Eminent historic researchers of dengue Emily C. Griffiths September 12, 2013

I’m compiling an historical record of the major findings relating to dengue fever, its vectors, and related vector-borne diseases. This is a work in progress, please send comments or suggestions to ecgriffi at ncsu dot edu

Benjamin Rush b. 24/12/1745 d. 19/04/1813 Physician who published in 1789 the first written description of the summer-autumn 1780 dengue outbreak in Philadelphia, USA. He called it bilious remitting fever [1].

Robineau-Desvoidy b. 01/01/1799 d. 25/06/1857 Described a mosquito in Cuba in 1827. Originally known as Culex mosquito Desv. it is now called Aedes aegypti, the main vector of dengue.

Louis Beauperthuy b. 1807 d. 1871 Traveled to Venezuela on a expedition for the Paris Museum in 1854. Concluded that malaria and yellow fever “are produced by a venomous fluid injected under the skin by mosquitoes like poison injected by snakes” [2].

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Patrick Manson b. 03/10/1844 d. 09/04/1922 In China in 1877 inferred that Culex fatigans (now Culex quinquefasciatus) transmitted lymphatic filariasis based on experiments with his infected gardener Hin Lo. Showed that mosquitoes reached embryonic stages in human blood and needed to enter a mosquito to complete their life cycle. This was the first evidence that mosquitoes could transmit infections, though he had the wrong mechanism; it was through blood meals, not laying eggs in water.

Carlos Finlay b. 03/12/1833 d. 20/08/1915 French-Scottish doctor working in Havana, Cuba. Noted that all yellow fever epidemics involved many mosquitoes. Implicated Aedes aegypti (then Stegomyia fasciata) as the vector of yellow fever based on the temperature and elevation of epidemic sites as early as 1881 [3]. However, his experiments to infect people with yellow fever using mosquitoes often failed and he was ridiculed as ”the mosquito man”. Supplied mosquito eggs for experiments that later confirmed his hypothesis [4].

Henry Rose Carter Worked for Public Health Service during 1898 epidemic on Mississippi River. Noted delay of 12 days to three weeks between one case to next symptomatic case of yellow fever. Also noted that visitors to houses of infected people did not become ill if they visited in the first two weeks of a person’s illness. Theorised there must be an external incubator for the infection. Went to work in Cuba.

Walter Reed b. 13/09/1851 d. 22/11/1902 As US army surgeon stationed in Cuba in 1898 he showed that the yellow fever that had dogged military efforts to build the Panama Canal was caused by mosquito biting. Appointed head of Yellow Fever Commission in June 1900. Microscopy failed to show any cellular parasites, but Reed’s 1900 experiment suggested that female mosquitoes spread yellow fever to humans. He received a hostile reaction when he presented his work in Minneapolis in November 1900. He resolved to gather more conclusive evidence and set up a new base just outside Havana. His work provoked general interest in mosquitoes,

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and general recognition of Aedes aegypti as a species in its own right (previously tropical Dipteran taxonomy had been confusing with many synonyms) [4].

Ronald Ross b. 13/05/1857 d. 16/09/1932 1895-98 described gregarine parasites of Aedes aegypti. 1895 found sexual reproduction of malaria in stomachs of Anopheles mosquitoes that had bitten malaria patients. In Calcutta, where human malaria was rare, he documented the Plasmodium vivax life cycle of malaria under the supervision of Patrick Manson. This gave some human significance to the discussions of mosquitoes that had begun with Aldrovando’s work in 1602. Giovanni Battista Grassi in Rome showed that an infected mosquito could bite a human and give them malaria. Ross was bitter toward him and won the Nobel Prize in 1902 [5]. Ross wrote books on malaria prevention recommending bed nets, quinine, and draining of stagnant water [3].

