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The history of malaria began before human history, as this ancient disease appears to have evolved before humans appeared on Earth. Similarly, it appears that malaria has infected people for much of human history. The biology of the malaria parasite, and how to treat and prevent malaria have been investigated in science and medicine for hundreds of years. These studies have continued up to the present day, since no effective vaccine has yet been developed and many of the older antimalarial drugs are losing effectiveness as the parasites evolve high levels of drug resistance.

Origin and early history

The mosquito and a fly in this Baltic amber necklace are between 40 and 60 million years old.

The first evidence of malaria parasites has been found in mosquitoes preserved in amber from the tertiary period that are approximately 30 million years old.^[1] Malaria may have been a human pathogen for the entire history of our species.^[2] Indeed, close relatives of the human malaria parasites remain common in chimpanzees, our closest relatives.^[3] About 10,000 years ago malaria started having a major impact on human survival which coincides with start of agriculture (neolithic revolution); a consequence was natural selection for the genes for sickle-cell disease, thalassaemias, glucose-6-phosphate dehydrogenase deficiency, ovalocytosis and elliptocytosis because such blood disorders confers a selective advantage against malaria infection (balancing selection). The three major types of inherited genetic resistance (sickle-cell disease, thalassaemias, and glucose-6-phosphate dehydrogenase deficiency) were present in the Mediterranean world by the time of the Roman Empire, about 2000 years ago.^[4]

References to the unique periodic fevers of malaria are found throughout recorded history. According to legend, the Chinese emperor Huang Di (Yellow Emperor, 2697-2590 BC) ordered the compilation of a canon of internal medicine. The Chinese Huangdi Neijing (The Inner Canon of the Yellow Emperor) apparently refers to repeated paroxysmal fevers associated with enlarged spleens and a tendency to epidemic occurrence – the earliest written report of malaria.^[5] In the Sushruta Samhita , a Sanskrit medical treatise (6th century BC), the symptoms of malarial fever were described and attributed to the bites of certain insects.^[6]

The name malaria, derived from ‘mal’aria’ (bad air in Medieval Italian) was probably first used by Cornaro in a publication of 1440. Malaria was once common in most of Europe and North America. In the coastal marshes of England, mortality from "marsh fever" or "the ague" (from Latin “febris acuta”) was comparable to that in sub-Saharan Africa today.^{[7] [8]} William Shakespeare was born at the start of the especially cold period that climatologists call the "Little Ice Age", yet he was aware enough of the ravages of the disease to mention it in eight of his plays.^[9] Throughout history the most critical factors in the spread or eradication of disease has been human behavior (shifting population centers, changing farming methods and the like) and living standards. Poverty has been and remains a reason for the disease to stay where it went in other places.^{[10] [11]}

Early research and treatment

The introduction of molecular methods confirmed the high prevalence of Plasmodium falciparum malaria in ancient Egypt.^[12] The fourth of the Plagues of Egypt was עָרוֹב (flies, the correct translation is unclear), capable of harming people (Exodus 8:16-28) and Mosquito nets were used in Egypt as early as 2700 BC. For thousands of years, traditional herbal remedies have been used to treat malaria; the historian Herodotus (484 – 425 BC) wrote that the builders of the Egyptian pyramids were given large amount of garlic, to protect them against malaria.^[13] Malaria became widely recognized in ancient Greece by the 4th century BC, and is impliated in the decline of many city-state populations. Hippocrates (460-370 BC), the "father of medicine", related the presence of intermittent fevers with climatic and environmental conditions and classified the fever according to periodicity into three types: febris tertiana (alternate days), quartana (every fourth day) and quotidiana or continua (now called tropica).^[14] Around 168 BC the herbal remedy Qing-hao came into use in China ("Recipes for 52 kinds of diseases" unearthed from the Mawangdui tombs).^[15]

Cinchona calisaya

In the 1500s AD, European settlers and slavery are likely to have brought malaria to America. Spanish missionaries found that fever was treated by Amerindians near Loxa (Peru) with powder from Peruvian bark ( Cinchona succiruba ). There are no references to malaria in the "medical books" of the Mayans or Aztecs; a bitter tea prepared from the bark of the Cinchona tree was most likely used by the indigenous Peruvian Indians to minimize shivering in the cold. The use of the “fever tree” bark was introduced into European medicine by Jesuitical missionaries (Jesuit's bark).^[16] Jesuit Barnabé de Cobo (1582-1657), who explored Mexico and Peru, is credited with taking cinchona bark to Europe. He brought the bark from Lima to Spain, and afterwards to Rome and other parts of Italy, in 1632. Francesco Torti published in 1712 that only “intermittent fever” was amenable to the fever tree bark (“Therapeutice Specialis ad Febres Periodicas Perniciosas”, 1712 Modena). This work is notable in that it brought about the general use of cinchona bark in italian practice.^[17]

In 1717 the graphite pigmentation of the spleen and brain postmortem was published by Giovanni Maria Lancisi in his malaria text book “De noxiis paludum effluviis eorumque remediis”. He related the prevalence of malaria in swampy areas to the presence of flies and recommended swamp drainage to prevent it.^[18]

19th century

Structure of quinine.

