Paul Muller

Paul Hermann Müller was born at Olten, Solothurn, Switzerland, on January 12th, 1899. He started working in 1916 as a laboratory assistant and later worked as an assistant chemist gaining a wealth of practical knowledge. He matriculated in 1918 and earned his Doctorate in 1925. He began his career with J. R. Geigy A.G., Basle, in May, 1925, to become Deputy Director of Scientific Research on Substances for Plant Protection in 1946. Müller worked on vegetable dyes and natural tanning agents, synthetic tanning agents, and on pesticides. Four years of intensive work led to the synthesis of dichlorodiphenyltrichloroethane (DDT) in 1939 and the basic Swiss patent was granted in 1940.

mullerpAlthough DDT was first synthesized in 1874 by a Viennese pharmacist, Othmar Zeidler, he did not investigate the properties of the new substance but simply published his synthesis. Field trials of the compound resynthesised by Muller showed it to be effective against a wide variety of pests including the common housefly, the louse, Colorado beetle, and mosquito. The Geigy Company began to market the substance in 1940-41 as a 5% dust called Gesarol spray insecticide and a 3% dust called Neocid dust insecticide. The now universally used name, DDT, was first applied by the British Ministry of Supply in 1943. DDT was first added to U.S. Army supply lists in May 1943. Gahan and colleagues, in August 1943, made the first practical tests of DDT as a residual insecticide against adult vector mosquitoes. The first field test in which residual DDT was applied to the interior surfaces of all habitations and outbuildings of a community to test its effect on Anopheles vectors and malaria incidence was begun in Italy in the spring of 1944. During World War II, when supplies of pyrethrum were not adequate to meet the demand, DDT proved to be of enormous value in combating typhus and malaria. In malaria-endemic areas, spraying DDT twice a year on the inside walls of houses could prevent mosquitoes from transmitting malaria. Indoor residual insecticide spraying contributed to the eradication of malaria from many countries (including the United States) during the 1950s – 1970s. These compounds have also had great value in agricultural entomology and they have provided a great stimulus in the search for other insecticides.

Paul Muller was awarded the Nobel Prize in Physiology and Medicine in 1948 “for his discovery of the high efficiency of DDT as a contact poison against several arthropods”.

Muller married Friedel Rüegsegger in 1927 and has two sons, Heinrich (b. 1929) and Niklaus (b. 1933), and one daughter, Margaretha (b. 1934), all married. Paul Müller died on October 12, 1965.

Sources:

  1. http://stevenlehrer.com/explorers/images/explor1.pdf
  2. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=188345
  3. http://www.libertyindia.org/pdfs/malaria_climatechange2002.pdf
  4. http://www.cdc.gov/malaria/history/panama_canal.htm
  5. http://www.cdc.gov/malaria/history/history_cdc.htm
  6. http://www.litsios.com/socrates/page5.php
  7. http://history.amedd.army.mil/booksdocs/wwii/Malaria/chapterI.htm
  8. From Nobel Lectures, Physiology or Medicine 1942-1962, Elsevier Publishing Company, Amsterdam, 1964. http://nobelprize.org/medicine/laureates/1948/muller-lecture.pdf

 ©malariasite.com ©BS Kakkilaya | Last Updated: Mar 11, 2015

Malaria Control in India

Long before the British colonised India, malaria was a serious problem for the country, imposing enormous economic costs and a great deal of human misery. Malaria epidemics occurred throughout India with varying intensity. In 1852, one malaria epidemic wiped out the entire village of Ula and then spread across the Bhagirathi River to Hooghly and continued to devastate populations for many years in Burdwan. The development of the Indian railways under the British administration contributed to the spread of malaria. While the construction of railway embankments provided a number of breeding sites for the malaria vectors, the labourers probably introduced different strains of the parasite to the areas in which they worked. The city of Bombay suffered greatly from malaria epidemics. The construction of railroads or bridges were often associated with increases in malaria, probably due to imported labour from malarious areas. There were significant outbreaks of malaria during the construction of the Colaba causeway between 1821 and 1841 and during the construction of Alexander Dock and Hughes Dry Dock. Malaria epidemics in the Punjab and Bengal both show a startlingly high morbidity and mortality. In the early 1920s, Bengal suffered a severe malaria epidemic which resulted in over 730 000 deaths in 1921 alone. Thereafter, the number of deaths from malaria slowly decreased to within 300 to 400 000 per annum. During the Second World War however malaria deaths rose again, particularly in 1943, when Bengal recorded over 680 000 deaths and in 1944 when there were an appalling 763 220 deaths from the disease. Although quinine was available at the time, its supply was probably inadequate and patients did not seek treatment on time.

On the other, some of the great successes in controlling the disease were also achieved in India. Formal malaria control programmes were started under British colonial rule and continued after Indian Independence in 1946. Early malaria control efforts invloved removal of breeding sites and later used chemicals such as the larvicides Paris green and kerosene. One of the first formal operations to control the disease was at at Mian Mir, near the city of Lahore (now in Pakistan). Mian Mir had an intricate system of irrigation canals which provided excellent breeding grounds for the vectors. The malariologists Drs. J.W.W. Stephens and S.R. Christophers, who had worked with Sir Ronald Ross in Freetown, Sierra Leone earlier, arrived at Mian Mir in 1901 with ambitious plans to remove all the breeding sites, evacuate the infected people and administer quinine as both a curative and preventative measure. Their programme developed into a massive effort, with between four and five hundred soldiers set to work full time at filling in the irrigation canals. The programme of constantly filling in ditches and removing puddles and any other potential breeding site continued until 1909. During 1909 there was a serious malaria epidemic, as there was in 1908 throughout the Punjab, and the courageous, but ultimately useless control programme was abandoned.

Indian Medical Service (IMS) and Malaria

ross

Ronald Ross

The diseases endemic to India provided a rich field for research and the work of some of the IMS officers led to landmark discoveries. The foundation was laid by Surgeon-Major Dempster in 1845 with his work on the spleen rate as a reliable guide to the incidence of malaria. Major general Ronald Ross carried forward this work with distinction. He identified the mosquito as carrier of the malarial parasite in 1897-99. He was awarded the Nobel Prize in 1902 and knighted in 1911 in recognition of his outstanding contribution. Sir Samuel Rickard Christophers, who directed the Central Malarial Bureau from 1919 to 1924, supplemented Ross’s work. Further work was done by John Alexander Sinton, when he was the Director of Malarial Survey of India from 1927-38. In 1948, Henry Edward Shortt demonstrated the tissue phases of P. vivax malarial parasite for the first time.

Sinton [Source]

JA Sinton [Source]

Larviciding operations were also conducted at Bombay, Jhansi, Poona, Meerut, Secunderabad and all other military posts. In 1917, the Bengal Nagpur Railway and the East India Railways formed a separate malaria control organisation, specifically to control the disease in and around stations. National Railways managed to dramatically reduce the incidence of malaria among its staff though a comprehensive larviciding programme. Similar larviciding and breeding pool removal programmes were undertaken during the 1920s in the tea plantations of Assam and in Mysore by the Rockefeller Foundation. In 1927 the Central Malaria Bureau was expanded and renamed as the Malaria Survey of India. The first reported aerial spraying of Paris Green was in 1937. In 1938, pyrethrum was first used in malaria control in Delhi. The Rockefeller Foundation began using pyrethrum sprays experimentally in India to great success. The use of pyrethrum was then expanded to Assam by Dr. D. K. Viswanathan in 1942. However, all these interventions were unable to sustain the control of the disease. Vast breeding , colossal numbers of malaria vectors, limited effectiveness of pyrethrum sprays in houses and cattle sheds against the An. culicifacies vector, but not against An. fluviatilis and An. minimus were some of the causes for this setback.

DDT was first used in India by the armed forces in 1944 for the control of malaria and other vector borne diseases. In 1945, DDT was made available for civilian use in Bombay to control malaria and produced some remarkable results within a very short period. On 1st July 1945, the first civilian home was sprayed in India with a 5% solution of DDT mixed in kerosene. In 1946, pilot schemes using DDT were set up in several areas, including Karnataka, Maharashtra, West Bengal and Assam. Between 1948 and 1952 the WHO set up DDT demonstration teams in Uttar Pradesh, Rayagada, Wynad and Malnad. Use of DDT not only helped in the control of mosquitoes and malaria, but also improved the life expectancy. After the spraying in the Kanara district, the population began to grow because of a decrease in the death rate. Prior to DDT being used, the district reported an average of 50,000 malaria cases every year, which was reduced by around 97% to only 1,500 cases after DDT was introduced. The project was also blessed by Mahatma Gandhi.

During 1949, it is estimated that over 6 million people in Bombay were protected from malaria through the use of DDT and that at least half a million cases of malaria were prevented. In the early 1950s India’s population was estimated to be around 360 million and every year around 75 million people suffered from malaria and approximately 800,000 died from the disease.

Usefulness of DDT prompted the launch of the National Malaria Control Programme (NMCP) in 1953. The control programme first set out to control the disease in the endemic and hyperendemic areas with 125 control units. Each of these control units consisted of between 130 and 275 men and was to protect approximately 1 million people each. By 1958, the malaria control programme had been increased to protect at least 165 million people from the disease with 160 control units. The programme saw tremendous impact and the annual number of cases came down to 49151 by 1961. With this success, the programme was renamed as National Malaria Eradication Program (NMEP) in 1958 with a belief that malaria could be eradicated in seven to nine years. On the contrary, malaria began to re-emerge in 1965 to reach well over 1 million in 1971. One of the major problems with the eradication programme was that the supervisors could not manage to inspect all of the buildings that had been sprayed. There was a decline in the morale of the spray men and inspectors. With the declining number of cases, complacency set in among spray workers as well as the general population, as people turned the sprayers away. With the incomplete spraying operations, by 1959, resistance to DDT began to develop in certain areas and added to the problem. Furthermore, malaria cases were not treated properly.

With increase in malaria cases in urban areas, The Urban Malaria Scheme (UMS) was launched in 1971 with the objective of controlling malaria by reducing the vector population in the urban areas through recurrent anti larval measures and detection and treatment of cases through the existing health care services. Passive surveillance (case detection and treatment) and anti-larval measures are the main components of UMS strategy.

The number of malaria cases rose gradually and consistently with a peak of 6.47 million cases in 1976. With this, the focus was again shifted to control of malaria and in 1977 the Modified Plan of Operation (MPO) was launched which also comprised the P. falciparum Containment Programme (PfPC). The objectives of the MPO were

  • Effective Control of Malaria to reduce Malaria Morbidity
  • Prevent deaths due to Malaria
  • Retention of the achievements gained.

Fever Treatment Deport and Drug Distribution Centers were established for distribution of chloroquine. Residual insecticide Spray was limited to areas with an API (Annual Parasite Index) above two. By 1985, the incidence rate stabilized at 2 million cases. However, many focal outbreaks, particularly of P. falciparum malaria and deaths from malaria have occurred throughout India since the 1990’s and large scale epidemics have been reported from eastern India and Western Rajasthan since 1994. Many of these are related to irrigation projects aided by global funding agencies.

The National Anti Malaria Programme (NAMP) was launched in 1995 as a Centrally Sponsored Scheme on 50:50 Cost Sharing Basis between the Centre and the State Govts. As the Central share, the Central Govt. provides drugs, insecticides and larvicides and also technical assistance/guidance as and when required by the State Govts. The State Govts. meet the operational cost including salary of the staff. However, considering the difficulties faced by the seven North-Eastern States namely Arunachal Pradesh, Assam, Manipur, Meghalaya, Mizoram, Nagaland and Tripura, 100% Central Assistance except salary of the staff, which is a Non-Plan activity, is being provided since December, 1994. The Union Territories without Legislatures are also covered under 100% Central Assistance. An Enhanced Malaria Control Project with World Bank support is being implemented since September, 1997 covering a population of around 62.2 million in 1045 PHCs in 100 predominantly P.falciparum malaria endemic and tribal dominated districts in the peninsular States namely Andhra Pradesh, Bihar/Jharkhand, Gujarat, Madhya Pradesh/Chattisgarh, Maharashtra, Orissa and Rajasthan. The project lays emphasis on Early diagnosis and prompt treatment; selective vector control, eco-friendly methods like introduction of medicated mosquito nets (MMNs), larvivorus fishes, bio-larvicides etc.; epidemic planning and rapid response including inter-sectoral coordination and institutional and human resources development through training/reorientation training; strengthening management Information System (MIS), Information, Education and Communication (IEC) and operational research. It also aims to cover the most problematic areas and also has the flexibility to divert resources to any needy areas in the country in case of any outbreak of malaria.

In 2004, the integrated National Vector Borne Disease Control Programme (NVBDCP) for the prevention and control of vector borne diseases i.e. Malaria, Dengue, Lymphatic Filariasis, Kala-azar and Japanese Encephalitis has been launched and it has been changed to Enhanced Vector Borne Disease Control Programme (EVBDCP) with the World Bank support. [See NVBDCP website; See World Bank Site]

Source:

http://www.libertyindia.org/pdfs/malaria_climatechange2002.pdf

 ©malariasite.com ©BS Kakkilaya | Last Updated: Mar 11, 2015

Ronald Ross

Ronald Ross, son of an Army Major, a brilliant and polyvalent mind, poet of romantic lyrics, part time novelist, playwright, painter, musician and mathematician, who never wanted to be a medical practitioner, became a researcher by accident, designed some of the most elegant experiments with sheer instincts and his own shrewd observations and ultimately won the second ever Nobel Prize in Medicine in the year 1902. Having faced a lot of hardship and administrative interference and apathy (what he called “administrative barbarism”) and spent from his own pocket to pay the assistants and ‘volunteers’ for his research, he converted adversity to advantage and overcame all odds with his single minded pursuit to carry out his well designed and elegant experiments. With his penchant for writing, he has left for posterity detailed and poetic accounts of his path-breaking research and work thereafter.

rossRoss was born on May 13, 1857 at Almora near the Himalayan Mountains, India only three days after the outbreak of the Indian Sepoy mutiny. Ross was the first of ten children of Sir Campbell Claye Grant Ross, a Scottish officer in the British Indian army, and Matilda Charlotte Elderton. Ross’ grandfather, Lieutenant Colonel Hugh Ross, had also been a fierce Indian border fighter. Young Ross was witness to his father falling seriously ill with malaria. At the age of eight, young Ronald was sent to England for his education. After completing his early education in two small schools at Ryde, he was sent to a boarding school at Springhill, near Southampton in 1869. When he was 14 years old, he won a prize for mathematics. The prize was a book titled Orbs of Heaven. It was later that this book inspired Ronald to study mathematics in depth. At the age of 16, Ronald was bracketed first in England in the Oxford and Cambridge local examination in drawing. He had made a pencil copy of Raphael’s painting titled Torchbearer, and that too in just a few minutes! At age 17, Ross declared his ambition to become a writer. But his father would have none of it. He was told in no uncertain terms what career to pursue. In Ross’s own words later: “I wished to be an artist, but my father was opposed to this. I wished also to enter the Army or Navy; but my father had set his heart upon my joining the medical profession and, finally, the Indian Medical Service, which was then well paid and possessed many good appointments; and, as I was a dreamy boy not too well inclined towards uninteresting mental exertion, I resigned myself to this scheme….” Forced by his father, he joined the St. Bartholomew’s Hospital in London in 1875. Most of his time in medical school was spent composing music or writing poems and plays. During the course of his medical school, Ross came across a woman from the Essex marshes who was complaining of headaches, pains in her muscles and feeling very hot and then very cold. Essex marshes who was complaining of headaches, pains in her muscles and feeling very hot and then very cold. Ross questioned her exhaustively and diagnosed her as suffering from malaria, which was unusual, as it was only found in hot tropical countries such as South America and India. His detailed diagnosis however, frightened the woman away and she never returned, so Ross was unable to prove his diagnosis. Not surprisingly, he completed his medical studies “without distinction” and flunked the qualifying examinations for the Indian Medical Service. When his father threatened to cancel his allowance, he took a job as ship’s surgeon on a vessel sailing between London and New York. In 1881 he repeated the qualifying examinations and this time ranked seventeenth of twenty-two successful candidates. After four months’ indoctrination at the Army Medical School, Ronald Ross finally fulfilled his father’s wish by entering the Indian Medical Service in 1881.

With his not-so-impressive result, Ross was commissioned for the Madras service, the least prestigious of the three Indian Presidencies (Bengal and Bombay were the more desirable appointments) and worked in many places like Mysore and Madras and also served in the Burma War and in the Andaman Islands. While in Madras, a large part of his work was treating soldiers ill with malaria. The treatment with quinine was successful, but many died because they failed to get treatment. He also studied mathematics which he applied to the study of malaria later on [See below].

From the early days of his work in India, mosquitoes engaged Ross one way or the other. In 1883, Ross obtained the post of Acting Garrison Surgeon at Bangalore. Although Ross found the bungalow that was provided for his accommodation pleasant to live in, he was irritated by the large number of mosquitoes which constantly buzzed around the rooms. He also noticed that there seemed to be more mosquitoes in his bungalow than in others and that there was a particularly large swarm around a barrel with water that was kept outside the window. When Ross looked in to the barrel he saw lots of “wriggling” grubs breeding in the water, which he identified as mosquito larvae. Ross tipped the barrel to empty the water and found that the number of mosquitoes reduced. This started him thinking that if the places where mosquito bred were removed it might be possible to eliminate them completely. But everyone did not approve of this solution. “When I told the adjutant of this miracle,” Ross wrote, “and pointed out that the mess house could be rid of mosquitoes in the same way (they were breeding in the garden tubs, in the tins under the dining table and even in the flower vases) much to my surprise he was very scornful and refused to allow men to deal with them, for he said it would be upsetting to the order of nature, and as mosquitoes were created for some purpose it was our duty to bear with them! I argued in vain that the same thesis would apply to bugs and fleas, and that according to him it was our duty to go about in a verminous condition.” Ross held these views on mosquito control till the very end and found the same apathy from governments!

But even with all this, he was not at all enthused. He spent his free time concocting equations he hoped would revolutionize mathematics and writing poetry, music, plays, and bad novels that he published at his own expense. However, he did develop some interest in tropical diseases, like all his peers would have during the period when these were rampant in most parts of India, particularly malaria that killed more than a million in India each year. His experience with malaria as a student also probably stirred Ross’s interest in malaria. True to his style, Ross composed this verse about his first impressions of malaria that killed millions:

In this, O Nature, yield I pray to me.
I pace and pace, and think and think, and take
The fever’d hands, and note down all I see,
That some dim distant light may haply break.
The painful faces ask, can we not cure?
We answer, No, not yet; we seek the laws.
O God, reveal thro’ all this thing obscure
The unseen, small, but million-murdering cause.

After working for 7 years in India from 1881, he got bored and returned to England on a furlough in 1888. But he was aware that his literary career was not promising, being unable to establish a readership beyond his family and friends. So he took a course of Diploma in public health in London and acquainted himself with microscopic skills and laboratory techniques. In between he found time to write another bad novel, invented a new shorthand system, devised a phonetic spelling for the writing of verse, and was elected secretary of a local golf club. During the same period, he courted and married Rosa Bessie Bloxam in April 1889 and returned to India with her. Their first daughter was born in 1891 and the second one in 1903.

Back in India, he was posted to a small military hospital in Bangalore. Here, Ross began to formulate theories of malaria. Ignorant of Laveran’s work, he hypothesized that malaria was probably due to some form of poisoning from the bowel and published his first paper with this claim. Even later, although he learned of Laveran’s discovery in 1892 from several papers published in Indian medical journals, he was not convinced. He pricked the fingers of anyone who came to him with fever and spent hours peering through his microscope at blood smears, yet was unable to see the crescents. Thoroughly exasperated, he strongly questioned the soundness of Laveran’s observations and concluded that the parasite had been some lucky microscopic finding without any value and turned this parasite into ridicule, even wondering if the Frenchman might have falsified his data. This inability to confirm Laveran’s work, a problem shared by many investigators, was apparently due to the crude microscopic techniques of the day and the inferior illustrations in the original articles.

When he took his second furlough to England in 1894, Ross believed he had accumulated overwhelming evidence that Laveran was incorrect. “Everything I had tried had failed,” he told his colleagues. But they informed him that the parasites did indeed exist and sent him to Dr. Patrick Manson, the foremost authority on tropical diseases in London.

Manson

Manson

On 9 April 1894, he called on Patrick Manson. But Manson was not at home, but with the help of the London post that had five or six deliveries a day, they got together the following day. “Within a few minutes,” Ross wrote, “he showed me the Laveran bodies which are technically called ‘crescents’ in a stained specimen of malaria blood, and I recognized at once that no such bodies could exist in healthy blood. My doubts were now removed….” Then Ross spent many hours following Manson on ward rounds at the Seamen’s Hospital and in Manson’s private laboratory. Manson was impressed with this eager, capable student and chose to expound upon his ideas to Ross. In 1894, one November afternoon at “half-past two”, as they were walking down Oxford street on the way to the hospital, Sir Patrick Manson told Ross: “Do you know, I have formed a theory that mosquitoes carry malaria just as they carry filaria.” This was to change Ross’s life forever. Ross saw himself as the man to prove it. Manson suggested that the filaments in the crescents were actually living bodies and the mosquito sucked the filamented crescents into its stomach while feeding on the blood of a malaria patient. The filaments proceeded to travel through the stomach into the insect’s tissues. After the mosquito died laying its eggs, the “flagellated spores” emerged into the water, ready to infect anyone who came to drink. These theories, which had earned for Manson the titles “pathological Jules Verne” and “Mosquito Manson,” sent the young Ross into raptures of ecstasy. Suddenly the fame that had eluded him despite years writing poems, music, plays, novels, and equations seemed within his grasp. He had but to prove what Manson had presented to sound like gospel truth. Ross returned to India in March 1895, determined to prove what he called Manson’s “grand induction” and went about it with an almost manic enthusiasm.

Manson guided Ross throughout his research, suggested new approaches, encouraged Ross when he became depressed and came to his aid whenever superiors thwarted him. There was a continuous exchange of ideas between the two men, first directly and then by letters. The 173 letters that the two men exchanged between 1895 and 1899 constitute one of the great scientific correspondences and offer a wonderful insight into the research that led Ross to his Nobel Prize. The two men were separated by thousands of miles and a 3-week transit time for a letter or a slide to reach the other; nevertheless, their intimacy grew apace. The avuncular Manson acted as Ross’s London agent and sounding board, offering advice, both good and bad, on the best way to nail down the mosquito hypothesis. Above all, he tried to cheer his young protégé in his frequent periods of discouragement and despair. He lost his temper only once, when Ross threatened to throw up his medical career, take early retirement from the Indian Medical Service, and devote himself to literature.

On the ship to India, Ross rushed among passengers and crew members, frantically pricking fingers and examining blood. At the ship’s ports of call, he besieged the local hospitals for blood specimens of malarious patients. He even tried to prepare himself for anatomical studies of Indian mosquitoes by dissecting the ship’s cockroaches.

Soon after returning to India, Ross continued looking for cases of malaria in his Military hospital. Patients ran from him for fear of getting their fingers repeatedly pricked and colleagues kept proven malaria cases from him. Spurned in his hospital, he haunted the municipal hospitals and the other regiment infirmaries looking for cases of malaria. He even offered a rupee a prick. Following Manson’s instructions, Ross captured the mosquitoes and tried to induce them to bite malaria patients. But they obdurately refused to bite any one, even Ross. He made the mosquitoes raised from the larvae bred in captivity to feed on persons carrying malaria crescents in their blood, by putting the patient under a mosquito net and releasing the insects into it. He then expressed their ingested blood on a glass slide, and examined it with his microscope. Just as Manson had prophesied, there were the parasites. To be certain of the results, Ross tried the same experiment with six more mosquitoes the next day. “Every point that you predicted seems to come true,” he wrote to Manson. “Certainly there is nothing contrary to the theory. The parasites are present in the blood of the mosquito, and what is even more, they appear to be there in greater numbers than in blood from the finger. Also, the development of the crescents, and the formation of the flagella, seem to be favored by conditions in the mosquito’s stomach. Yes, the crescent-sphere-flagella metamorphosis does go on inside the mosquito to a much greater degree than in control specimens of finger blood.”

Manson immediately wrote back with more instructions. “Let mosquitoes bite people sick with malaria,” he advised, “then put those mosquitoes in a bottle of water and let them lay eggs and hatch out grubs. Then give that mosquito-water to people to drink.” So Ross allowed four mosquitoes to feed on a patient named Abdul Kadir. These insects were then kept in a bottle full of water until they died. After the promise of a suitable emolument, Lutchman, Ross’s native servant, and two others were persuaded to drink the sample of water in which mosquitoes had died. Lutchman developed a fever, but recovered three days later, and Ross could not find any malaria parasites in his blood; the other men remained healthy.

Ross was thoroughly discouraged and he began writing poems again. But Manson desperately tried to re-energize hm: “Above everything, don’t give it up. Look upon it as a Holy Grail and yourself as Galahad and never give up the search, for be assured that you are on the right track. The malaria germ does not go into the mosquito for nothing, for fun, or for the confusion of the pathologist. It has no notion of a practical joke. It is there for a purpose and that purpose, depend upon it, is its own interests–germs are selfish brutes.” Manson was also worried that someone else who would give him no credit might appropriate his precious theory. “The Frenchies and Italians will pooh-pooh it, then adopt it, and then claim it as their own,” he warned Ross in one letter, “see if they don’t. But push on with it, and don’t let them forestall you. They won’t have this autumn, and they will not have a chance to work seriously at the matter until next June or so. You have got a year ahead of them.”

But his superiors had other ideas for Ross. He was transferred to Bangalore on the 9th September 1895 to combat a serious outbreak of cholera. During his eighteen months stay at Bangalore, he tried to continue his work on malaria finding time in between with great difficulty. Finding that he was unable to transmit malaria through the ‘mosquito water’, he wrote to Manson at the end of May 1896: “The belief is growing on me that the disease is communicated by the bite of the mosquito… She always injects a small quantity of fluid with her bite – what if the parasites get into the system in this manner.” To test this idea, Ross allowed mosquitoes that had fed on a malaria patient to bite a healthy man. Nothing happened. The experiment was repeated again and again but in vain. Unfortunately, as he was using Culex mosquitoes, which do not transmit malaria, experiments to test this theory came to nothing. Writing to his wife he said: “I have failed in finding parasites in mosquitoes fed on malaria patients, but perhaps am not using the proper kind of mosquitoes “. On the other, Manson, who believed that the mosquito bit only once during its life, was not convinced about that Ross’s idea. “Follow the flagella,” he wrote back, and forget this crazy idea. Ross obediently went back to dissecting mosquitoes and in February 1897 was able to observe the true fate of the flagella. Within a blood smear he saw two parasites near each other. The first was giving off flagella, while the second, which was spherical and unsegmented, had a single flagellum wiggling slowly inside. He surmised that the single wiggling flagellum was trying to escape the sphere rather than fertilize it. When McCallum in Baltimore correctly interpreted the process a few weeks later, Ross was deeply humiliated, and “always felt disgraced as a man of science” for incorrectly interpreting his own observation.

In 1897, he went to the Sigur Ghat near the hill station of Ooty. Three days later he went down with malaria, despite having slept under a mosquito net and behind closed windows. Feeling depressed with no success in sight, he wrote poetry:

What ails the solitude?
Is this the Judgment Day?
The sky is red as blood;
The very rocks decay
And crack and crumble, and
There is a flame of wind
Wherewith the burning sand
Is ever mass’d and thin’d
The world is white with heat;
The world is rent and riven;
The world and heavens meet;
The lost stars cry in heav’n

Then one day, his attention was drawn to a mosquito that was sitting on a wall in a peculiar posture and had what he called “dappled-wings”. He was inspired again and was reminded of the fact that only one species of mosquito among the four found in Amoy, Culex fatigans, was capable of carrying filariasis. Manson had also suggested that each form of the malarial plasmodia might require a particular mosquito species. Ross suddenly realized he had used the wrong species of mosquito.

