The Mosquito
Page 45
The unintended consequence of DDT’s resounding initial success was that during its potent reign, research on malaria drugs and other pesticides languished. After all, “if it ain’t broke don’t fix it.” Research and development for alternatives stagnated from the 1950s through the 1970s. Following widespread mosquito resistance to DDT, the world was left without the proper tools to carry on the fight against our reconstituted and resurgent enemy. “Between 1950 and 1972, various U.S. agencies spent roughly $1.2 billion on malaria control activities, almost all of which employed DDT,” points out Randall Packard in his well-crafted book The Making of a Tropical Disease. “The declaration of the World Health Assembly, terminating the Malaria Eradication Programme in 1969, resulted in a decline in interest in malaria-control activities.” As a result, says Packard, this “declining interest in malaria control, combined with a general recognition of the difficulties of demonstrating the economic benefits of control, led to a parallel decline in studies directed at this problem during the late 1970s and the 1980s.” During these decades, the birds and bees returned but so, too, did a worldwide onslaught of strutting mosquitoes and a shattering surge of mosquito-borne disease. Her immunity to DDT developed relatively quickly, adhering to Friedrich Nietzsche’s 1888 will-to-power proverb that “Out of life’s school of war: What does not kill me makes me stronger.” Draped in her invincible cloak of immunity, she was resurrected from her hibernating slumber stronger and more starving than ever.
In 1968, for example, Sri Lanka ceased spraying DDT, prematurely as it turned out. Immediately, malaria tore through the island, infecting 100,000 people. The following year infection rates had climbed to half a million. By 1969, the year the WHO ended its fourteen-year Malaria Eradication Programme costing $1.6 billion (roughly $11 billion in 2018 dollars), India reported 1.5 million cases of malaria. In 1975, there were over 6.5 million documented cases of malaria in India. Mosquito-borne disease rates in South and Central America, the Middle East, and central Asia reached pre-DDT rates by the early 1970s. Africa, as always, was consumed by mosquito-borne disease. Even Europe experienced a malaria outbreak in 1995, with 90,000 reported cases. Currently, European clinics and hospitals treat eight times more malaria patients than in the 1970s, and malaria rates in central Asia and the Middle East have increased tenfold.
As DDT-resistant mosquitoes multiplied and expanded their range, given the chemical’s poisonous, carcinogenic properties, it was now under siege, peppered by a cloudburst of intense media, academic, and governmental scrutiny. Biologically outflanking our best weapon of extermination, mosquito populations and their diseases had rebounded and made a career comeback for world domination. Not that they ever officially retired from nature’s game of evolution or Darwin’s eternal struggle of survival of the fittest. “In 1969, WHO officially gave up the goal of eradication for most countries,” explains Columbia University professor of history Nancy Leys Stepan, in her comprehensive book Eradication, “recommending instead that they return to malaria control—a policy prescription that in many cases turned out to be a recipe for the collapse of antimalaria efforts. Malaria returned, often in epidemic form.” General MacArthur’s wartime mosquito crusader, Dr. Paul Russell, blamed “resistant strains of Homo sapiens” for the botched program, explicitly calling out corrupt bureaucrats, scaremongering and ignorant environmentalists, and a capitalist crusade that squandered money and resources.
Although the failures of DDT were well documented and America banned its domestic use in 1972, the US, as the largest producer of the pesticide, continued its export until January 1981. Five days before leaving office, President Jimmy Carter issued an executive order prohibiting the export of domestically banned substances from the United States under the Environmental Protection Agency, which had been established in 1970 as a result of Rachel Carson’s green revolution. “It emphasizes to other countries,” Carter announced, “that they can trust goods bearing the label ‘Made in USA.’” Following America’s lead, a domino effect of DDT bans toppled the short-lived reign of the insecticide. China ceased production in 2007, leaving India and North Korea as the sole manufacturers (roughly 3,000 tons per year) of the forlorn relic once championed as a miracle cure. DDT, once a matchless mosquito killer and dignified lifesaver, was dead in the water. Unfortunately, so, too, were our frontline drugs to combat malaria.