Pierre Joseph Pelletier and Joseph Bienaimé Caventou separated in 1820 the alkaloids Cinchonine and Kinine (quinine) from powdered fever tree bark, allowing for the creation of standardized doses of the active ingredients.^[19]

Meckel recorded in 1848 innumerable black-brown pigment granules in the blood and spleen of a patient who had died in a hospital for insane people. Meckel was probably looking at the parasites of malaria without realizing it; malaria was not mentioned in his report. He thought the pigment was melanin.^[20]

An English trader, Charles Ledger, and his Amerindian servant, Manuel Incra Manami, had spent four years collecting cinchona seeds in the Andean region of Bolivia, highly prized for their quinine but a prohibited export. Ledger managed to get some seeds out; in 1865 the Dutch government bought a small parcel, and 20 000 trees of the famous Cinchona ledgeriana were successfully cultivated in Java (Indonesia). By the end of the nineteenth century the Dutch established a world monopoly in the supply of quinine.^[21]

Paul Ehrlich started the scientific study of drugs.

Attempts by William Henry Perkin in the 1850s to synthesize quinine in a commercially practicable process were unsuccessful. However, Perkin's Mauve was produced when attempting quinine total synthesis via the oxidation of o-toluidine.^[22] Before Perkin's discovery all the dyes and paints were colored by roots, leaves, insects, or, in the case of purple, mollusks. Perkin's discovery of artificially synthesized dyes led to important advances in medicine, photography, and many other fields. In 1891 Guttmann and Paul Ehrlich noted that Methylene blue has a high affinity for some tissue cells and that this dye exerts a slight antimalarial property.^[23] Ehrlich, the founder of chemotherapy, advocated a rational development of drugs by exploiting biochemical differences (“magic bullets”).^[24]

The causal relationship of pigment to the parasite was established in 1880, when the French physician Charles Louis Alphonse Laveran, working in the military hospital of Constantine Algeria, observed pigmented parasites inside the red blood cells of people suffering from malaria. He witnessed the events of exflagellation and became convinced that the moving flagellae were parasitic microorganisms. He called this microscopic organism Oscillaria malariae and proposed that malaria was caused by this protozoan. In 1885 Ettore Marchiafava, Angelo Celli and Camillo Golgi studied the reproduction cycles in human blood (Golgi cycles) and observed that all parasites present in the blood divided almost simultaneously at regular intervals and that division coincided with attacks of fever. Golgi recognized that the three types of malaria are caused by different protozoan organisms. By 1890 Laveran's germ was generally accepted but most of Laveran's initial ideas had been discarded in favor of the taxonomic work and clinical pathology of the Italian school. Ettore Marchiafava and Angelo Celli called the new microorganism Plasmodium.^[25] Laveran was awarded the 1907 Nobel Prize for Physiology or Medicine "in recognition of his work on the role played by protozoa in causing diseases".^[26]

Charles Louis Alphonse Laveran observed the exflagellation of a male gametocyte

Ronald Ross proved that malaria is transmitted by mosquitoes.

It was Britain's Sir Ronald Ross, an army surgeon working in Secunderabad India, who proved in 1897 that malaria is transmitted by mosquitoes. He continued his research into malaria by showing that certain mosquito species (Culex fatigans) transmit malaria to sparrows and isolated malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.^[27] Giovanni Battista Grassi showed that human malaria could only be transmitted by Anopheles mosquitoes.^[28] Ross received the 1902 Nobel Prize for Physiology or Medicine "for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it". After resigning from the Indian Medical Service, Ross worked at the newly-established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius.^[29] The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900, and its recommendations implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal.^[30]

20th century

In the early twentieth century, before antibiotics, patients with syphilis were intentionally infected with malaria to create a fever. In the 1920s Julius Wagner-Jauregg, a Viennese psychiatrist, began to treat neurosyphilitics with induced P. vivax malaria. Three or four bouts of fever were enough to burn up the temperature-sensitive syphilis bacteria (Treponema pallidum). P. vivax infections were terminated by quinine. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable than the almost-certain death from syphilis.^[31] Therapeutic malaria opened up a wide field of chemotherapeutic research and was practiced until 1950. Wagner-Jauregg was awarded the 1927 Nobel Prize in Physiology or Medicine for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica.^[32]

Chloroquine was developed in Germany in the 1930s.