He returned to Secunderabad in June 1897 but was down with cholera, only to recover with a cup of hot tea. Once up, he commenced work by making a careful survey of the various kinds of mosquitoes. He continued his study by examining the dissected mosquitoes under the microscope. After feeding on patients, the gorged insects were collected in small bottles containing a little water and were kept for several days before being dissected. Almost every cell was examined under the microscope, even the integument and legs were not neglected. With the facilities that he had in the hot Secunderabad weather, Ross really toiled hard. In his own words: “But the weather became very hot again in August. At first I toiled comfortably, but as failure followed failure, I became exasperated and worked till I could hardly see my way home late in the afternoons. Well do I remember that dark hot little office in the hospital at Begumpett, with the necessary gleam of light coming in from under the eaves of the veranda. I did not allow the punka to be used because it blew about my dissected mosquitoes, which were partly examined without a cover glass; and the result was that swarms of ‘ eye-flies ‘-minute little insects which try to get into one’s ears and eyelids-tormented me at their pleasure, while an occasional Stegomyia revenged herself on me for the death of her friends. The screws of my microscope were rusted with sweat from my forehead and hands, and its last remaining eye-piece was cracked”.

Page from notebook where Ronald Ross recorded his discovery of the mosquito transmission of malaria, 20 August 1897

Page from notebook where Ronald Ross recorded his discovery of the mosquito transmission of malaria, 20 August 1897

On the 15th August, 1897, one of his assistants brought a bottle of larvae, many of which hatched out next day and among them he found several “dappled-winged mosquitoes”. Delighted with this capture, on August 16th, he fed them on his malaria patient, Husein Khan,with crescents in his blood. (Husein Khan was paid 1 anna per mosquito he was bitten by; he came away with 10 annas.) That evening he wrote to his wife: “I have found another kind of mosquito with which I am now experimenting, and hope for more satisfactory results with it.” On the 17th he dissected two of these mosquitoes but found nothing unusual. On the 19th he killed another and found “some peculiar vacuolated cells in the stomach about 10 microns in diameter.” On August 20th, a dull, hot day, Ross went to the hospital at 7 a.m., examined his patients, dealt with his correspondence and had a hurried breakfast in the mess. One of his mosquitoes had died and this he dissected without noting anything significant. He had two mosquitoes left of the batch fed on Husein Khan on the 16th and at about 1 p.m. he began to sacrifice one. Dissecting it he scrutinized the tissues micron by micron, when suddenly, in the stomach wall he “saw a clear and almost perfectly circular outline.. of about 12 microns in diameter. The outline was much too sharp, the cell too small to be an ordinary stomach-cell of a mosquito..” On looking a little further, there “was another and another exactly similar cell “. He changed the focus of his microscope and there within each of these new cells was a cluster of black pigment. He made rough drawings in his notebook, sealed his specimen, went home to tea and slept for an hour.

The pigment puzzled him, for the flagella contained no pigment, but the thought struck him that if the cells were really parasites they should grow in size in the last remaining mosquito during the night. He spent the night in agony lest his last remaining mosquito should die and decompose before morning. Next day he killed and dissected this remaining specimen. There were the cells again, twenty-one of them, just as before, only now much larger… The cells were therefore parasites, and, as they contained the characteristic malarial pigment, were almost certainly the malaria parasites growing in the mosquito’s tissues. He wrote to Manson with his exciting news: “Now prick up your ears because the hunt is up again.” Next morning Ross wrote a poem which he sent to Manson on Aug. 22:

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?

August 20th continues to be celebrated as Mosquito Day! On the 4 September he joined his family at Bangalore where he wrote a paper on his findings. This paper titled “On Some Peculiar Pigmented Cells Found in Two Mosquitoes Fed on Malarial Blood,” was published in the British Medical Journal on December 18, 1897.

Yet Ross still had his doubts. Perhaps, circular cells might not be related to the malarial parasites at all. “I really believe the problem is solved,” he wrote to Manson, “although I don’t like to say so. I look at them myself daily; those of the fifth day have grown bigger than those of the fourth day….Pigment-it is almost proof already! What else can the thing be? What are we to think: What do you think?”

Now eager to take his work to its logical conclusion, Ross wrote to Manson on September 22, 1897: “I shall be much disappointed if I don’t get a practical proof in a week’s time,” and continued his attempts to transmit malaria with the newly found mosquitoes. But two days later, he was asked to proceed to Bombay.

Then he was transferred to Kherwara, a distant village in the deserts of Rajasthan where malaria was very rare. But true his style, Ross did not quite languish. He knew of Danielewsky’s studies of bird malaria, and verified for himself that some types of pigeons carried the disease. At the time, many biologists believed that mosquitoes did not attack birds. After studies of pigeons, sparrows, and crows, Ross verified that birds were indeed bitten by mosquitoes, as well as by other insects.

In the meantime, after much lobbying by Manson and others he was transferred to Calcutta on January 29, 1898.

ross1

Ronald Ross, Mrs. Ross, Mohammed Bux and assistants at the laboratory in Calcutta

He managed to get a dilapidated laboratory of a recently retired physiologist. Now Ross advertised for assistants who would be paid from his own pocket. Of the twenty or so job applicants, Ross chose one Mohammed Bux, because “he looked the most rascally of the lot and was therefore likely to have considerable intelligence” and another named Purboona who disappeared after the first payday. But Mohammed Bux became quite devoted to Ross, so much so that he would even sleep on the laboratory floor at night to keep stray cats from killing the experimental animals.

Ross directed Mohammed Bux to capture mosquitoes, hoping again to find the circular, pigmented cells within the insects’ stomachs. Bux climbed through the sewers, the drains, the stinking tanks that abounded in Calcutta and brought back all kinds of mosquitoes. At this time, plague was raging and the people were scared of inoculations. Ross tried his best to get some human volunteers for his study. He sent his assistants into the bazaar (the market) to try to induce patients to come to him on payment. Although several beggars with fever were induced to come on large payment, they generally left their money, took up their crutches, and fled without a word when he proposed to prick their fingers to examine their blood! Left with no choice, Ross turned to the birds again. His laboratory soon became filled with a number of live crows, pigeons, weaver-birds, sparrows and larks that Mohammed Bux had snared. Into the cages covered with mosquito netting went the mosquitoes. Ross found that five out of nine mosquitoes fed on birds infected with Proteosoma contained the pigmented cells in the stomach and he brought in his mathematics to calculate the probability suggesting that the pigmented cells had been derived from the Proteosoma. He then commenced a long series of differential experiments in order to establish the fact thoroughly. It was also established that the common gray mosquito (Culex) was the carrier of bird malaria and that the brown, dapple-winged vector of human malaria could not be infected by the bird parasite.

These studies were carried on in desperate haste, haunted by the fear that hostile superiors would once again interrupt his work. He was forbidden to publish any of his results, though compelled to send detailed summaries to headquarters. The only outsider aware of the research was Manson, who often received whimsical accounts, like this one with Ross taking the role of the pigmented circular cell:

“I find that I exist constantly in three out of four mosquitoes fed on bird malaria parasites, and that I increase regularly in size from about a seven-thousandth of an inch after about thirty hours to about one seven-hundredth of an inch after about eighty-five hours… I find myself in large numbers in about one out of two mosquitoes fed on two crows with blood parasites…”

During this period, Ross tried to obtain some assistance for his work. But his superiors never obliged him for reasons he found inexplicable.

Unperturbed by all this, Ross continued his single-minded work. To test Manson’s hypothesis that the parasites were ingested with water in which the mosquitoes had died while laying eggs, Ross fed the infected mosquitoes to healthy sparrows but the birds remained free of malaria. Now convinced that malaria did not spread that way, he continued to study infected mosquitoes. On the 2nd July 1898, he found in the thorax of a mosquito a large cell which contained within it several of the thread-like bodies. On July 4, 1898, examining the insect’s head, he found the the part of the mosquito to which these bodies were destined – the gland lay in the neck and upper thorax and it was the salivary gland. By July 8th, he was very sure: Malaria was passed back to the birds in the mosquito’s saliva during the act of biting. The exact route of infection was thus revealed.

This remarkable finding, Ross later wrote, “brought him up standing.” As a final verification, he sent Mohammed Bux to capture a group of healthy sparrows. Mosquitoes that had fed on infected birds were allowed to bite these healthy ones. Within a few days the blood of the new birds was loaded with malarial parasites. At the same time he kept as controls a number of healthy birds in mosquito-nets, safe from the bites of mosquitoes, and found that none of them became infected.

Ross communicated his results to Manson in a state of intense excitement. “I think I may now say Q.E.D.,” he wrote, “and congratulate you on the mosquito theory indeed. The door is unlocked, and I am walking in and collecting the treasures. Well, I have become unbearable with conceit…. I brag openly about it!”

Manson received the news at a meeting of the new Tropical Diseases Section of the British Medical Association. When he read Ross’s report to the assembled delegates it was greeted with a standing ovation. “I am sure you will agree with me,” Manson said, “that the medical world, I might even say humanity, is extremely indebted to Surgeon Major Ross for what he has already done, and I am sure you will agree with me that every encouragement and assistance should be given to so hard-working, so intelligent, and so successful an investigator to continue his work.”

But the Indian Medical Service was again not on his side. Ross was ordered to abandon the malaria work and report to a new post in Assam to do research on kala azar. “Columbus having sighted America was ordered off to discover the North Pole,” he remarked bitterly. “No, the man who can do is not allowed to do, because the man who cannot do is put in authority over him.”

Unhappy with the administrative apathy and exhausted by work and heat, Ross decided to quit. He closed his small laboratory, set his feathered prisoners free from their cages, emptied the jars of mosquitoes. After sadly wishing Mohammed Bux good-bye, Ronald Ross left Calcutta on the 13th August, 1898. Before leaving, he urged upon Government the importance of taking active measures for the prevention of malaria in accordance with his observations. Besides advising the strict use of mosquito-nets for a personal prophylaxis, he urged especially a campaign against mosquitoes as the best measure for towns and cantonments, particularly against the dappled-winged mosquitoes, which breed principally in water on the ground.

Ronald Ross did not stop at identifying the vector for malaria and its habits. He was thrilled at the possibility of controlling this scourge for millions by controlling the breeding of the mosquito vector. Ross had proved that malaria was related more to the stagnant water in the pots, tubs, and tanks scattered around human dwellings where its vector bred in millions than to the marshes and pools as was believed until then. Ross’s discovery also explained the seasonal variations, the increase in cases during the rainy season, and how subsoil drainage that was practiced for centuries helped in controlling it. It was therefore enough to clear the breeding sites rather than drain a whole area, thus bringing down the expenses considerably. Ross did not stop at writing about malaria control either. He accepted the challenge to implement his ideas.

Major General Ronald Ross

Major General Ronald Ross

He stood at the vanguard of implementing his ideas till his end. Ross attempted to eradicate malaria from England by forming ‘mosquito brigades’ to eliminate mosquito larvae from stagnant pools and marshes. In August-September 1899, he was sent to Freetown, the capital of Sierra Leone where he organised a sanitation drive, clearing the streets of tyres, bottles and empty cans and levelling roads so that rain water would not gather into puddles. But the Freetown malaria control programme did not yield desired results, probably because Ross had underestimated the number of breeding pools as well as the sheer number of vectors that he was trying to control. Ross had very limited funding and the best available technology was to pour oil on the numerous breeding sites around Freetown. As soon as the oil treatment stopped, breeding would begin again. Ross redoubled his efforts with increased funding from private sources and ensured the removal of all potential breeding sites, including rubbish, broken bottles and other potential water containers. Despite these concerted efforts, the programme was remembered more for its impact on the Freetown’s rubbish than for malaria control. J.W.W. Stephens and S.R. Christophers, who had worked with Ronald Ross in Freetown, organised a similar drive in Mian Mir in Lahore, India in 1901, without much success either.

The sanitation drive suggested by Ronald Ross was successfully tried elsewhere. During the U.S. military occupation of Cuba, a campaign against yellow fever and malaria was commenced at Havana early in 1901. Under the leadership of the Assistant Surgeon General William Crawford Gorgas of the United States Army the anti mosquito measures produced very marked results. Pyrethrum, a natural insecticide derived from the chrysanthemum flower, was first used by William Gorgas in Cuba where it was burned inside sealed dwellings. Mosquitoes entirely disappeared from many parts of the city, and were decreased everywhere.

At the end of 1902, Prince Auguste d’Arenberg, President of the Suez Canal Company asked Ross to save Ismailia, the city that was built as a base for construction of the canal. It was gravely threatened by malaria for a long time. Ross led a sanitation drive so successful that by the following year, the city officials announced that they no longer needed mosquito nets and by 1904, a whole year had passed without a single reported case of malaria in Ismailia. Ross’s drastic sanitary measures were even dubbed as “sanitary Bolshevism”.

In the following years, Mosquito Ross, as he was called, lent his services to Greece, Mauritius, Spain and Panama and during World War I, at various places on the battle front, always preaching the gospel of war against the anopheline mosquitoes. His position within malaria research gave him special kudos, even if his stridency and concentration on mosquito control at the expense of social betterment or the systematic use of quinine sometimes marginalized him from the malaria community.

The experience of the US Army in Cuba was replicated during the construction of the Panama Canal between 1905-1910, where Ronald Ross and William Gorgas worked together. Yellow fever was eliminated and malaria incidence markedly reduced through an integrated program of insect and malaria control.

In 1910, Ross wrote his sanitary axiom: “Widespread diseases … cause much pain, poverty, sorrow, expense and loss of prosperity … and the rule is to grudge spending a hundred pounds for disease which costs thousands…[Therefore] “for economic reasons alone, governments are justified in spending for the prevention of [malaria] a sum of money equal to the loss which the diseases inflict on the people”. [Ross, R. The Prevention of Malaria. London, John Murray. 1910. pp. 295-296.]

During World War I (1914-1918) Ross was appointed a consultant physician on tropical diseases to Indian troops and was sent to Alexandria for four months to investigate an outbreak of dysentery which was hampering troops in the Dardanelles.

Ross also initiated organizations for the prevention of malaria within the planting industries of India and Ceylon.

Ross’s Prevention of Malaria ebook

Ross made many contributions to the epidemiology of malaria and to methods of its survey and assessment, greatest being the development of mathematical models for the study of its epidemiology. He worked on the mathematical theory of epidemics. Through the survey of the parasite index and the assessment of the spleen rate in children he founded the malariometry as a epidemiological tool, focused attention on the relation of malaria and the community and on the complexity of the transmission dynamics. It provided the basis for calculating the rate at which malaria spreads and the quantity of material and personnel required for checking the epidemic. By demonstrating how much malaria cost the governments of malarious countries, and how it was much more efficient to prevent it in the first place, Ross offered a sober reminder of the economics of prevention. He demonstrated mathematically how reducing the concentration of anopheline mosquitoes could have a real and potentially cumulative effect, but his mathematics went over the heads of his contemporaries. His pioneering contributions to malarial epidemiology were not appreciated until two decades after his death. Ross’s analysis of the economics of malaria control also went largely unheeded. The message is still relevant and is still too little-heeded by politicians and health planners.

Ross had lot of appreciation for Laveran, Koch and of course his mentor, Sir Patrick Manson. Koch’s suggestions on immunity in malaria also impressed Ross. Koch’s support for control efforts was also praised by Ross.

But Ross had a bitter feud with Italian physician Giovanni Battista Grassi, who in September 1898, reported that Anopheles claviger was the carrier of human malaria. Grassi, Amico Bignami and and Giuseppe Bastianelli made the mosquitoes bite a human volunteer and on the eleventh day, the patient developed a malarial chill. Examination of his blood revealed large numbers of plasmodia. But when he published, Grassi failed to give credit to Ross. Ross was furious. Thoroughly convinced that Grassi was trying to steal his discovery from him, Ross sent angry letters to the journals that had published Grassi’s papers, asserting that Grassi was a mountebank, a cheap crook, a parasite who survived on the ideas of others. Grassi replied in equally acrimonious terms. So vicious did the correspondence become that journal editors, fearful of libel, hesitated to publish the letters. But Ross and Grassi did not stop feuding. Both enlisted the aid of the authorities on tropical medicine. Ross was able to obtain letters from Dr. T. Edmundston Charles, an English observer of the Italian work in Rome. Using this evidence, Ross asserted that Grassi had been aware of the studies on bird malaria, though Grassi later denied such awareness. When Ross could not find a publisher for a book containing his case against his Italian adversary, he paid for the printing himself, carrying the work through two editions. This bitter conflict lasted for more than two decades. But the Nobel Committee had no difficulty in identifying the merits. Ross was awarded the Nobel Prize in 1902.

Awards and recognition came behind Ross. In 1901 Ross was elected a Fellow of the Royal College of Surgeons of England and also a Fellow of the Royal Society, of which he became Vice-President from 1911 to 1913. In 1902 he was appointed a Companion of the Most Honourable Order of Bath by His Majesty the King of Great Britain.

In 1902 he was awarded the Nobel Prize for 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”. (Nobel Prize in physiology and medicine has never been awarded for work in biostatistics or epidemiology. The “exception who proves the rule” is Ronald Ross, who won the second medical Nobel; but Ross himself considered the mathematics of epidemic theory as his most important scientific contribution).

That Sir Patrick Manson missed the Nobel Prize also did not go down well with those who knew of his contribution to Ross’s work. The 100 or so letters that they wrote to each other in the two decades afterward poignantly document the gradual cooling of a creative friendship and the difficulty of a teacher-pupil relationship evolving naturally into one of equals.

In 1911 he was Knighted. In Belgium, he was made an Officer in the Order of Leopold II. He was given Honorary Membership of learned societies of most countries of Europe, and of many other continents. He got an honorary M.D. degree in Stockholm in 1910 at the centenary celebration of the Karolinska Institute. Whilst his vivacity and single-minded search for truth caused friction with some people, he enjoyed a vast circle of friends in Europe, Asia and America who respected him for his personality as well as for his genius. He was the Editor of Science Progress from 1913 until his death in 1932. In 1926, Ross Institute and Hospital for Tropical Diseases was opened and the Prince of Wales came down to honour Ross, who was named its director in chief.

Sir Ronald Ross

Sir Ronald Ross

But these awards and recognitions brought him little contentment. Despite receiving many other awards and honours during his life, he felt embittered that he did not receive monetary reward for his discovery and petitioned the Government on this subject. He resented the fact that his medical practice (and income) had never thrived (like Manson’s), and that his life as a researcher seemed undervalued and underpaid. He had always longed to be in London, not Liverpool, although by the time he settled there in 1912, even London offered him no real peace. Above all, he was aggrieved that the growing band of malariologists did not support his ideas on the control of malaria and was not satisfied with the attitude of the administration towards malaria control efforts. Ronald Ross hoped that the difficulties that he faced during his research and work would open the eyes of the powers-that-be and hoped that the life would be easier for the future generation of scientists.

Ronald Ross’s literary works include the novel The Child of Ocean (1899 and 1932); The Emigrants; Edgar; The Judgement of Tithonus; Philosophies, Psychologies, and other Poems; novel, The Revels of Orsera; novel, The Spirit of Storm; selected Poems (1928); Fables and Satires (1930); collection of melancholy poems In Exile (1931); Lyra Modulatu (1931); five mathematical works (1929-1931). He also compiled an extensive account The Prevention of Malaria in 1910 and another Studies on Malaria in 1928. His autobiography, The Memoirs was published in 1923; it is a long (547 pages) and powerful account of his trials and tribulations. Its subtitle –“with a full Account of the Great Malaria Problem and its Solution”–speaks volumes about his assessment of his own worth. Ross saved virtually everything about himself: correspondence, telegrams, newspaper cuttings, drafts of published and unpublished material, and all manner of ephemera; he also retrieved a fair number of his own letters while preparing his memoirs. In 1928, Ross advertised his papers for sale in Science Progress, making it known that he needed the money for the provision of his wife and family. They were bought by Lady Houston for £2000, who offered them to the British Museum. They refused the collection, partly due to Ross’ stipulation that his arrangement of the papers had to be retained and also due to some canvassing from members of the Ross Institute who thought that the collection would be better placed with them. The majority of these papers are now held by the London School of Hygiene & Tropical Medicine (See http://www.lshtm.ac.uk/library/archives/rossproject.html). Altogether, there are some 30,000 catalogued items in the two major Ross repositories, at the London School of Hygiene and Tropical Medicine (LSHTM), and the University of Glasgow.

Ross and Rosa had two sons, Ronald and Charles, and two daughters, Dorothy and Sylvia. He lost his elder son in the British retreat from Mons and his own health deteriorated during the war. In 1925, his older daughter died. In 1927, Ross had a stroke. His wife died in 1931. Ross survived her until a year later and died at the Ross Institute, London, on September 16, 1932. The Nobel Prize winning scientist, mathematician, epidemiologist, sanitarian, editor, novelist, dramatist, poet, and an amateur musician, composer and artist was buried next to his wife at Putney Vale Cemetary.

Like many prophets before and since, he said things that we forget at our peril. Three things stand out. First, Ross quantified the economic costs of malaria. Both the figures and the percentages will have changed over time, but Ross’s approach should still command assent. He showed in hard figures that had the money spent in treating and burying soldiers and civilians been turned to prevention, the result would be a world with less malaria. His bitter contempt for penny-pinching governments who could respond only to the crisis at hand rather than legislate for the future earned him few friends. Second, Ross was an eloquent spokesman for what later would be called the vertical program. Even during Ross’s lifetime, malariologists were divided into those who believed that socioeconomic amelioration would in itself largely solve the malaria problem (as was happening in Europe) and those who held that holoendemic malaria was itself a block to economic improvement. Despite the fact that horizontal approaches are now in fashion, focused campaigns targeted at specific diseases can still pay off. Ross firmly believed that malaria was one disease ripe for deliberate control. Ross came to see that anopheline mosquitoes were not so delicate as he had once thought, and malaria would require longer and more sustained effort. But the scientific understanding was in place, he argued, and all that was really lacking was the political will. Finally, Ronald Ross passionately believed in the social value of biomedical research. Such research should be adequately rewarded, he insisted, and society should always hold its scientists in high regard, whose worth, he always thought, was socially undervalued. But he also worked tirelessly on behalf of the scientific community as a whole, campaigning for comrades who needed his help; and, through his long editorship of Science Progress, furthering the cause of what is now called the public understanding of science. His heart was almost certainly in the right place.

Even after more than a century of Ronald Ross’s painstaking efforts at control of malaria, the ‘administrative apathy’ towards malaria control programmes continues for “inexplicable” reasons as Ross put it. And unfortunately, the building of the Military Hospital at Secunderabad, where this discovery was made, now lies in ruins and little is done to remember the person who worked tirelessly to make a discovery that would benefit humanity. The super-sensitive, single-minded Ross went to his grave still holding the firm conviction that malaria could be eradicated if only weak-willed governments would commit themselves to exploit his discovery and attack the anopheline in their watery lairs.

Ross’s three part paper on the theory of epidemics is available on the web:

Sources:

  1. http://stevenlehrer.com/explorers/images/explor1.pdf
  2. http://www.cdc.gov/malaria/history/ross.htm
  3. Breslow NE. Are Statistical Contributions to Medicine Undervalued? Biometrics, Volume 59, Number 1, March 2003, pp. 1-8(8) Available at http://www.ingentaconnect.com/content/bpl/biom/2003/00000059/00000001/art00001
  4. http://www.lshtm.ac.uk/library/archives/rossproject.html
  5. http://www.libertyindia.org/pdfs/malaria_climatechange2002.pdf
  6. Bendiner E. Ronald Ross and the mystery of malaria. Hospital Practice. Oct 15, 1994:95-112
  7. Robert E Sinden. Malaria, mosquitoes and the legacy of Ronald Ross. At http://www.who.int/bulletin/volumes/85/11/04-020735/en/index.html
  8. http://www.litsios.com/socrates/page5.php
  9. http://www.zephyrus.co.uk/ronaldross.html
  10. http://www.tribuneindia.com/1999/99apr17/saturday/fact.htm
  11. http://www.aim25.ac.uk/cgi-bin/frames/fulldesc?inst_id=37&coll_id=4046
  12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9989333&dopt=Abstract
  13. http://banglapedia.search.com.bd/HT/R_0220.htm
  14. http://www.theotherpages.org/poems/gp1_14.html
  15. http://medicine.nobel.brainparad.com/ronald_ross.html
  16. http://www.aim25.ac.uk/cgi-bin/frames/fulldesc?inst_id=37&coll_id=4046&full=1&template=1
  17. http://www.lshtm.ac.uk/library/archives/rossbio.html
  18. http://www.geocities.com/~bblair/reflections_twp.htm
  19. http://www.bartleby.com/266/53.html
  20. http://www.answers.com/topic/ronald-ross
  21. http://www.sciencemag.org/cgi/content/full/295/5552/47
  22. http://www.cdc.gov/malaria/history/panama_canal.htm
  23. Ross R. Researches on malaria. Nobel Lecture, December, 12, 1902. (From Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam, 1967) Available at http://nobelprize.org/medicine/laureates/1902/ross-lecture.html
  24. http://nobelprize.org/medicine/laureates/1902/ross-bio.html
  25. Chidanand Rajghatta. India’s Nobel connections. Available At http://timesofindia.indiatimes.com/India/Indias_Nobel_connections/articleshow/2456211.cms

©malariasite.com ©BS Kakkilaya | Last Updated: Mar 9, 2015

Laveran

Charles Louis Alphonse Laveran, a calm, reserved, unemotional French Military Surgeon, won the Nobel Prize for Medicine and Physiology in 1907 for his discovery of the malaria parasite and other significant contribution to parasitology. Laveran, a stiff, aloof, quiet man, as slow and methodical in his speech as in his work, was exceptionally astute both as physician and scientist.

See The Journey of Scientific Discoveries

Laveran

Laveran

Laveran was born in Paris on June 18, 1845 in a family of doctors, in the house which was formerly No. 19 rue de l’Est but later became, when this district was rebuilt, a hotel, Boulevard St. Michel. His father, Dr. Louis Théodore Laveran, was an army doctor and a Professor at the École de Val-de-Grâce; his mother, née Guénard de la Tour, was the daughter and granddaughter of high-ranking army commanders. When he was very young, Alphonse went with his family to Algeria. His father returned to France as Professor at the École de Val-de-Grâce, of which he became Director with the rank of Army Medical Inspector. Alphonse, after completing his education in Paris at the Collège Saint Baube and later at the Lycée Louis-le-Grand, wished to follow his father’s profession and in 1863 he joined the Public Health School at Strasbourg. In 1866 he was appointed as a resident medical student in the Strasbourg civil hospitals. In 1867 he submitted a thesis on the regeneration of nerves. After his training, he was assigned as surgeon to Paris’s St. Martin Hospital. In 1870, when the Franco-German war broke out, he was a medical assistant-major and was sent to the army at Metz as ambulance officer. He took part in the battles of Gravelotte and Saint-Privat and in the siege of Metz where he was taken prisoner. At the end of the war the young surgeon returned first to Lille hospital and then to the St. Martin Hospital, where he took a particular interest in studying the infectious diseases of soldiers. In 1874 he was appointed, after competitive examination, to the Chair of Military Diseases and Epidemics at the École de Val-de-Grâce, previously occupied by his father. But in his new job Laveran found that teaching and administration precluded most research. Finally in 1878 these burdens were removed when he was transferred to Bône in Algeria and later to the military hospital at Constantine, Algeria.

In Constantine, Laveran was confronted with hospitals full of malaria. Whole platoons were decimated by it, and rarely could an entire squadron be assembled at once for active duty. New recruits succumbed with sickening regularity. Laveran conducted autopsies on patients who had died of ‘malignant fever’ (P. falciparum) and the blood and the internal organs like the the brain and spleen always showed the ‘black granular microscopic bodies’. Laveran followed these ‘black pigments’, first described by Lancisi and then by the German scientist Meckel in 1847. For two years Laveran struggled with the tissue specimen, but found nothing more than the ‘black pigments’. In desperation he decided to confine his search to the fresh blood of malaria patients, an extremely felicitous choice.

