A Mystery of the Tropics

Some years ago I listened to an emotional appeal by a director of the World Health Organization to fight against the parasitic infections that kill millions of children in the Poor World every year. His speech fell flat, partly because the audience regarded it as a well-rehearsed and often repeated performance, and partly because mere numbers fail to arouse people’s emotions. By contrast, the opening of Desowitz’s book on tropical diseases strikes to the heart with the story of the illness and unnecessary death of a single child in India. Unnecessary, because the mother could have saved her child had she or the Indian government been able to afford $15 worth of medicine.

The disease was a parasitic infection known as kala azar. Desowitz’s book tells the story of the search for the organism that causes it and the way that organism is transmitted from patient to patient. Its heroes are the physicians of the British Indian Medical Services, many of them amateurs in science who, beginning in the late nineteenth century, pursued their research as a hobby with primitive means and often with more devotion than competence. They had many patients with the symptoms of the disease—enlarged spleen and liver, irregular fever, and anemia, among them—but could not find out what caused it. The first clue came at the turn of the century when Dr. William Leishman in London found microscopic egg-shaped bodies in the spleen of a soldier who had died from kala azar; later Charles Donovan in Madras found the same bodies in the spleen of a live patient and recognized them as protozoa, single-celled organisms a little larger and more complex than bacteria. They were aptly named Leishmania donovani.

How were they transmitted from patient to patient? First suspicions fell on the ubiquitous bedbugs. Dr. W.S. Patton in Madras spent five years patiently encouraging bedbugs to feed on his kala azar patients, hoping that the bedbugs would suck up the parasites, and was encouraged when he found some in their intestine. Later Mrs. Helen Adie, a researcher in Calcutta, claimed enthusiastically that she had actually seen them in the bedbugs’ salivary glands. Her findings were hailed as a breakthrough until others proved that she had looked at the wrong protozoa. People continued to probe in the dark until one man had a bright idea. This was Major John Stinton, the only man known to hold both the Victoria Cross for his bravery in battle and the fellowship of the Royal Society for his scientific achievements. Stinton took a map of India and compared the incidence of parasitic diseases with the distribution of various biting insects. His map showed a coincidence between the prevalence of kala azar and that of a tiny silvery sandfly, Phlebotomus argentipes.

Stinton published his findings in 1925, but it took another seventeen years until he was proved right. In 1923 a kala azar commission had been set up in Assam under the English parasitologist Henry Edward Shortt. He found that even the first problem, the breeding of the sandflies in the laboratory, needed years of research before it could be solved. When that had been accomplished, his sandflies died after their first blood meal, before they could transmit the disease to a healthy host. Shortt became so depressed by years of failure that he recommended that the commission be closed down, but next day a hamster that had been bitten 1,434 times by infected sandflies over a period of seventeen months was found to be infected.

Even after this event, infected sandflies failed to transmit the disease to human volunteers, until in 1939 the physician-entomologist R.O. Smith observed that the sandflies needed refreshment to make the parasites grow. When he fed them on raisins, the Leishmania inside them multiplied so prodigiously that they plugged the flies’ throats. Smith thought that they might infect their next host in their desperate efforts to cough out these accumulations of protozoa. In 1942 Shortt, together with an Indian scientist and physician, C.S. Swaminath, and L.A.P. Anderson, tested Smith’s idea by feeding infected and “raisined” sandflies on six volunteers and found final proof when three of them contracted kala azar.¹ By then it could be cured by a drug containing antimony; the same drug is still in use today, but the Indian child’s mother could not afford it, even though it is cheap.

In the early Fifties the great DDT campaign against malaria eradicated kala azar from India until it became a forgotten disease, but in the Seventies the ending of the DDT campaign caused it to revive. It is now more endemic than before, because improved means of transport have favored its spread. Desowitz charges that it has become a neglected disease and that too little money is being spent on kala azar research because it does not afflict Americans.