While the mosquito was reinforcing her armor-plating against DDT, the malaria plasmodium evolved to resist every successive generation of new medications. “Despite the fact that we’ve known about malaria since ancient times,” surmises Sonia Shah, “something about this disease still short-circuits our weaponry.” Quinine, chloroquine, mefloquine, and others have all been rendered obsolete, outsmarted by the primal survival instincts of stalwart, stubborn malaria parasites. Definitive quinine resistance was discovered in 1910, although most certainly occurred much earlier. In 1957, twelve years after chloroquine’s introduction, doctors in the US encountered chloroquine-resistant malaria parasites in the blood of oil drillers, backpackers, geologists, and aid workers returning home from Colombia, Thailand, and Cambodia. Subsequent tests on local populations confirmed the malariologists worst fears.
In just over a decade, the doughty parasite had refurbished itself to confront and defy the top-tier antimalarial drug chloroquine. By the 1960s, “chloroquine was being consumed around the world on a massive scale,” acknowledges Leo Slater, “and the parasites were adapting.” By this time, the drug was useless across most of Southeast Asia and South America, while chloroquine-resistant mosquitoes were thriving in the heavily dosed regions of India and Africa. By the 1980s, it was no longer effective anywhere. With no suitable alternatives or new-generation treatments available, cheap stockpiles of chloroquine were administered by aid organizations in Africa until the mid-2000s, making up 95% of antimalarial doses.
The parasite continued to spit out our successive frontline defensive drugs as fast as we could produce them. Resistance to mefloquine was confirmed only one year after its commercial release in 1975. A decade later, mefloquine-defiant malaria cases were being reported worldwide. During the recent combat deployments of coalition troops to malarious zones, including Somalia, Rwanda, Haiti, Sudan, Liberia, Afghanistan, and Iraq, the side effects of mefloquine surfaced like the ghosts of atabrine from the Second World War. In 2012, during a United States Senate committee hearing, researchers listed “vivid nightmares, profound anxiety, aggression, delusional paranoia, dissociative psychosis, and severe memory loss” as common, sometimes permanent, side effects labeled “severe intoxication syndrome.” These symptoms are certainly not beneficial to a soldier in combat. Along with post-traumatic stress disorder (PTSD) and traumatic brain injury, the expert testimony entered this syndrome as “the third recognized signature injury of modern war.” This mefloquine poisoning has gradually been receiving reinforced media attention, as soldiers and veterans are speaking out about their symptoms and grievances. Although the numbers are relatively small, American troops, and soldiers from other contributing nations of the coalition, have contracted malaria and dengue in all these recent operations.
The best treatments currently available, particularly for the lethal falciparum strain, are called artemisinin-based combination therapies (ACTs)—essentially a cocktail of various antimalarial drugs layered around an artemisinin core (think of a jawbreaker with assorted candy coatings surrounding a gumball center). ACTs, however, are relatively expensive, costing roughly twenty times as much as other, less effective antimalarials, including primaquine. Artemisinin-based combination therapies work by bombarding the parasite with multiple drugs that target different proteins and pathways of the malaria plasmodium, essentially overwhelming its ability to fight back on so many simultaneous fronts. Malaria finds it difficult to continue its impressive generative cycle, including its furtive dormancy in the liver, while fighting for its life. The artemisinin component is the knockout punch as it reinforces other drugs by j
amming and targeting multiple sites and processes rather than a single protein or pathway.
The medical properties of artemisinin, derived from a common wormwood plant indigenous throughout Asia, have been both known and forgotten by the Chinese for millennia. As you may recall from Chapter 2, tucked away inside a 2,200-year-old Chinese medical text with the uninspired title “52 Prescriptions” is a blunt description of the fever-curing benefits of consuming bitter tea made from the small unassuming shrub Artemisia annua. We have come full circle with artemisinin, paradoxically one of the oldest and newest antimalarials in our evolving medicine chest.