Still not knowing what he was looking for, Laveran began taking blood specimens from pinpricks in the fingers of sick soldiers. After spreading a droplet into a thin film on a glass slide, he would peer at it for hours through a small, crude microscope. He could easily find the tiny black granules that were already accepted without question as the result of malarial infection. But on November 6, 1880, while examining a fresh blood specimen taken from a new hospital arrival, he found pigmented spherical bodies of variable size possessing amoeboid movement (free or adherent to the red cells), non-pigmented corpuscles forming clear spots in the red cells and pigmented elements, crescentic in shape in addition to the melaniferous leucocytes. The moving object on the slide caught Laveran’s eye. Under high power, this proved to be a tiny malarial body wriggling vigorously. Laveran watched amazed as the little crescent-shaped object lashed about so energetically that an entire red blood cell jiggled. Even the pigment granules appeared to be in frenzied motion. This was made possible probably because Laveran had used wet blood films.

Instantly, Laveran realized that he had found the cause of malaria, a tiny, living organism. He identified it within the blood of 148 other patients out of a total of 192 examined. It developed, he observed, from a small, colorless structure one-sixth the size of a red cell, gradually growing as large as the cell and meanwhile forming pigment granules. The larger malarial parasites had a crescent shape with pigment granules arranged in a ring. These organisms, often quite active, would suddenly produce lashing, whip-like filaments.

From his observations, Laveran deduced that the large, crescent-shaped organism was the fully developed parasite or “perfect form,” as he called it. After growing over a period of days, imbibing nourishment from the red cell, the parasite could survive independently in the blood. The appearance of filaments represented the climax of the process. Tertian, quartan, and quotidian malaria, he believed, occurred during different stages in the parasite’s development.

In 1880, the technique of examination of the blood was very imperfect, which contributed to the confusion. Although it was impossible to classify accurately, certain resemblances to other micro-organisms put it in the same group as the protozoa. He named his protozoan as Oscillaria malariae.

On December 24, 1880 in Italy, Laveran communicated the identification of pigmented erythrocytic cells in 26 malaria patients. Laveran wrote a letter to the Academy of Medicine in Paris, communicating his discovery. [Laveran, A. 1880. A new parasite found in the blood of malarial patients. Parasitic origin of malarial attacks. Bull. mem. soc. med. hosp. Paris. 17: 158-164] The observations were quickly confirmed. Laveran reported them to a friend, Dr. E. Richard, stationed at Philippeville, a French Mediterranean military base fifty miles from Constantine. After finding the fully developed, wriggling parasite, Richard identified an even younger form than Laveran had seen, merely a tiny, colorless spot in the red cell. Laveran believed that the organism lived on the surface of the cell, but Richard correctly observed that it developed within the cell, growing larger and larger until it finally burst out.

But under the sway of bacteriology, the scientific community remained unconvinced about Laveran’s discovery. So powerful an influence was the new bacteriology that no one could believe the pigmented malarial bodies were the cause of malaria. This haematozoon did not resemble bacteria, was present in strange forms, and “was completely outside the circle of the known pathogenic microbes”. The arguments presented by Klebs and Tommasi-Crudeli for their “Bacillus malariae” had been accepted almost without question, and an Italian pathologist, Ettore Marchiafava, even claimed to have found the bacillus in several dead malaria patients. In 1882, Laveran went to Rome to look for these parasites in the blood of those infected with malaria in the Roman Campagna at the San Spirito Hospital and he confirmed his findings that the parasites that he had described were in fact the cause of malaria. He demonstrated the parasites to Marchiafava and Agnello Celli, but these two could not be convinced.

Major George Sternberg of the US Army, a bacteriologist of considerable standing, made bacterial cultures from the air, from mud, and from nearby marshes and no organism he found was capable of producing malaria in an animal. By 1881 he had shown positively that the Bacillus malariae of Klebs and Tommasi-Crudeli was not responsible for malaria.

Meanwhile, in 1884, Russian physiologist, Basil Danielewsky was able to observe parasites of malaria in the blood of wild birds. By 1884, Louis Pasteur became convinced of the soundness of Laveran’s observations.

In 1884, Marchiafava and Celli, while studying wet blood smears from malarious patients with the new oil-immersion lens, looked at unstained blood and saw a active amoeboid ring (trophozoite) in the red blood cells. They published this finding and named it Plasmodium, but did not refer to Laveran since they thought it was something different from what he showed them. The name chosen for the parasite by them turned out to be an incorrect one, since the organism is not actually a plasmodium. But the name stuck and the one suggested by Laveran lost out.

Dr. William Osler, an authority on blood microscopy, was also skeptical of Laveran’s theory. In 1886 he stated that the malarial bodies were nothing more than incidental findings. When his colleague, Dr. William T. Councilman, persuaded him to reconsider, Osler spent many hours looking at wet-blood films and confirmed Laveran’s findings with his own description of blood film examinations from 70 patients.

By 1885-86, Camillo Golgi, an Italian neurophysiologist and his pupils not only accepted and defended Laveran’s theory of a parasitic origin for malaria, but they also provided many new pieces of evidence and wholeheartedly threw their weight in support of Laveran.

Gradually, confirmative researches were published by scientists of every country and, in 1889, the Academy of Sciences awarded him the Bréant Prize for his discovery, putting a full stop to any doubts.

Maj. Laveran

Maj. Laveran

Laveran was also one of the first to suggest a role for mosquitoes in transmission of malaria. From extensive negative results searching for the parasite in samples of water, soil, and air, Laveran hypothesized that the parasite must undergo one phase of its development in mosquitoes and that the mosquito acted as a temporary host of the malarial parasite. He made an analogy with Manson’s mosquito-borne mode of transmission of the Filariasis. In 1894, he wrote about his ideas in a report to the International Congress of Hygiene at Budapest on the aetiology of malaria. He also noted that this opinion on the role of mosquitoes was considered by most observers at that time as not very likely. King, Robert Koch and Patrick Manson had also suggested that mosquitoes may be involved in the spread of malaria and this fact was later confirmed by Ronald Ross.

Laveran was a finest gentleman. He made the following observations about his work and its criticism:

“In 1878, after having completed my agrégation at the School of Military Medicine of the Val de Grâce, I was sent to Algeria and put in charge of a ward at the Bône Hospital. Many of my patients were suffering from malarial fevers and I was naturally drawn to studying these fevers of which in France I had observed only rare and benign forms.

…I had the opportunity to carry out autopsies on patients who had died from these pernicious fevers and to study melanemia- or the formation of black pigment in the blood of subjects suffering from malarial fevers. Melanemia had been described by several observers, but neither the constancy of this alteration in malaria, nor the causes for the production of the pigment had been determined.

… I was struck by the particular characteristics present in the pigment grains, particularly in the capillaries of the liver and the cerebrospinal centres and I sought to study- in the blood of patients suffering from malarial fever- the formation of the pigment. In their blood, I found leukocytes more or less coloured with the pigment, but besides melaniferous leukocytes, I found pigmented spheric bodies, of variable volume, with ameba-like movements, free or glued to erythrocytes, non pigmented corpuscles which made light spots in the erythrocytes; finally pigmented elements shaped like crescents retained my attention: I guessed then that these were parasites.

…In 1880, at the military hospital in Constantine, I discovered on the edges of the pigmented spheric bodies, in the blood of a patient suffering from malarial fever, thread-like elements resembling whips which were scurrying about with great vivacity, displacing neighboring erythrocytes; from the on, I had no further doubts as to the parasitic nature of the elements I had found; I described the main forms which the hemacytozoon of malaria took in notes which I submitted to the Academy of Medicine and the Academy of Sciences (1880-1882) and in a short treatise entitled:

The Parasitic Nature of Accidents of Impaludation, Description of A New Parasite Found in The Blood of Patients Suffering from Malarial Fever, Paris 1881.

The first results of my research were greeted with much skepticism.

In 1879, Klebs and Tommasi Crudeli had described by the name of Bacillus malariae a bacillus found in the ground and water of malarial sites and quite a few Italian observers had published works confirming the findings of these authors.

The hemacytozoon which I defined as the agent of malaria did not resemble bacteria; it was found in singular forms; in a word, it did not belong to the world of known pathogenic microbes, and many observers, not knowing where to classify it, found it easier simply to doubt its existence.

In 1880, techniques for examining blood were unfortunately far from perfect, a fact which contributed to drawing out discussions on the new hemacytozoon. Techniques had to be perfected and new methods of coloration invented in order that the structure of the hemacytozoon be shown up.

Studies which confirmed my findings, at first few in number, began to grow; at the same time, endoglobular parasites bearing a great resemblance to the hemacytozoon of malaria were being discovered in animals. By 1889, my hemacytozoon had been found in most malarial regions; it was no longer possible to doubt its existence, nor its pathogenic role.

Before myself, numerous observers had searched in vain for the agent of malaria; I too would have failed, had I been satisfied with examining the air, water, and earth of malarial sites, as had been practiced up to then; as a basis for my research, I took pathological anatomy and the study in vivo of malarial blood, and that is how I arrived at my destination.

… After having discovered the parasite of malaria in patients’ blood, there remained an important question to be solved: in what form did the hemacytozoon exist in the exterior environment and how did the infection come about? The solution to this problem required long and laborious research.

After having made futile attempts to detect the parasite in the air, water, and earth of malarial sites, and to cultivate it in the most varied of environments, I was convinced that the microbe existed outside the human body, in a parasitic state, and most probably in the shape of a parasite of mosquitoes.

I advanced this opinion as early as 1894 in my Treatise on malarial fevers and I came back to it on several occasions.

In 1894, in a report to the International Congress of Hygiene in Budapest concerning the etiology of malaria, I wrote: ‘The failure of my attempts to cultivate the hemacytozoon have led me to believe that the microbe of malaria lives in the outside environment in the form of a parasite and I suspect the mosquitoes which are so abundant in all malarial sites and which already play such an important role in the spread of filariasis.’

This opinion on the role of mosquitoes was considered at the time, by most observers, as highly unlikely.

Having myself left malarial countries, I was unable to verify the hypothesis I had advanced. It was Dr. Ronald Ross who had the merit of proving that the hemacytozoon of malaria and a hemacytozoon of birds very similar to the Hoemamoeba malariae went through several phases of their evolution in culicides and were spread by these insects.

R. Ross, whose admirable and patient research was very justly rewarded in 1902 by the Nobel Prize in medicine, was good enough to recognize in several of his writings that he had been usefully guided by my inductions and those of P. Manson.

Today, the transformations which the hematozoon of malaria undergoes in mosquitoes of the Anopheles types are well known and there are no more doubts possible as to the role of these insects in the spread of malaria.

… Before discovering the hemacytozoon of malaria, there was no known pathogenic endoglobular hemacytozoon ; today, the Haemocytozoa constitute an important family by the number of types and species and by the role that some of these protozoa play in human and veterinary pathology.

The discovery of these new pathogenic agents shed new and bright light on a great number of questions which had remained obscure up to then. The progress carried out shows once again how right is the expression formulated by Bacon: Bene est scire, per causas scire.”

In 1885 Laveran married Mlle Pidancet.

In 1884, he was appointed Professor of Military Hygiene at the École de Val-de-Grâce. In 1893, Laveran was elected a Member of the Academy of Sciences. In 1894, his period of office as professor having ended, he was appointed Chief Medical Officer of the military hospital at Lille and then Director of Health Services of the 11th Army Corps at Nantes. He had neither a Laboratory nor patients, but he wished to continue his scientific investigations. He now held the rank of Principal Medical Officer of the First Class and in 1896 he entered the Pasteur Institute as Chief of the Honorary Service.

From 1897 until 1907, he carried out many original researches on endoglobular Haematozoa and on Sporozoa and Trypanosomes, eventually identifying more than twenty new organisms. This work certainly enhanced his reputation as a scrupulous, perservering, wise investigator of perfect technicity. His special focus was on the trypanosomes and he published either independently or in collaboration with others, a large number of papers on these blood parasites. He successively studied: the trypanosomes of the rat, the trypanosomes that cause Nagana and Surra, the trypanosome of horses in Gambia, a trypanosome of cattle in the Transvaal, the trypanosomiases of the Upper Niger, the trypanosomes of birds, Chelonians, Batrachians and Fishes and finally and especially the trypanosome which causes the terrible endemic disease of Equatorial Africa known as sleeping sickness.

In 1907 he was awarded the Nobel Prize for his work on protozoa in causing diseases and he gave half the Prize to found the Laboratory of Tropical Medicine at the Pasteur Institute. In 1908 he founded the Société de Pathologie Exotique, over which he presided for 12 years.

He did not abandon his interest in malaria. He visited the malarious areas of France (the Vendée, Camargue and Corsica) and played a large part in the enquiry on the relationships between Anopheles and malaria in the campaign undertaken against endemic disease in swamps, notably in Corsica and Algeria.

In 1912, he became a Commander of the Legion of Honour. During the years 1914-1918, he took part in all the committees concerned with the maintenance of the good health of the troops, visiting Army Corps, compiling reports and appropriate instructions. He was a member, associate or honorary member of a vast number of learned societies in France, Great Britain, Belgium, Italy, Portugal, Hungary, Rumania, Russia, the U.S.A., the Netherlands Indies, Mexico, Cuba and Brazil.

laveransrLaveran did not, for 27 years, cease to work on pathogenic Protozoa and the field he opened up by his discovery of the malarial parasites has been increasingly enlarged. Protozoal diseases constitute today one of the most interesting chapters in both medical and veterinary pathology.

Those who were closely acquainted with Laveran knew that underneath a somewhat distant and reserved exterior there lay hidden a very sensitive soul. His character was invariably upright, his speech slow and thoughtful, enhanced by precision and free of solemn gestures. His physionomy, the clarity of his gaze reflected the serenity and honesty of his intelligence. He surrounded his research with silent discretion up until the time he decided to publish his results.

Journalists knocked vainly at this door. He never gave any interviews. And thus the public hardly knew of him and he could not have cared less!

For a long time, he suffered from the indifference, hostility or disdain with which his discoveries were met. The ignorance and ingratitute of military leaders who obstinately barred the way for his reaching the higher ranks of the army were particularly painful for him.

But he had his revenge, and what a glorious revenge! The Pasteur Institute offered him a laboratory, the Academy of Sciences, the Royal Society of London, all the scientific associations of the world sought to welcome and honour him. The Carolin Institute awarded him the Nobel Prize and the Academy of Medicine wished him to preside their one hundredth anniversary!

Until a few weeks before his death, although he already had no more illusions as to the fatal outcome of the illness which had struck him, he was still working, keeping in touch with his laboratory- to which he no longer had the strength to go- through the faithful Léon Breton and his student, Dr. Franchini. On May 18, 1922, he succumbed to his prolonged illness.

Sources:

  1. http://stevenlehrer.com/explorers/images/explor1.pdf
  2. Obituary of Prof. A. Laveran. Bulletin de la Société de pathologie exotique, 1922, vol 15, n°6. Available at: http://www.pathexo.fr/pages/english/ObitLav.html
  3. http://www.geocities.com/med_for222nat/laveran.html
  4. Alphonse Laveran. Protozoa as Causes of Diseases. Nobel Lecture, December 11, 1907. Available at http://nobelprize.org/medicine/laureates/1907/laveran-lecture.html
  5. http://nobelprize.org/medicine/laureates/1907/laveran-bio.html (From Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam, 1967)
  6. http://crishunt.8bit.co.uk/alphonse_laveran.html
  7. http://www.todayinsci.com/cgi-bin/indexpage.pl?http://www.todayinsci.com/L/Laveran_Alphonse/Laveran_Alphonse.htm

©malariasite.com ©BS Kakkilaya | Last Updated: Mar 9, 2015

Malaria in Wars and Victims

Malaria has shaped the course of history for millennia. It has always been part of the ups and downs of nations; of wars and of upheavals. Kings, popes, and military leaders were struck down in their prime by malaria [See below]. Many great warriors succumbed to malaria after returning from the warfront and advance of armies into continents was prevented by malaria. In many conflicts, more troops were killed by malaria than in combat. The activities of the armed forces would create thousands of breeding places for the vector mosquitoes and thus greatly increase the transmission. Even in recent years, night vigils and other activities like cine-viewing, lack of mosquito nets and other protection, failure to take chemoprophylaxis, due mainly to its adverse effects has contributed to the rising cases of malaria in war time.

In 1910, Col. C. H. Melville, Professor of hygiene, Royal Army Medical College, London, wrote a chapter on malaria prevention in war in Ronald Ross’s book The Prevention of Malaria. He wrote: “The history of malaria in war might almost be taken to be the history of war itself, certainly the history of war in the Christian era.” He suggested that a specially selected medical officer should be placed in charge of antimalaria operations with executive and disciplinary powers.

Malaria has also been a great stimulus for research into newer anti malaria drugs. Cinchona bark and Quinine were “hot properties” during the two World Wars and inability to procure or maintain adequate stocks of quinine spurred research into other drugs to treat malaria so that the troops could be treated effectively. Thus it appears that probably a lot of money was spent on anti-malaria efforts during wars, if not more than what was spent on the war itself. The Navy Medical Research Center, Walter Reed Army Institute of Research , and the U.S. Army Medical Research Institute of Infectious Diseases of the US Armed Forces is continuously engaged in research into developing newer drugs and vaccines against malaria.

history-warsSome well known conflicts marred by malaria include:

  • It is believed that Alexander the Great was killed by malaria at the height of his power. In alliance with Greek states, this Macedonian general had conquered the Persians, capturing the entire coastline of the eastern Mediterranean, Syria, Phoenicia, Arabia, and Egypt. Alexander also humbled the valiant tribes of northern India, virtually conquering the entire known world. He had set out to subjugate the earth but just as he was to depart with his army in early June 323 B.C., he contracted a fever and the voyage was postponed. At first the thirty-three-year-old general regarded his illness as nothing more than a temporary setback. But Alexander continued to deteriorate until he lapsed into a deep coma and died. Malaria, by striking Alexander, had altered the course of history. Had the military leader survived, he might well have succeeded in uniting east and west, fusing Greeks and Asians into a single nation. But in his absence, his empire crumbled, his army collapsed. Still later, historians believe, malaria was instrumental in the downfall of all Greek civilization by sapping the strength of the people and depopulating the countryside.
  • In the fourth century A.D., Alaric, King of the Goths, attacked Rome and triumphed. But his triumph was short lived for he got sick with malaria and died soon after entering the town.
  • The invading army of Attila (452 AD) was stopped in Rome by malaria
  • In 536 Belisarius, leading the army of the Eastern Empire, surrounded Rome, planning to starve the city into submission. To facilitate their plan, the soldiers ravaged the farms producing food and destroyed aqueducts to cut off the Roman water supply. But they made a fatal error by digging their entrenchments in the Campagna. With summer came malaria, which quickly decimated the ranks. Belisarius himself was severely stricken with fever but survived, a beaten man.
  • Emperor Otto I attacked Rome in 964 to suppress a revolt there but almost all his men died of malaria and those who still kept their health only dared to hope to live from one evening to the next morning. On 7 Dec., 983, his eldest son, Otto II, died of malaria at the age of 28 years in spite of medical intervention.
  • Frederick I, called Barbarossa, also failed in his attempt to conquer Rome. The army of Henry II was wiped out by malaria, but Henry IV managed to besiege Rome four times, always withdrawing the bulk of his soldiers during the summer months from the Campagna. The tiny force left behind was invariably annihilated by fever.
  • Malaria probably played a part in dissuading Genghis Khan (1162-1227) from invading Western Europe
  • After the death of Pope Alexander VI in 1503, his son Cesare Borgia plotted to dominate all Italy. But shortly , Cesare contracted severe malaria and was saved by his family doctor. By the time Cesare Borgia recoverd, his opportunity had passed.
  • By the end of 15th century, Columbus dropped anchor at the site of an old Indian village on Hispaniola to build a fort and colony on his second voyage to the New World. After a month, an epidemic of terrible fever afflicted the entire party, including Columbus himself.
  • Malaria continued to spread throughout North America during the Revolutionary War. Whole British garrisons are recorded as having succumbed to the disease, and some historians even speculate that the eventual British surrender at Yorktown may have been partly due to a severe fever epidemic.
  • One of the first military expenditures of the Continental Congress, around 1775, was for $300 to buy quinine to protect General Washington’s troops.
  • Malaria and yellow fever kept Napoleon Bonaparte from putting down the uprising in Hati in 1801
  • Malaria was used as a biological warfare agent in the Walcheren Expedition in the Low Countries, when the British were conquered by malaria before a battle could be fought. Starting on July 30, 1809 a British armed force of 39,000 men landed on Walcheren with a view to assisting the Austrians in their war against Napoleon, and attacking the French fleet moored at Flushing (Vlissingen). Napoleon had consolidated his grip on the continent by defeating the Austrians at Wagram earlier in the month. Napoleon reportedly flooded the Holland countryside to allow malaria to become rampant. Napoleon reportedly stated: “We must oppose the English with nothing but fever, which will soon devour them all.”  The British Army expedition became so stricken between August and October of that year that they were unable to sustain the campaign. In early August there were fewer than 700 men sick, but by 3 September over 8000 were in hospital. In late October 9000 troops were sick and easily outnumbered those fit for duty. Hospitals were set up in houses, churches, and warehouses, and conditions were appalling. The typical treatment included laxatives and emetics combined with other treatments such as venesection, blistering, and dousing with cold water. Alcohol and tobacco were regarded as panaceas. By the time the expedition ended in February 1810 the fever had caused the death of 60 officers and 3900 soldiers. Over 40% of the force had been struck down by disease, and six months later around 11000 men were still registered sick. This compared with only 100 killed in the sporadic fighting of what had become an irrelevant military adventure.  It has been estimated that in all theatres of war between 1793 and 1815 the total British losses were in the region of 240 000 men, with probably less than 30 000 of these deaths being caused by wounds.
  • During the American civil war in 1861-1865, malaria accounted for 1,316,000 episodes of illness and 10,000 deaths. It has been estimated that 50% of the white soldiers and 80% of the black soldiers got malaria annually.
  • The Italian campaigns of French and Austrian armies in 1859
  • In the 1864 West African campaigns, the troops were defeated by disease without the enemy ever seen or a “grain of powder expended”
  • The French campaign in Madagascar in 1895 saw 13 deaths in action and over 4,000 deaths due to malaria
  • World War I (1914–1918): In Macedonia, British, French, and German armies were immobilized for 3 years by malaria. On one occasion, when the French commanding general was ordered to attack, he replied: “Regret that my army is in hospital with malaria.” Nearly 80 percent of 120,000 French troops in this area were hospitalized with malaria. In an average British strength of 124,000, there were 162,512 admissions to hospital for malaria during the years 1916 to 1918, in contrast to 23,762 killed, wounded, prisoner, and missing in action. In the spring of 1918, about 25,000 British soldiers were sent home from Macedonia with chronic malaria, and, apart from these evacuees, over 2,000,000 man-days were lost to the British Army in this area in 1918 because of malaria. Approximately 7.5/1,000 Americans quartered in the U.S. were infected with malaria in 1917.

How mosquitoes helped win the American Revolution By John R. McNeill | The mosquito has played a leading role in the rise and fall of empires throughout history By John R. McNeill

Ronald Ross was asked to assist the British troops during the war and as a consultant he followed the troops to Egypt, Gallipoli, Salonika and Taranto. His health suffered during the war and he lost his older son in the British retreat from Mons.

  • World War II: Many troops had to suffer casualties by inflicted malaria even in World War II. Gen. Douglas MacArthur’s predicament in May 1943 is very clear: “This will be a long war if for every division I have facing the enemy I must count on a second division in hospital with malaria and a third division convalescing from this debilitating disease!” It appears that the general was not at all worried about defeating the Japanese, but was greatly concerned about the failure to defeat the Anopheles mosquito! 60,000 U.S. troops died in Africa and the South Pacific from malaria. U.S. Forces could succeed only after organising a successful attack on malaria.

Development and use of synthetic antimalarial drugs and residual insecticides like DDT were greatest “contributions” to malariology from World War II. The dependency on quinine as the only antimalarial was relieved and many new antimalarials like chloroquine, amodiaquin, primaquine, proquanil and pyrimethamine came into use.

  • Korean War (1950–1953): U.S. military hospitals were inundated with cases of malaria, with as many as 629 cases per week. More than 3,000 cases of malaria were documented in U.S. troops that served during the war.
  • Vietnam War (1962–1975): Malaria felled more combatants during the war than bullets. The disease reduced the combat strength of some units by half. Over 40,000 cases of Malaria were reported in US Army troops alone between 1965 and 70 with 78 deaths. The U.S. Army established a malaria drug research program when U.S. troops first encountered drug resistant malaria during the war. In 1967, the Chinese scientists set up Project 523 – a secret military project –  to help the Vietnamese military defeat malaria by developing artemisinin based anti malarial formulations.
  • Operation Restore Hope (1992–1994): Malaria was the No. 1 cause of casualties among US troops during the operation. From the time of deployment through April 1993, malaria was diagnosed in 48 military personnel. Malaria was diagnosed in 83 military personnel (21 Marine and 62 Army) following their return from Somalia.
  • Malaria in Afghanistan, Iraq, and Liberia (2001–2003): Many US soldiers in Iraq walked while eating just to avoid being bitten and infected by mosquitoes. In October 2001, a falciparum malaria epidemic that erupted in Afghanistan claimed 53 lives. When 290 marines went ashore in Liberia in September 2003, 80 contracted malaria. Of the 157 troops who spent at least one night ashore, 69 became infected. In Liberia, over a third of U.S. Marines sent in as military advisors to oversee a civil transition have contracted malaria.

Malaria has posed major problems during natural calamities. Outbreaks of malaria was a problem during many major constructions like that of the Suez canal and the Panama Canal. The Vatican was moved from a lower lying area to its present location, with work beginning in 1574, due to malaria. Malaria continues to be challenge in such situations even today.