By contrast, from early colonial times until about 1940 malaria was one of the most visible American diseases. During the American Civil War half the white and four fifths of the black soldiers got malaria every year. Desowitz’s history describes the “confusion and sometimes chaos” that for seventy years handicapped malaria research, before the life cycle of the malaria parasite and its transmission were understood. He begins in the present with the moving story of a pregnant young woman in Thailand who had moved from her malaria-free but overpopulated mountain region to the mosquito-infested lowlands; there malaria at its most virulent suddenly struck and killed her and her baby.

More than a hundred years ago a French army doctor in Algeria, Alphonse Laveran, discovered the parasite that causes malaria. This is how his notebook described it:

D. aged 24, soldier in the eighth squadron of artillery, had been in Algeria since December 5th 1879 and entered the Constantine Hospital on November 4th 1880. The patient had grown thin; was markedly anemic; the skin had the earthy tint characteristic of the wasting of malaria. Temperature 39.5°. 5th November. Temperature 38.5° in the morning. Examination of blood…numerous crescent-shaped bodies. I prescribed sulphate of quinine 0.60 grams. Examination of blood on 6th November; crescent-shaped bodies still numerous; spherical bodies with mobile flagella whose existence I noticed for the first time.

Later Laveran added:

These parasites evidently live at the expense of the red blood corpuscles which become pale as the parasites grow.²

Like the organisms that were found to cause kala azar, they were protozoa, single-celled organisms of the kind first noticed in stagnant water by Antony van Leeuwenhoek more than two hundred years earlier, but never before associated with disease. The individual protozoon became known as Plasmodium falciparum. It eats hemoglobin, the protein of the red blood cells. In 1990 scientists at the Rockefeller University in New York finally discovered how Plasmodium digests it, which may open new approaches to the design of antimalarial drugs.³

Desowitz writes:

[Laveran’s] was a remarkable discernment; modern malariologists claim that Laveran’s microscope was so optically defective it had only one half the magnification power necessary to reveal what he so accurately saw and described.

The thirty-five-year-old colonial army doctor’s discovery is all the more impressive when seen in historical perspective. He made it only a few years after Louis Pasteur’s discovery of the bacterial origin of a silkworm disease, and Robert Koch’s of a disease in sheep, and before anyone else had found the microorganism that caused a human disease.

As often happens when an outsider makes a discovery, nobody believed Laveran. Italian doctors rejected his thesis even when he showed them the parasites in the red blood cells of malaria patients. According to Desowitz, Koch went so far as to dismiss as an idiot anyone who believed Laveran. All the same, in 1907, twenty-seven years after his discovery, Laveran was to receive the Nobel Prize for Physiology or Medicine, only two years after Koch got his prize for discovering the cause of tuberculosis.

It took eighteen years’ detective work from Laveran’s discovery of the malaria parasite to the discovery of the creature that transmitted it. Unnecessarily so, Desowitz believes, because many inhabitants of Africa and Asia apparently realized that mosquitoes were the culprits, but educated Westerners dismissed such primitive tales. One of them was Ronald Ross, a young physician in the Indian Army Medical Service who even refused to believe Laveran. As late as 1893 he published a paper in the Indian Medical Gazette claiming malaria to be an intestinal infection by bacteria that should be treated with calomel, i.e., mercurous chloride, a toxic laxative and cure-all that must have aggravated the already severe debilitating effects of malaria. It was one of the many futile and counterproductive drugs with which doctors used to torture patients.

Ross might have continued on his mistaken track but for a visit to London in 1894, where he met Patrick Manson, a physician described as the father of tropical medicine, who had discovered that filariasis, a parasitic worm infection, is transmitted by mosquitoes.⁴ In his memoirs Ross wrote:

In November I called upon [Manson] again and found him just starting for the Seamen’s Hospital. I went with him, and remember distinctly that as we were walking along Oxford Street at about 2:30 p.m. he said to me: “Do you know, I have formed the theory that mosquitoes carry malaria just as they carry Filariae.” I replied at once that I had seen the same conjecture in one of Laveran’s books.⁵

Manson believed malaria to be transmitted by drinking water from wells contaminated with infected mosquitoes, on the model of typhoid fever that was known to be spread by infected water. Ross bought a microscope to take back to India and began his search for the carriers of malaria.

