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Authors: Laurie Garrett

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“What's the problem?” Spielman asked.
“I should never have accepted you into graduate school. I should never have encouraged you to pursue medical entomology. It's a dead field. DDT is killing it,” Rozeboom said.
Spielman argued it was too early in the game to call the score. But Rozeboom was adamant.
“It's all over. There will be no career for you. By the time you've finished your thesis all the insect-borne disease problems will be solved,” Rozeboom insisted.
Undaunted, Spielman pursued his Ph. D. despite Rozeboom's warning. He was a firm believer in evolution—he had practically memorized his favorite text on the subject—and he told Rozeboom that “DDT isn't the final answer.”
While Congress reviewed Russell's IDAB proposal, Spielman took some courses at the Woods Hole Oceanographic Institute in Massachusetts. There he met a middle-aged marine biologist who was quietly rethinking the whole DDT question. She told Spielman that evolution would come between DDT and the dream of malaria eradication. DDT-resistant strains of
Anopheles
mosquitoes were turning up all over the world, she said.
Her name was Rachel Carson, and the same year the United States and WHO embarked on their ambitious campaign to eliminate malarial mosquitoes, Carson started writing
Silent Spring
.
43
Carson never completely opposed pesticide use; rather, she favored their rational and limited application. Prophetically, she worried that widespread agricultural use of insecticides would endanger efforts to control malaria, typhus, African sleeping sickness, yellow fever, and encephalitis. She wrote:
 
No responsible person contends that insect-borne disease should be ignored. The question that has now urgently presented itself is whether it is either wise or responsible to attack the problem by methods that are rapidly making it worse. The world has heard much of the triumphant war against disease through the control of insect vectors of infection, but it has heard little of the other side of the story—the defeats, the short-lived triumphs that now strongly support the alarming view that the insect enemy has been made stronger by our efforts. Even worse, we may have destroyed our very means of fighting.
44
 
She noted that the first public health use of DDT occurred in 1943. Allied troops sprayed the chemical liberally to eliminate typhus-carrying lice in Italy. The lice were, in fact, killed, and typhus halted, but a year later DDT-resistant
Culex
mosquitoes and houseflies stepped into the vacuum. By 1951, mosquitoes and flies in the region were resistant to DDT, methoxychlor, chlordane, heptachlor, and benzene hexachloride, and Italians had returned to time-honored tactics for insect control: screened windows, flypaper, and flyswatters.
In 1959 Spielman joined the faculty of the Harvard School of Public Health and discovered that no courses on malaria or
Anopheles
mosquitoes were on the curriculum. With the leader of the world's malaria eradication campaign on the faculty, it was considered distasteful to offer such courses. Training young scientists in techniques of mosquito control implied that
Paul Russell's efforts would fail and such knowledge would actually be necessary for future practitioners of public health.
Russell, an ex-missionary, was a kindly, elderly gentleman, and although Spielman had never believed the campaign would succeed, it broke his heart to see the dejection Russell felt when 1963 arrived.
Malaria had, indeed, reached its nadir. But it had not been eliminated. In some countries success was so close that people were already celebrating. Sri Lanka, for example, had 1 million malaria cases in 1955; just eighteen in 1963.
 
But a deal's a deal. Russell promised success by 1963, and Congress was in no mood to entertain extending funds for another year, or two. As far as Congress was concerned, failure to reach eradication by 1963 simply meant it couldn't be done, in any time frame. And at the time virtually all the spare cash was American; without steady infusions of U. S. dollars, the effort died abruptly.
In 1963 Harvard put malaria control back on its curriculum.
Spielman shook his head and wondered out loud, “How can they just abandon all these people?” He knew that, thanks to the near-eradication effort, hundreds of millions of people now lacked immunity to the disease, but lived in areas where the Anopheles would undoubtedly return. Pulling the plug abruptly on their control programs virtually guaranteed future surges in malaria deaths, particularly in poor countries lacking their own disease control infrastructures. As malaria relentlessly increased again after 1963, developing countries were forced to commit ever-larger amounts of scarce public health dollars to the problem. India, for example, dedicated over a third of its entire health budget in 1965 to malaria control.
45
Everything started to unravel. The Green Revolution—a World Bankbacked scheme to improve Third World economies through large-scale cash crop production—got underway. Turning thousands of acres of formerly diversely planted and fallow land into monocultured farms for export production of coffee, rice, sorghum, wheat, pineapples, or other cash crops necessitated ever-increasing pesticide use. When an area had very diverse plant life, its insect population was also diverse and no single pest species generally had an opportunity to so dominate that it could destroy a crop. As plant diversity decreased, however, competition and predation among insects also declined. As a result, croplands could be overwhelmed rapidly by destructive insects. Farmers responded during the 1960s with heavy pesticide use, which often worked in the short term. But in the long run pesticides usually killed off beneficial insects, while the crop-attacking pests became resistant to chemicals. A vicious cycle set in, forcing use of a wider assortment of insecticides to protect crops.