Famous Victims of Malaria

Malaria has killed millions and many more have suffered from it. During the past 100 years, nearly 150 million to 300 million people would have died from the effects of malaria, accounting for 2-5% of all deaths. In the early part of the century, malaria probably accounted for 10% of global deaths to malaria and in India it probably accounted for over half. Here is a list of some of the more famous human beings who died or suffered from malaria.

history-victims1The Rich and the Famous Who Died of Malaria:

  • Emperor Titus Caesar Vespasianus Augustus died of fever, probably malaria, in AD 81
  • Alexander the Great is believed to have died of malaria in 323 BC, on the route to India beyond Mesopotamia
  • Alaric, King of the Goths, died of malaria in fourth century AD
  • St. Augustine, the first Archbishop of Canterbury, died after a 10 day febrile illness that could have been malaria
  • Otto II, King of the Germans and Emperor of Rome died on malaria on 7 Dec., 983
  • Pope Gregory V is thought to have died of malaria in 999
  • Pope Damasus II died in 1048 after only about 3 weeks in office, probably of malaria
  • Friedrich IV, Herzog von Schwaben died of malaria on 19 August 1167
  • German King and Holy Roman Emperor Heinrich died of malaria in 1197
  • Genghis Khan, the Mongol overlord of the 13th Century who set up the largest land empire ever known, is believed to have suffered from a malaria like illness in the spring of 1227, even as he was nursing his injuries. After several months of sickness, the Great Khan died. He was about sixty years old.
  • Richard, Earl of Cornwall died on 2 April 1272 of having been bled for ague
  • Henry of Luxemburg died at Siena of a fever, probably malaria, on 24 August 1313
  • Dante, Italian poet died of malaria 1321
  • Byzantine Emperor Andronicus III Palaeologus is thought to have died of malaria in 1341
  • In 1351, the much feared and ruthless ruler, Sultan Muhammed bin Tughluk contracted malaria while on a military campaign against rebels and within a short time succumbed to the disease.
  • King Edward IV died in 1483 of various complications, including malaria
  • One pope after another succumbed to malaria. Pontiffs from the north were especially vulnerable, and sometimes candidates for the papacy were difficult to find. The cardinals, too, were not immune, and consistently lost members to fever when gathering to choose a new pope. Finally, in the fourteenth century, foreign popes were no longer permitted to live in Rome, due to fear of “Roman fever.”
    • Pope Leo X died of malaria in 1521
    • Pope Sixtus V died of malaria in 1590
    • Giambattista Castana was elected Pope Urban VII in 1590, but died of malaria before his coronation
    • In 1623, when the Sacred College of Cardinals was convened to choose a successor to Pope Gregory XV, malaria felled many of these clergymen.
  • Roman Emperor Charles V supposedly died of malaria in 1558
  • Ethiopian Emperor Minas became ill with malaria and then died in 1563
  • Spanish Explorer Alvaro Mendana de Neira, discoverer of the Soloman Islands in 1568, died of malaria in 1595
  • Caravaggio, Italian painter probably died of malaria in 1610
  • Oliver Cromwell, Lord Protector, died of malaria in 1658
  • Lord Byron died of malaria in Greece in 1824
  • Commodore Oliver Hazard Perry supposedly contracted malaria in Venezuela and died of the disease in 1819
  • Josef Ressel, inventor of the propeller, died in 1857 of malaria
  • King Mongkut of Thailand died of malaria in 1868
  • Rebka Chenashu (Ethiopian 200m and 400m bonze medalist) died of malaria in 2003 at age 17
  • Amrish Puri (Indian Film Actor) died in January 2005 of a blood clot to the brain while being treated for malaria
  • Francis Ona, the Bougainville secessionist leader of Papua New Guinea, died of malaria at the age of 52 on 24 July, 2005

The Rich and Tthe Famous Who Suffered from Malaria:

  • American Presidents Who Suffered From Malaria:
  • George Washington, (1st President, 1789-1797): Developed his first bout with malaria in Virginia in 1749 at age 17. He had periodic attacks, recorded in 1752, 1761, 1784, and 1798.
  • James Monroe (5th President, 1817-1825) caught malaria while visiting a swampy area along the Mississippi in 1785. He continued to have bouts for many years
  • Andrew Jackson (7th President, 1829-1837) is thought to have contracted malaria in Florida swamps during the Seminole campaigns of 1818-1821
  • Abraham Lincoln (16th President, 1861-1865) had periodic bouts of malaria when growing up
  • Ulysses S. Grant (18th President, 1869-1877) had malaria throughout the 1850’s
  • James A. Garfield (20th President, 1881) developed malaria in 1848 in Ohio at age 16
  • Theodore Roosevelt (26th President, 1901-1909) acquired malaria during a visit to Brazil in 1914
  • history-victims2John F. Kennedy (35th President, 1961-1963) acquired malaria during World War II, about 1943
  • Royalty
    • Belisarius in Rome in 536
    • Emperor Kangxi (Emperor of the Qing dynasty, 1661-1722) was cured of malaria by French Jesuit missionaries in about 1693
    • Louisa Maria, Queen of Spain, was cured of malaria with quinine in 1678
    • James I
    • King Charles II had recorded bouts of malaria in 1678 and 1679 and was cured using quinine
    • Hannibal’s wife and son
    • Emperor Isabel
    • Felipe II
    • Felipe IV
    • Felipe V
    • Fernando VI
    • Carlos II
    • And many others…..
  • Christopher Columbus (had to cut short his fourth voyage to the new world in 1503, again attempting to find a sea route to Asia, due (in part) to malaria)
  • Cesare Borgia in 1503
  • Sir Arthur Conan Doyle, surgeon and writer of Sherlock Holmes fame
  • Alfred Russell Wallace, co-discoverer along with Charles Darwin of the concept of Natural Selection
  • Meriwether Lewis, explorer
  • Henry Morton Stanley and Dr. David Livingstone, famed explorers
  • Jefferson Davis, Politician and Provisional President of the Confederate States of America
  • Lucretia Garfield, first lady to President Garfield
  • George B. McClellan, Civil war general
  • Ho Chi Minh, Vietnam revolutionary leader
  • Jesse James
  • General John J. Pershing
  • Mahatma Gandhi, Father of Indian nation
  • Ernest Hemingway, celebrated author
  • Lord Horatio Nelson
  • Leon Trotsky
  • Eugene O’Neill, Playwrite
  • Sir Harry Secombe
  • Ross Kemp (Former East Enders star)
  • Santa Teresa de Jesús
  • Hernán Cortés
  • Don Adams (Actor and director)
  • Errol Flynn (Actor)
  • Peta Wilson (Actress)
  • Carol Landis (Actress)
  • Raymond Burr (Actor)
  • Audie Murphy (Actor and war hero)
  • Michael Caine (Actor)
  • Christopher Lee (Actor)
  • Michael Dudikoff (Actor)
  • Jeremy Piven (Actor)
  • Al Jolson
  • Jane Goodall, naturalist
  • Davy Crockett, outdoorsman and congressman
  • Steve Reeves (Body builder)
  • Chris Matthews (MSNBCs Hardball)
  • Anderson Cooper (Former ABC news correspondent)
  • Roberto Clemente (Baseball player)
  • history-victims3Wilson Kipeter (800m champion)
  • Yakubu Aiyegbeni (Soccer star)
  • Dikembe Mutombo (Star center for the New Jersey Nets)
  • Ezekiel Kemboi (Olympic 3000m steeplechase champion of Kenya)
  • Mother Teresa was hospitalized with malaria in 1993
  • Leander Paes, Indian tennis star

and many others…..

Some NEW victims of malaria:

  • Didier Zokora, the Ivory Coast international playing for Tottenham had a mild bout of malaria in Oct 2006 [See]
  • Paul Smith, aged 30, a British oil worker kidnapped by gunmen in Nigeria died of malaria while still a hostage held in mosquito infested swamps. Paul and colleagues were snatched on October 3, 2006 inside the Exxon Mobil residential compound in Eket [See]
  • DR Congo’s Lomana Lua Lua was struck down by malaria while on international duty in September 2005 [See]

Sources:

©malariasite.com ©BS Kakkilaya | Last Updated: June 7, 2016

Malaria in Literature

Mentions of malaria can be found in the ancient Roman, Chinese, Indian and Egyptian manuscripts and later in numerous Shakespearean plays. The belief that mosquitoes transmit disease also is an ancient one.

history-litOne of the oldest scripts, written several thousand years ago in cuneiform script on clay tablets, attributes malaria to Nergal, the Babylonian god of destruction and pestilence, pictured as a double-winged, mosquito-like insect. A few centuries later, the natives told Philistines settling in Canaan, on the eastern shore of the Mediterranean, of the god Beelzebub, lord of the insects. The evil reputation of this deity increased through the ages until the early Jews named him “Prince of the Devils.”

The connection between malaria and swamps was known even in antiquity and the evil spirits or malaria gods were believed to live within the marshes. This belief is likely the origin of the Greek fable of Hercules and Hydra.

The chinese Nei Ching (The Canon of Medicine), dated 4,700 years ago, apparently refers to repeated paroxysmal fevers associated with enlarged spleens and a tendency to epidemic occurrence, suggesting P. vivax and P. malariae infections.

Sumerian and Egyptian texts dating from 3,500 to 4,000 years ago refer to fevers and splenomegaly, suggestive of malaria. The Sumerian records apparently make frequent reference to deadly epidemic fevers, probably due to P. falciparum.

The Vedic (3,500 to 2,800 years ago) and Brahmanic (2,800 to 1,900 years ago) scriptures of Northern India (Indus valley) contain many references to fevers akin to malaria. They are also said to make reference to autumnal fevers as the “King of diseases”. The Atharva Veda specifically details the fact that fevers were particularly common after excessive rains (mahavarsha) or when there was a great deal of grass cover (mujavanta). The ancient Hindus were also aware of the mosquito’s harmful potential. In 800 B.C. the sage Dhanvantari wrote, “Their bite is as painful as that of the serpents, and causes diseases… [The wound] as if burnt with caustic or fire, is red, yellow, white, and pink color, accompanied by fever, pain of limbs, hair standing on end, pains, vomiting, diarrhea, thirst, heat, giddiness, yawning, shivering, hiccups, burning sensation, intense cold…” Charaka Samhita, one of the ancient Indian texts on Ayurvedic medicine which was written in approximately 300 BC, and the Susruta Samhita, written about 100 BC, refer to diseases where fever is the main symptom. The Charaka Samhita classifies the fevers into five different categories, namely continuous fevers (samatah), remittent fevers (satatah), quotidian fevers (anyedyuskah), tertian fevers (trtiyakah) and quartan fevers (caturthakah) and Susruta Samhita even associated fevers with the bites of the insects.

Malaria appeared in the writings of the Greeks from around 500 BC. Hippocrates, “The Father of Medicine” and probably the the first malariologist, described the various malaria fevers of man by 400BC. Hippocratic corpus distinguished the intermittent malarial fever from the continuous fever of other infectious diseases, and also noted the daily, every-other-day, and every-third-day temperature rise. The Hippocratic corpus was the first document to mention about splenic change in malaria and also it attributed malaria to ingestion of stagnant water:  “Those who drink [stagnant water] have always large, stiff spleens and hard, thin, hot stomachs, while their shoulders, collarbones, and faces are emaciated; the fact is that their flesh dissolves to feed the spleen…” Hippocrates also related the fever to the time of the year and to where the patients lived.

The recurrence of malaria is a phenomenon that was known to the ancients and first recorded by Roman Poet Horace (December 8, 65 BC – November 27, 8 BC) in his third satire.

A number of Roman writers attributed malarial diseases to the swamps. In the first century A.D., Marcus Terentius Varro, the Roman scholar whom Caesar named director of the imperial library, suggested in his book on agriculture, De Rerum Rusticarum that swamps breed “certain animalcula which cannot be seen with the eyes and which we breathe through the nose and mouth into the body, where they cause grave maladies.”

By the age of Pericles, there were extensive references to malaria in the literature and depopulation of rural areas was recorded. By about 30 A.D., Celsus described two types of tertian fevers and agreed with the views expressed by Varro. 150 years later, Galen, a famed and influential physician in Rome, recognized the appearance of these fevers with the summer season and a jaundice in infected people. But he believed that malaria was due to a disorder in the four humors of the body. According to him, tertian fever was the result of an imbalance of yellow bile; quartan was caused by too much black bile, and quotidian by an excess of phlegm and a blood abnormality was the cause of continuous fever. Galen suggested that the normal humoral balance should be restored by bleeding, purging, or, even better, by both. These tenets were accepted without question for the next fifteen hundred years.

Dante [1265-1321] wrote this on malaria: “As one who has the shivering of the quartan so near,/ that he has his nails already pale/ and trembles all, still keeping the shade,/ such I became when those words were uttered.” (The Inferno) He died of malaria.

Artist Albrecht Dürer, who contracted malaria in 1520 during a trip to the province of Zeeland in Holland, sought medical advice by sending his physician a sketch showing the upper half of the his body, with an index finger pointing to a yellow spot over the spleen, noting that he felt hurt over that area.

William Shakespeare (1564–1616), mentioned ague (English word for malaria) in eight of his plays. For example, in The Tempest (Act II, Scene II), the slave Caliban curses Prosper, his master: “All the infections that the sun sucks up/ From bogs, fens, flats, on Prosper fall and make him / By inch-meal a disease!” Later, Caliban is terrified by the appearance of Stephano, who, mistaking his trembling and apparent delirium for an attack of malaria, tries to cure the symptoms with alcohol: “…(he) hath got, as I take it, an ague . . . he’s in his fit now and does not talk after the wisest. He shall taste of my bottle: if he have never drunk wine afore it will go near to remove his fit… Open your mouth: this will shake your shaking . . . if all the wine in my bottle will recover him, I will help his ague.”

Sources:

 ©malariasite.com ©BS Kakkilaya | Last Updated: Mar 9, 2015

Efforts of Malaria Control

history-control300Malaria has caused unimaginable hardship to humanity as well as loss of millions of human life, from kings to commoners, from time immemorial. Many human settlements were decimated, civilizations declined, wars lost and advance of humanity halted due to malaria. Until 1897, when the mosquito vector was identified by Ronald Ross, people tried to protect themselves by various methods that they deemed fit.

The connection between malaria and swamps was known even in antiquity and the evil spirits or malaria gods were believed to live within the marshes.

The connection between malaria and mosquitoes was suspected from ancient times. One of the oldest scripts, written several thousand years ago in cuneiform script on clay tablets, attributed malaria to Nergal, the Babylonian god of destruction and pestilence, pictured as a double-winged, mosquito-like insect. A few centuries later, the natives told Philistines settling in Canaan, on the eastern shore of the Mediterranean, of the god Beelzebub, lord of the insects. The evil reputation of this deity increased through the ages until the early Jews named him “Prince of the Devils.”

The ancient Hindus were also conscious of the mosquito’s harmful potential. In 800 B.C. the Indian sage Dhanvantari wrote about the diseases caused by bites of the mosquitoes. Susrutha Samhita also mentions about a possible link between fevers and insects like mosquitoes.

Hippocrates, Greek Physician in 400 BC, attributed malaria to ingestion of stagnant water; also related the fever to the time of the year and to where the patients lived.

Use of mosquito nets has been dated to prehistroic times. It is said that Cleopatra, Queen of Egypt, also slept under a mosquito net.

So conscious were the ancient Romans of the association between mosquitoes and malaria that city officials would routinely prohibit human habitation in mosquito-infested districts. To protect themselves from the notorious Campagna mosquitoes, shepherds returning from a summer in the Apennines furnished their small cabins with a few sheep to satisfy the ravenous insects, thereby hoping to avoid malaria. The association with stagnant waters (breeding grounds for Anopheles) led the Romans to begin drainage programs, the first intervention against malaria. It is said that Emperor Nero drained the swamps near ancient Rome, in order to rid the city of malaria. By the Middle Ages, Kings and feudal lords feared marshes as breeding grounds of plagues and incurable fevers and a royal decree was passed in 11th century Valencia, sentencing any farmer to death who planted rice too close to villages and towns. In Britain, the ‘Roman technology’ of draining swamps protected some areas from malaria during this time. Italian physician Lancisi in 1717 had suggested a possible role for mosquitoes in transmission of malaria and proposed the draining of marshes to eradicate malaria.

Malaria’s decline in the United States and Europe in the late 1800s was due mainly to draining swamps and removing mill ponds. Draining swamps also exposed good agricultural land, enabling people to afford better houses and thus isolate the sick. Increasing livestock densities may have diverted biting from humans toward cattle, pigs, or horses. Improved housing, isolation of sick people in mosquito-proof areas, better access to health care and medication, and improved nutrition, sanitation, and hygiene all may have reduced transmission and/or mortality rates.

In 1882, Albert Freeman Africanus King (1841-1915), a US Physician, proposed a method to eradicate malaria from Washington, DC. He suggested to encircle the city with a wire screen as high as the Washington Monument. Although many people took this as a jest, his hypothesis to link mosquitoes with malaria transmission was proved five years later.

Major Ronald Ross

majrossRonald Ross’s discovery of Anopheles mosquito as the vector for malaria in 1897 opened a new chapter in malaria control. With his brilliant research, he not only identified the habits and habitats of these mosquitoes but also proposed detailed plan of action to contain their breeding. Ronald Ross did not stop at writing about malaria control either. He stood at the vanguard of implementing his ideas till his end. Ross attempted to eradicate malaria from England by forming ‘mosquito brigades’ to eliminate mosquito larvae from stagnant pools and marshes. In 1899, he was sent to Freetown, the capital of Sierra Leone where he organised a sanitation drive, clearing the streets of tyres, bottles and empty cans and levelling roads so that rain water would not gather into puddles. But the Freetown malaria control programme did not yield desired results, probably because Ross had underestimated the number of breeding pools and the sheer number of vectors that he was trying to control. Ross had very limited funding and the best available technology was to pour oil on the numerous breeding sites around Freetown. As soon as the oil treatments stopped, breeding would begin again. Ross redoubled his efforts with increased funding from private sources and ensured the removal of all potential breeding sites, including rubbish, broken bottles and other potential water containers. Despite these concerted efforts, the programme was remembered more for its impact on the Freetown’s rubbish than with malaria control. J.W.W. Stephens and S.R. Christophers, who had worked with Ronald Ross in Freetown, organised a similar drive in Mian Mir in Lahore, India in 1901, without much success.

GB Grassi

grassiItalian physician Giovanni Battista Grassi, who demonstrated transmission of malaria from mosquitoes in man, did his own bit in controlling malaria. He warned against taking walks in the twilight, the prime mosquito feeding time. “Don’t go out in the warm evenings,” he announced, “unless you wear heavy cotton gloves and veils.” Naturally he was laughed at. To prove his point, Grassi set up an experiment to prevent malaria in the most heavily diseased region in Italy, the railroad line that ran through the plain of Capaccio. With funds from the queen of Italy and authority from the railroad, Grassi installed fine mesh screens on the doors and windows of ten stationmasters’ houses. One hundred twelve employees were paid to stay inside during the twilight. Another four hundred fifteen workers went out as usual. At the end of the summer, almost all the unprotected developed malaria. But of the hundred and twelve protected individuals, only five got sick. “In the so much feared station of Albanella,” wrote Grassi triumphantly, “from which for years so many coffins had been carried, one could live as healthily as in the healthiest spot in Italy!”

During the same period, Watson organised draining the salt marshes on the parts of the west coast of Malaya so as to make it habitable.

The sanitation drive suggested by Ronald Ross was successfully tried elsewhere. During the U.S. military occupation of Cuba, a campaign against yellow fever and malaria was commenced at Havana early in 1901. Under the leadership of the Assistant Surgeon General William Gorgas of the United States Army the anti mosquito measures produced very marked results. Pyrethrum, a natural insecticide derived from the chrysanthemum flower, was first used by William Gorgas in Cuba where it was burned inside sealed dwellings. Mosquitoes entirely disappeared from many parts of the city, and were decreased everywhere.

At the end of 1902, Prince Auguste d’Arenberg, President of the Suez Canal Company asked Ross to save Ismailia, the city that was built as a base for construction of the canal. It was gravely threatened by malaria for a long time. Ross led a sanitation drive so successful that by the following year, the city officials announced that they no longer needed mosquito nets and by 1904, a whole year had passed without a single reported case of malaria in Ismailia. Ross’s drastic sanitary measures were even dubbed as “sanitary Bolshevism”. Ross conducted similar campaigns in Greece, Mauritius, Spain and during World War I at various places on the battle front.

William Gorgas

gorgasThe experience of the US Army in Cuba was replicated during the construction of the Panama Canal between 1905-1910. The construction was made possible only after yellow fever and malaria, major causes of death and disease among workers in the area, were controlled. During the French reign between 1882 and 1888, an estimated 10000-20000 workers had died at the canal zone owing to these diseases. Therefore, before the construction could begin, Gorgas surveyed the area. Ronald Ross and William Crawford Gorgas worked together to eradicate malaria from Panama. In 1906, there were over 26,000 employees working on the Canal. Of these, over 21,000 were hospitalized for malaria at some time during their work. By 1912, there were over 50,000 employees, and the number of hospitalized workers had decreased to approximately 5,600. Through the leadership and efforts of William Crawford Gorgas, Joseph Augustin LePrince, and Samuel Taylor Darling, yellow fever was eliminated and malaria incidence markedly reduced through an integrated program of insect and malaria control. Drainage, brush and grass cutting, oiling and larviciding (when oiling was not sufficient) were all done. At the time, there were no commercial insecticides. Joseph Augustin LePrince, Chief Sanitary Inspector for the Canal Zone developed a larvacide mixture of carbolic acid, resin and caustic soda that was spread in great quantity. In addition, quinine was provided freely to all workers. Screening was provided to dwellings and attempts were made to kill the adult mosquitoes. Because the mosquitoes usually stayed in the tent or the house after feeding, collectors were hired to gather the adult mosquitoes that remained in the houses during the daytime.

In 1916, Dr. A.R. Campbell, a Bacteriologist at San Antonio, Texas constructed a bat house to colonize bats in order to destroy the malaria carrying mosquitoes. [See]

The best method of malaria control was a topic of hot debate during this period. Battista Grassi, Italian parasitologist, suggested tighter netting. The renowned German microbiologist Robert Koch thought is possible to eradicate malaria by giving quinine as a prophylactic (“cinchonisation”). Ross did not agree with these views. SP James suggested that malaria will only disappear with improvements in housing and the separation of mosquitoes from humans. Thus malaria was considered to be a social disease and the remedy was to improve the economic life of the subjugated populations by good housing, good nutrition, good health and education services coupled with modern agricultural practices. Economic betterment was advanced as the cause of the disappearance of malaria from northern Europe and England – where more than 10,000 cases had been admitted to London’s St. Thomas’s Hospital alone between 1860 and 1870, followed by a rapid decline to four or five cases each year by 1925. Malcolm Watson and LW Hackett of England and the Americans Fred Soper (See below) and Paul Russell supported Ronald Ross’s emphasis on vector control. There was also another view that nothing should be done so as to allow immunity to develop, even at the cost of a few young lives. Until 1944, when pesticide DDT was rediscovered as a new weapon against mosquito control, only quinine and insecticides pyrethrum and Paris green were available to help in malaria control efforts.

Paris Green (a mixture of diesel oil and copper acetoarsenite) was first used in malaria control in the 1920s in many countries like India, South Africa and Brazil.

In 1921-22, a fish called Gambusia affinis or mosquitofish was the released into water collections for its larvivorous habits and was found useful in the control of mosquitoes in California.

In 1933 Tennessee River valley authority and the Public Health Service played a vital role in the control operations of malaria in the area and by 1947, the disease was essentially eliminated. Mosquito breeding sites were reduced by controlling water levels and insecticide applications.

Fred Soper

soperAnother great success story in malaria control during this period was in Brazil. And the man who campaigned vigorously for the eradication of the mosquito from this part of the world was an unusual American named Fred Soper, who was born in Kansas in 1893 and was educated at Johns Hopkins School of Public Health. He was a man of legendary energy endowed with great common sense. When thousands of larvae of the malarial mosquito A. gambiae were discovered in 1930 along a river in Brazil, thousands of miles from their homeland in Africa, Soper recommended opening the dykes damming the tidal flats, given that salt water destroys the breeding areas. But the Government refused, and malaria began to spread infecting 100,000 people, and killing 20,000 in 1938. The Brazilian President, Getulio Vargas enlisted the services of Soper to eradicate the mosquito – a kind of ‘mission impossible’ and in 1939, the Malaria Service of Northeast Brazil was organized to combat the populations of Anopheles gambiae. Soper and his team of 40,000 workers fumigated houses and buildings with Pyrethrum and sprayed Paris Green on pools of water. In just 22 months, he was able to eradicate the mosquito from an area of about 18,000 square miles in Brazil. Fred Soper’s success was considered a great public health achievement in Brazil, and he was rewarded with medals and citations. This effort at species eradication was so successful that the mosquito is still absent from the area. This was before DDT was used in anti-malaria programmes.

The Centers for Disease Control (CDC) was organized in Atlanta, Georgia, on July 1, 1946. Office of Malaria Control in War Areas, an agency established in 1942 to limit the impact of malaria and other vector borne diseases (such as murine typhus) in the southeastern US during World War II was the predecessor of CDC. Dr. Justin M. Andrews, director of CDC from 1947 to 1951, was also the state malariologist for the state of Georgia. In the ensuing years, CDC oversaw the US national malaria eradication program and provided technical support to activities in the 13 states where malaria was still endemic. By 1951, malaria was considered eradicated from the United States. However, to the present day, malaria remains a major field of activities at CDC.

Up to 1950s, malaria control programmes in many countries involved treatment with quinine, personal protection with bednets and anti larval measures that included drainage, soil modification, proscription of urban agriculture (potatoes and other ridge-and-furrow type cultivation). The efforts were most often concentrated in urban areas. Some countries passed very strict, even draconian, legislations like the Mosquito Extermination Act for ensuring source reduction. These required all householders to prevent mosquito breeding sites by clearing all vegetation surrounding the house to a distance of ten metres in all directions. Any container that could possibly hold water and therefore provide a breeding site was to be removed from the household area. Regular inspections were made by the government health department in order to ensure that all households were complying with the legislation. Those households that did not comply were either subjected to a fine or the head of the household could be imprisoned. Such acts also required all mines, quarries, irrigation, water supply and other works to take specific measures to ensure that mosquito breeding sites were destroyed. With the availability of DDT in 1943, adult insecticidal operations were initiated by spraying and misting with adulticidal devices in tents and buildings, and by release from aircraft. By 1934-49, malaria was eradicated from Brazil and Egypt, largely due to extensive DDT spraying.

The WHO took up malaria eradication programme in 1955. In 1953, Brazilian malariologist Marcolino Candau, who campaigned on the promise of malaria eradication won the elections to the post of the director general of WHO defeating the psychiatrist Brock Chisholm. The Global Malaria Eradication Programme was launched in 1955 emphasising on vector control with DDT residual spraying and surveillance in all national programmes. The goal was to reduce infected vector populations feeding on humans sufficiently to interrupt parasite transmission. The programme imposed an uniform strategy for all countries and areas, ignoring the diversity of malaria and economy of nations, particularly the new governments then emerging from colonial rule. Sub-Saharan Africa was not included (or even ignored) due to its massive reservoir of malaria and insufficient infrastructure to support the programme. However, malaria was eradicated in nations with temperate climates and seasonal malaria transmission. The last indigenous case in England had been in the 1950s and in Holland in 1961. By 1969, many European countries namely Hungary, Bulgaria, Romania, Yugoslavia, Spain, Poland, Italy, Netherlands and Portugal managed to completely eradicate their endemic malaria. (In 1975, the World Health Organization declared that Europe was free of malaria). Some countries such as India and Sri Lanka had sharp reductions in the number of cases, followed by increases to substantial levels after efforts ceased. Other nations had negligible progress (such as Indonesia, Afghanistan, Haiti, and Nicaragua). Despite initial success in countries like India, by 1965, it started falling apart due to a number of factors: technical difficulties such as vector and parasite drug resistance, social and political factors preventing efficient application of control measures, wars and massive population movements, difficulties in obtaining sustained funding from donor countries, and lack of community participation that made the long-term maintenance of the effort untenable. The programme was criticized for being too inflexible like a military operation and received little support or even opposition from the local populations. By 1969 WHO admitted the failure of this campaign and the global eradication policy was abandoned. Several years later, the WHO’s Malaria Eradication Division changed its name to the Division of Malaria and Other Parasitic Diseases.

Between 1969-1976, the World Health Organisation co-ordinated an intensive study of malaria in the Garki district of Northern Nigeria. Many problems that could have a bearing on malaria control, like high bite intensity, high proportion of vectors carrying the parasite, mosquitoes resting outdoors after blood meals instead of indoors on insecticide treated walls, were revealed by this study. It was concluded that the use of drugs and insecticides could markedly reduce the incidence of malaria in the short term but was not enough to break transmission and achieve long-term success.

From the early 1970’s the malaria situation has slowly and progressively deteriorated. The concept of eradication was replaced with that of control as a part of primary health care. Reduced control measures between 1972 and 1976 due to financial constraints lead to a massive 2-3 fold increase in cases globally. Spraying never truly eradicated the mosquitoes anywhere, and the reduction in the more persistent P.vivax infections were much less than for P.falciparum – though the latter returned in much greater strength as control measures waned. The growing interchange of populations between malarious countries and malaria free countries is responsible for the continuous increase in the number of imported malaria cases in developed countries. Since 1976, several new pockets of malaria transmission have evolved.

Malaria control in the 1980s was neglected in many areas. The optimism of the eradication campaign was replaced by a belief that malaria could not be controlled. The systems set up for eradication, which were very centrally organised and directed were discredited, and support was withheld without offering alternative systems and strategies. Whilst it was said that malaria control should be integrated into the general health systems, instead of being a vertical programme, the means to do this were neglected. At the end of the 1980s and in the early 1990s the World Health Organisation (WHO) worked with all malarious countries to develop a global strategy for malaria control. This strategy was adopted by a Global Ministerial Conference on Malaria in Amsterdam in 1992. The strategy had four elements:

  • To provide early diagnosis and prompt treatment
  • To plan and implement selective and sustainable preventive measures, including vector control
  • To detect early, contain or prevent epidemics
  • To strengthen local capacities in basic and applied research.