In June 1885 Manson wrote to him, “Mosquito water or mosquito dust should be taken or inhaled first thing in the morning and on an empty stomach, so that there would be no danger of its included germs being destroyed by the stomach juices.” In August Ross replied: “All the facts can be explained best on the supposition that the poison is conveyed by mosquitoes into isolated pots of drinking water in the houses of men,” but when he drank about 1,500 to 2,000 malaria “sperms” on two occasions, he felt nothing. In April 1897 Ross suffered a severe attack of malaria and still attributed it to contaminated air or water. One of Ross’s great problems was to find which mosquitoes carried the disease. Desowitz suggests that he could have saved himself years of labor if he had only bothered to study the characteristics of the known varieties of Indian mosquitoes. This is unjustified. Ross did ask an expert, A. Alcock, who replied that the mosquitoes had not been subjected to scientific study. In 1895 the first entomology of European mosquitoes had only just been published in Italy.

On August 16th, 1897, a servant brought Ross ten mosquitoes of a kind he had never seen before. They were of the type called Anopheles.

Ross let them feed on a malaria patient in a ward of the local hospital. Desowitz writes:

Twenty-five minutes after all the mosquitoes had their blood meal…two were killed and dissected. Nothing; and then there were eight. Twenty-four hours later, two were found dead in the cage and two more were dissected. Nothing; and then there were four. On the fourth day, August 20, 1897, one had died a natural death and Ross dissected one of the three remaining mosquitoes. There it was. A minute, round cyst on the exterior of the stomach wall. “The Angel of Fate fortunately laid his hand upon my head” was Ross’s dramatic description of that moment. The last mosquito was sacrificed the next day. Not only were there cysts on the stomach wall but they were larger than those of the day before and had malarial pigment granules within them. They were alive and growing.

Ross’s observation proved that the Plasmodium falciparum protozoon moves from the human host into the Anopheles mosquito and multiplies there, but it did not reveal how Plasmodium gets from the mosquito into the next human host. Ross had just started to work on this problem when the army ordered his transfer to a semidesert station that was almost free from malaria. He wrote “a humble letter” to the surgeon-major general asking to be transferred to a station where he could finish his malaria work, but received the blunt reply: “I don’t know what this officer means. He was sent to his command by H.E. (His Excellency) the Commander-in-Chief and there he will remain until H.E. orders him away.”

After five months in the wilderness Ross wrote to Manson: “I have just received orders to be off to Calcutta at once, thanks to your action,” but at first Calcutta was a disappointment because Ross found no malaria patients on whom to feed his mosquitoes. Having discovered malaria parasites in two sparrows at his desert station, he set to work on bird malaria instead. On May 9, 1898, he complained to Manson: “I am nearly mad. Sparrows all round and I can’t catch them.” On July 6 he wrote, “I am nearly dead and blind with exhaustion—but triumphant.” Ross had made two decisive observations. He had let the Anopheles mosquitoes feed on three healthy sparrows and later found the sparrows to be swarming with the parasites; he had also dissected mosquitoes that had fed on infected sparrows and found the parasites first in the mosquitoes’ stomachs, later in their thorax, and finally in their salivary glands, ready for injection into another victim.

At last Ross had incontrovertible proof that malaria is transmitted by mosquitoes, not as Manson and he had thought, through drinking water, but simply by their bite. He wrote: “Such moments come only to one or two persons in a generation. The pleasure is greater than that given by any triumph of the orator, the statesman or the conqueror.” Four years later, in 1902, Ross received the Nobel Prize for Physiology or Medicine, only the second one ever to be awarded; the first had gone to Emil Adolf von Behring for his discovery that diphtheria could be cured by injection of the serum of immunized horses.