At the very time malaria control efforts were splintering or collapsing, the agricultural use of DDT and its sister compounds was soaring. Almost overnight
46
resistant mosquito populations appeared all over the world.
As Russell kept a worried eye on the pesticide resistance problem, a
new crisis appeared: two people who were taking chloroquine developed malaria in South America.
47
Almost simultaneously, chloroquine-resistant malaria turned up in Colombia,
48
Thailand,
49
Venezuela,
50
and Brazil.
51
The drug had been in use for only fifteen years; widespread use spanned less than a decade's time.
52
By 1950 a second drug, primaquine, was available, and many countries returned to the use of the ancient antimalarial, quinine. But resistance soon developed to those and other drugs introduced in the 1960s.
53
By 1963 U.S. forces fighting in Vietnam encountered chloroquine-resistant malaria, and the Army began a major effort to research and develop new antimalarial drugs.
54
The drug-resistance problem could only have been aggravated by government decisions in some countries—notably New Guinea—to add chloroquine to all table salt.
55
By the time the smallpox campaign was approaching victory in 1975, parasite resistance to chloroquine and mosquito resistance to DDT and other pesticides were both so widespread that nobody spoke of eliminating malaria. Increasingly, experts saw the grand smallpox success as an aberration, rather than a goal that could easily be replicated with other diseases.
56
In 1975 the worldwide incidence of malaria was about 2.5 times what it had been in 1961, midway through Paul Russell's campaign. In some countries the disease was claiming horrendous numbers of people. China, for example, had an estimated 9 million cases in 1975, compared to about 1 million in 1961. India jumped in that time period from 1 million to over 6 million cases.
57
A new global iatrogenic form of malaria was emerging—“iatrogenic” meaning created as a result of medical treatment. In its well-meaning zeal to treat the world's malaria scourge, humanity had created a new epidemic.
Monkey Kidneys and the Ebbing Tides
MARBURG VIRUS, YELLOW FEVER, AND THE BRAZILIAN MENINGITIS EPIDEMIC
When the tide is receding from the beach it is easy to have the illusion that one can empty the ocean by removing water with a pail.
—René Dubos
 
 
The failures of malaria eradication were overshadowed by the tremendous triumphs of polio control and the campaign for the elimination of smallpox. Western scientists in the late 1960s saw the history of disease as an arrow shooting straight toward a
Homo sapiens
victory over the microbes. Machupo was considered a distant anomaly, news of which hadn't reached most Western physicians or scientists. And more than another decade would pass before the global public health community would stop using the term “eradication” when referring to malaria.
But other “anomalies” soon followed.
In August 1967 three factory workers in Marburg, Germany, reported in sick, suffering from muscle aches and mild fevers. The three men were employed at Behringwerke AG, the vaccine-producing subsidiary of pharmaceutical giant Hoechst AG, and though their ailments looked like nothing more than the flu, it was quite unusual for influenza to appear during Germany's hot summer months. The men were referred to the Marburg University Hospital.
The following day the three became nauseated, their spleens enlarged and were tender to the touch, and their eyes became increasingly bloodshot. The attending physicians noted that “the patients had a sullen, slightly aggressive or negativistic behavior.”
1
Day by day more workers from the pharmaceutical plant fell ill, as did a doctor and a nurse who tended the patients. By September, twenty-three patients lay in agony in the Marburg University Hospital wards. Some fifty miles away in Frankfurt, six more individuals contracted the same mysterious disease at the German government's Paul Ehrlich Institute. Four were also workers employed in pharmaceutical research, one was their treating physician, and the sixth was a pathologist who performed laboratory analysis of the cases.
At the same time a third outbreak occurred in Belgrade, Yugoslavia, involving a veterinarian and his wife.
The thirty-one cases struck terror in European research circles because of the ferocity of the disease and its spread from patients to their health care providers. Nobody knew what caused the ailment, how it was spread, what treatments might be effective, and/or how many more people might eventually be stricken.
Because the wives of the Yugoslavian veterinarian and one of the Marburg workers had become ill, there was fear the disease could be passed in the air. Nobody knew how the husbands had originally become infected.
They did know the disease was terrible; the adjective most commonly used to describe it was “agonizing.” Each patient suffered the same excruciating chain of events. After a couple of days of flu-like muscle aches and fever, they began to show classic symptoms of acute viremia (physical responses to a flood of newly made viruses into their bloodstreams): large tender lymph nodes along their throats, inflamed spleens, a marked drop in the number of disease-fighting white blood cells, and a sudden shortage of blood platelets and other factors that are necessary to stop bleeding.