The strategy was widely endorsed, and efforts to implement it have shaped the development of malaria control in most malarious countries. It has been adapted to the needs of different regions; in Africa, for instance, a Regional Malaria Control Strategy for 1996 to 2001 was developed by a Task Force for Malaria Control convened by the WHO African Regional Office (AFRO).

In 1998 Dr. Gro Harlem Brundtland, Director General, World Health Organization launched a Global Roll Back Malaria Initiative against malaria. The RBM Strategy included Early case detection and prompt treatment, Integrated vector management and Containment of focal epidemics. However, the programme is far from being successful.

Today, it’s a much worse scenario. Thoughtless man-made irrigation schemes and dams provided new habitats for Anopheles, and resulted in ‘man-made’ malaria. The extension of urban areas lead to epidemics in the peripheries of the growing cities. Mass migrations of non-immune populations into endemic areas for political reasons has further complicated matters. More than 300 million cases with 2 million deaths, multi-insecticide and multi-drug resistance, non-use of DDT, non-availability of cheap and effective chemo-therapeutics and prophylactics, steady-state, benign holoendemic malaria replaced by unstable hyperendemicity, functional immunity impaired by the ad hoc chemotherapy distributed from the primary health centres – It is déjà vu all over again. New technology promises to bring the always-in-the-pipeline vaccine and the more flashy bed nets dipped in permethrin. The super-sensitive, single-minded Ross went to his grave still holding the firm conviction that malaria could be eradicated if only weak-willed governments would commit themselves to exploit his discovery and attack the anopheline in their watery lairs.

Use of Insecticides: As early as 1825 Michael Faraday reported to the Royal Society of London the formation of benzene hexachloride. However, it had to wait for more than 115 years to become useful as a pesticide. Similarly, Dichlorodiphenyltrichloroethane (DDT) was first synthesized in 1874 by a Viennese pharmacist, Othmar Zeidler, but he did not investigate the properties of the new substance. The use of chemicals to control troublesome insects so as to save food crops started by mid 19th century. Paris green was used as an insecticide in 1867. Production of pyrethrum, which is a natural insecticide derived from the chrysanthemum flower, started in the US by 1870. In 1882, Petroleum was first recommended in the US for insect bites and stings. By 1897 oil of citronella was used as insect repellent. Pyrethrum was first used by William Gorgas in Cuba where it was burned inside sealed dwellings. In around 1910, the German scientist G. Giemsa was experimenting with different ways of using pyrethrum and developed a way of spraying pyrethrum on walls with a spray pump. This method took over two decades to catch on, and it was used with great success in South Africa for the control of malaria on sugar estates. In 1920 Oil-soaked sawdust was first recommended for mosquito control and Paris green was considered as the a mosquito larvicide. Paris Green was first used in malaria control in the 1920s. It was used in countries like India, South Africa and Brazil.

In 1924, Paris green dust was applied to swamps in Louisiana for control of Anopheles mosquitoes. In 1942, many chemicals were tested for control of insect-borne disease among Armed Forces. By 1947, more than 13,000 such chemicals had been tested and classified, but the glory went to DDT, resynthesised by Paul Muller in 1939 [See below] In 1943, Van Linden gave the name lindane to the pesticide made with the active isomers of the benzene hexachloride mixture.

Paul Müller [Also See]

mullerpAlthough DDT was first synthesized in 1874 by a Viennese pharmacist, Othmar Zeidler, he did not investigate the properties of the new substance but simply published his synthesis. Then in 1939 in Switzerland, Paul Müller of the Geigy Company, resynthesized this compound and discovered its insecticidal properties. The Geigy Company began to market the substance in 1940-41 as a 5% dust called Gesarol spray insecticide and a 3% dust called Neocid dust insecticide. The now universally used name, DDT, was first applied by the British Ministry of Supply in 1943. DDT was first added to U.S. Army supply lists in May 1943. Gahan and colleagues, in August 1943, made the first practical tests of DDT as a residual insecticide against adult vector mosquitoes. The first field test in which residual DDT was applied to the interior surfaces of all habitations and outbuildings of a community to test its effect on Anopheles vectors and malaria incidence was begun in Italy in the spring of 1944. This experiment was carried out in the town of Castel Volturno at the mouth of the Volturno River, north of Naples, by the Malaria Control Demonstration Unit of the Malaria Control Branch of the Public Health Sub-Commission, Allied Control Commission, Italy. Spraying began on 17 May 1944, and this experiment, together with a second one started later in the Tiber Delta area, lasted 2 years. The war needs and experiments greatly accelerated its acceptance and use and led to the discovery and application of similar insecticides such as benzene hexachloride and dieldrin. However, by 1949 mosquitoes resistant to DDT and other new insecticides were found. In 1962, Rachel Carson published Silent Spring. In it, she discussed the decline in certain regions of the United States of the America robin, due to its consumption of earthworms that were laden with the DDT used in massive amounts to combat Dutch elm disease. Carson’s book stimulated widespread public concern about DDT and other pesticides. Through a series of legal hearings in the United States instigated by lawyers and scientists working with the Environmental Defense Fund, DDT was eventually banned or severely restricted in most states. In 1972, the U.S. Environmental Protection Agency banned all DDT uses except those essential to public health. Similar bans were instituted by Sweden in 1969 and later in most of the developed countries. But DDT is still being used in some developing countries to control malaria, but the debate is continuing.

Sources:

  1. http://stevenlehrer.com/explorers/images/explor1.pdf
  2. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=188345
  3. http://www.libertyindia.org/pdfs/malaria_climatechange2002.pdf
  4. http://www.cdc.gov/malaria/history/panama_canal.htm
  5. http://www.cdc.gov/malaria/history/history_cdc.htm
  6. http://www.litsios.com/socrates/page5.php
  7. http://history.amedd.army.mil/booksdocs/wwii/Malaria/chapterI.htm

©malariasite.com ©BS Kakkilaya | Last Updated: Mar 9, 2015

Saga of Malaria Treatment

Fevers have always haunted mankind and several ingenious remedies were tried to combat the fevers. In the ancient times, limb blood-letting, emesis, amputation and skull operations were tried in the treatment of malarial fever. In England, opium from locally grown poppies and opium-laced beer were tried. Even the help of astrology was sought as the periodicity of malarial fevers suggested a connection with astronomical phenomena!

Galen

Galen

Claudius Galenus of Pergamum (131-201 AD), more popularly known as Galen, was an ancient Greek physician who worked in Rome from 162 AD. He suggested that the normal humoral balance should be restored by bleeding, purging, or both. Vomiting accompanying malaria was believed to be the body’s attempt to expel poisons. The bleeding supposedly rid the body of “corrupt humors.” These tenets were accepted without question for the next fifteen hundred years. Countless malaria patients were subjected to blood-letting and purgation with disastrous results: repeated bleedings only made the anemia of malaria much worse and the powerful purgatives on top of the debilitating effects of the disease itself often finished off most sufferers in a short time. The country folk and very poor who could not afford the help of the medical profession managed to survive!

Many turned to witchcraft. Allowing the insects to devour 77 small cakes made from a dough prepared by mixing flour and patient’s urine was one such suggested by the Dominican scholar Albertus Magnus. If this did not work, Albertus had another remedy: Let the matron of a noble family cut the ear of a cat, add three drops of its blood to brandy along with some pepper and administer it to the patient. Rubbing the patient’s body with chips from a gallows on which a criminal had been recently executed was yet another method.

Thus, until the early 17th century, European physicians had found no truly effective cure for malaria and their patients continued to die.

Artemisia annua

Artemisia annua

Artemisinin: The herb Artemisia annua (sweet wormwood) was known to the Chinese as qing-hao for more than 2000 years. The Mawanhgolui Han dynasty tombs, dating to 168 BC, mention it as a treatment for hemorrhoids. In 340 AD, the anti-fever properties of qinghao were first described by Ge Hong of the East Yin Dynasty.

An appeal for help from Ho Chi Minh to Zhou En Lai during the Vietnam War triggered the work on this herb and in 1967, the Chinese scientists set up Project 523. The active ingredient of qinghao was isolated by Chinese scientists in 1971. An ethyl ether extract of qinghao fed to mice infected with the rodent malaria strain, Plasmodium berghei, was found to be as effective as chloroquine and quinine at clearing the parasite. The human trails were published in the Chinese Medical Journal in 1979. Many active derivatives of artemisinin have since been synthesized and it is today a very potent and effective antimalarial drug, particularly against drug resistant malaria in many areas of southeast Asia. So far, clinically relevant genetic resistance to artemisinin has not been reported, although tolerance has been noted.

Cinchona Tree

Cinchona Tree

The history of cinchona bark, of more than 350 years, is full of intrigue and drama, greatly influencing that of pharmacy, botany, medicine, trade, theoretical and practical chemistry and tropical agriculture.

The origin of cinchona remains shrouded in mystery. Historians debate whether cinchona was an indigenous medicine or was discovered by Europeans. Evidence suggests that malaria did not exist in the New World before the arrival of the Spanish. It is said that the early Inca pharmacopoeias do not mention of cinchona, suggesting that its use followed the entry of the spaniards. However, even if malaria was not indigenous to South America, many years passed between the first arrival of the Spanish (and, presumably, malaria) and the earliest writings about cinchona by Europeans. Apparently during this interval, the native people would have developed a cure. Such a view is supported by the vast array of medicinal plants used by native healers and the large number of these plants transplanted to Europe from South and Central America at this time. Native plant remedies and treatment from native healers were more effective than the techniques of European physicians of the time.

One of the tales attributes the identification of cinchona bark to South American Indians. These natives supposedly noted that sick mountain lions chewed on the bark of certain trees. Malaria patients were given the bark and were helped.

Another holds that a member of a Peruvian Spanish garrison first discovered the bark. This soldier, overcome by malaria, was left behind to die by his comrades. Tortured by thirst, he crawled to a shallow pond, where he drank deeply and fell asleep. On awakening he found that his fever had disappeared, and then he remembered that the water had a bitter taste. A large tree trunk, split by lightning, had fallen into the pool; the bark from this tree, the soldier soon discovered, had both the bitter taste and the remarkable power to cure malaria.

history-treatment250It is widely accepted that the source of the bark was clearly identified by Jesuit priests. After Francisco Pizarro’s conquest of Peru in 1532, the Jesuit priests arrived there in 1568. Although the Jesuit doctrine forbid them from studying medicine, as it could detract from their primary focus of spiritual matters, they were allowed to study pharmacy and herbalism. In their studies of medical botany, the Jesuit priests undertook numerous field expeditions to describe and characterize the flora of remote forests in this newly discovered land. During an expedition between 1620 and 1630, to Loxa in the Southern district of Equador, bordering Peru, the Jesuit’s observed that the Incans, the indigenous people, were making teas out of the bark of certain trees to treat shivers from exposure to the cold. It is said that at Malacatos, 30 Km away from Loja, the Indian chief of the community, Pedro de Leiva provided tea made of this bark to a Jesuit priest who was sick with malaria and thereby cured him. Loxa (or Loja) being the natural habitat of this tree, the bark also came to be known as the Loja Bark.

The priest took samples of the bark to Lima, capital of Perú. The first written record of a malaria cure with cinchona bark dates back to 1630, mentioning that Juan López de Cañizares, Spanish governor of Loja (Ecuador), sent the same bark to Lima to cure the wife of the Count of Cinchón who was also sick with malaria fever, and this name also stuck to the bark.

Cinchona Bark

Cinchona Bark

It is not very clear as to who brought the cinchona bark to Europe. Sebastiano Bado, an Italian, gives this honor to the Countess of Chinchón, in an account published in 1663. The fourth Count of Chinchón, Don Luis Gerónimo Fernández de Cabrera de Bobadilla Cerda y Mendoza, was appointed by Philip IV to rule the vast Spanish South American Empire. The count and his wife, Señora Ana de Osorio, arrived in Lima in 1629. Shortly thereafter, according to Bado, the countess became severely ill with tertian fever, and news of her suffering soon spread throughout the colony. The governor of Loxa wrote the count, recommending that some of the same medicine by which he had been recently cured be given to Señora Ana. Don Juan was summoned to Lima, the remedy given, and the countess cured. Soon the natives were swarming around the palace, both to express their joy at the recovery and to learn the secret of the remedy. Upon hearing the people’s pleas, the generous Señora Ana ordered a large quantity of the bark and gave it personally to the sick. The grateful sufferers, all of whom were cured, named the new remedy los polvos de la condeça, “the countess’ powder.” In 1639, according to Bado, the countess returned to Spain, bringing a large quantity of bark with her. She distributed her remedy among the peons on the Chinchón estate, and also sent some to an ailing theology professor at the University of Alcalá de Henares. At the same time, Juan de Vega, Señora Ana’s physician, who had also returned to Spain with a supply of bark, sold part in Seville at an exorbitant price, one hundred reals per pound. This unscrupulous practice was to be repeated by many men in many places before the precious bark became readily available.

But the official diary of the Count of Chinchón, written by his secretary Don Antonio Suardo, was discovered in 1930. This contradicts many of the claims made by Bodo. The diary states that Ana de Osorio, the first Countess of Chinchón, died in Spain at least three years before Philip IV appointed the count viceroy of Peru. The second countess, Francisca Henríquez de Ribera, accompanied her husband to South America. And while Doña Francisca continued to enjoy excellent health, the count had several episodes of fever, none of which was treated with bark. Don Antonio also records that even the second countess never returned to Spain; instead, she died in the port of Cartagena, Colombia, during the trip home. Juan de Vega, her supposed physician, who, according to Bado, extorted enormous prices in Seville for the bark, never in fact left Peru because of an appointment as professor of medicine at the University of Lima. The count himself did return to Spain in 1641, and though he probably brought some bark with him, none reached the professor at the University of Alcalde de Henares, for this theologian had already been cured of his fever two years earlier.

In light of the evidence in Don Antonio’s diary, historians have been forced to conclude that cinchona bark appeared in Europe entirely by accident.

The first Europeans to appreciate the true value of cinchona were the Jesuits. As they cared for the natives throughout the Spanish New World Empire, Jesuit priests ascertained the medicinal properties of the Peruvian bark. Jesuit Barnabé de Cobo (1582-1657), who explored Mexico and Peru, is credited with taking Cinchona bark to Europe (hence called the Cobæa plant). He brought the bark from Lima to Spain, and afterwards to Rome and other parts of Italy, in 1632. The properties of the bark of the cinchona tree in the treatment of malaria were first written around 1633 by an Augustinian monk, Father Antanio de la Calancha, who lived in Peru. He wrote thus in a work on the Augustinian Order: “A tree grows which they call ‘the fever tree’ in the country of Loxa, whose bark, of the color of cinnamon, made into powder amounting to the weight of two small silver coins and given as a beverage, cures the fevers and tertiana; it has produced miraculous results in Lima.” Another Jesuit Bartolomé Tafur, came to Spain in 1643 and proceeded through France and took it to Italy as far as Rome.

Juan Lugo

Juan Lugo

The celebrated Jesuit theologian Juan de Lugo heard of the cinchona from Tafur. In 1640, Juan de Lugo first employed the tincture of the cinchona bark for treating malaria. Juan de Lugo (made cardinal in 1643) was entrusted by Pope Innocent X to learn more about the bark. De Lugo had the bark analysed by the pope’s physician, Gabriele Fonseca, who reported on it very favourably. In the late 1640s, directions for the use of the bark were published as the Schedula Romana. While on a visit to Paris in 1649 the cardinal even used some of his cinchona to treat the young Louis XIV. After the king’s recovery, the French eagerly embraced the new remedy. Juan de Lugo remained a faithful advocate, zealous defender, and generous, disinterested dispenser of the bark in Italy and the rest of Europe until his death in 1660. He was honoured at many places and several portraits of him were painted.

The Jesuit priests got natives to harvest the bark and the workers were made to replant five trees, arranged in the shape of a cross, for every tree they cut down. The bark was harvested around what is now the Peruvian and Ecuadorian border. From there it was carried to Paita on the coast and transferred onto ships bound for Panama. Once in Panama, it was carried north across the isthmus to Portobelo during the dry season, or taken via the Chagres River during the rainy season. At Portobelo the bark was once again loaded onto ships and sent to Spain via Havana. Occasionally, smuggling also took place, but rather than transport the bark via the western seaboard, smugglers carried it eastward, across most of the continent, following the course of rivers to the Atlantic. Once in Europe, the bark was distributed by a variety of means. Jesuits often gave it away, merchants sold it, and the nobility sometimes used it as gifts.

Pietro Paolo Pucciarini of Rome, Honoré Fabri, a French Jesuit and others helped in spreading the use of the bark across Europe and the “Jesuit Bark” also reached England. By 1657, it reached India. Under the pseudonym of Antimus Conygius, Fabri wrote in 1655 the first paper on cinchona published in Italy. The first prescription of cinchona  in England is attributed to Robert Brady, a Professor of Physic in Cambridge, who in 1658 began prescribing the powder of the ‘Jesuits’ bark’ to treat an outbreak of malaria. Thomas Sydenham, an eminent English physician, published a book called Method for Curing the Fever (Methodus curandi febres) in 1666. A firm believer in the remedies of Hippocrates and Galen, Sydenham staunchly adhered to the old humoral theory of malaria. Grudgingly, though, he admitted that cinchona might be of some benefit if given after the fever had declined. Physician Bado declared that this bark had proved more precious to mankind than all the gold and silver which the Spaniards obtained from South America. The Italian professor of medicine Ramazzini said that the introduction of Peruvian bark would be of the same importance to medicine that the discovery of gunpowder was to the art of war.

Despite positive results and the backing of the Vatican, the use of cinchona was not universally adopted in 17th century Europe; many orthodox physicians in Protestant England in particular were prejudiced against its use. Many factors contributed to the delay in acceptance. First, the bark often did not work. Cinchona could not cure all fevers except those of malaria. Furthermore, unscrupulous dealers might have sold inferior bark or the bark of some other tree, and after the long journey from New Spain to Europe the bark sometimes arrived too rotten to use. The use of cinchona had not been mentioned in and even contradicted the teachings of the ancient author Galen, according to whom, a patient with malaria needed to release humors, making bleeding, purging, and the use of emetics the preferred treatments. The use of a hot, bitter drink seemed to conflict with both Galenic medicine and common sense. Lack of a reliable prescription also distanced physicians from prescribing it. The support of the Vatican for the drug and the fact that its export from Peru and Bolivia was in the hands of Catholics also worked against its acceptance in some regions, particularly in England. The close association of the drug with Catholicism made many Protestants fear it was part of a “Popish plot” against them. Oliver Cromwell, who had ordered the execution of Charles I, steadfastly refused cinchona during a severe attack of malaria in 1658, and died as a result (and that supposedly changed the history of England!).

In other countries that initially accepted cinchona the drug was sometimes used improperly. For example, the Austrian governor general of the Netherlands, Archduke Leopold William, was given cinchona with excellent results by Chifflet, his physician. But when the malaria recurred a month later, the archduke blamed the cinchona and foolishly refused to take more. His subsequent demise gave the medicine a bad name throughout Europe, and even Chifflet somehow came to believe that cinchona “fixed the humors” while reducing the fever, making recurrence certain and death likely.

It took an untrained “quack” to popularize cinchona in England in a highly unorthodox manner. Robert Talbor was born in Cambridge in 1642. He entered St. John’s College but dropped out at the age of twenty-one, becoming apprenticed to a Cambridge apothecary from whom he first learned of cinchona. He abandoned his apprenticeship and moved to Essex and then to London. He used the prevalent fears and confusion about the Jesuits’ Bark to make his name as a “feverologist” by treating malaria patients with what he called a ‘secret remedy’. He developed a safe dosage and an effective treatment regimen: “I planted myself in Essex near the sea side, in a place where agues are the epidemical diseases, where you will find but few persons but either are, or have been afflicted with a tedious quartan.” After several years of study and testing, he developed a secret formulation that was essentially an infusion of cinchona powder, skillfully disguising the bitter taste of the cinchona with opium and wine. His secret remedy cured many sufferers in the Fens and Essex marshes. In 1672, Talbor wrote a small book titled “Pyretologia: A Rational Account of the Cause and Cure of Agues”. But all along, Talbor avoided mention of actually having used ‘Jesuit’s bark’ himself and to protect his secret, he made careful slurs against the Jesuit’s bark. He solemnly warned his patients and the public to “Beware of all palliative Cures and especially of that known by the name of Jesuits powder….. for I have seen most dangerous effects following the taking of that medicine,” thus cornering himself a lucrative monopoly of both the patients and the remedy. Thanks to this book, his reputation grew. The success of his treatments became widely known and brought him rapid fame and fortune. Charles II appointed him Physician Royal in 1672 and he was knighted in 1678. The Royal College of Physicians was furious at Talbor’s doings and advocated his prosecution for practicing medicine without a license. But the king would not hear of such a thing; in an angry, threatening letter, he warned the College members that any interference with Talbor would be certain to arouse the royal displeasure. When the dauphin, last living son of Louis XIV, became ill with fever, Charles II sent Talbor to the French court as a gesture of goodwill. Louis had sheltered the English monarch in his period of exile during the Protectorate of Cromwell. Now the favor was returned. Sir Robert cured the stricken dauphin. With the additional title of Chevalier Talbot, he became famous throughout Europe, curing Louisa Maria, Queen of Spain, Prince de Condé, the Duc de Roche-foucauld, and hundreds of other royal and aristocratic persons. But this again met with hostility from physicians in Paris and Madrid. Forbidden to employ the new remedy, the jealous French physicians tried vainly to humiliate this foreign upstart. “What is fever?” they asked. “I do not know,” replied the wily Talbor. “You gentlemen may explain the nature of fever; but I can cure it, which you cannot.”

talbor

The English Remedy: Talbor’s Wonderful Secret for Curing of Agues and Feavers (1682) [Source]

In 1679, King Charles II fell ill with tertian fever and was cured by Talbor’s ‘remedy’. Louis XIV of France, in recognition of the life of his son being saved, paid 3000 gold crowns, a large pension and a title and sought to know the ‘secret’ of his ‘remedy’. Talbor agreed on the condition that the formula would not be revealed during his lifetime. After returning to England, Talbor, now rich, tried to become even richer. Covertly he cornered the cinchona market by buying all the bark he could find. But he did not live long enough to enjoy his wealth. He died in 1681 at the age of thirty-nine, and was interred in Cambridge’s Holy Trinity Church. Fearing that in death his enemies in the medical profession would defame his memory, Talbor included a bit of professional advertising in his epitaph: “most honourable Robert Talbor, Knight and Singular Physician, unique in curing Fevers of which he had delivered Charles II King of England, Louis XIV King of France, the Most Serene Dauphin, Princes, many a Duke and a large number of lesser personages.”

In the same church, another imposing tablet hailed him even more eloquently as “Febrium Malleus,” smasher of fevers. In 1682, King Louis arranged for a small volume to be published that year. Nicholas de Blegny, physician-in-ordinary to the king, thereupon wrote a small book which was quickly translated into English: The English Remedy: Or Talbor’s Wonderful Secret for the Curing of Agues and Fevers–Sold by the Author, Sir Robert Talbor to the Most Christian King and since his Death ordered by His Majesty to be published in French, for the Benefit of his Subjects. The formula contained rose leaves, lemon juice, wine and a strong infusion of Peruvian bark! These revelations and a subsequent book, in 1712, on the therapeutic properties of the bark, by Fransesco Torti, professor of medicine at Modena, helped to popuarize the use of the treatment.

Linnaeus

Linnaeus

For a hundred years after it had been brought to Europe the bark remained difficult to obtain and Peru was its only source. Attempts to remove cinchona plants from the country were not successful. Charles de la Condamine, a French naturalist and explorer, was one of the first to make such an attempt in 1735. Condamine was determined to bring the trees back to France and grow rich selling the bark. He collected a large number of seedlings, planted them in boxes of earth, and then braved swamps, jungles, hostile natives, dangerous animals, and wild river rapids to reach the coast. After a perilous eight-month journey, within sight of the ship for Paris, his small boat was swamped by a wave and his plants washed away. However, with the help of the specimens of the bark that Condamine had obtained, Carolus Linnaeus, a Swedish botanist, classified the family of the Peruvian bark in 1742. He named the tree cinchona after the Countess, apparently accepting Sebastiano Bado’s account. Linnaeus misspelled the name, or rather he spelled it as had Bado, who had partially Italianized the count’s name, since c before i in Italian is pronounced like the Spanish (and English) ch. After Linnaeus’s death the error was discovered, much too late to change.

One member of Condamine’s expedition, Joseph de Jussieu, remained in the South American jungles for seventeen years to study cinchona. When he decided to return to France in 1761, he carried with him cinchona seeds packed into a wooden strongbox. But on the day of departure from Buenos Aires, a “trusted servant” made off with the box in the mistaken belief that it was filled with money. Jussieu returned to France ten years later, hopelessly insane. A Jesuit expedition was able to transport cinchona seedlings to Algeria, but the plants died in their new home. Success in this regard had to wait for another century.

At the beginning of the eighteenth century, as the use of cinchona spread throughout Europe, apothecaries and chemists attempted to extract the active ingredient of the bark so as to standardise the treatment. The first attempt to isolate the active principle in cinchona was made by Count Claude de la Garaye, a French pharmacist. In 1745 Garaye announced that he had successfully extracted the “essential salt,” but this was soon found to be not effective against malaria. Another French chemist, Antoine François Fourcroy in 1790 extracted a resinous substance with the characteristic color of the bark but that was not effective in treatment of malaria. Armand Seguin, Fourcroy’s student, came to the absurd conclusion that the active principle in cinchona was gelatin and published his findings despite inadequate experimental data. For years thereafter, many physicians reading Seguin’s paper adopted clarified glue to treat their malaria patients.

The first partially successful separation of the active principle from cinchona was achieved in 1811 by a Portuguese naval surgeon named Bernadino A. Gomez. He extracted the gray bark of poor variety with dilute acid and then neutralized it with alkali and managed to obtain a few crystals which he named cinchonin (later, to be known as cinchonine).

Pelletier

Pelletier

French pharmacists, Joseph Pelletier and Joseph Bienaimé Caventou, appointed a full professor of toxicology at the École de Pharmacie in Paris at age 22, isolated a medicinally worthless quinine poor powder, from the gray bark in 1817. In 1819, Friedlieb Runge isolated a base from cinchona, which he named “China base” – which was different from cinchonine. Later, in 1820, Pelletier and Caventou isolated from the yellow bark a sticky, pale yellow gum that could not be induced to crystallize. The gum was soluble in acid, alcohol, and ether and highly effective against malaria. The properties of the gum were seen to be identical to “China” base; but Runge`s prior discovery was overlooked. The two men named the new chemical quinine after quinquina, the name given by Peruvian Indians to the bark, meaning medicine of medicines or bark of barks. Pelletier and Caventou refused any profit from their discovery. Instead of patenting the extraction process, they published all the details so that anyone could manufacture quinine. They received many honors, the most lucrative of which was the Prix Monthyon of ten thousand francs awarded by the French Institute of Science. A monument was erected in Paris commemorating this achievement of Pelletier and Caventou.

pellcave

Paris monument of Pelletier and Caventou [1,2]

More than 30 alkaloids are known from the bark of this genus. Formerly, the bark in different forms was used as a drug, but later natural harvesting formed the base of the production of cinchona alkaloids. This industry was carried on principally in Germany, and the Dutch and English cinchona plantations in Java, Ceylon and India were the chief sources whence the raw material was supplied. Its main active principle, quinine is now chemically synthesized. In 1823, Dr. John Sappington of Philadelphia acquired several pounds of quinine and issued “Dr. Sappington’s Fever Pills.” He persuaded ministers in the Mississippi River Valley to ring the church bells every evening to alert people to take the pills, and through that enterprise, Sappington became a very wealthy man.

