The Mystery of Malaria: An Exchange

To the Editors:

I am a bit surprised to read in the review of a book on tropical diseases that bird malaria is transmitted by Anopheles mosquitoes [NYR, January 16]. According to the Encyclopedia Britannica (1971 edition), “In 1898 in India the British physician Sir Ronald Ross proved that bird malaria is transmitted by Culex mosquitoes.” It is human malaria that is transmitted by Anopheles mosquitoes. To quote again from the Britannica, “In November 1898 the Italian investigators A. Bignami, G.B. Grassi and G. Bastianelli first infected man by mosquitoes, described the full development in man and noted that malaria is probably transmitted only by anopheline mosquitoes, an observation that continues to hold time.”

The fact that only Anopheles mosquitoes transmit human disease explains why, to use the words of the reviewer, educated westerners dismissed as primitive tales the belief of many inhabitants of Africa and Asia that mosquitoes were the culprits. Everyone was bitten by mosquitoes in Rome, without any risk of catching malaria, even in the presence of many infected individuals, farmers coming to town wrapped in heavy cloaks in the heat of the summer to protect themselves from the chill of the fever as illustrated in the prints of the period, often to die in the hospital with the pernicious form of the disease. (See illustration.) In order to experimentally transmit the disease in Rome, infected Anopheles had to be carried in from the Campagna, a few miles outside the city. In other words, the localities where humans are at risk of being infected with malaria are geographically extremely well defined and do not correspond to the distribution of mosquitoes. They correspond in fact to the distribution of Anopheles mosquitoes.

Amico Bignami MD
Harvard Medical School
Boston, Massachusetts

M.F Perutz replies:

I thank Dr. Bignami for pointing out my error in writing that Ronald Ross let his infected Anopheles mosquitoes feed on healthy sparrows. Of course I should have written Culex. As to Dr. Bignami’s second paragraph, L.W. Hackett, in his beautifully written book Malaria in Europe described a more complex situation.¹ He and his Italian coworkers found areas in Italy where Anopheles were abundant, but people were free from malaria, because the mosquitoes preferred feeding on farm animals.

I now come to the Britannica’s statement that in November 1898 A. Grassi and his coworkers first infected man by mosquitoes, etc. This recalls the fierce arguments over priority between Ross and the Italian workers and their disappointment at having been excluded from the Nobel prizes, which still lingers in Italy to this day.

The results of G. Bastianelli, A. Bignami, and B. Grassi were communicated to the Reale Accademia dei Lincei on December 4, 1898.² They first found mosquitoes that had been infected with malaria parasites by man, as Ross had done the previous year.³ They did not describe the development of the parasites in man, because Alphonse Laveran had already done this many years earlier.⁴ They mentioned in the final, short paragraph of their one-page communication that they had just succeeded in inducing malaria in a healthy man by allowing him to be bitten by infected mosquitoes, which Ross had not been able to do.

In their initial experiment Bastianelli and his colleagues collected three species of mosquitoes from a room where four patients lay acutely ill with malaria. In one of the species, which they recognized as Anopheles claviger, they found parasites in their first stages “corresponding to those already described by Ross in the proteosoma of birds (4th day). Probably the two mosquitoes with dappled wings in which Ross in India found states of development similar to those of proteosoma (on about the 3rd day) also belonged to the species of Anopheles claviger.”⁵

The last part of this sentence refers to Ross’s discovery of malarial parasites, including their characteristic dark granules which we now know to be made of polymerized human blood pigment, in mosquitoes that he had fed on two malaria patients. In 1897, he published a detailed description of these mosquitoes and of their eggs “shaped curiously like ancient boats with raised stern and prow,” but he failed to name the species of mosquito.⁶ However, this hardly detracts from his credit, because “as Ross distinctly describes the egg of this species, there is no doubt whatever but that he was dealing with a species of Anopheles.”⁷ The Italian workers ignored Ross’s detailed description of the mosquitoes and their eggs and, in a footnote, dismissed his mention of their dappled wings as an inconclusive mark of identity, saying that in Europe there existed five species of Culex mosquitoes which also had dappled wings, and that they had found no data for India.⁸ This ungenerous and misleading footnote may have done the Italian workers more harm than it did Ross.

In 1901 the first Nobel Prize for Physiology or Medicine was awarded to Emil von Behring “for his work on serum therapy, especially its application against diphtheria.” When considering the next prize, the Medical Faculty of the Karolinska Institute had before them twelve nominations of Ronald Ross from seven different countries, including one by Lord Lister, then president of the Royal Society of London, who nominated him “for his discovery of the development of the malaria parasite in the mosquito.” Three of the nominators proposed Grassi jointly with Ross; one, H.F. Bowditsch, a physiologist at Harvard, nominated Bastianelli, Bignami, Grassi, Ross, and Manson all together.

The Medical Nobel Committee of the Karolinska Institute met on September 25, 1902, and decided that fourteen of the candidates who had been proposed should not be considered in that year. That list included Grassi and several other famous men who were to receive the prize later, including Robert Koch, Paul Ehrlich, Alphonse Laveran, Jean Bordet, Camillo Golgi, and Ilja Mecnikov. This left only three candidates. One member of the committee, Professor E. Holmgren, then expressed the view that “of the three scholars among whom the Committee agree that the choice of prize-winners should be made—namely I. Pavlov, N. Finson and R. Ross—I consider that Ross by reason of his researches into malaria, which are of the greatest practical and theoretical importance, should without reservation be nominated as the most meritorious candidate.”

Ross therefore received the prize in 1902, Finson in 1903 for his treatment of lupus vulgaris with ultraviolet light, which was used for more than forty years, and Pavlov in 1904 for his work on the physiology of digestion. Laveran, who should really have received the prize before Ross, was finally awarded it in 1907, after he had been nominated by Ross, as well as several French academicians. Grassi does not seem to have been considered again. The entry “Malaria” in the Britannica fails to mention either Laveran or Ross. Like the Bible, it is not always infallible.

Material for this letter was kindly provided from the Nobel archives by the Nobel Committee for Physiology or Medicine.