Milking the Tsetse for All its Worth

February 19, 2012 • Cures, Print, Slideshow, Theme • Views: 1926

by Sophie Broach:

A soft buzzing filled the air in Yale’s tsetse fly insectary, as Brian Weiss heated a pool of cow blood on a metal tray. The warm, humid room mimicked the climate of the tsetse flies’ native African range, where they feast on the blood of live cattle and humans. Weiss, an associate research scientist, carefully fed the flies through a whitish synthetic membrane, and within seconds, their bellies swelled into round scarlet beads.

Weiss hopes that the lab-bred flies in this small, white room will one day yield high-tech ways to fight sleeping sickness in the jungles and savannas of Africa, where the deadly disease ravages communities. But others argue work like his siphons funding and attention away from old-fashioned eradication techniques, such as fly trapping, that could be saving lives today.

From a research standpoint, though, the tsetse fly is one of the most fascinating insects around. Only three in 10,000,000 known insects reproduce the way they do: with live births. “The mother tsetse fly ovulates into a uterus where she supplies [the larva] with milk––like a mammal,” Weiss said, grinning. Tsetse fly milk contains many of the same proteins as human milk and transmits tsetse flies’ unique symbiotic bacteria directly to the young.

Tsetse flies often harbor parasites known as trypanosomes, which rival their hosts in sheer bizarreness. As one of the most ancient eukaryotes, trypanosomes exhibit fascinating variations in their metabolism and genetics. Trypanosomes also cause sleeping sickness.

“It’s a terrible disease. If it’s not treated, it’s 100 percent lethal,” said Weiss, breaking out of his usual cheerfulness for a moment. Clad in a t-shirt that spelled out “Hawaiian Style” in loopy, colorful font, Weiss seemed an incongruous figure to describe the gruesome effects of the disease. Once the parasites cross into the central nervous system, patients experience insomnia, overwhelming daytime drowsiness, and neurological deterioration. Some become violent or suicidal, and finally, all slip into a coma from which they never wake. The World Health Organization (WHO) estimates some 30,000 people suffer from the disease today, and 60 million more may be at risk.

Sleeping sickness affects people exclusively in rural Sub-Saharan Africa. For this reason, it falls into the category of neglected diseases: those tropical diseases First World companies cannot turn a profit from treating. If sleeping sickness affected people in the developed world, Weiss thinks we would already have a cure. “Pharmaceutical companies couldn’t care less about producing drugs or vaccines for [sleeping sickness] because there’s no money in it,” he said.

David Molyneux, a professor of tropical health sciences at the Liverpool School of Medicine, however, doesn’t think we need a new drug or vaccine to eliminate sleeping sickness from Africa. Over the last 50 years, Molyneux has studied trypanosomes and advised health organizations on control programs both from his home in Britain and from West Africa.

“I apologize for being sort of a Luddite,” Molyneux told me at the beginning of our conversation. “It’s just staggering that people don’t apply what we know already. It’s amazing that people have a very narrow view that only high-tech can work,” he said. He advocates simply screening at-risk populations and limiting tsetse fly populations with insecticides and traps.

Molyneux estimates that researchers now know more about the molecular biology and biochemistry of trypanosomes than about any other non-mammal cells, but this deep knowledge has rarely translated into new ways to fight the disease. If all the money spent on high-tech research in labs like the one at Yale had been used for simple, short-term ways to limit sleeping sickness on the ground in Africa, Molyneux said, the disease would no longer exist. He and a small but vocal group of other scientists find the funds spent on research shockingly disproportionate to the funds spent on easy, proven control strategies.

Molyneux points out that French, British, and Belgian colonizers nearly managed to eliminate sleeping sickness from vast swathes of Africa by screening vulnerable populations and trapping tsetse flies. In the early 1900s, the Portuguese completely eradicated sleeping sickness from the island of Principe by enlisting agricultural workers to wear backpacks covered in sticky flypapers. When the colonial powers fell in the 1960s, so did the health programs they had established, and sleeping sickness resurged.

Joseph Ndung’u has replicated earlier colonial successes in modern day Kenya. He served as director of the Kenya Trypanosomiasis Research Institute from 1995 to 2004, and when he first began, Kenya was reporting over 100 new cases of sleeping sickness per year. “By 2004 we were hardly reporting any cases of the disease,” he said. Ndung’u largely credits bands of motorcycle-riding mobile screening teams for the decline.