Its antimalarial properties were rediscovered only in 1972, by Mao’s Zedong’s Project 523—a secret, highly classified malaria research venture run by the People’s Liberation Army at the request of North Vietnam, which was embroiled in a quagmire of war and disease with the United States. Malaria was a constant burden for all combatants during the protracted conflict. With the insertion of foreign troops popping ineffective chloroquine tablets and the upheaval and mass migrations of unseasoned populations in Vietnam, Laos, Cambodia, and the southern provinces of China, malaria flourished in this tropical “Pearl of the Far East” paradise. “The Vietnamese jungle soon became the world’s premier incubator of drug-resistant malaria,” reports Sonia Shah in her analysis of Project 523.
Zhou Yiqing, a Chinese physician and member of Project 523, remembered being “ordered to conduct field research on tropical diseases in Viet Nam. China was supporting North Viet Nam and providing it with medical aid. Following orders, my comrades and I travelled along the Beibu (Tonkin) Gulf and through the Ho Chi Minh Trail in the jungle—it was the only way to maintain supplies for North Viet Nam because the United States of America had bombed it so intensely. We were accompanied by showers of bombs during the trip. There, I witnessed rampant malaria that reduced the combat strength by half, sometimes by up to 90% when the soldiers became ill. There was a saying, ‘We’re not afraid of American imperialists, but we are afraid of malaria,’ although in fact the disease took a huge toll on both sides.”
Combating the Mosquito Enemy in Hoa Long, South Vietnam, 1968: Corporal Les Nunn of the 1st Australian Civil Affairs Unit sprays a Vietnamese village using a portable swing-fog insecticide machine in a bid to cut down the high rates of malaria among Australian soldiers and Vietnamese civilians. The spraying teams were preceded by mobile loudspeaker vans broadcasting an explanatory message to villagers. (Australian War Memorial)
During peak mosquito season, North Vietnamese columns pouring down the Ho Chi Minh Trail, snaking south through the jungles of Laos and Cambodia, reported malaria rates reaching 90%, confirmed by Zhou Yiqing’s eyewitness account. Only by comparison were the Americans better off. Between 1965 and 1973, there were roughly 68,000 in-country admissions for malaria, translating to 1.2 million sick days. It is likely that the actual infection rate, including those who did not seek medical attention, was much higher.* Repeatedly, as we have seen, human conflict has been the catalyst for innovation and invention in our war on mosquitoes. The resurrection of artemisinin as a malarial assassin from the pages of antiquity was no different.
In 1967, the father figure and leader of North Vietnam, Ho Chi Minh, appealed for help from Zhou Enlai, a senior Chinese politician who had survived the sweeping purges of Mao’s Cultural Revolution. With China already fortifying their Vietnamese ally with military hardware and financial handouts, the call for aid had nothing to do with the South Vietnamese or the Americans. Assistance was requested to neutralize and defuse a far more lethal and debilitating enemy. Malaria was sapping the combat strength and hampering the campaigns of Ho Chi Minh’s North Vietnamese Army regulars and his Vietcong communist guerrillas. Zhou Enlai encouraged Mao to initiate a malaria program “to keep allies’ [North Vietnam] troops combat-ready.” Mao didn’t need much convincing as 20 million Chinese contracted malaria during the 1960s. “To solve your problem,” Mao responded, acquiescing to Ho Chi Minh’s request, “is to solve our problem.”
On May 23, 1967, roughly 500 scientists initiated the military-malaria program code-named Project 523 after the calendar day (5/23) of its official launch. “The story I will tell today,” began Tu Youyou when accepting the 2015 Nobel Prize, “is about the diligence and dedication of Chinese scientists during searching for antimalarial drugs from traditional Chinese medicine forty years ago under considerably under-resourced research conditions.” Ironically, the cutting-edge malaria research conducted by Tu Youyou and her team materialized during Mao’s Cultural Revolution, which, like his earlier Great Leap Forward fiasco, was defined by systematic oppression, wholesale famine and starvation, and mass executions. During Mao’s sociocultural crusade to install his own perverted brand of socialist industrial and agricultural collectivism, universities and schools of higher education were closed and academics and scientists, among other intellectuals, were targeted for execution or “reeducation.” Project 523 likely saved many of these avant-garde malaria scholars from a death sentence. Working in utter secrecy and lockdown conditions, these scientists were divided into two streams of study: one seeking synthetic drugs while the other scoured traditional medical texts and tested organic plant-based remedies.