Desowitz describes Ross as arrogant and opinionated, a poet manqué who had only just scraped through his medical exams, a determined and ambitious but ignorant romantic. Reading Ross’s regular reports to Manson shows this view to be unfair. Ross emerges as exceedingly able, resourceful, and energetic, a scientist who goes for what is most important with superb skill and acute powers of observation. Who else would have discovered malaria in sparrows and gone out into the streets of Calcutta to catch them when human patients failed him, or stopped the fan that made only just bearable the hours peering down his microscope in stifling heat, because its draft blew away the delicate organs that he had teased out of his mosquitoes in search of parasites? Imagine the strength of character Ross needed to carry on with his work for years in isolation, with primitive means, in an appalling climate, and without encouragement from his superiors! After his great discovery Ross devoted the remainder of his life to the eradication of malaria and yellow fever from British colonies. His methods of mosquito control proved decisive in the building of the Panama Canal. In his spare time, he wrote creditable poems about India.⁶

Desowitz does not mention any of Ross’s later work and he gives a biased account of recent malaria eradication programs. Malaria has now been eliminated, thanks mainly to DDT, from most regions of Europe and North America where it used to be endemic. In Italy 400,000 cases were reported in 1946 and 1947, with a mortality rate of 40 people per 1,000 inhabitants. Following an intensive DDT campaign, no indigenous case has been reported there since 1952. The report of the World Health Organization for 1973 states that eradication programs had completely eliminated malaria from thirty-five countries with a total population of 193 million people.⁷

By contrast, according to the report, about 500 million people in sixty-six countries still lived in areas where malaria was endemic. These included Sri Lanka, where there had been nearly three million cases of malaria in 1946. After an efficient DDT spraying campaign only a hundred cases were reported there in 1961, and only 150 in 1964, the year that spraying was stopped. Four years later there were again nearly 450,000 cases and by 1970 that figure had risen to one and a half million. Much the same happened in India, where the number of cases reached a peak of over six million in 1976, but thanks to public health measures went down again to two million by 1988.

Desowitz largely ignores these developments. He dismisses the World Health Organization’s eradication campaigns of the 1950s and 1960s as scientifically ill-conceived and therefore doomed to failure. He is scathing about its higher officials and those of the United States Agency for International Development (AID), “the agency that gives our money away to foreigners.” He writes first that from 1956 to 1969, the United States, through the US Agency for International Development (AID), gave $790 million to the global Eradication of Malaria Program. Later in the book he writes: “From 1955 to about 1970, AID contributed approximately $1 billion to the World Health Organization and various national malaria eradication programs. All that taxpayer money down the drain.” Desowitz mentions the temporary elimination of kala azar throughout India, but stays silent about the millions of lives saved by the complete eradication of malaria in some countries and its temporary near eradication in others. According to the World Health Organization’s latest report, 1.5 billion people now live in countries where successful malaria eradication programs are being maintained. In China the number of cases has been reduced to a few hundred thousand. How can Desowitz describe the cost of saving these lives as “money down the drain”? In view of the early successes of the DDT campaign in temperate climates as well as in tropical British Guiana, it was surely worth trying to organize similar campaigns in India and Sri Lanka.

Desowitz stresses that the Anopheles mosquitoes eventually became resistant to DDT, not because of the anti-malaria campaigns but because of the excessive and inappropriate use of DDT by farmers and especially cotton growers, which he rightly calls a crime, not least because of the environmental damage it caused. He writes: “It was not recognized that DDT used for medical purposes never killed an osprey.”

Desowitz traces the history of anti-malarial drugs from a young Englishman’s discovery of a quinine-rich tree in Peru in the 1830s to a newly rediscovered two-thousand-year-old Chinese drug called Qinghaosu. He claims that Qinghaosu is not yet being manufactured, and believes this is particularly unfortunate because the malaria parasites have evolved resistance to all other antimalarial drugs, including synthetic forms of quinine, except possibly quinine itself, which is now hard to get. The cinchona plantations in Java that used to provide most of the world’s supply, he writes, were replanted with other crops during the carefree years when synthetic antimalarial drugs proved effective.