Concern for fighting sleeping sickness rarely foregrounds research on trypanosomes and tsetse flies. Rather, the fascinating biological characteristics of the parasite and fly draw scientists. But simply studying the organisms that cause the disease does not mean the research will ever affect sleeping sickness control strategies. “There’s no relationship between a trypanosome in a mouse at Yale… and the realities of stopping sleeping sickness in Africa,” insisted Molyneux. “And the people who are doing this research have probably not set foot in Africa anyway,” he said sneeringly.

Weiss has visited Africa, but only on a family vacation. He candidly described the path that led him to study tsetse flies, which had nothing to do with suffering Africans. “Since as long as I can remember, I’ve been interested in insects. Since I was a kid I was playing with bugs and ants,” he said. Weiss eventually decided to pursue a career in entomology. “And I was advised early on that if you ever want to prosper… you should consider working with some sort of insect that spreads disease. Granting agencies are more interested in curing malaria or sleeping sickness than studying the flight patterns of a butterfly,” he said.

One scientist, who edits medical journals on tropical diseases and wished to remain anonymous, has found researchers often overstate the practical implications of their studies on trypanosomes and tsetse flies in grant proposals. Meanwhile, he, like Molyneux, does not see research into new treatment development as “a major priority.” “Some of the figures we see quoted in proposals are outrageous. It’s a bit worrying,” he said. Some exaggerate the number of new cases reported each year or overemphasize the toxicity of available drugs to make their cases for funding seem more urgent,” he said.

“Most of the drugs needed to treat [sleeping sickness] are extremely toxic, and I think five percent of people who are treated die from toxicity of the drugs before the parasites can get them,” said Weiss. The medicine Melarsoprol, to which he was referring, contains both arsenic and antifreeze, and the death rate does indeed fall somewhere between 5 and 10 percent.

Some sleeping sickness patients still receive Melarsoprol today, but now less toxic drugs exist and have largely replaced it. The WHO has used the relatively nontoxic and more effective drug Eflornithine since 2001. Nicknamed the “resurrection drug,” Eflornithine miraculously jolts sleeping sickness patients out of comas, but researchers at Aventis originally developed the ingredient in hopes of creating a lucrative cancer treatment. Another less toxic drug, Nifurtimox, has also appeared recently, but it initially aimed to cure Chagas disease in South America. Neither of these emerged from the sleeping sickness research community.

Some controversial, high-tech ways to combat sleeping sickness, such as Sterile Insect Technique (SIT), have emerged from labs studying tsetse flies and trypanosomes. While Ndung’u’s conventional strategies were reducing disease in Kenya, the International Atomic Energy Agency (IAEA) and the government of Tanzania were using this expensive method to wipe out sleeping sickness on the island of Zanzibar. First, they used low-tech strategies to reduce the number of tsetses, but these efforts stopped just short of completely eradicating them, to Molyneux’s bewilderment. “Why wouldn’t you just use insecticides a little longer and get the numbers down completely?” he asked. Then the IAEA used radiation to sterilize millions of tsetse fly males and released them into the wild. Hapless tsetse females unwittingly mated with sterile males, and the population eventually died out. These sterile males could of course have become infected with trypanosomes themselves, and in the short-term, they might have actually spread the disease the IAEA wanted to eradicate.

Despite the success of SIT on Zanzibar in achieving its end goal, neither Molyneux nor Ndung’u advocated the strategy. Applying the technique on a large scale on mainland Africa would prove absurdly time-consuming and costly, they said. Molyneux called it “completely mad.” When asked about this subject, Ndung’u laughed, explaining that planning for any SIT technology has to begin 10 to 15 years in advance. By Molyneux’s estimates, using SIT to eradicate tsetse flies across all of Africa, after raising and sterilizing male flies from all 23 existing subspecies, would require roughly $19 quadrillion—around 17,000 times the Sub-Saharan Africa’s 2010 GDP.