William Gorgas b. 1854 d. 04/07/1920 Witnessed many yellow fever epidemics while working with the US army, including near the Mexican border in 1882. Trialled vaccination by mosquito bites, but abandoned it after half of the sixteen volunteers fell ill and three died. Persuading people to control mosquitoes became his favored approach. Became Chief Sanitary Officer in Havana, Cuba in 1899. Set up an experiment because he was still skeptical of the “mosquito hypothesis” of yellow fever transmission. In 1901 he fumigated homes against mosquitoes and removed or poured oil on top of containers to suffocate larvae, rather than calling for wholesale disinfection of all filth. This was the first Aedes aegypti -specific control program [4]. Took the same approach when he moved to Panama in June 1904, but was initially refused many of the requests he made against his $50000 budget. He persisted in negotiations and spent $90000 on copper window screening alone, with a total expenditure topping $2 million. This was the single largest tropical health program ever before [6]. Each case of yellow fever was watched by a public health official for five days. Issued rewards for reports of yellow fever cases, but also fines if larvae were found on a property. To kill larvae 700 000 gallons of oil and 124 000 gallons of larvicide were distributed by the sanitary department each year [6]. Gorgas worked in Panama until he became Army General Surgeon in 1914. He later worked in Ecuador advising on yellow fever and plague [4, 7].

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Robert Doerr b. 1871 d. 06/01/1952 Early proponent of the theory that viruses replicated within host cells. Founded the first journal devoted to virus research that became known as the Archives of Virology. Professor at the Institute of Bacteriology and Hygiene, University of Basel. Wrote the first Handbook of Virology and subsequent volumes as well as monographs on antibodies and anaphylaxis. His virological research did not cover dengue but included fowl plague virus, sandfly papataci fever (temperature-dependence and overwintering was a puzzle, also speculated on the mutability of the virus within sandlfies), typhus, bacteriophages, and herpes [8].

Albert Bruce Sabin b. 26/08/1906 d. 03/03/1993 Developed vaccines against polio administering a weakened form of the virus orally and Japanese encephalitis. Also worked on dengue vaccination with R. Walter Schlesinger, after they met at the Army Medical Corps viral diseases unit.

Susumu Hotta b. 1918 d. 17/11/2011 Worked on dengue over seven decades. Graduated with an MD from Kyoto Imperial University in 1942 at a time when dengue outbreaks occurred in Japanese port cities, particularly Nagasaki in which he focused his work over the next three summers. He successfully isolated DENV serotype 1 from a patient called Mochizuki, and inoculated it into mice intracerebrally. He published the first book on Dengue Haemorragic Fever, Dengue and Related Hemorrhagic Diseases, in 1969. Also supervised work on other arboviruses like chikungunya and Japanese encephalitis, and after his second retirement oversaw the genome sequencing of Mochizuki strain.

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Robert Walter Schlesinger b. 1903 d. 11/01/2003 Completed final two years of medical training under Robert Doerr. Studied viral infections of the central nervous system, focusing on dengue fever. Worked on dengue and Japanese encephalitis vaccination with Albert Sabin. Wrote a 1977 monograph on dengue. At a symposium on arboviruses in the Mediterranean in 1978 he noted that arboviruses e.g. Sindbis in Aedes albopictus exert little pathogenic effects on arthropod hosts, hence adaptation of virus my differ depending on the host species [8].

William Hammon b. 1904 d. 19/09/1989 Isolated dengue virus from wild mosquitoes during dengue outbreak in Manila in 1958. Isolated all four dengue serotypes from SE Asia from the 1950s to early 60s.

References [1] R Walter Schlesinger. Dengue Viruses, volume 16. Springer Virology Monographs, 1977. [2] D. McCullough. The Path Between the Seas: The Creation of the Panama Canal, 1870-1914. Touchstone, 1977. [3] D.A. Howarth. Panama: four hundred years of dreams and cruelty. McGraw-Hill, 1966. [4] Matthew Parker. Panama Fever: The epic story of one of the greatest human achievements of all time–the building of the Panama Canal. Doubleday, 2007. [5] S.R. Christophers. Aedes aegypti: the yellow fever mosquito. Cambridge University Press, 1960. [6] N. Maurer and C. Yu. The Big Ditch: How America Took, Built, Ran, and Ultimately Gave Away the Panama Canal. Princeton University Press, 2010. [7] J.T. Hoffman. The Panama Canal: An Army’s Enterprise: An Army’s Enterprise. United States Department of Defense Center of Military History, 2010. [8] RW Schlesinger. Robert Doerr-prophet of the nature of viruses, founder of the Archives of Virology. Archives of Virology, 142(4):861–873, 1997.

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