Malaria on biologinen ase. Malarian historiaa ( engl.)

SITAATTI Lancetista käännöstä varten
The Lancet, Volume 376, Issue 9752, Pages 1534 - 1535, 6 November 2010
Experimenting with fire: giving malaria
Original Text Willian Bynum
Like death and taxes, malaria is always with us. Not normally in developed countries, but if “us” means humanity, its burden in terms of mortality, morbidity, and depressed economic productivity seems part of the human condition. Much can and should be done to minimize its burden, but eradication will probably require not simply more money, but what W H Auden long ago styled “a change of heart”. Malaria is still a disease of poverty.
Elucidating a new causative agent of disease, or its treatment or mechanism of action, can lead to a Nobel Prize—typhus, yellow fever, hepatitis, peptic ulcer, HIV, and cervical cancer are some examples.

• Malaria has had two Prizes awarded and both were contentious, for different reasons. The first of these, and only the second Nobel Prize in Physiology or Medicine awarded, in 1902, went to Ronald Ross (1857—1932). It was fully deserved, since Ross had shown experimentally that the malaria parasite is transmitted through the bite of the mosquito.

This brought malaria (mal aria, “bad air”) from the realm of swampy conditions and bad drainage, into the age of causal specificity. It promised scientific eradication: get rid of the Anopheles mosquitoes, and you will get rid of malaria.
Ross clearly deserved his award. But did he deserve it alone?

The Italian school of malariologists, led by Giovanni Battista Grassi (1854—1925) thought not, and said so publicly.

Ross's experimental model was for bird malaria, but almost simultaneously, Grassi and his colleagues implicated the Anopheles mosquito in the transmission of human malaria.

Grassi felt cheated out of his and his countrymen's just international recognition, and he and Ross carried on an increasingly acrimonious priority dispute that ended only with Grassi's death. Grassi was overlooked not because his research was unimportant, but because of its timing in the history of Nobel Prizes.

The Nobel committees these days often make joint awards, up to the maximum of three specified by Nobel's will.

They rarely did so in the early years of the award, when single prizes were the default mode.

• The second malaria Nobel Prize raised a different set of issues. It was one of only two given for psychiatry (the other one was in 1949 to the Portuguese neurologist and neurosurgeon Antonio Egas Moniz, for the development of frontal leucotomy to treat psychiatric disorders).
• In 1927, the Austrian psychiatrist Julius Wagner-Jauregg (1857—1940) received the ultimate accolade for a new therapy for what was still a common condition within psychiatric hospitals: the malaria treatment of general paralysis of the insane.

• Ross, Grassi, and Wagner-Jauregg each deliberately infected patients with malaria. Their aims and contexts were different, but each man played with fire. Ross was born in India into a British military family, although, like many children of the Empire, he was raised by relatives in England. He would have preferred to become a poet and man of letters, but economic necessity (and his father) steered him into medicine. An undistinguished student, he barely passed his exams and, in 1881, got one of the less prestigious postings in the Indian Medical Service. He only gradually acquired a spirit of enquiry, and on his second furlough back to England, in 1894, he put himself in the way of Patrick Manson (1844—1922), the leading tropical medicine expert in London. Manson had already shown that the parasitic disease filariasis is spread by mosquitoes, and Manson suspected that malaria might also be so spread. Ross returned to India determined to prove Manson's hypothesis.

The two men were separated by 4000 miles and had to cope with a postal service that took up to 6 weeks for a reply. Between 1895 and 1899, when Ross returned to England, they exchanged more than 200 letters, which provide a remarkable record of the making of a Nobel Prize. Almost from the beginning, deliberate exposure to malaria was on the cards. Manson thought that malaria might well be spread by dead, infected mosquitoes in drinking water. He proposed to Ross that drinking water thus infected would be “interesting but perhaps not altogether safe. Dulce et decorum est pro patria mori. But don't do it yourself”.
The patriotism of these two correspondents was ardent: the Italians, French, and Germans were all investigating malaria transmission, and Ross and Manson were anxious that the spoils should go to Britain (although both were Scotsmen, they invariably wrote “England”). Ross for his part was only too happy to try to infect soldiers in the Indian Army with malaria. He was careful to tell Manson that his subjects had consented, and his human experiments eventually included placing mosquitoes next to them. Ross performed several experiments of this kind, but they were before he realized that only certain species of mosquito transmit malaria, so his results were inconclusive. He himself contracted malaria once during the 5 years he was corresponding with Manson from India. By the time he was able to observe the developing Plasmodia in the guts and salivary glands of Anophelines, he had been posted to Calcutta, where there was no malaria. His experimental proof of the role of infected mosquitoes in the transmission of malaria was thus conducted on birds, with the bird malaria parasite. By late 1898, the experiments were complete and he resigned from the Indian Medical Service and returned to England in February, 1899.