By the sixth day the patients were covered with red rashes that made their skin too sensitive to be touched. Their throats were so raw that they couldn't eat and had to be fed intravenous fluids, sugars, and vitamins. Within a week, all were suffering acute diarrhea.
By the eighth day, the rashes gave way to a far more painful and alarming reddening of the entire body caused by microscopic blockages throughout the thousands of tiny capillary networks immediately under the surface of the skin. Because the capillaries were blocked, red blood cells backed up, giving the patients a crimson glow. With the red blood cells immobilized, the oxygen those cells normally carried throughout the body was not reaching its destinations. Nerves responded by causing searing pain.
By the tenth day patients were vomiting blood.
At the three-week mark their skin peeled off, as oxygen- and nutrient-starved cells died by the millions. Most painful was the peeling along the patients' genitals; the testes of some of the men were damaged, shrinking in size.
The doctors noticed a remarkable similarity between their patients' symptoms and those of the acute phase of hemophilia. In both diseases blood loses its ability to coagulate properly, and some larger blood particles such
as platelets get blocked up in peripheral capillaries, while the smaller blood-clotting molecules that normally prevent uncontrolled bleeding simply disappear.
The patients were bleeding to death. As the Frankfurt doctors put it: “Blood is pouring from all apertures.”
2
But this wasn't hemophilia—it was a contagious disease; one of the Marburg medical team led by Drs. Rudolf Siegert and Gustav Adolf Martini felt justified in labeling it “a new and up to now unknown disease.”
3
By December 1967 seven of the patients had died. Most succumbed within sixteen days of their first symptoms. Some had clearly suffered a brain-related stage of the disease, becoming severely confused, even demented, in the second week of their illness and then falling into deep comas from which they never recovered. Two of the patients' hearts simply couldn't bear the burden of pumping so much thick blood, and eventually gave out; they died of massive heart attacks.
For the survivors, the long-term effects of the disease were often serious. Several had permanent damage to their livers, leaving them in a lifelong state of chronic hepatitis. All had lost large amounts of weight. One man became psychotic and never recovered from the psychiatric impact of the ailment. A few of the men were left impotent and with no sex drive.
While physicians in Frankfurt, Marburg, and Belgrade tended to their patients, the World Health Organization assembled a multinational search for the cause of the disease. It seemed obvious the patients had a viral hemorrhagic disease, but attempts to extract the virus based on probes used for other known hemorrhagic diseases (including Machupo and Junin) failed. It seemed this was something altogether new.
All of the original cases in Germany and Yugoslavia involved men who worked with monkeys. Furthermore, investigators discovered, each of the men had handled animals, or the tissue of animals, from the East African nation of Uganda. The investigation narrowed when it was learned the monkeys were all of the same species:
Cercopithecus aethiops
, a type of vervet monkey common throughout Africa.
The investigators hit pay dirt when they determined that all the monkeys came from three shipments of wild animals transported from Uganda to Belgrade, then on to Marburg and Frankfurt. When the first shipment of animals arrived in Belgrade, 49 of 99 monkeys were dead, and the survivors were placed under quarantine. The Yugoslavian veterinarian who autopsied the dead animals contracted the disease a week later. Shortly after that, his wife, having nursed her husband at home, also developed what would eventually be dubbed Marburg disease. The veterinarian's autopsies of the dead monkeys revealed that the animals also had suffered massive hemorrhages. Two subsequent shipments of Ugandan monkeys contained large numbers of dead animals.
Martini, Siegert, and their colleagues discovered strange viruses in the blood and tissue of the monkeys. When samples were injected into guinea
pigs, the laboratory animals died in a matter of days. But when mice were injected, nothing happened; the mice were somehow able to withstand the virus.
Microscopic studies revealed that the Marburg virus could be found in two different forms. The first looked like a caterpillar, with its long, thin, tubular shape coated with “fuzz.” Inside the tube was RNA (ribonucleic acid), the genetic blueprint of the virus. The “fuzz” along the outside of the virus's protein tube was a constellation of extruding protein receptors the virus used to gain entry into target cells.
In its more mature and dangerous form, the viral tube was rolled up into a tight round coil that appeared virtually invulnerable to assaults from the cells and antibodies of an ailing creature's immune system.
In late August, Jordi Casals answered his phone at the Rockefeller Foundation laboratory in New Haven, Connecticut, to hear an operator say, “Now listen carefully, this is Germany talking to you.” The Barcelona-born scientist waited patiently, listening to the roar of the transatlantic telephone cable.
“Dr. Casals?” the caller shouted over the noisy line. “This is Dr. Lehmann-Gruber calling from Marburg, Germany. We need your help.”