After four years of unsuccessful trials on over 2,000 “recipes” from more than 200 plants, in 1971, Tu Youyou and her colleagues unearthed the ancient reference to artemisinin wormwood as a fever cure. Having honed down the proper preparations of the plant and refined its heat-sensitive active medicinal compound of artemisinin (qinghaosu), in March 1972 she reported that an old remedy was in fact the most promising new antimalarial ever discovered or, in this case, rediscovered. “By the late 1970s, China reported that it had made enormous strides against malaria,” reports historian James Webb, “and the infection rate had been cut by almost 97 percent.” Malaria, at least in China, had finally met its match. By 1990, only 90,000 cases of malaria were reported in China, down from over 2 million only a decade earlier.
The Chinese initially safeguarded their potent antimalarial weapon. The participants of Project 523 were sworn to secrecy. Following the hurried American flight from Saigon marking the end of direct US involvement in Vietnam, the proof of artemisinin’s power was first revealed and published (outside of China) in English in a 1979 academic article in the Chinese Medical Journal, authored by the collective “Qinghaosu Antimalaria Coordinating Research Group.” Seven years after its lifesaving discovery, artemisinin was finally made public and disclosed to the world. Beyond China and Southeast Asia, however, the international scientific community was not initially captivated by, or particularly interested in, ancient Chinese folklore and homeopathic analgesics. When Project 523 was officially terminated in 1981, artemisinin and Tu Youyou’s findings failed to make a global impact or catch the eye of and be courted by any corporate pharmaceutical investors. The only artemisinin production and research taking place outside of China was ongoing at the Walter Reed Army Institute of Research biomedical facility, opened in 1953 near Fort Detrick, Maryland.
“We Are Determined to Eradicate Malaria”: With the aid of DDT and the secret anti-malarial drug artemisinin rediscovered by Project 523, the Chinese launched a dynamic, vigorous, and highly successful mosquito and malaria eradication campaign from the 1950s through the 1970s. The six images depicted in this 1970 antimalaria poster illustrate the propagation and prevention of malaria. (U.S. National Library of Medicine)
Although she had published her work anonymously within China in 1977, Tu Youyou presented her great leap forward with artemisinin to an expert malaria panel at the World Health Organization in 1981. Further delays in mass production were caused by the WHO’s refusal to approve the drug unless production was centered in American facilities. After all, it was the United States that supplied the international agency with the bulk of its operating budget and funding. The height of the Cold War also necessitated that production of such a valuable comm
odity, especially in times of elevated conflict, be housed in a “friendly” nation. The Chinese flat-out refused. By this time, the appeal and the profit of dealing in antimalarials had slowly melted away. Demand and dollar signs were being siphoned away from malaria analysis toward a cutthroat, mad scramble to find a lucrative cure for a new global menace—AIDS.
For wealthy pop-cultured and plugged-in MTV-era westerners, this new bloodcurdling threat hit significantly closer to home than did mosquito-borne disease. With the televised HIV-positive announcement of National Basketball Association (NBA) superstar Magic Johnson to a stunned press on November 7, 1991, followed seventeen days later by the death of Queen’s virtuoso frontman Freddie Mercury from AIDS-related pneumonia, there was no real money left to be made in antimalarials. The mysterious, perplexing human immunodeficiency virus (HIV) and its symptomatic counterpart, acquired immunodeficiency syndrome (AIDS), were consuming public commentary, driving cultural fear, and monopolizing medical research budgets. The promise of a cure meant money-spinning prescription payouts.
When the pharmaceutical giants finally acquired the drug rights to artemisinin in 1994, Western governments began the long process of trials and tests on artemisinin-based combination therapies (ACTs), which were launched in 1999, with approval secured from the US Food and Drug Administration a decade later. ACTs quickly became the antimalarial of choice, earning Tu Youyou, the trailblazer of Project 523, her overdue Nobel Prize in 2015 “for her discoveries concerning a novel therapy against Malaria.” She shared this honor with William Campbell and Satoshi Omura, who developed the drug ivermectin for eradicating parasitic worm infections, including mosquito-borne filariasis and canine heartworm.