Peru’s wife (The countess of Chichon, from which the tree takes its name)8. The bark of the tree was first introduced to Europe around 1640, where it spread from England to Spain as a popular antimalarial compound. Even when botanists finally classified the plant in the 1700s, it was still known colloquially as the cinchona tree8. However, the active chemical components of the cinchona plant were not isolated by chemists until 1920. By the 20th Century, the main supply of cinchona trees had shifted to plantations in the Dutch East Indies, a geographical displacement that would cause problems for America in WWII (see below)8. Racing to develop antimalarial compounds at this time, German chemists developed a drug named Resochin that would late be known as the popular pharmacologic agent chloroquine8.
World War II: Quinine Shortage and Wartime Research
As previously noted, the major source of cinchona trees had moved to the Dutch East Indies by the early 20th century. With the expansion of the Japanese Empire during WWII, Americans suffered from a lack of antimalarial drugs while fighting in the South Pacific, a region in which the disease was a major threat12. To combat this shortage, a campaign to collect quinine supplies scattered around the United States began in 1942. This period was also notable for the emergency-prompted bolstering of research on antimalarial compounds. Spurred by government support and a sense of national crisis during the war, many advances were made in the biological, chemical, and immunological understanding of the disease as well as methods to treat it, Among the discoveries from this period were alkaloid compounds, including the hydrangea extract febrifuge (which unfortunately proved far too toxic in clinical trials to be used as a treatment). Another was the identification of the insecticidal properties of DDT (a compound first synthesized in 1874) in 1939 by Paul Muller, a contribution for which he was awarded the 1948 Nobel Prize in Medicine12.
The Birth of the CDC and the Worldwide Campaign Against Malaria
During its expansion into Cuba and the construction of the Panama Canal, the US Government took an active interest in controlling malaria outbreaks. The US Public Health Service (USPHS) obtained funding in the early 20th century to combat malaria within the United States itself. Additionally, North Carolina’s Cape Fear was known as a malarial hotspot, which, along with the perilous offshore waters, may explain the region’s ominous name12,13. On July 1st, 1946, the Center for Communicable Diseases was formed. This center, which would eventually become the modern CDC, dedicated itself to the eradication of malaria in the US, a goal that was accomplished by 195112. Among the strategies used in this campaign were improved drainage to remove mosquito breeding sites and large-scale insecticide spraying over affected areas14.
With this task completed, it turned its attention to the global issues of malaria treatment, the continuing focus of the present-day CDC’s malaria research branch12. Following the CDC’s campaign in the United States, the World Health Organization (WHO) began a program in 1955 to eliminate malaria globally, utilizing the advent of new antimalarial compounds and DDT in its mission12. While some countries, such as India, benefited remarkably from the WHO’s efforts, others, such as sub-Saharan Africa, remained largely unaffected12. Difficulties such as drug-resistant strains of malarial parasites have ultimately made the WHO’s original mission unfeasible, necessitating its transition to a mission of control rather than eradication12,15.
Economics, Ecology, and Etiology: Geographical Pressures on Malarial Parasites
Looking at a map of the globe highlighting malarial “hotspots,” a few primary themes begin to emerge. Malaria prevalence overlaps the habitats of the Anopheles mosquitoes, shown in the boxed diagram16,1. However, as you can see, these insects are found around the globe, while incidents of malaria are concentrated in the tropics. Even if more Anopheles are found in the tropics, due to their faster development in temperate water, this still does not fully explain historical accounts in which malaria is reported in some regions earlier in more ancient time than others.
These differences might be explained if the disease arose in one particular place – the current theory is that Africa was the continent of origin6. After this beginning, malaria spread, the parasites either flourishing or declining based on the new climate6. For example, Native Americans may have been rendered malaria-free by their migration to North America during the ice age, entering a zone unfavorable to the life cycle of the mosquito vector6,17. More recent historical events that may have spread the parasites include the African slave trade of the 16th through 18th centuries and foreign travelers in ancient Greece6. Thus, the success of the parasite’s adaptation to new climates, in addition to the fitness of their Anopheles carriers, may explain the distribution of malaria as humans spread across the globe6.
While this paradigm of environmental adaptation is plausible, factors outside the world of scientific theory may also help explain the geographical distribution of malaria; in fact, economics may play a pivotal role. The link between geography and economic prosperity was noted in the 18th century by economic pioneer Adam Smith in The Wealth of Nations18. Simply put, coastal regions have better access to shipping routes and thus outperform inland nations. In the case of malaria, these economic and epidemiological factors are reciprocal: on the one hand, the geography of the interior tropics limits economic development, leading to fewer health care resources and ability to combat malaria18. Conversely, the disease retards economic growth, inasmuch as high infant mortality results in less investment in education and the market potentials enabled by educated individuals18. Thus, the “vicious cycle” of disease and economic underdevelopment makes treatment of malaria in the tropics an appreciably difficult task18.
Epidemiological figures underscore the disparity of the malarial burden between the developed and developing worlds. In 2002, there were 8 malarial deaths reported in the US, while some areas of Africa had 2700 deaths a day in 1995 from the disease – that is 2 deaths a minute19. The disease’s impact on child mortality is also profound, causing 10.7% of all children’s deaths in developing countries (the fourth highest cause)19.
1. Why might coastal regions be more prosperous than inland ones?
2. Why might it be economically significant that malaria is a major cause of child mortality?