Casals had the largest collection in the world of insect-carried and hemorrhagic viruses, stored under careful security in deep freezers inside the Yale arbovirus laboratory. A few hours after Lehmann-Gruber's entreaty, a similar call for Casals's expert assistance came from the Frankfurt group, which told the Rockefeller scientist they were terrified. Both groups, the callers said, had been doing research using monkey kidney cells, and in just three weeks' time sixteen people had come down with severe hemorrhagic disease and seven had died.
“The people go into shock, they hemorrhage from their noses, anuses, stomachs, mouths,” a very anxious Lehmann-Gruber said. “We are at our wit's end. We need your help.”
As the Germans described the frightening symptoms, Casals thought of his friend Karl Johnson's near-death bout with Machupo. Since the Bolivian incident, Casals and Johnson had become the world's experts on hemorrhagic diseases, Johnson operating out of Panama and Casals at Yale University, where he ran the Rockefeller Foundation's arbovirus laboratory.
The Germans desperately wanted to know what was killing their laboratory workers, and they begged Casals to screen patient blood samples against all the viruses in his Rockefeller facility. Casals agreed, with the stipulation that they only send serum samples from patients who had survived the disease. That way, he reasoned, the samples would be free of lethal viruses but would contain antibodies that should react against some virus in his vast Yale collection.
For several weeks Casals and his staff tested the German blood samples against hundreds of viruses, but none gave a positive reaction.
Casals called Lehmann-Gruber, telling him, “It's not anything we have
here in the laboratory. It might be something distinct, something completely new.”
In September 1967 a WHO team was sent into Uganda to find out where exactly the monkey virus originated. They tested monkey serum samples taken from wild animals that had been processed for shipments to zoos and research laboratories all over the world. As early as 1961 some monkeys captured near Entebbe and Kidera were infected with Marburg, and the numbers of infected animals, as evidenced by their stored blood samples, increased each year thereafter until late 1967, when a third of some monkey groups carried the virus.
All the actively infected monkeys were of two species: the vervets (African green monkeys) and red-tailed monkeys. Some other animals captured for the study had antibodies to Marburg virus, indicating they had been exposed to the microbe: chimpanzees, baboons, talapoins, and gorillas. It seemed an epidemic had broken out among Ugandan monkeys sometime around 1961, reaching a serious level by 1967. In laboratory studies, it was possible to infect rhesus macaques and a variety of other primates from the Old World (African and Asian animals), but it was not possible to infect New World monkeys or apes (those species from the American continents).
Experimental infection of Old World primates proved, alarmingly, to be 100 percent fatal. Yet it was clear that many, if not most, monkeys that were infected in the wild survived. The paradox was, indeed, puzzling.
In years to come researchers would make many forays into East African wilderness areas in pursuit of solutions to that paradox, as well as a larger one: where did the virus come from? As with most viruses, it was assumed Marburg had a reservoir, a species of some insect or warm-blooded animal in which the virus harmlessly resided and quietly reproduced. The relationship between such viruses and their reservoirs was commensal; neither organism was harmed, over decade after decade of coexistence. But if that reservoir species came in contact with a vulnerable animal, such as a human being, the virus might jump its peaceful ship for the new, highly susceptible vessel, producing an epidemic. When that happened a disease that had existed unnoticed for centuries in other species might suddenly appear “new” when it attacked human beings.
For three years researchers from the United States, Europe, and East Africa scoured Uganda and Kenya in search of a Marburg reservoir. They tested every monkey, ape, rodent, mosquito, tick, hyena, canine, feline, and bovine they could get their hands on. But no reservoir of the virus was ever found.
In the face of this mystery, WHO could not anticipate when or where Marburg might reappear. The agency could only remark on two facets of the German/Yugoslavian outbreak that were responsible for the spread of the virus from monkeys to humans.
4
First, said the agency, it was clear that quarantine and export procedures for wild primates were inadequate. All wild animals should be quarantined
in the country in which they were captured for a minimum of three weeks, and once quarantine was completed, transport outside the country should be very rapid, preferably by air. The numbers of human beings exposed to the animals during quarantine and transport should be kept at a strict minimum. And during transport, animals, particularly primates, should be separately caged and kept a sufficient distance from one another to ensure there is no clawing or biting during the stressful voyage.
Once animals reached their destination, WHO said, “it is recommended that national veterinary authorities should supervise import and quarantine” for a minimum of six weeks. During the lengthy quarantine period, the animals should, again, be separately caged to avoid spread of disease within the colony, and the numbers of human handlers ought to be minimized. It was considered too obvious to mention that animal caretakers every step of the way should wear appropriate gloves and protective garb, take steps to ensure that they are not bitten by the animals, and remain ever vigilant against allowing animal fluids or tissues to come in contact with any skin cuts or their mouths.
5

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