By the mid-19th century the Dutch and English began claiming that the South American supply of cinchona was threatened by the non-sustainable cutting practices of the indigenous harvesters. In 1839, William Dawson Hooker, son of the renowned botanist William Jackson Hooker, wrote his dissertation on cinchona. He claimed that completely cutting the trees, rather than harvesting pieces of bark, was a better method, because insects would attack cinchona plants that had simply been debarked. On completely cut plants, new growth quickly appeared, and could be harvested again in 6 years. Years later it was also discovered that cut and regrown cinchona had higher levels of the effective alkaloids in its bark, and this method of harvesting became common on many plantations.

Attempts were continued to grow cinchona in other parts of the world. Seeds carried to Paris and Java by French and Dutch expeditions failed to germinate. In 1860 an English government clerk, Clements Robert Markham, carried seedlings to England; shortly thereafter, a distinguished botanist, Dr. Richard Spruce, did the same. These plants supplied the London market for only six years before being destroyed by insects.

In the meantime, to protect their monopoly, Peruvian authorities had barred foreigners from the cinchona forests. But in 1865 Charles Ledger, an Englishman living in Peru, obtained sixteen pounds of seed from a loyal native servant Manuel Incra Mamani for a fee of about 20 dollars. Mamani was jailed, beaten, and eventually starved to death for his act. A pound of this seed was sold to the Dutch in Java, and though apparently decayed on arrival, it germinated readily, giving birth to an enormous Dutch cinchona industry, destroying the South American monopoly on quinine and establishing a new Dutch monopoly. By grafting what was eventually named C. ledgeriana onto the hardier C. succirubra, the Dutch soon dominated cinchona cultivation, eventually producing 80 percent of the world’s quinine on the Indonesian island of Java. The high price of quinine was driven down and the drug was made available to large numbers of impoverished malaria sufferers.

The widespread use of cinchona came about because of the colonizing efforts of Europeans, and the drug, in turn, aided Europe in expanding its colonization even further. However, the world supply of cultivated quinine trees in Asia (especially in Indonesia and Java) was captured by Japan in 1942 during World War II and Germany captured the quinine reserves in Amsterdam, so Allied forces had to use emergency measures during World War II. Before the fall of the Philippines, the U.S. managed to escape with four million seeds, which were germinated back in Maryland and then transplanted in Costa Rica and other Latin American countries. Meanwhile, a Smithsonian botanist named Raymond Fosberg was able to secure millions of pounds ofCinchona bark in 1943 and 1944 for the Allies from forests and plantations in northern South America.

Even today quinine remains an important and effective treatment for malaria in most parts of the world, although resistance has been reported sporadically in 1844 and 1910.

Chloroquine: Many drugs were developed to protect the troops from malaria, particularly during World War II. Chloroquine, Primaquine, Proguanil, amodiaquine and Sulfadoxine/Pyrimethamine were all developed during this time.

During World War I, Java and its valuable quinine stores fell into Japanese forces. As a result, the German troops in East Africa suffered heavy casualties from malaria. In a bid to have their own antimalarial drugs, the German government initiated research into quinine substitutes and entrusted it to Bayer Dye Works. Most of the work was done at Bayer Farbenindustrie A.G. laboratories in Eberfeld, Germany. Several thousands of compounds were tested and some were found to be useful. Plasmochin naphthoate (Pamaquine) in 1926 and quinacrine, mepacrine (Atabrine) in 1932 were the first to be found. Plasmochin, an 8 amino quinoline, was quickly abandoned due to toxicity, although its close structural analog primaquine is now used to treat latent liver parasites of P. vivax and P. ovale. Atabrine, although found superior and persisting in the blood for at least a week, had to be abandoned due to side effects like yellowing of the skin and psychotic reactions. The breakthrough came in 1934 with the synthesis of Resochin (chloroquine) by Hans Andersag, followed by Sontochin or Sontoquine (3 methyl chloroquine). These compounds belonged to a new class of antimalarials known as 4 amino quinolines. But Farben scientists overestimated the compounds’ toxicity and failed to explore them further. Moreover, they passed the formula for Resochin to Winthrop Stearns, Farben’s U.S. sister company, in the late 1930s. Resochin was then forgotten until the outbreak of World War II.

With the German invasion of Holland and the Japanese occupation of Java, the Allied forces were cut off from quinine. This stimulated a renewed search for other antimalarials both in the United Kingdom and in the United States. After the Allied occupation of North Africa, the French soldiers raided a supply of German manufactured Sontochin in Tunis and handed it over to the Americans. Winthrop researchers made slight adjustments to the captured drug and this new formulation was called chloroquine. Later, it was found to be identical to the older and supposedly toxic Resochin. However it was not available for the troops until the end of the War. But following World War II, chloroquine and DDT became the two principal weapons in the global malaria control campaign.

However, after only about ten to twelve years of use, chloroquine resistance appeared in P. falciparum. Two initial foci of resistance developed simultaneously in Colombia and on the Cambodia-Thailand border. From these loci, resistance spread throughout South America and southern Asia. By the late 1970s chloroquine resistance had reached Africa and has since spread across sub-Saharan Africa.

Other antimalaria drugs: The formula of Atabrine (mepacrine, a 9-amino-acridine), was also soon solved by Allied chemists and it was produced in large scale in the U.S. It immediately gained widespread acceptance as an excellent therapeutic agent. After the experiments of Brigadier N. Hamilton Fairley in Australia in l943, it was also found to be useful as a prophylactic agent, protecting the troops in malarious areas. It is no longer used in view of many undesirable side effects.

The success of chloroquine led to the exploration of many (nearly 15000) compounds in the United States and another 4-aminoquinoline Camoquin (amodiaquin) was discovered. Studies on 8-aminoquinolines led to the discovery of Primaquine by Elderfield in 1950. Meanwhile, British investigators at ICI also carried out extensive studies on malaria drugs and Curd, Davey and Rose synthesised antifolate drugs proguanil or Paludrine (chlorguanide hydrochloride) in 1944 and Daraprim or Malocide (pyrimethamine) was developed in 1952. However, resistance to proguanil was observed within a year of introduction in Malaya in 1947. P. falciparum strains resistant to pyrimethamine, and cross-resistant to proguanil emerged in 1953 in Muheza, Tanzania. Sulfadoxine-pyrimethamine combination was introduced in Thailand in 1967. Resistance to this was first reported in Thailand later that year and spread quickly throughout Southeast Asia and recently appeared in Africa.

Mefloquine was jointly developed by the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche, Inc. After World War II, about 120 compounds were produced at the Walter Reed Army Institute of Research and WR142490 (mefloquine), a 4-quinoline methanol was developed. Its efficacy in preventing and treating resistant P. falciparum was proved in 1974-75 and was useful for the US Army in Southeast Asia and South America. By the time the drug became widely available in 1985, evidence of resistance to mefloquine also began to appear in Asia.

Malarone: In 1998 a new drug combination was released in Australia called Malarone. This is a combination of proguanil and atovaquone. Atovaquone became available 1992 and was used with success for the treatment of Pneumocystis carrinii. The synergistic combination with proguanil is found to be an effective antimalarial treatment.

It is thus clear that the plant-derived drugs have outlived many of the synthetic drugs, to which resistance has developed!

Sources:

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 ©malariasite.com ©BS Kakkilaya | Last Updated: Mar 9, 2015

Journey of Scientific Discoveries

Malaria has always been the subject of research for medical practitioners from time immemorial. Many ancient texts, especially medical literature, mention of various aspects of malaria and even of its possible link with mosquitoes and insects.

Susruta

Susruta

Early man, confronting the manifestations of malaria, attributed the fevers to supernatural influences: evil spirits, angered deities, or the black magic of sorcerers. The ancient Chinese believed the frightening symptoms and signs to be the work of three demons, one with a hammer, one with a pail of cold water, and a third with a stove. The ancient Romans worshiped a fever goddess, three demons rolled into one. The connection between malaria and swamps was known even in antiquity and the evil spirits or malaria gods were believed to live within the marshes.

Time Line For Scientific Discoveries
Ancient Times
Early man attributed the fevers to evil spirits, angry deities, demons, or the black magic of sorcerers
Several thousand years ago
Babylonian cuneiform script attributed malaria to a god, pictured as a mosquito-like insect
800 BC
Indian sage Dhanvantari supposedly wrote that bites of mosquitoes could cause diseases, fever, shivering etc.
400 BC
Hippocrates described the various malaria fevers of man; distinguished the intermittent malarial fever from the other continuous fevers;
noted the daily, every-other-day, and every-third-day temperature rise; mentioned about splenic change in malaria; attributed malaria to ingestion of stagnant water; also related the fever to the time of the year and to where the patients lived.
300 BC
Charaka Samhita in India classified the fevers into five different categories, namely continuous, remittent, quotidian, tertian and quartan fevers.
100 BC
Susruta Samhita in India associated fevers with the bites of the insects
First Century BC
Roman agriculturist Collumella suggested that diseases could be caused by animals that bred in the marshes
First Century AD
Roman scholar Marcus Terentius Varro suggested that the grave maladies were caused by inhalation of certain animalcula that bred in the swamps
30 AD
Celsus described two types of tertian fevers
160-200 AD
Galen suggested that malaria was due to a disorder in the four humors of the body and suggested bleeding and/or purging as treatment; this view stayed for 1500 years
1696 AD
Morton presented the first detailed description of the clinical picture of malaria and its treatment with cinchona.
1712 AD
Fransesco Torti accurately described the intricate course of the disease that was curable by cinchona
1716-1717 AD
Lancisi first described a characteristic black pigmentation of the brain and spleen in the victims of malaria. He linked malaria with poisonous vapours of swamps or stagnant water on the ground. In 1717, in his monograph titled Noxious Emanations of Swamps and Their Cure, he echoed the view that malaria was due to minute “bugs” or “worms” which entered the blood; revived the old idea that mosquitoes might play a role.
1796 AD
John Crawford, an American physician, contradicted the bad-air theory and suggested that the eggs, laid during a mosquito bite, hatched in the wound and migrated through the host’s body, producing the manifestations of malaria
1816 AD
Giovanni Rasori doubted the “bad air” theory and suggested that a microorganism may be responsible for the disease
1847 AD
German physician, Heinrich Meckel, identified round, ovoid, or spindle-shaped structures containing black pigment granules in protoplasmic masses in the blood and in the spleen; he probably saw the malaria parasites for the first time, but could not recognize the true importance of his finding
1848-1850 AD
Schutz, Virchow and Hischl confirmed the presence of pigment with intermittent fevers.
1850 AD
American Josiah Clark Nott dismissed the miasma theory and suggested that microscopic “insects” transmitted by mosquitoes caused both malaria and yellow fever
1854 AD
Beauperthy, American naturalist, wrote that malaria and yellow fever were produced by venomous fluid injected under the skin by mosquitoes
1878-79 AD
Edwin Klebs and Corrado Tommasi-Crudeli announced the “discovery” of Bacillus malariae, a bacteria that supposedly caused malaria
November 6, 1880
Charles Louis Alphonse Laveran, a French physician working in Algeria , found a moving object while examining a fresh blood film from a patient of malaria. He called this parasite Oscillaria malariae.
1881
George Sternberg, American bacteriologist proved that the Bacillus malariae was not responsible for malaria
1882
Albert Freeman Africanus King, a gynecologist at George Washington University, suggested that the mosquito was the real source of malaria
1884
Russian physiologist, Basil Danielewsky identified malaria parasites in the blood of wild birds
1884
Marchiafava and Celli demonstrated active amoeboid ring in the unstained blood and named it Plasmodium
1886
Louis Pasteur, William Osler and Camillo Golgi confirmec Laveran’s finding
1886
Pel suggested the existence of a tissue stage of the parasite
1886
Golgi observed that the tertian and quartan forms produced differing numbers of segmentations on maturity; also demonstrated that the fever coincided with the rupture and release of merozoites into the blood stream
1889-90
Sakharov in 1889 and Marchiafava and Celli in 1890 identified the parasites that caused malignant tertian fever separately from the ones causing tertian and quartan fevers. Grassi and Raimondo Filetti first differentiated and introduced the names Haemamoeba vivax and H. malariae for two of the malaria parasites in 1890
1891
Romanowsky described better staining methods for identifying malarial parasites
1893
Golgi suggested that malaria parasites may have an undiscovered tissue phase in endothelial cells not affected by antimalarial drugs and could be the source of relapses.
1897
William G. McCallum and Opie demonstrated the sexual process of the malaria parasite.
August 20, 1897
Ronald Ross demonstrated oocysts in the gut of anopheline mosquito at Secunderabad, India, proving that mosquito was the vector for malaria
July, 1898
Ronald Ross demonstrated the sporozoites in the salivary glands of the mosquito and also transmitted malaria to birds through infected mosquitoes.
September, 1898
Giovanni Battista Grassi transmitted vivax malaria to a human volunteer
1900
Patrick Manson transmitted malaria to volunteers in London from infected mosquitoes brought from Italy.
1911
Brown suggested the hematin origin of the ‘black pigment’ and suggested the action of a proteolytic enzyme on hemoglobin to be the most probable mode of elaboration of the malaria pigment
1922
P. ovale was identified by John WW Stephens
1948
Shortt & Garnham demonstrated the tissue form of P. vivax malaria
1975
William Trager cultured P. faliciparum inside red blood cells
1977
Lysenko et al suggested that latent forms of P. vivax malaria caused relapses
1987
Manuel Elkin Patarroyo, a Colombian biochemist, developed the first synthetic Spf66 vaccine against P. falciparum
2002
The genome of Anopheles gambiae and Plasmodium falciparum sequenced
2008
The genome of P. vivax and P. knowlesi sequenced

One of the oldest scripts, written several thousand years ago in cuneiform script on clay tablets, attributes malaria to Nergal, the Babylonian god of destruction and pestilence, pictured as a double-winged, mosquito-like insect. In 800 BCE the Indian sage Dhanvantari wrote that bites of mosquitoes could causes diseases, fever, shivering etc. The Charaka Samhita written in approximately 300 BCE, classified the fevers into five different categories, namely continuous fevers, remittent fevers, quotidian fevers, tertian fevers and quartan fevers. Susruta Samhita, written about 100 BCE, associated fevers with the bites of the insects.

Hippocrates

Hippocrates

Hippocrates was probably the the first malariologist. By 400 BCE, he described the various malaria fevers of man. Hippocratic corpus distinguished the intermittent malarial fever from the continuous fever of other infectious diseases, and also noted the daily, every-other-day, and every-third-day temperature rise. The Hippocratic corpus was the first document to mention about splenic change in malaria and also it attributed malaria to ingestion of stagnant water:  “Those who drink [stagnant water] have always large, stiff spleens and hard, thin, hot stomachs, while their shoulders, collarbones, and faces are emaciated; the fact is that their flesh dissolves to feed the spleen…” Hippocrates also related the fever to the time of the year and to where the patients lived.

The recurrence of malaria is a phenomenon that was known to the ancients and first recorded by Roman Poet Horace (December 8, 65 BCE – November 27, 8 BCE) in his third satire.

Varro

Varro

Noting the phenomenon of shaking chills recurring consistently, the ancient Romans named the disease by measuring the elapsed time from the beginning of the first episode to the end of the second. Thus, fever recurring on Tuesday and Thursday was called a tertian or “every third day” fever, although only forty-eight hours separated the two attacks. A fever appearing on Tuesday and Friday was be called quartan. A number of Roman writers attributed malarial diseases to the swamps. In ancient Rome, human habitation in mosquito-infested districts were routinely prohibited and shepherds returning from a summer in the Apennines furnished their small cabins with a few sheep to satisfy the mosquitoes so as to protect themselves from malaria. In first century B.C., a Roman agriculturist Collumella wrote thus: “A marsh always throws up noxious and poisonous steams during the heats and breeds animals armed with mischievous stings which fly upon us in exceeding thick swarms… whereby hidden diseases are often contracted, the cause of which even the physicians themselves cannot thoroughly understand.”

In the first century CE, Roman scholar Marcus Terentius Varro (116-27 BCE) suggested that swamps breed “certain animalcula which cannot be seen with the eyes and which we breathe through the nose and mouth into the body, where they cause grave maladies.”

Celsus

Celsus

By about 30 CE, Celsus described two types of tertian fevers and agreed with the views expressed by Varro. However, all these excellent observations were subverted for centuries by Galen’s dogmatic, widely accepted medical theories that attributed malaria to internal causes.

Galen

Galen

Claudius Galenus of Pergamum (131-201 CE), more popularly known as Galen, was an ancient Greek physician who worked in Rome from 162 CE, where he attained a brilliant reputation as a practitioner and a public demonstrator of anatomy. His influence held sway for more than 1500 years. He recognized the appearance of fevers with the summer season and a jaundice in infected people. But he believed that malaria was due to a disorder in the four humors of the body. According to him, tertian fever was the result of an imbalance of yellow bile; quartan was caused by too much black bile, and quotidian by an excess of phlegm and a blood abnormality was the cause of continuous fever. Galen suggested that the normal humoral balance should be restored by bleeding, purging, or both. Vomiting accompanying malaria was believed to be the body’s attempt to expel poisons. The bleeding supposedly rid the body of “corrupt humors.” These tenets were accepted without question for the next fifteen hundred years.

In 1696 Morton presented the first detailed description of the clinical picture of malaria and its treatment with cinchona. Morton also suggested that the disease is produced by some poison which enters the body from without. Fransesco Torti, professor of medicine at Modena, accurately described the intricate course of the disease that was curable by the cinchona in 1712.

Giovanni Maria Lancisi (1654-1720)

By early seventeenth century, Italian physician Giovanni Maria Lancisi made some astounding observations on malaria.

Lancici

Lancici

Lancisi was born in Rome in 1654 and studied theology before turning to natural science. After mastering anatomy, chemistry, and botany at the Collegio de Sapienza, he was awarded his doctorate at age eighteen. By age thirty he had been appointed professor of anatomy at his alma mater, and at age forty-three he was named professor of the theory and practice of medicine, a position he held until his death in 1720.

Lancisi’s extraordinary powers of observation  soon attracted the attention of Pope Innocent XI, who appointed him a papal physician in 1688. Innocent XII and his successor, Clement XI, renewed the appointment. When Clement commissioned Lancisi to investigate the cause of sudden death in Rome, the resulting study became a classic in the history of cardiology. A voluminous writer, Lancisi composed three other major treatises, including the importantAneurysms of the Heart and Blood Vessels, a work that lucidly describes the vascular changes in syphilis. But today he is best known for his two-volume monograph Noxious Emanations of Swamps and Their Cure.

In 1716, Lancisi first described a characteristic black pigmentation of the brain and spleen in the victims of malaria. Lancisi linked malaria with poisonous vapours of swamps or stagnant water on the ground. In 1717, in his monograph titled Noxious Emanations of Swamps and Their Cure, he echoed the old theories of Varro and Celsus by speculating that malaria was due to minute “bugs” or “worms” which entered the blood and revived the old idea that mosquitoes might play a role.

Lancisi postulated two ways in which malaria might be spread by mosquitoes. In one, the insects deposit microscopic organisms in uncovered food and drink, and the human consumption of this contaminated material produces the disease. Lancisi’s second postulated mechanism was the correct one for malaria. Mosquitoes, he writes, “always inject their salivary juices into the small wounds which are opened by the insects on the surface of the body.” Because “all their viscera are filled with deleterious liquids…no controversy can arise among professional men concerning the harmful effect which the insects of the swamps, by mixing their injurious juices with the saliva…inflict upon us.”  But, lacking proof, Lancisi conceded that there might still be some validity in the old bad-air theory. Lancisi also proposed the draining of marshes to eradicate malaria.

For considerable time it was believed that the vapours were given off by marsh vegetation and some held that microscopic animals elaborated them. One American physician, James K. Mitchell, wrote that malaria was due to certain spores present in marshy regions. In 1796, John Crawford, physician living in America, wrote a series of essays contradicting the bad-air theory. He asserted that malaria was “occasioned by eggs insinuated, without our knowledge, into our bodies.” These eggs, laid during a mosquito bite, hatched in the wound and migrated through the host’s body, producing the manifestations of malaria. But these notions were considered  as absurd by contemporaries and the local medical journals summarily rejected all of Crawford’s articles. Soon he was being disparaged so loudly that his medical practice began to suffer. Fearing ruin, he carried his ideas no further.

Rasori

Rasori

But the swamp theory finally started to crumble. In 1816, Giovanni Rasori (1766-1837) of Parma, while suffering from malarial fever in prison, doubted the “bad air” theory and  suggested that a microorganism is responsible for the disease. “For many years,” he wrote, “I have held the opinion that the intermittent fevers are produced by parasites which renew the paroxysm by the act of their reproduction which recurs more or less rapidly according to the nature of the species.”

Nott

Nott

Two other Americans, Josiah Clark Nott and Lewis Daniel Beauperthy, echoed Crawford’s ideas. Nott in his essay “Yellow Fever Contrasted with Bilious Fever,” published in 1850, dismissed the miasma theory as worthless, arguing that microscopic “insects” somehow transmitted by mosquitoes caused both malaria and yellow fever. In 1854, Beauperthy, a “traveling naturalist”, wrote that malaria and yellow fever “are produced by venomous fluid injected under the skin by mosquitoes like poison injected by snakes.” Marshes and swamps, he added, were not made treacherous by their miasmic vapors but by the mosquitoes that proliferated within them.

The black pigment, first noted by Lancisi 1716, was again identified by many workers in mid nineteenth century. In 1847, a German physician, Heinrich Meckel, identified round, ovoid, or spindle-shaped structures containing black pigment granules in protoplasmic masses in the blood of a patient with fever and in the spleen during an autopsy of an insane person. Thus Meckel probably saw the malaria parasites for the first time, but could not recognize the true importance of his finding. In 1848 Schutz specifically associated these pigments with malaria when he observed it in the internal organs of patients who had died of malaria. In 1849, Virchow demonstrated pigmented bodies in the blood of a patient who had died from chronic malaria. In 1850, Hischl confirmed the presence of pigment with intermittent fevers. In 1878, a Mississippi jury convicted a person for murder on the basis of finding malaria pigment in the blood stains. But even with all this, the black granular bodies were somehow never suspected to be the cause of malaria until 1879, when Afanasiev proposed that these bodies might be the agents of the disease.

Klebs

Klebs

By 1878-79, malaria research took a wrong turn. It was announced that a a malaria bacillus had been found. Under the spell of the germ theory of disease when all epidemic diseases were sought to be blamed on bacteria, this announcement was greeted with much excitement and very little skepticism. Edwin Klebs, the German pathologist who had isolated the diphtheria bacillus, and Corrado Tommasi-Crudeli, an Italian bacteriologist, isolated a microbe from the soil, a short rod that they named Bacillus malariae, in Roman Campagna. This organism, they wrote, could be found in damp soil and low-lying air in malarious regions, and would grow on fish gelatin. Soil infested with the bacteria, when injected into rabbits, was said to produce a malarial fever and enlargement of the spleen; soil from malaria-free regions caused a different sort of fever and splenic change. The two authors even asserted that humans receiving an injection of pure Bacillus malariae cultures would develop the symptoms of malaria. Probably no scientific article ever written has contained more wishful thinking than this one. In an 1879 editorial, one prestigious British medical journal even declared that the malaria problem had been solved.

Laveran

Laveran

Finally, it was Charles Louis Alphonse Laveran, a French physician working in Algeria and a student of Pasteur, who identified the malaria parasite in 1888. After his medical school and war time duties, Laveran was transferred to the military hospital at Constantine, Algeria in 1878. In Constantine, Laveran was confronted with hospitals full of malaria. The calm, reserved, unemotional but exceptionally astute Laveran sweated under the burning Algerian sun for two years as he pored over tissue specimens from malaria victims. The autopsies of victims showed the graphite pigmentation of the brain and spleen and black granular microscopic bodies in the blood that were long ago described by others. When all his efforts revealed nothing more he decided to confine his search to the fresh blood of malaria patients and began taking blood specimens from pinpricks in the fingers of sick soldiers. After spreading a droplet into a thin film on a glass slide, he would peer at it for hours through a small, crude microscope. On November 6, 1880, while examining a fresh blood specimen taken from a new hospital arrival, a moving object on the slide caught Laveran’s eye. Under high power, this proved to be a tiny malarial body wriggling vigorously. Laveran watched amazed as the little crescent-shaped object lashed about so energetically that an entire red blood cell jiggled. Even the pigment granules appeared to be in frenzied motion. This important observation could never be made before, probably because no previous investigator had used wet blood films. Laveran immediately knew that he had found a living organism that caused malaria and named the parasite Oscillaria malariae. He identified it within the blood of 148 other patients out of a total of 192 examined. Laveran believed that the tertian, quartan, and quotidian malaria occurred during different stages in the parasite’s development.  On December 24, 1880 in Italy, Laveran communicated the identification of pigmented erythrocytic cells in 26 malaria patients. His descriptions included crescents (gametocytes), pigmented trophozoites, and the process of exflagellation.

Laveran wrote a letter to the Academy of Medicine in Paris, communicating his discovery. The observations were quickly confirmed. Laveran reported them to a friend, Dr. E. Richard, stationed at Philippeville, a French Mediterranean military base fifty miles from Constantine. After finding the fully developed, wriggling parasite, Richard identified an even younger form than Laveran had seen, merely a tiny, colorless spot in the red cell. Laveran believed that the organism lived on the surface of the cell, but Richard correctly observed that it developed within the cell, growing larger and larger until it finally burst out.

But under the sway of bacteriology, the scientific community remained unconvinced about Laveran’s discovery. The arguments presented by Klebs and Tommasi-Crudeli for their Bacillus malariae had been accepted almost without question, and an Italian pathologist, Ettore Marchiafava, even claimed to have found the bacillus in several dead malaria patients. Laveran traveled to Rome in 1882 to demonstrate the parasites to Marchiafava and Agnello Celli, but these two could not be convinced.

sternberg

Sternberg

The US Army sent Major George Sternberg, a bacteriologist of considerable standing, to study malaria in New Orleans, where the incidence was particularly high. He made bacterial cultures from the air, from mud, and from nearby marshes and no organism he found was capable of producing malaria in an animal. By 1881 he had shown positively that the Bacillus malariae of Klebs and Tommasi-Crudeli was not responsible for malaria.

Meanwhile, in 1884, Russian physiologist, Basil Danielewsky was able to observe parasites of malaria in the blood of wild birds. The same year, Louis Pasteur became convinced of the soundness of Laveran’s observations.

In 1884, Marchiafava and Celli, while studying wet blood smears from malarious patients with the new oil-immersion lens, looked at unstained blood and saw a active amoeboid ring (trophozoite) in the red blood cells. They published this finding and named it Plasmodium, but did not refer to Laveran since they thought it was something different from what he showed them. The name chosen for the parasite by them turned out to be an incorrect one, since the organism is not actually a plasmodium. But the name stuck despite years of haggling.

Councilman

Councilman

In 1884, at the Bayview hospital in Baltimore, Maryland, Dr. William T. Councilman performed autopsies on two fatal cases of malaria. He described the brain as a dull chocolate color, lungs inflated and contained much pigment, the liver large, soft and of a dark slatey color. Pigment was the consistent pathologic link of severe fatal disease to malaria.

Osler

Osler

Dr. William Osler, an authority on blood microscopy, was also skeptical of Laveran’s theory. In 1886 he stated that the malarial bodies were nothing more than incidental findings. When his colleague, Dr. William T. Councilman, persuaded him to reconsider, Osler spent many hours looking at wet-blood films and confirmed Laveran’s findings with his own description of blood film examinations from 70 patients. He also detailed excellent drawings of the parasites and related forms seen with different types of malaria fever. Osler also instituted routine blood smear analyses to diagnose malaria in the work-up of febrile patients at Johns Hopkins Hospital. Yet in the first edition of his textbook, The Principles and Practice of Medicine, in 1892, Osler continued to maintain a peculiar ambivalence toward the cause of malaria.

In 1885 Camillo Golgi, an Italian neurophysiologist, established that there were at least two forms of the disease, one with tertian periodicity (fever every other day) and one with quartan periodicity (fever every third day).