• Working in Rome and the highly malarious Roman Campania, Grassi had no trouble finding human malaria. From late 1898 to late 1899, he and his colleagues showed conclusively that previously healthy people could be infected with malaria by being subjected to the bite of an infected mosquito.

• He went further: only a female mosquito of the genus Anopheles. He described his subjects always as “volunteers”, and doctors at the time were aware that malaria was one of the few diseases for which there was an effective treatment: quinine.
• As if also to join the party, in 1900 Patrick Manson infected his own son, Thurburn, with an infected mosquito, just days before the latter's final medical examinations. Thurburn dutifully developed all the signs of malaria, was dosed with quinine and passed his exams.

• Giving people malaria was an important step in establishing the aetiology of the disease. Within two decades, malaria had also become a therapeutic modality.
• The idea of one disease casting out or preventing another disease has a long, if marginal place in the history of medicine.
• Gout was the quintessential disorder that was supposed to protect against other maladies. Take care of your gout and you won't be bothered by other afflictions, doctors were prone to inform their wealthy patients. Acute fevers, too, were sometimes observed to have a positive benefit on other diseases.

From the late 19th century, doctors in psychiatric asylums began to report that some patients got better after they had had a bout of pneumonia, erysipelas, typhoid, or other febrile illness. They became more rational, less delusional, and altogether better able to relate to their surroundings. Wagner-Jauregg became intrigued with these publications, and from the late 1880s, began giving his patients injections of various substances, to see if they would improve. He tried tuberculin, the spirilla of recurrent fever, the streptococcus of erysipelas, and finally, the Plasmodium of malaria, given as a blood transfusion from an acutely ill donor. He tried these treatments on a variety of his psychiatric patients, but his careful record keeping and rough case controlling suggested that patients with general paralysis of the insane were most likely to benefit from his therapies. That general paralysis of the insane was a consequence of end-stage syphilis had been shown by August von Wassermann (of the Wassermann test) in 1906, and confirmed by Noguchi in 1912. Was this a possible causal mechanism: the organism was simply killed by the heat of the fever?
Wagner-Jauregg's decision that a malarial infection was the best remedy was reached only after a good deal of trial and error. His patients were dysfunctional and institutionalised, and thereby in no position to refuse. He combined his malaria therapy with the accepted treatment for syphilis, mercury, iodine, and neo-salvarsan. The combination of all four worked better than the ordinary anti-syphilis therapies by themselves. A course of quinine therapy followed the acute fever, and his reported results indicated that more than half of his patients benefited to such an extent that they could be released from the hospital, and in some instances, resume their former occupations.
Wagner-Jauregg proselytised his new treatment in papers and conferences before and after World War I, and it was taken up in many countries, with some success, despite frequent reports that “cures” were temporary and relapses common. In Britain, the Horton Mental Hospital, a psychiatric hospital run by the London County Council in Surrey, became the fulcrum for the therapy. The laboratory there was run by Sydney Price James (1870—1946), a distinguished malariologist, and he and his colleagues supplied the infected mosquitoes (instead of blood transfusions) and used the human experiments to study clinical manifestations of malaria, its periodicity, and the various strains of the parasite that can affect human beings. They also used the treatment to compare some newer anti-malarial drugs with quinine.
Careful as his record keeping was, Wagner-Jauregg's seems hardly the stuff of Nobel Prizes. It was, as he admitted, only an empirical investigation. We should not judge the past by standards of the present, however, and general paralysis of the insane was a common, debilitating, and ultimately fatal disorder. That his therapy was rendered obsolete by penicillin should not allow us retrospectively to denigrate the Nobel Committee's decision. Dangerous diseases may need dangerous remedies.