Molyneaux, Ndung’u, and others worry that the quest for expensive new solutions will lead to more inefficient campaigns like Zanzibar’s and draw money away from simpler methods like those used in colonial Principe and modern Kenya. The research community and groups working on sleeping sickness control in the field sometimes draw funding from the same sources. Ndung’u ticked off a few examples, his voice growing faster and more agitated: “The Wellcome Trust, the E.U., the Gates Foundation.” Such groups have poured money into a search for new drugs that will probably take 10 years to develop, but in Kenya, Ndung’u saw sleeping sickness fall from epidemic proportions to near elimination in less than that amount of time.

Even if a new solution emerged in less than 10 years, it might make little difference. Sleeping sickness continues to plague Africa not so much because health workers lack tools to fight it, but because they lack the opportunities to use existing tools. “Too often, scientists, whoever they are wherever they are, fail to take into account the realities of health in Africa, and how you deliver health in Africa,” Molyneux said.

Few in the developed world can imagine these realities. In the United States, yearly spending on health care exceeds $7,000 per person, according to the WHO. But in the Central African Republic (CAR), that number is $32, and in the Congo, $23. “It doesn’t matter if you have the new magic bullet solution or an old technology, you’re still going to have [the same] problems. This is not a scientific problem. This is a health systems problem,” said Molyneux.

Conflict exacerbates the problemsposed by poor health systems, limiting aid workers’ access to vulnerable populations. Last year, only the war-torn CAR and the Democratic Republic of the Congo reported over 1,000 new cases of sleeping sickness, according to Ndung’u. “You can map sleeping sickness by the number of Kalashnikovs out there,” said Molyneux. The lack of established infrastructure also hinders control efforts. The DRC, a country nearly the size of Western Europe, has only around 300 miles of passable roads.

Weiss’s research at Yale, though, could provide a solution to these previously insurmountable obstacles. He has been working to create tsetse flies that resist trypanosome infection, in other words, tsetse flies that won’t carry sleeping sickness. Trypanosomes live in tsetse flies’ guts along with a kind of symbiotic bacterium called Sodalis. Weiss plans to genetically modify Sodalis to produce a compound that kills trypanosomes. Ideally, millions of these designer flies would be released in Africa, not unlike what occurs during SIT. However, these flies could never spread infection. This plan also takes advantage of tsetse flies’ unique reproductive biology: Tsetse fly mothers would transmit these special genetically modified bacteria to their children when nursing them. Eventually, this kind of trypanosome-killing bacteria would exist in all tsetse flies’ guts in an area, and sleeping sickness could become a thing of the past.

Unlike screening people or administering treatments, no aid workers would need to penetrate dangerous or extremely remote areas to implement Weiss’s technique successfully. “That’s the beauty of it. You could just drop ‘em from an airplane,” he said.

When asked how long before anyone might benefit from this research, Weiss groaned and after a pause, said, “Oh god. Well maybe in an ideal world, if everything worked perfectly… I don’t know, 10 to 15 years.” He has successfully managed to remove Sodalis from the tsetse fly gut, genetically modify it, and reinsert it, but the quest to find a way to make Sodalis produce something that kills trypanosomes without harming the fly continues.

Serap Aksoy, the principal investigator at Yale’s lab, also thinks Weiss’s work will have many applications for the field—eventually. But in the meantime, she hopes studying these organisms could produce unforeseen medical discoveries affecting diseases beyond sleeping sickness. A soft-spoken woman who smiles often, Aksoy explained how research on trypanosomes has already produced important medical discoveries. Scientists studying trypanosomes were the first to learn how infectious organisms can change their surface molecules to repel a host’s immune system, and this knowledge has influenced understanding of diseases ranging from HIV to malaria. “Maybe this didn’t generate immediate solutions for the sleeping sickness community, but people forget about the wide-ranging impact of this kind of research on trypanosomes,” Aksoy said.

“I think this foundation that we’re building will probably open up huge avenues for future generations [to control sleeping sickness],” Aksoy said of her lab’s research in general. She rejected the notion that control efforts in Africa should take precedence over lab research. “I think it’s like comparing apples and oranges. We need both,” she said. So, for now, the dream of a new, better way to fight sleeping sickness thrives in the warm air of the Yale lab, right alongside its humming, well-fed tsetse flies.

Sophie Broach ’13 is a History major in Pierson College. Contact her at sophie.broach@yale.edu.

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