Golgi

Golgi

Camillo Golgi was a rare scientist to develop both a new instrument and new ideas. He was the inventor of a revolutionary staining technique for nerve tissue. The “reazione nera,” or black reaction, which he discovered in 1873 after systematic experiments, consisted of immersing specimens in silver nitrate after fixation with potassium dichromate. He also formulated a theory that nerve-cell processes formed a giant anastomotic network. His name is also linked with the discovery of several microscopic cellular structures (tendon organ, muscle spindle) and subcellular structures (the Golgi apparatus). He is also known for his contributions to general medicine with regard to intestinal-worm infections, Bright’s disease of the kidney, and especially malaria.

In 1886 he was the first to observe that the tertian and quartan forms produced differing numbers of segmentations on maturity, implying that the two diseases were caused by two distinct parasites. He also demonstrated that the fever coincided with the rupture and release of merozoites into the blood stream and that the severity of symptoms correlated with the number of parasites in the blood. (He was awarded a Nobel Prize in Medicine for his discoveries in neurophysiology in 1906). Camillo Golgi was also the first to photograph the pigmented quartan malaria parasite in 1890. Many scientists accepted Golgi’s findings, but others, including Laveran, did not. The dissenters were apparently not ready to accept the fact that there existed many varieties of malaria parasite that caused the same disease in birds, monkeys and man (as was known by then from studies of Danielewsky and others). In 1891, Romanowsky described staining methods for identifying malarial parasites and with the better blood-staining methods available, Golgi was shown to be correct. It became clear that many parasite varieties did indeed exist, developing in the blood at different rates and that in each species there was a segmented form that reproduced by division and an ovoid form that never segmented. In 1893, presaging discovery of tissue stages of human malarial parasites by over 50 years, Golgi suggested that parasites of human malaria may have an undiscovered tissue phase in endothelial cells not affected by antimalarial drugs and that the protected parasites could be the source of relapses.

However, the first to publish a theory regarding the existence of a tissue stage of the parasite was Pel in 1886. Pel’s explanation of long-term malarial latency was as follows. “During the latent period the germ is fixed somewhere or not able to reproduce, until by some cause its conditions for life become more favorable. Then the germs can multiply or shift to another more active stage of development, reach the blood and cause particular disease symptoms.”

Stephens

Stephens

The nomenclature of malaria parasites has been a matter of intense debate and acrimonious confusion. Laveran had seen different forms of the malaria parasite in 1880 and firmly believed that all of the parasites belonged to one species, and he called them Oscillaria malariae. In 1884 Marchiafava and Celli called the same forms as Plasmodium. Sakharov in 1889 and Marchiafava and Celli in 1890 identified the parasites that caused malignant tertian fever separately from the ones causing tertian and quartan fevers. The Italian investigators Giovanni Batista Grassi and Raimondo Filetti first differentiated and introduced the names Haemamoeba vivax and H. malariae for two of the malaria parasites in 1890. In 1892, Grassi and Feletti, as an honor to Laveran, proposed the genus name Laverania which was zoologically correct. In 1897, an American, William H. Welch, proposed the name Haematozoon falciparum for the parasite with the crescent-shaped gametocytes and causes malignant tertian malaria.  A generic name Haemomonas was also proposed. Confusion continued well into the 20th century over whether all of the parasites belonged to one species or to several. The genus name Plasmodium of Marchiafava and Celli was maintained for all species. The species name of the parasite suggested by Laveran as malariae, by Grassi and Feletti as vivax and by Welch as falciparum continued. What parasites Laveran saw and described thus came to be known later as P. malariae and gametocytes of P. falciparum. A change back to the name given by Laveran was not possible as the use of these terms had already become extensive in the literature. The fourth human parasite, P. ovale was identified by John William Watson Stephens in 1922.

Thayer

Thayer

Meanwhile in 1895, Thayer and Barker  compiled 616 well documented malaria cases complete with fever curves and species-specific blood film microscopy, plus four autopsies of three P. falciparum cases and one P. vivax case. In 1897 Thayer published a series of lectures with several references to relapse in vivax malaria. In his speculations to explain latency, which must obtain preceding a relapse, he postulated that there must be an undiscovered form of the parasite. He wrote “the organism may remain perhaps within the cell body of certain phagocytes for long periods of time, only to be set free again as a result of some insult, the nature of which is not as yet appreciable to us.”

McCallum

McCallum

The true nature of the ovoid forms seen by Laveran and others was unclear. Many scientists, noting that this phenomenon took place only in blood removed from the body, believed with Laveran that they were witnessing nothing more than a “death spasm.” Such a notion fit in with the old Hippocratic idea that malaria might come from ingesting stagnant water, and it also conformed to a newer theory that the organism was transmitted by contaminated water, as was cholera.

In 1897, Dr. William G. McCallum and Opie of the Johns Hopkins Hospital demonstrated the sexual process of the malaria parasite. By using the pigmented Halteridian species, Haemoproteus columbae MacCallum observed under a glass slide the penetration of a vermicule from a male gametocyte into a rounded female gametocyte. Later, they confirmed their findings in the case of P. falciparum. More study suggested that only plasmodia outside the body behaved in this fashion.

King

King

Meanwhile, on February 10, 1882, Albert Freeman Africanus King, a gynecologist at George Washington University and author of an obstetrics textbook, presented his ideas on malaria to the Philosophical Society of Washington, and in September 1883 this lecture was published in Popular Science Monthly.  The characteristics of malaria, King said, “may be explicable by the supposition that the mosquito is the real source of the disease rather than the inhalation or cutaneous absorption of a marsh vapor.” After listing nineteen sound reasons for implicating the mosquito as the vector, he added, “While the data to be presented cannot be held to prove the theory, they may go so far as to initiate and encourage experiment and observation by which the truth or fallacy of the views held may be demonstrated.. which either way, will be a step in the line of progress….” He went on to suggest a grandiose and impractical plan for malaria control in Washington DC. He claimed that Washington could be ridded of malaria by surrounding the entire city with an enormous screen of fine mosquito netting as high as the Washington Monument. This was greeted with an enormous guffaw and even today no one is certain whether King was serious or attempting a joke. But this certainly discouraged anyone reading his paper from testing the highly sensible mosquito hypothesis.

Many others thought of mosquitoes as a possible cause for transmission of malaria. Laveran expressed such an idea briefly in 1884, evidently independently of King. Seven years later he mooted the same idea again very briefly and without giving many reasons. Robert Koch during his first visit to India in the winter of 1883-1884 for research on cholera came in contact with malaria and thought of a possibility of mosquitoes spreading the disease. R. Pfeiffer talked about the same idea in 1892.

Manson

Manson

Patrick Manson then working in China was also speculating about the nature of malaria. He sought to draw a comparison between malaria and filariasis, for which the mode of transmission by mosquitoes was discovered by him. In 1878 Manson had begun to study the blood of malaria patients looking for a blood borne agent as its cause, but abandoned the effort when he could not find any. In 1881, when he learned of the supposed discovery of the “Bacillus malariae” by Klebs and Tommasi-Crudeli he tried again but was never able to isolate the bacillus from the blood of a malaria victim. Having moved rom Amoy to Hong Kong in December 1883, he learned of Laveran’s discovery in 1884 and immediately set out to identify the parasite for himself, but failed yet again. After returning to Scot land in 1889, he joined the Seamen’s Hospital Society in London in 1890 where he could get the the blood specimens of sailors from all parts of the world. He could finally see Laveran’s malarial parasite and he studied the observations of Golgi, Laveran, and others. He then confirmed to his own satisfaction that there were indeed several species of parasite that could infect a human being, each having its own appearance and producing its own symptoms and signs.

Especially intriguing to Manson was “exflagellation,” the formation by the ovoid form of the tiny, whip-like appendages first reported by Laveran. Manson did not agree with the death spasm theory. To him, the exflagellation represented another phase in the parasite’s development. “Since the flagella appear only when malarial blood gets outside the body,” he reasoned, “their purpose must be to continue the life of the parasite in the outer world.” This logic had stimulated him to seek an extracorporeal form of the filaria of elephantiasis and had led directly to his discovery of the mosquito as the vector. In addition, an American doctor, Theobald Smith, and an epidemiologist, F. L. Kilborne had proved in 1893 that Texas cattle fever was produced by a parasite that went through a developmental phase within cattle ticks that transmitted the disease and in 1894, David Bruce, a British medical officer, identified the trypanosome as the causative organism and tsetse fly as the vector of an African animal infection, called nagana.

Reasoning by analogy with the findings of Smith, Kilborne, and Bruce, Manson postulated a mechanism for the transmission of malaria. According to his schema, when a mosquito fed on the blood of a human with malaria, the flagellated form of the plasmodium ended up in the insect’s stomach. From there it migrated into the tissues, where it grew into a form capable of infecting another human. But Manson tripped up when postulating how the parasite passed from the mosquito back to man because entomologists at the time believed that the insect died after depositing its eggs in water. The parasites, Manson theorized, escaped from the dead mosquito’s body and were carried to the next victim by contaminated water. Thus he had neatly fitted in another piece of the puzzle, yet was still forced to fall back on the old Hippocratic notion that attributed malaria to the ingestion of stagnant water. This new theory of malarial transmission was quickly published. To allow it to gain acceptance, Manson eagerly accepted invitations to lecture on it and discuss it. The scientific establishment considered the theory wildly speculative, and Manson was not able to get hold of the malaria-carrying mosquitoes that would enable him to clinch his argument. He applied for a scientific grant so that he might travel to a malarious area abroad and collect the evidence he needed, but no money was forthcoming. Manson, however, was an indefatigable teacher and demonstrator, whose reputation as a tropical medicine expert continued to grow. Invariably younger men returning from the far comers of the Empire solicited his medical advice. And one of these men was Surgeon Major Ronald Ross of the Indian Medical Service.

ross

Ronald Ross

Ronald Ross was a reluctant physician who had hoped to revolutionize mathematics and write poetry, music, plays, and novels that he did not mind publishing at his own expense, but was stimulated into research by Manson that finally brought him the Nobel prize! Ross apparently set out on his scientific experiments without much expert reading on the literature that existed at the time, he came to know most of the things on his own! The mosquitoes that he encountered soon after landing in India were to occupy him for the rest of his life. During his work in many hospitals in India, Ross studied these insects in great detail and noticed many facts about their habits and habitats besides finding in them the vector for malaria. This single minded work paved the way for malaria control efforts later on.

Ross joined the Indian Medical Service in 1881 and during his initial years, was forced to tackle the mosquitoes. Outside his bungalow quarters he saw mosquitoes breeding in a barrel, swarming in to attack him through an open window. Ross solved the problem by simply tipping over the barrel. “When I told the adjutant of this miracle,” Ross wrote, “and pointed out that the mess house could be rid of mosquitoes in the same way (they were breeding in the garden tubs, in the tins under the dining table and even in the flower vases) much to my surprise he was very scornful and refused to allow men to deal with them..” He made such observations at many places and this later helped him to explain that malaria did not emanate from the marshes as was believed, but from pots and tubs thrown everywhere!

In 1892 Ross learned of Laveran’s discovery but was unable to see the parasites even after spending hours peering through his microscope at blood smears. Thoroughly exasperated, he strongly questioned the soundness of Laveran’s observations and even wondered if the Frenchman might have falsified his data. When he took his second furlough to England in 1894, he told his colleagues about his failure to see what Laveran had described. They sent him to Dr. Patrick Manson. Ross spent many hours following Manson on ward rounds at the Seamen’s Hospital and in Manson’s private laboratory. There, for the first time, Ross was able to locate the tiny malarial parasites under the microscope. Manson, impressed with this eager, capable student, expounded upon his ideas to Ross one November afternoon in 1894:  “Do you know,” he remarked to Ross while the two were on the way to the hospital, “I have formed a theory that mosquitoes carry malaria just as they carry filaria.” This meeting with Manson was to change his life forever. Manson guided Ross throughout his research, suggested new approaches, encouraged Ross when he became depressed and came to his aid whenever superiors thwarted him. There was a continuous exchange of ideas between the two men, first directly and then by letter.

Manson suggested that the filaments in the crescents were actually living bodies and the mosquito sucked the filamented crescents into its stomach while feeding on the blood of a malaria patient. The filaments proceeded to travel through the stomach into the insect’s tissues. After the mosquito died laying its eggs, the “flagellated spores” emerged into the water, ready to infect anyone who came to drink.

These theories, which had earned for Manson the titles “pathological Jules Verne” and “Mosquito Manson,” sent the young Ross into raptures of ecstasy. Suddenly the fame that had eluded him despite years writing poems, music, plays, novels, and equations seemed within his grasp. He had but to prove what Manson had presented to sound like gospel truth. He went about it with an almost manic enthusiasm.

Following Manson’s instructions, Ross captured the ubiquitous mosquitoes and tried to induce them to bite malaria patients. But they obdurately refused to bite any one, even Ross. The mosquitoes caught were probably too frightened to bite, Ross reasoned. So he raised new mosquitoes from grubs. Still no luck. He baked the patients in the hot sun “to bring their flavor out.” Nothing happened. On May 13, 1895, Ross’ birthday, a heavy rain soaked the bed and netting of a malaria patient. Made ravenous by the moisture, the mosquitoes attacked the patient with alacrity. Ross grabbed four of them, expressed their ingested blood on a glass slide, and peered at it with his microscope. Just as Manson had prophesied, there were the parasites. To be certain of the results, Ross tried the same experiment with six more mosquitoes the next day. “Every point that you predicted seems to come true,” he wrote to Manson. “Certainly there is nothing contrary to the theory. The parasites are present in the blood of the mosquito, and what is even more, they appear to be there in greater numbers than in blood from the finger. Also, the development of the crescents, and the formation of the flagella, seem to be favored by conditions in the mosquito’s stomach. Yes, the crescent-sphere-flagella metamorphosis does go on inside the mosquito to a much greater degree than in control specimens of finger blood.”

Manson immediately wrote back with more instructions. “Let mosquitoes bite people sick with malaria,” he advised, “then put those mosquitoes in a bottle of water and let them lay eggs and hatch out grubs. Then give that mosquito-water to people to drink.”

So Ross allowed four mosquitoes to feed on a patient named Abdul Kadir. These insects were then kept in a bottle full of water until they died. After the promise of a suitable emolument, Lutchman, Ross’s native servant, was persuaded to swallow the liquid in the bottle. Ross waited anxiously for ten days for Lutchman to develop fever. On day eleven, Lutchman complained of a headache and was found to have a slight temperature elevation. Now thoroughly excited, Ross admitted his experimental subject to the hospital and impatiently sat by him, measuring his temperature every thirty minutes. Not a parasite was to be seen in his blood. Lutchman probably only had the flu and recovered completely a few days later. Ross repeated the experiment with other volunteers, and these men were totally unaffected by the mosquito water.

Meanwhile in 1896, Amico Bignami, an Italian scientist, attempted to prove Manson’s mosquito theory in man. Bignami captured mosquitoes from regions with a high incidence of malaria and allowed them to bite healthy human beings. But he failed and this threw the mosquito theory into some disrepute.

The repeated failures to introduce malaria by ‘mosquito water’ had prompted Ross to question Manson’s theory. So he began to formulate his own theories. “She always injects a small quantity of fluid with her bite,” Ross noticed. “What if the parasites get into the system in this manner?” To test this, Ross allowed mosquitoes that had fed on a malaria patient to bite a healthy man. Nothing happened. The experiment was repeated again and again. No fever developed. Still enthusiastic, he communicated his new notion to Manson.

Manson, however, had quite an imperfect understanding of mosquito behavior. Believing that the insect bit only once during its life, he was convinced that Ross could not be correct. “Follow the flagella,” he wrote back, and forget this crazy idea.

In February 1897 Ross was able to observe the true fate of the flagella. Within a blood smear he saw two parasites near each other. The first was giving off flagella, while the second, which was spherical and unsegmented, had a single flagellum wiggling slowly inside. Had Ross begun a moment earlier, he might have watched the flagellum emitted by the first parasite penetrate the second and so perceive the true nature of the process. But from his vantage point, he surmised that the single wiggling flagellum was trying to escape the sphere rather than fertilize it. When McCallum in Baltimore correctly interpreted the process a few weeks later, Ross was deeply humiliated, and “always felt disgraced as a man of science” for incorrectly interpreting his own observation.

When his experiments did not yield the desired results, Ross found inspiration while re-reading Manson’s original article on filariasis, being reminded of the fact that only one species of mosquito was capable of carrying filariasis. Manson had also suggested that each form of the malarial plasmodia might require a particular mosquito species. Ross suddenly realized he had used the wrong species of mosquito. Most of his cases had been falciparum malaria, and he had consistently employed the common house mosquito. After a little searching, Ross was able to come up with another species of mosquito. This “dappled winged mosquito,” as he called it, had no breathing tube and floated parallel to the water surface in its larval form. The adult sat with its tail pointed upward.

A malaria patient named Hussein Khan was the first experimental subject. Ross let loose a dozen of these mosquitoes under the mosquito netting of Hussein Khan’s bed, and trapped each one, after it had fed, in a separate bottle. Two mosquitoes were then examined immediately. Two days later others were dissected. More of the insects died during the night and quickly decomposed. In all of them Ross found nothing. On August 20, 1897, a tired, discouraged Ronald Ross dissected one of the two remaining mosquitoes. Just as he was about to give up, he noted a queer structure within the cells lining the insect’s stomach: an almost perfectly circular cell containing a group of black pigment granules very similar to those seen in the malarial parasites found in blood smears. Nearby were identical circular cells. Ecstatic with joy, Ross wrote, “Those circles in the wall of the stomach of the mosquito–those circles with their dots of black pigment, they can’t be anything else than the malarial parasite, growing there….” On August 21 he dissected and examined the last mosquito, and again saw the pigment-filled circles. With this he had proved that the malaria parasite developed in the mosquito’s gut. His report, “On Some Peculiar Pigmented Cells Found in Two Mosquitoes Fed on Malarial Blood,” was published in the December 18, 1897 issue of the British Medical Journal.

Soon after, he was transferred Kherwara in the deserts of Rajasthan, a place that had hardly any cases of malaria. Yet the resourceful Ross did not quite languish. He knew of Danielewsky’s studies of bird malaria, and verified for himself that some types of pigeons carried the disease. At the time, many biologists believed that mosquitoes did not attack birds. After studies of pigeons, sparrows, and crows, Ross verified that birds were indeed bitten by mosquitoes, as well as by other insects.

He was transferred again to Calcutta in February 1898, but he could not get human volunteers to continue his work. So Ross turned to the study of bird malaria again. He got an able assistant called Mohammed Bux who brought in many live sparrows, larks, and crows. Into the cages covered with mosquito netting went the mosquitoes. In almost no time Ross could demonstrate that the plasmodium passed from bird to mosquito, just as it did in humans. Moreover, the same pigmented, circular cells would form in the wall of the insect’s stomach. Only one difference was noted. The common gray mosquito was the carrier of bird malaria. The brown, dapple-winged vector of human malaria could not be infected by the bird parasite.

But how did the parasite pass from the mosquitoes to the birds? According to Manson’s theory, the parasites were ingested with water in which the mosquitoes had died while laying eggs. Ross easily tested this theory by feeding infected mosquitoes to healthy sparrows. The result: The birds remained free of malaria.

The true answer finally emerged as Ross continued to study infected mosquitoes. As the circular cells within the mosquito’s stomach enlarged, the pigmented granules grew into little rod-shaped bodies. Soon, Ross discovered that the circular cells in the stomachs of the mosquitoes ruptured and the rods migrated to the insect’s thorax. On July 4, 1898, Ross discovered their final destination. Examining the insect’s head, he noted the salivary gland to be so loaded with rods that it quivered. Here then was the answer. Malaria was passed back to the birds in the mosquito’s saliva during the act of biting. This remarkable finding, Ross later wrote, “brought him up standing.” As a final verification, he sent Mohammed Bux to capture a group of healthy sparrows. Mosquitoes that had fed on infected birds were allowed to bite these healthy ones. Within a few days the blood of the new birds was loaded with malarial parasites.

Manson received the news at a meeting of the new Tropical Diseases Section of the British Medical Association. When he read Ross’s report to the assembled delegates, it generated intense excitement. “I am sure you will agree with me,” Manson said, “that the medical world, I might even say humanity, is extremely indebted to Surgeon Major Ross for what he has already done, and I am sure you will agree with me that every encouragement and assistance should be given to so hard-working, so intelligent, and so successful an investigator to continue his work.”

But that was not to be. Ross did not receive any such support and disgusted, he decided to abandon any further work on his malaria research and returned to England.

But things were different in Italy, where malaria was rampant in the Roman Campagna. By the mid-nineteenth century, any scientist wishing to study the disease could be assured of financial support from Italian industrialists and agriculturists.

Koch

Koch

Robert Koch, who had developed interest in malaria and the role of the mosquito during his visit to India in 1883, rekindled his interest in the topic and in 1898 went to Italy to try and demonstrate that human malaria was caused by a mosquito bite. But he too did not succeed in his efforts, like Bignami, as he did not believe that a particular species of mosquito was necessary to transmit human malaria. Koch also thought that the infant mosquito inherited the parasite from its mother, probably based on the observations of Theobald Smith with regard to the transmission in the ticks of Texas cattle fever.

grassi

Grassi

In September 1898, Italian physician Giovanni Battista Grassi was able to report that this insect, Anopheles claviger, was the carrier of human malaria. The proof was obtained by means of a human experiment. The subject, a Mr. Abele Sola, had been for six years a patient in the Hospital of the Holy Spirit, atop one of the hills of Rome. Malaria had never been seen in this vicinity and neither had the anopheles mosquito. With Mr. Sola’s permission, Grassi, Amico Bignami and Dr. Giuseppe Bastianelli, a hospital physician, shut Mr. Sola in a room with anopheles mosquitoes every night for ten nights. On the eleventh day, the patient developed a malarial chill. Examination of his blood revealed large numbers of plasmodia: “The rest of the history of Sola’s case has no interest for us,” Grassi wrote, “but it is now certain that mosquitoes can carry malaria, to a place where there are no mosquitoes in nature, to a place where no case of malaria has ever occurred, to a man who has never had malaria–Mr. Sola!”.

Grassi’s successful repetition of the experiment on other patients somehow leaked out. The newspapers were incensed and implied that Grassi was ruthlessly endangering the lives of his human guinea pigs. He ignored them and continued with his work.

To refute Robert Koch’s assertion that the infant anopheles inherited the malarial infection from its mother, Grassi raised anopheles mosquitoes from eggs, as was done by Ross in all his experiments earlier. Then he allowed the mosquitoes to bite him and six other volunteers. All remained free of malaria.

The complete cycle of P. falciparum was observed by Grassi, Bignami, and Bastianelli in 1899 and in the same year, Bastianelli and Bignami accomplished the same feat with P. vivax. The Italian studies on the sporogonic cycle of malaria were summarized in what was to become a classical monograph by Grassi in 1900.

In the course of his experiments, Grassi came to read Ronald Ross’s articles on bird malaria. But when he published, he failed to give Ross credit. Ross was furious. Thoroughly convinced that Grassi was trying to steal his discovery from him, Ross sent angry letters to the journals that had published Grassi’s papers, asserting that Grassi was a mountebank, a cheap crook, a parasite who survived on the ideas of others. Grassi replied in equally acrimonious terms. So vicious did the correspondence become that journal editors, fearful of libel, hesitated to publish the letters.

But Ross and Grassi did not stop feuding. Both enlisted the aid of the authorities on tropical medicine. Ross was able to obtain letters from Dr. T. Edmundston Charles, an English observer of the Italian work in Rome. Using this evidence, Ross asserted that Grassi had been aware of the studies on bird malaria, though Grassi later denied such awareness. When Ross could not find a publisher for a book containing his case against his Italian adversary, he paid for the printing himself, carrying the work through two editions. This bitter conflict lasted for more than two decades. But the Nobel Prize Committee had no trouble deciding who deserved the recognition and Grassi was ignored or dismissed as the author of an important footnote to Ross’s discovery.

Meanwhile, Patrick Manson repeated Grassi’s experiment on select human volunteers. In 1900, Manson arranged for three people from the London School of Tropical Medicine to spend the summer near Ostia in the Roman Campagna. Their days were spent in various excursions in the vicinity, but each night was passed in special mosquito-proof tents where they stayed until an hour after sunrise. The three did not come down with the disease, although transmission of malaria continued at its usual high rate in the vicinity and many around them contracted malaria. This outcome was dramatized by the fate of a police detachment sent from Rome to capture a criminal in the Campagna while the Englishmen were there. Though they remained in the Campagna for only a day, all the policemen developed malaria shortly after returning to Rome. The second part of Manson’s experiment was most chilling, though it ended happily. Manson managed to obtain live, malarious Italian mosquitoes, which he made to bite his own healthy son, P. Thurburn Manson. In fourteen days, the young medical student was ill with typical vivax malaria. Manson’s laboratory assistant, George Warren, then allowed a few more of the infected mosquitoes to bite him, remarking that it would have been “a great pity to waste them.” He too quickly contracted malaria. Both young men survived after treatment with quinine. After these results had been reported in newspapers and magazines throughout the world, the last resistance to the mosquito theory finally crumbled. This experiment also proved to be the first experimental evidence of relapse in P. vivax malaria. Following treatment, young Manson continued in good health until 9 months later when he had a typical relapse which he himself reported in detail in 1901. Another volunteer in the same time period, Major C. F. Fearnside who had a similar experience of relapse which he reported in 1903.

In 1900 Battista Grassi, having observed morphological differences between the nuclei of the sporozoite and of the youngest red cell trophozoite, hypothesized that an intermediate stage would occur between the two forms and that the sporozoite did not develop directly into blood parasites. In 1900, Bignami and Bastianelli found that they could not infect an individual with blood containing only gametocytes. Three years later in 1903, in a memorable paper on P. vivax, Fritz Schaudinn described in detail the penetration of the red cell by the sporozoite. In that paper, which for three decades stood as a classic work in malariology, he considered Grassi’s hypothesis to be improbable. Fritz Schaudinn in 1902 claimed that the Plasmodium vivax sporozoite penetrated the erythrocyte. Schaudinn’s accompanying drawings even showed the entry of a malaria sporozoite into a red blood cell. The first doubts of Schaudinn’s theory came from the malariatherapy centres treating patients with neurosyphilis (General Paresis). For such treatment, mostly P. vivax was induced either by direct inoculation of infected blood or by inoculating sporozoites by mosquito bites.

It was demonstrated by Yorke and Macfie in 1924 and Yorke in 1925 that there was a difference in the response to therapy in blood-induced and sporozoite induced infections. The blood-inoculated patients were radically cured with quinine but the sporozoite-induced infections relapsed after the same therapy. In 1931, James suggested that sporozoites, after being injected by the mosquito, are carried to the internal organs where they enter reticulo-endothelial cells and go through a cycle of development with the eventual production of merozoites which parasitize red blood cells. This proposal was based primarily on the fact that therapeutic regimens known to be effective against malaria could not cure an infection when administered during the incubation period. It was reasoned, that if sporozoites entered directly into the red blood cells and became trophozoites and schizonts, they would have been destroyed by the drugs and no active infection could have resulted. In 1935, Huff and Bloom clearly demonstrated exoerythrocytic stages to be a fundamental part of the life cycle of bird malaria parasite, P. elongatum. As data about fixed tissue parasites from birds accumulated, mainly the work of James and Tate (1937) and the brilliantly executed studies of Huff and his co-workers (1943 to 1948), it became abundantly clear that such a cycle must also occur in primate malarias. In 1946, Sapero presented presumptive evidence for the link between fixed tissue stages and relapse. Sir Neil Hamilton Fairley in Australia in 1947 showed that the blood of volunteers injected with large numbers of P. vivax sporozoites was infectious to other volunteers for only 30 minutes. The blood then became “sterile” until 7 days later when it once again became infectious to volunteers. In 1948,Coatney and Cooper reported that 8-aminoquinolines and certain biguanides were active against the presumed exoerythrocytic forms of human and simian malarias. In 1947 Garnham discovered the exoerythrocytic schizogony of the related parasite Hepatocystis kochi.

Soon thereafter in 1948, Shortt & Garnham (at the Ross Institute of the London School of Hygiene and Tropical Medicine, England) and Malamos published their milestone finding of the cyst-like body, filled with thousands of merozoites, in the liver of a rhesus monkey that had been inoculated 102 days before with  from 500 mosquitoes.