In fact, the active principle of Qinghaosu has been manufactured and exported by a Chinese pharmaceutical company for some years; a French company has recently become its partner and says it will encourage wide distribution of the drug. Only the most virulent species of parasite, Plasmodium falciparum, has become resistant to most antimalarial drugs. Quinine is readily available, thanks to new plantations of the cinchona tree in South America and Central Africa, but quinine derivatives are equally effective and cause fewer side effects.

The principal remaining hope for dealing with Plasmodium falciparum is to develop a vaccine, but this is proving to be exceedingly difficult. Desowitz is harshly critical of the vaccine program financed mainly by AID and the scientific fraud and financial corruption that pervaded it. In this case, American taxpayers’ money was wasted not on foreigners but on dishonest US citizens. The agency’s own chief administrator of the malaria program is awaiting trial for misappropriation of public funds, and several of the scientists involved in the program improperly used the research funds entrusted to them. Peter Medawar once pointed out that if among the thousands of scientists there are just a few odd crooks, then he would draw a “clear distinction between the scientific profession and the pursuit of mercantile business, politics or the law, professions of which the practitioners are inflexibly upright all the time.” I was therefore disturbed most of all by Desowitz’s allegation that “the respectable, established, and honored scientists” in the field knew of these shady goings on, but kept silent.

Desowitz regards the search for a vaccine against malaria as fundamentally flawed and suggests that AID’s initiative may have failed among other reasons “because the human constitution is such that no vaccine can confer protective immunity” against malaria. Scientific opinion on this point is divided, but a review of recent progress in the field suggests that this gloomy view is unjustified. ⁸ Besides, the history of science is replete with discoveries that expert opinion ridiculed as impossible, including my own, and I know of no other way by which malaria could be brought fully under control. Desowitz is contemptuous of the “molecular type” of scientist, “more concerned with the exquisite intellectual challenges of modish science than with seeking practical solutions,” types who are replacing the last generation of truly experienced “field hands” of tropical diseases.

He advocates an “integrated” approach to malaria control, but does not say what specific measures such an approach would require; the only practical method he suggests is the use of mosquito nets dipped in the insecticide permethrin.

Surely the “molecular types” are needed today, because the experienced public health experts who work in the afflicted countries have reached a dead end. When mosquitoes have become resistant to insecticides and parasites to drugs, vaccination offers the only hope for radically reducing the incidence of malaria, which affects about 100 million people a year;⁹ and recombinant DNA technology is the only way I know of by which an effective vaccine might eventually be produced. Ruth and Victor Nussenzweig at New York University were among the first to realize this and have pioneered the development of genetically engineered malaria vaccines. Desowitz attacks them for AID’s premature claim that such a vaccine is just around the corner and for having entered into an agreement with a commercial company for personal profit for work that was supported by the taxpayer. According to my inquiries both allegations are unjustified. The Nussenzweigs were not responsible for AID’s public statements, and they have assigned all patent rights to New York University.

Desowitz’s readable and lively book contains many anecdotes about the personalities of the doctors and scientists who have been concerned with tropical diseases, the erratic paths they took, and the squabbles among them. He frankly describes the corruption and sloth of third world countries and exposes the incompetent use of aid funds by international agencies there. But his book shows a corruption of another kind, his own corruption by familiar modern fashions. Admiration is out, debunking is in. Often on very partial evidence, he runs down scientists, drug firms, the motives of Western governments in providing aid and promoting research on tropical diseases, the World Health Organization’s officials, Indian doctors, and American do-gooders. He expresses compassion for the Indian poor who are afflicted by malaria and other parasitic diseases, but he shows a cynical contempt for most of those who are now trying—he would say pretending—to help them. Such a view makes his book provocative, but it does an injustice to the many honest people in medicine, science, drug firms, and international agencies who are devoted to their work and jeopardizes support for valid and much-needed malaria research.