Andersag and colleagues synthesized and tested at the Elberfeld laboratories of the IG Farben (Germany) about 12000 different compounds and succeeded in producing Resochin as substitutes for quinine in the 1930s; it is chemically related to quinine through the possession of a quinoline nucleus. Resochin (a RESOrcinate of a 4-aminoCHINoline) (7-chloro-4-[[4- (diethylamino) - 1 - methylbutyl] amino] quinoline) and a similar compound Sontochin (3-methyl Resochin) were synthesized in 1934 in close cooperation with American companies.^[33] There were over 2,000 cartel agreements between IG Farben and foreign firms — including Standard Oil of New Jersey, DuPont, Alcoa, Dow Chemical, Winthrop Chemical Company and others in the United States .^[34] The drug was later named Chloroquine. Chloroquine is an inhibitor of pigment biocrystallization and one of the best antimicrobials ever developed. ^[35] Quinine and chloroquine affect malarial parasites only at stages in their life cycle when the parasites are forming hematin-pigment (hemozoin) as a byproduct of hemoglobin degradation. The drug target is host-derived and it took P. falciparum 19 years to build resistance to chloroquine.

Plasmodium falciparum hemozoin crystals under polarised light. Chloroquine and probably other quinolines act in interfering in the biocrystallization of hemozoin.

The insecticidal contact property of DDT (dichloro diphenyl trichloro- ethane) were established by Paul Hermann Müller at Geigy Pharmaceutical , Basel, Switzerland in 1939. Together with Pyrethrum, which is made from crushed flowers (chrysanthemum cinerariaefolium) , DDT spraying is the standard method of protection against insects. For his discovery of the high efficiency of DDT as a contact poison against several arthropods he was awarded the Nobel Prize in Physiology or Medicine in 1948. ^[36] However, the combination of the environmental effects of DDT and the development of resistance among mosquitos has led to a decline in the use of DDT, especially in areas where malaria is not endemic.^[37]

In 1949 J.B.S. Haldane suggested that thalassemia heterozygotes may be more resistant to malaria. In November 1949, Linus Pauling, Harvey Itano, S. J. Singer and Ibert Wells published in the journal Science the first proof of a human disease caused by an abnormal protein.^[38] Using an Arne Tiselius electrophoresis apparatus , they demonstrated that individuals with sickle cell disease had a modified form of hemoglobin in their red blood cells, and that individuals with sickle cell trait had both the normal and abnormal forms of hemoglobin, which conferred resistants to malaria infections. This was also the first demonstration that Mendelian inheritance determined the specific physical properties of proteins, not simply their presence or absence—the dawn of molecular genetics.

Structure of artemisinin.

A systematic screening of more than 200 traditional Chinese medical herbs was carried out under the direction of Tu Youyou and her research group in Beijing in 1971. Qinghaosu, later named artemisinin in the West, was low-heat-extracted in a neutral milieu (pH 7.0) from the dried plant Qing-hao according to the intructions of Ge Hong. Ge Hong (284–343) was the first in medical history to recommend the drug qinghao for the treatment of "intermittent fever" in his book „Handbook of Prescriptions for Emergencies“. His recommendation was to soak the fresh leaves and branches of the artemisia herb in cold water overnight, wring it out and ingest the expressed bitter juice in its raw state. The artemisinin molecule contains a peroxide chemical bond, which is believed to be essential to its anti-malarial activity.^[39] Artemisinin combination treatments (ACTs) are now first-line drugs for uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries. Improved agricultural practices, selection of high-yielding hybrids, microbial production, and the development of synthetic peroxides will lower prices.^{[40] [41]}

The first successful continuous Malaria culture was established in 1976 by Trager and Jensen, which facilitated the development of new drugs substantially.^[42]

The latent or dormant liver form of the parasite (hypnozoite), responsible for the late relapses characteristic of Plasmodium vivax and Plasmodium ovale infections, was observed in the 1980s.^[43]

21st century

The application of genomics to malaria research is now of central importance. With the sequencing of the three genomes of the malaria parasite Plasmodium falciparum, its vector Anopheles gambiae, and the human genome, the genetics of all three organisms in the malaria lifecycle can now be studied.^[44] This breakthrough is expected to produce advances in the understanding of the interactions between the parasite and its human host - such as between virulence factors and the human immune system - as wel as allowing the identification of the factors that restrict one species of parasite to one or a few species of mosquitoes. Another particularly exciting application of genetic technology is the ability to produce genetically-modified mosquitoes that are unable to transmit malaria, allowing biological control of malaria transmission.^[45]

External links

• Alphonse Laveran Nobel Lecture
• Cinchona Bark
• Grassi versus Ross
• Julius Wagner-Jauregg Nobel Lecture
• Malaria Around the North Sea
• Paul H Müller Nobel Lecture
• Ronald Ross Nobel Lecture
• The malaria genome

References

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