Both Shortt and Garnham were physician-naturalists and devoted protozoologists known for many seminal contributions to medical protozoology. Henry Edward Shortt (CIE,FRS,MD, DTM&H; 15 Apr. 1887-9 Nov. 1987) worked for the Indian Medical Service in his initial years. He had varied interests – from single-celled parasites, tigers, trout to houseflies. —was a retiring man and yet generous and caring to his associates and students. SR Christophers and Shortt carried out the first scientific malaria survey of war during 1914-1918, modelled on Christophers’ earlier malaria surveys in India. Shortt later worked with Indian Medical Service as Director, King Institute of Preventive Medicine, Madras from 1935-1939; Inspector-General of Civil Hospitals and Prisons in Assam during World War II and later as Professor of Parasitology at London School of Hygiene and Tropical Medicine from 1945-1951. Shortt was very generous and caring to his associates and students.At the time of his famous work on malaria, he was nearing retirement.

Garnham

Garnham

Percy Cyril Claude Garnham (CMG, MD, DSc, FRCP, Hon. FRCP(E), FRS; 15 January 1901-25 December 1994) belonged to East African Medical Service. He was an aesthete who skied and played the cello. He was as comfortable in discussing the theatre, opera and literature as he was in eruditely explaining the lives and times of the Haemosporidia. In 1947 he returned to London to the London School of Tropical Medicine and Hygiene where he subsequently became Head of the Department of Parasitology and Professor of Medical Protozoology at the University of London. Shortt and Garnham were awarded the Darling Foundation Prize of WHO in 1951. In 1970, Garnham was honoured with the unusual and highly regarded appointment as a Pontifical Academician, Academy of Science, to the Vatican.

Although relapses were known since antiquity and Pel in 1886 and Golgi in 1893, and Thayer in 1897 (See above) had made some suggestions in this regard, the hiding place of the parasite, during long periods when the patients were clinically and parasitologically negative, had been debated for many years. In 1926, even before the full life cycle of malaria parasites was disclosed, Marchoux outlined three possible mechanisms to account for relapse: (i) parthenogenesis of macrogametocytes; (ii) persistence of schizonts in small numbers in the blood where their multiplication is inhibited by immunity and this immunity disappears; and (iii) reactivation of an encysted body in the blood. The theory of parthenogenesis of gametocytes was put to rest with Bignami and Bastianelli in 1900 and again Gainham in 1930 not being able to infect individuals with blood containing only gametocytes. The second theory, a persistent blood stage infection, had been proposed by Ross and Thompson in 1910 and also by Corradetti and held true for P. malariae, which can remain in the blood at undetectable levels for many years.

In 1946, Shute, who was infecting large numbers of mosquitoes with vivax malaria for malariotherapy of neurosyphilis, noticed that, even though heavily infected mosquitoes fed on a patient, an immediate malarial infection did not always result, although symptoms would be exhibited several months later. He speculated that this was due to a “resting parasite.” Sapero proposed in 1947 that perhaps a link existed between a tissue stage not yet discovered in patients with malaria and the phenomenon of relapse.

In their experiment, in a laboratory near St. Albans, Hertfordshire, Shortt and Garnham put a rhesus monkey into a cage with 500 mosquitoes carrying Plasmodium cynomolgi sporozoites (previous experiments had used 20 to 100). A solution of killed the mosquitoes was also injected into the monkey’s muscles and chest. With their bold experiment they solved a centuries-old mystery — the source of malaria’s parasitaemic relapses. P.G. Shute and Sir Gordon Covell, placed the discovery of the exoerythrocytic (EE) hepatic phase of mammalian malaria parasites in the following historical context: “Just as the name of Ross will forever be associated with the discovery that mosquitoes transmit malaria, so too, will the names of Shortt and Garnham be remembered in connection with the primary tissue phase of the parasite.” To test this in humans, a patient with general paresis who was to be treated with inoculation ofP. vivax malaria was used. The patient and his wife agreed that doctors could perform a  liver biopsy, seven days after he had been bitten by infected mosquitoes. At 5 o’clock one morning Dr. Shortt got the sliver of liver, rushed to his laboratory and worked until 11 that night. The tissue stage of P. vivax was thus demonstrated by Shortt, Garnham, Covell and Shute in 1948. Later, similar preerythrocytic forms were demonstrated for P. falciparum (Shortt et al, 1949; Jeffery et al, 1952). Tissue stages of P. ovale (Garnham et al., 1954), and P. malariae (Bray, 1959) were also identified later on.

The demonstration of the exoerythrocytic stages of avian and primate malarias revealed the hiding place of the parasites and opened new proposals to explain the phenomenon of relapse in malaria. With the report of an exoerythrocytic schizont in the liver of a monkey 3½ months after sporozoite inoculation by Shortt and Garnham in 1948, it was thought that a direct relationship existed between these fixed tissue stages and true relapses. Various workers, involved in experimental therapy of malaria, had predicted that an exoerythrocytic stage of the parasite was responsible for long term relapses in Shannon and Earle in 1945 and Fairley in 1947 proposed that a persistent tissue phase was absent in and these workers as well as Huff in 1947 supported the view that persistent tissue phase was the source of the parasites in typical relapses. When the work of Coatney and Cooper in 1948, showing that massive blood transfusions during latency, following treatment of the initial attack, failed to produce infections in recipients, although the donors’ infections relapsed later, was combined with the demonstration of an exoerythrocytic schizont of 3½ months after sporozoite inoculation, most workers considered the relapse story to be complete.

The specific mechanism proposed was that merozoites from mature exoerythrocytic schizonts enter red blood cells, producing the familiar clinical and parasitological features of malaria. It was thought that merozoites erupting from mature schizonts would reinvade hepatic parenchymal cells in a more or less continuous cycle until waning immunity allowed them to invade erythrocytes and initiate another blood cycle. This concept of Shortt and Garnham was widely accepted as the most likely explanation for the production of relapses in certain species of both human and simian malaria but it did not account for several subsequent observations. Lysenko et al. in 1977 suggested a series of postulates to explain the phenomena of long incubation periods and relapses. They theorized that the duration of the preerythrocytic development of is a polymorphic characteristic controlled by several gene loci and that sporozoites are divided into two complex groups of phenotypes, i.e., the slow-developing and fast-developing types advocated by Ungureanu et al in 1976. A latent tissue stage was found by Krotoski and coworkers in the liver of a monkey heavily infected with in 1980. In 1981, Krotoski et al. described the 48-h preerythrocytic form of by using the indirect fluorescent-antibody method (IFA). Routine use of this technique to examine heavily infected monkey liver eventually led to the discovery of a uninucleate stage of the parasite seen initially at 7 days postinfection in animals infected with in 1982. These uninucleate forms, found by immunofluorescence and restained with Giemsa-colophonium stain, were thought to be the long-sought dormant stage of the parasite. Experiments were undertaken to establish the true nature of this form, and it was subsequently found by Bray et al in 1985 to be present from 3 to 229 days after sporozoite inoculation and to remain virtually unchanged during that period. This finding served to underscore the latent nature of this stage, named the hypnozoite (sleeping animalcule) stage by Garnham in 1977.

In 1985 it was demonstrated by Krotoski, Garnham, Bray and others that hypnozoites were in fact present in two strains of , the first such demonstration in a human malaria species. To determine whether hypnozoites were present in a nonrelapsing type of malaria, Krotoski and Collins examined liver biopsy samples from monkeys infected with with IFA and no hypnozoites were seen. Thus, hypnozoites were demonstrated species of Plasmodium causing relapsing malaria and had not been found in a Plasmodium species causing a nonrelapsing malaria. These stages had been shown to be dormant, present in 229 days after sporozoite inoculation and undoubtedly malarial in nature. In keeping with the history of malaria research, however, the theory had its detractors. In 1981, Shortt, one of the original discoverers of malaria tissue stages, took issue with the preliminary report of the discovery of hypnozoites. He questioned their malarial nature, speculating that they might be contaminants from the mosquito (microsporidia etc.) or even merozoites from early schizonts that had reinvaded liver cells.

Trager

Trager

His objections were answered systematically by Garnham in a published reply. In 1985, Bray et al. recorded a hypnozoite of P. cynomolgi having two nuclei at 49 days after sporozoite inoculation suggestive of a dividing form. In 1989, Atkinson et al. published what may be the first electron micrograph of a hypnozoite. (See) The first to observe hypnozoites in culture were Hollingdale et al. in 1985. They observed persistent non-dividing P. vivax parasites in cultured hepatoma cells. In 1975 William Trager cultured P. falciparum inside red blood cells.

In 1911, Brown distinguished melanin from malarial pigment by deducing the hematin origin of the latter and stated that the black malarial pigment could hardly be pure hematin, but should contain impurities. He astutely suggested the action of a proteolytic enzyme on hemoglobin to be the most probable mode of elaboration of the malaria pigment. Controversy on the biochemical composition of hemozoin continued for more than 80 years until the 1990s, when several workers showed hemozoin to be composed solely of heme arranged in a crystal structure. Only then was hemozoin formation proved to be the target of widely used antimalarial drugs such as chloroquine and quinine.

Pattarroyo

Pattarroyo

In 1973 human protection from malaria by vaccination was first reported. However, the vaccination consisted of the bites of about a thousand mosquitoes infected with malaria parasites that had been X irradiated. For about 20 years, progress occurred mainly in experimental models rather than in human vaccine trials. In 1987, Dr. Manuel Elkin Patarroyo, a Colombian biochemist, developed the first synthetic Spf66 vaccine against P. falciparum parasite. But phase III trials showed that  lacked efficacy. During the past 5 years, many candidate vaccine approaches have been tested in clinical trials.

The genome sequences of Anopheles gambiae and Plasmodium falciparum were published in 2002, and those of P. vivax and P. knowlesi in 2008.[21-24]

Newer diagnostic tests have been developed for malaria. Becton and Dickenson developed a fluorescene staining technique using a capillary tube called as Quantitative Buffy Coat test in 1991-92. Many non-microscopic, rapid dip stick test shav ebeen developed based on the detection of various antigens of malaria parasites. P. falciparum Histidine Rich Protein II (Rock et al, 1987), parasite aldolase (Meier et al 1992) and parasite Lactate dehydrogenase (Makler et al 1998) are the target antigens used for such tests.

Nobel Prizes for Malaria Research

There have been 4 Nobel Prizes for malaria related research so far.

Rrosssmonald Ross (1857-1932) in 1902: “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”. Ronald Ross demonstrated the oocyst of malarial parasite in the gut wall of a mosquito on August 20, 1897 in Secunderabad, India. Read More…

Alaveransmlphonse Laveran (1845-1922) in 1907: “In recognition of his work on the role played by protozoa in causing diseases”. Laveran was the first to notice parasites in the blood of a patient suffering from malaria on November 6, 1880 at Constantine, Algeria. Read More…

jaureggJulius Wagner-Jauregg (1857-1949) in 1927: “For his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica”. A professor of psychiatry and neurology in Vienna (Austria), Wagner-Jauregg developed methods for treating general paresis (advanced stage of neurosyphilis) by inducing fever through deliberate infection of patients with malaria parasites. This method was used in the 1920s and 1930s. In the 1940s, the advent of penicillin and more modern methods of treatment made such “malaria therapy” obsolete.

mullersmPaul Hermann Müller, (1899-1965) in 1948: “For his discovery of the high efficiency of DDT as a contact poison against several arthropods”. Read More…

golgismAnd for Camillo Golgi for his work on the nervous system: Camillo Golgi, 1906: Golgi shared the Nobel Prize with Santiago Ramón Cajal for their studies on the structure of the nervous system. Golgi made significant contributions to malaria research as well.

Sources:

  1. http://stevenlehrer.com/explorers/images/explor1.pdf
  2. http://www.wiley-vch.de/books/biopoly/pdf_v09/vol09_13.pdf
  3. http://164.67.39.27/168-2005/intro_files/ppt/intro.ppt
  4. See Marchiafava’s biography
  5. Moody A. Rapid Diagnostic Tests for Malaria Parasites Clin Microbiol Rev. 2002 January; 15(1): 66–78. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=118060
  6. Robert E Sinden. Malaria, mosquitoes and the legacy of Ronald Ross. At http://www.who.int/bulletin/volumes/85/11/04-020735/en/index.html
  7. Moorthy VS, Good MF, Hill AVS. Malaria vaccine developments. Lancet. 2004;363:150–56. Available at http://www.malariavaccineroadmap.net/pdfs/developments.pdf
  8. Desowitz RS. The fate of sporozoites. Bull World Health Organ 2000;78(12) Available at http://www.scielosp.org/scielo.php?pid=S0042-96862000001200011&script=sci_arttext
  9. Capanna E. Grassi versus Ross: who solved the riddle of malaria? Int. Microbiol. 2006;9(1) Available at http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1139-67092006000100010&lng=pt&nrm=
  10. http://biology.bard.edu/ferguson/course/nsci102/Lecture_24.pdf
  11. http://www.wiley-vch.de/books/biopoly/pdf_v09/vol09_13.pdf
  12. http://etd.fcla.edu/CF/CFE0000100/DaSilva_Thiago_G_200407_MS.pdf
  13. http://memorias.ioc.fiocruz.br/994/historicalreview.pdf
  14. http://www.dpd.cdc.gov/dpdx/HTML/PDF_Files/Primate%20Malarias%20Chapters/chap_04.pdf
  15. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=358221
  16. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=96166
  17. Shortt HE, Garnham PCC. Demonstration of a persisting exo-erythrocytic cycle in Plasmodium cynomolgi and its bearing on the production of relapses Available at http://www.scielosp.org/pdf/bwho/v78n12/78n12a12.pdf
  18. The Hidden Structure: A Scientific Biography of Camillo Golgi. NEJM. 344 (14):1102. Available at http://content.nejm.org/cgi/content/full/344/14/1102
  19. http://time-proxy.yaga.com/time/archive/preview/0,10987,798416,00.html
  20. http://www.who.int/docstore/bulletin/pdf/2000/issue12/classics.pdf
  21. Holt RA, Subramanian GM, Halpern A et al. The genome sequence of the malaria mosquito Anopheles gambiae. Science. 4 Oct 2002;298(5591):129-49
  22. The malaria genome — and beyond. Nature. 3 October 2002. Full issue at http://www.nature.com/nature/malaria/
  23. Jane M. Carlton, John H. Adams, Joana C. Silva et al. Comparative genomics of the neglected human malaria parasite Plasmodium vivax. Nature. October 2008;455:757-763. Full text at http://www.nature.com/nature/journal/v455/n7214/pdf/nature07327.pdf
  24. Pain A, Böhme U, Berry AE et al. The genome of the simian and human malaria parasite Plasmodium knowlesi. Nature. October 2008;455:799-803. Full text at http://www.nature.com/nature/journal/v455/n7214/pdf/nature07306.pdf
  25. http://www.cdc.gov/malaria/features/index_20041220.htm
  26. http://nobelprize.org/medicine/educational/malaria/readmore/history.html
  27. Chidanand Rajghatta. India’s Nobel connections. Available At http://timesofindia.indiatimes.com/India/Indias_Nobel_connections/articleshow/2456211.cms

©malariasite.com ©BS Kakkilaya | Last Updated: Apr 28, 2015

Evolution of Malaria Parasites

Man and Malaria seem to have evolved together. It is believed that most, if not all, of today’s populations of human malaria may have had their origin in West Africa (P. falciparum) and West and Central Africa (P. vivax) on the basis of the presence of homozygous alleles for hemoglobin C and RBC Duffy negativity that confer protection against P. falciparum and P. vivax respectively. Recent molecular studies have found evidence that human malaria parasites probably jumped onto humans from the great apes, probably through the bites of vector mosquitoes.

history-parasite250The ancestors of the malaria parasites have probably existed at least half a billion years ago. Molecular genetic evidence strongly suggests that the pre-parasitic ancestor for malaria parasite was a choroplast-containing, free-living protozoan which became adapted to live in the gut of a group of aquatic invertebrates. This single-celled organism probably had obligate sexual reproduction, within the midgut lumen of a host species. At some relatively early stage in their evolution, these “premalaria parasites” acquired an asexual, intracellular form of reproduction called schizogony and with this, the parasites greatly increased their proliferative potential. (This schizogony in the RBCs of humans causes the clinical manifestations of malaria). Among the invertebrates to which the ancestors of the malaria parasites became adapted were probably aquatic insect larvae, including those of early Dipterans, the taxonomic order to which mosquitoes and other blood-sucking flies belong. These insects first appeared around 150 million to 200 million years ago. During or following this period, certain lines of the ancestral malaria parasites achieved two-host life cycles which were adapted to the blood-feeding habits of the insect hosts. In the 150 million years since the appearance of the early Diptera, many different lines of malaria and malaria-like parasites evolved and radiated. The malaria parasites of humans evolved on this line with alternate cycles between human and the blood-feeding female Anopheles mosquito hosts. Fossil mosquitoes have been found in geological strata 30 million years old.[1]

From Great Apes to Man: P. falciparum is found to be very closely related to a malaria parasites of chimpanzees, P. reichenowi and these two are more closely related to the malaria parasites of birds than to those of other mammals. The lineage of these parasites possibly occurred around 130 million years ago, nearly about the same time as the origin of the two-host life cycle involving blood-feeding Dipterans and land vertebrates. The separation of the lines that led to P. falciparum and P. reichenowi probably occurred only 4 million to 10 million years ago, overlapping the period in which the human line diverged from that of the African great apes. Recent phylogenetic analysis indicates that all extant P. falciparum populations originated from P. reichenowi, likely by a single host transfer, occurring as early as 2–3 million years ago, or as recently as 10,000 years ago.[1,2] The modern, lethal strains of P. falciparum probably emerged within the last 5,000– 10,000 years, after agriculture took roots in Africa.[1]

Pg-23-malaria-alamy_458808aP. falciparum probably jumped from Gorillas: Different studies have suggested that P. falciparum malaria probably jumped from great apes to man, probably by a single host transfer by vector mosquitoes. While earlier reports suggested the origin from chimpanzees[2] or bonobos[3], a new study from central Africa points to Gorillas. A single-genome amplification strategy to identify and characterize Plasmodium spp., DNA sequences in nearly 3,000 faecal samples from wild-living apes from field sites throughout central Africa, found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin.[4-8]

P. malariae, P. ovale, and P. vivax diverged over 100 million years ago along the lineage of the mammalian malaria parasites. P. ovale is the the sole known surviving representative of its line and causes infection only in humans. P. malariae was a parasite of the ancestor of both humans and African great apes and had the ability to parasitize and cross-infect both host lineages as they diverged around five million years ago. P. malariae is found as a natural parasite of chimpanzees in West Africa and P. brazilianum that infects New World monkeys in Central and South America is morphologically indistinguishable from P. malariae. P. malariae, like P. ovale, is the only confirmed and extant representative of its line. P. vivax, closely related to P. shwetzi, a parasite of African great apes, belongs to a group of malaria parasites like P. cynomolgi, that infect monkeys. The time of divergence of P. vivax from P. cynomolgi is put at 2-3 million years ago.[1] Several cases of P. knowlesi infection, zoonotic from macaque monkeys, have been recently reported from Southeast Asia, including Malaysia, Thailand, Viet Nam, Myanmar and Phillippines.[9-13]

Mosquitoes adapt: End of the last glacial period and warmer global climate heralded the beginnings of agriculture about 10000 years ago. It is argued that the entry of agricultural practice into Africa was pivotal to the subsequent evolution and history of human malaria. The Neolithic agrarian revolution, which is believed to have begun about 8,000 years ago in the “Fertile Crescent,” southern Turkey and northeastern Iraq, reached the western and Central Africa around 4,000 to 5,000 years ago. This led to the adaptations in the Anopheles vectors of human malaria. The human populations in sub-Saharan Africa changed from a low-density and mobile hunting and gathering life-style to communal living in settlements cleared in the tropical forest. This new, man-made environment led to an increase in the numbers and densities of humans on the one hand and generated numerous small water collections close to the human habitations on the other. This led to an increase in the mosquito population and the mosquitoes in turn had large, stable, and accessible sources of blood in the human population, leading to very high anthropophily and great efficiency of the vectors of African malaria. Even though the practice of agriculture had developed throughout the tropics and subtropics of Asia and the Middle East up to several thousand years before those in Africa, simultaneous animal domestication in Asia probably prevented the mosquitoes from developing exclusive anthropophilic habits. In most parts of the world, the anthropophilic index (the probability of a blood meal being on a human) of the vectors of malaria is much less than 50% and often less than 10 to 20%, but in sub-Saharan Africa, it is 80 to almost 100%. This is probably the most important single factor responsible for the stability and intensity of malaria transmission in tropical Africa today.[1]

history-spread250Spread of Malaria: From its origin in the West and Central Africa, malaria spread all across the globe to become the worst killer disease ever suffered by mankind. The parasites spread to other areas through the journey of man, following the human migrations to the Mediterranean, Mesopotamia, the Indian peninsula and South-East Asia.[1] Although P. vivax and P. malariae had achieved the widest global distribution, today P. malariae has lost its predominance and P. vivax and P. falciparum are the most commonly encountered malaria parasites. Almost 85% of the nearly 500 million annual malaria cases occur in sub-Saharan Africa and about 85% of cases in Africa are caused by P. falciparum, the remaining cases being caused by the other three strains. P. vivax is now the most geographically widespread of the human malarias, estimated to account for 100-300 million clinical cases across much of Asia, Central and South America, the Middle East, where 70–90% of the malaria burden is of this species and the rest due to P. falciparum.[1,14] P. malariae causes sporadic infections in Africa, parts of India, western Pacific and South America, whereas P. ovale is restricted to tropical Africa, New Guinea, and the Philippines.[1]

Malaria seems to have been known in China for almost 5,000 years. (Men from ancient China, who traveled to malarious areas were advised to arrange for their wives to be remarried). Sumerian and Egyptian texts dating from 3,500 to 4,000 years ago mention about fevers and splenomegaly suggestive of malaria. (The enlarged spleens of Egyptian mummies are believed to have been caused by malaria). It appears that P. falciparum had reached India by around 3,000 years ago. It is believed that malaria reached the shores of the Mediterranean Sea between 2,500 and 2,000 years ago and northern Europe probably mainly between 1,000 and 500 years ago. The waves of invasions that swept across the continents helped the cause of malaria parasite as well. By the Middle Ages, Kings and feudal lords had the best wetlands under their control, but in turn had to fear marshes as breeding grounds of plagues and incurable fevers (The term ‘paludismo’ comes from the Latin ‘Palus’ for lagoon). A royal decree was passed in 11th-century Valencia sentencing any farmer to death who planted rice too close to villages and towns and the conflict between rice growers and the authorities continued for centuries. The disease continued spread and decimated local populations with the increase in rice farming.

By the beginning of the Christian era, malaria was widespread around the shores of the Mediterranean, in southern Europe, across the Arabian peninsula and in Central, South, and Southeast Asia, China, Manchuria, Korea, and Japan. Malaria probably began to spread into northern Europe in the Dark and Middle Ages via France and Britain. The growth in international trade in the sixteenth century contributed to the spread of disease, as international traders introduced new sources of infection. Europeans and West Africans introduced malaria in the New World at the end of 15th century AD. P. vivax and P. malariae were possibly brought to the New World from South-East Asia by early trans-Pacific voyages. P. falciparum probably reached the Americas through the African slaves brought by the Spanish colonisers of Central America. At first the Caribbean and parts of Central and South America were affected and from the mid-18th century, it spread across the North American continent. Over the next 100 years, malaria spread across the United States of America and Canada and by around 1850 A.D., it prevailed through the length and breadth of the two American continents. At this time, malaria was common in Italy, Greece, London, Versailles, Paris, Washington D.C., and even New York City.

Thus by 19th century, malaria reached its global limits with over one-half of the world’s population at significant risk and 1 in 10 affected expected to die from it. From the time of the voyages of Columbus until the mid-19th century, European trade and colonization in the tropics were marked by enormous losses of life from malaria. On the coasts of West Africa, mortality rates often exceeding 50% of a company per year of contact were the norm. From the mid-19th century onward, with the use of the Cinchona bark, mortality rates fell rapidly to less than one-quarter of this. Up to early 20th century, repeated untreated infections of P. vivax and prolonged infections of P. malariae also contributed significantly to the mortality along with the lethal P. falciparum. Poor living conditions, poverty and famine probably contributed to the high mortality. During the past 100 years, nearly 150 million to 300 million people would have died from the effects of malaria, accounting for 2-5% of all deaths. In the early part of the century, malaria probably accounted for 10% of global deaths to malaria and in India it probably accounted for over half.

By mid 20th century, the mortality started dropping, mainly as a result of the spontaneous decline in contact between human and vector populations as a result of improved living conditions as well as by the vector control measures. By the early 1950s, malaria almost disappeared from North America and from almost all of Europe. However, from the tropics where it is endemic, it can spread across continents through the vectors (mosquitoes) and the hosts (men) carried on the boats, trawlers, ships, jets and surface transport.

Further Reading:

  1. Carter R, Mendis KN. Evolutionary and Historical Aspects of the Burden of Malaria. Clinical Microbiology Reviews. October 2002;15(4):564-594. Full text at http://cmr.asm.org/cgi/content/full/15/4/564
  2. Rich SM, Leendertz FH, Xu G et al. The origin of malignant malaria. PNAS 2009;106:14902-14907. Full Text at http://www.pnas.org/content/early/2009/07/31/0907740106.full.pdf
  3. Krief S et al. On the Diversity of Malaria Parasites in African Apes and the Origin of P. falciparum from Bonobos. PLoS Pathog 2010;6(2): e1000765.[Full Text]
  4. Liu W et al. Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature. 23 September 2010;467:420–425. doi:10.1038/nature09442. Available at http://www.nature.com/nature/journal/v467/n7314/full/nature09442.html
  5. Holmes EC. Malaria: The gorilla connection. Nature 23 September 2010;467:404–405. doi:10.1038/467404a. Available at http://www.nature.com/nature/journal/v467/n7314/full/467404a.html
  6. Prugnollea F et al. African great apes are natural hosts of multiple related malaria species, including Plasmodium falciparum. PNAS January 19, 2010. 10.1073/pnas.0914440107. Available at http://www.pnas.org/content/early/2010/01/11/0914440107.full.pdf+html
  7. Connor S. Evolution of malaria is traced back to greatest ape: Research may open new avenues of study to halt disease. Available at http://www.independent.co.uk/news/science/evolution-of-malaria-is-traced-back-to-greatest-ape-2087035.html
  8. Alcock K. Cerebral malaria may have passed from gorillas to us. Available at http://www.bbc.co.uk/news/science-environment-11393664
  9. Daneshvar C et al. Clinical and Laboratory Features of Human Plasmodium knowlesi Infection. Clinical Infectious Diseases 2009;49:852–860
  10. Putaporntip C, Hongsrimuang T, Seethamchai S et al. Differential Prevalence of Plasmodium Infections and Cryptic Plasmodium knowlesi Malaria in Humans in Thailand. The Journal of Infectious Diseases 2009;199:1143–1150
  11. Singh B, Sung LK, Radhakrishnan A et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. The Lancet 2004;363(9414):1017-1024
  12. Cox-Singh J, Singh B. Knowlesi malaria: newly emergent and of public health importance? Trends in Parasitology. 2008;24(9):406-410.
  13. Peter Van den Eede, Hong Nguyen Van, Chantal Van Overmeir et al. Human Plasmodium knowlesi infections in young children in central Vietnam. Malaria Journal 2009;8:249. Full Text at http://www.malariajournal.com/content/8/1/249
  14. Rich SM, Ayala FJ. Evolutionary Origins of Human Malaria Parasites. In Krishna R. Dronamraju, Paolo Arese (Ed). Emerging Infectious Diseases of the 21st Century: Malaria – Genetic and Evolutionary Aspects. Springer US 2006. pp.125-146.

 ©malariasite.com ©BS Kakkilaya | Last Updated: Mar 6, 2015