In the 1970s, William Campbell and Satoshi Ōmura discovered a class of drugs called avermectins that have helped to control two of the world’s most debilitating tropical diseases: lymphatic filariasis and onchocerciasis. For their efforts, they were jointly awarded the 2015 Nobel Prize for Physiology and Medicine this week.
But even while the duo are being justly lauded for their work, the diseases they have helped to control still affect more than 150 million people around the world. And the drugs they discovered have arguably reached the limits of their abilities, thanks to a critical limitation that other scientists are now trying to get around.
Lymphatic filariasis is caused by nematodes—parasitic worms that spread through the bites of mosquitoes. They enter a new victim as larvae, which swim to the lymph nodes of the legs and genitals, and mature into adults. When these worms die, they trigger intense inflammation. This blocks the flow of lymph, which accumulates under the skin and causes limbs and groins to swell to gigantic proportions. Thighs can become as wide as torsos. Scrotums can become head-sized. There’s a reason why this disease is also called elephantiasis.
Onchocerciasis is also caused by filarial nematodes, but of a different species. These spread by blackfly bites, entomb themselves in deeper tissues, and release larvae that migrate to the skin (where they cause severe itching) and the eyes (which they can cause blindness). Hence the disease’s other name: river blindness.
The avermectins that Campbell and Ōmura discovered, and especially their most potent member ivermectin, can control the symptoms of these diseases by killing the larval nematodes. But they aren’t cures, because they don’t damage the astonishingly sturdy adults. And since these worms can live for a decade, and can release thousands of new larvae every day, their hosts must resign themselves to years of regular treatments.
So, why can’t we just kill the adult worms?
The answer involves a bacterium called Wolbachia, which colonizes the cells of up to 40 percent of insect species. Since its hosts are themselves the most numerous animals on the planet, Wolbachia can lay a strong claim to being one of Earth’s most successful bacteria. And beyond its normal insect hosts, it also lives in filarial nematodes.
No one is entirely sure what it does in the worms, but it is clearly essential. The nematodes cannot complete their life cycles without these microbes. They couldn’t trigger intense disease, either. When the worms die, they release their Wolbachia into their hosts. And while these bacteria can’t infect us, they can trigger inflammation. Mark Taylor from the University of Liverpool thinks that it’s the combination of immune responses against the worms and their bacteria that leads to the intense symptoms of filarial diseases.
And unfortunately, this means that killing the worms would make everything much worse, because they’d release all their Wolbachia in their death throes. “You get exploding nodules, and scrotal inflammation,” he told me. “You don’t want that. You want to kill the worms slowly, and it’s hard to think how you’d do that with an anti-nematode drug.”
So, Taylor has been aggressively pursuing another option: He’s ignoring the worms and going after the Wolbachia.
In lab tests, he and others showed that removing the bacteria with antibiotics has fatal results for the worms. The larvae fail to mature. The existing adults stop reproducing. And after some time, their cells start to self-destruct. The process is slow, taking up to 18 months, but a slow death is still a death. And since these worms have no Wolbachia to release, they can be slaughtered with impunity.
In the 1990s, Taylor and his colleagues showed that an antibiotic called doxycycline could eliminate Wolbachia from people with filariasis. In Ghana, Achim Hoerauf from the Bernhard Nocht Institute for Tropical Medicine found that doxycycline could sterilize female nematodes in villagers with river blindness. Meanwhile, in Tanzania, Taylor showed that it wiped out nematode larvae in people with elephantiasis. And at both sites, it killed the adult nematodes in around three-quarters of the volunteers, without triggering any catastrophic immune responses.
“For the first time, we were able to cure people of filariasis,” says Taylor. “We can’t do that with standard drugs.”
Doxycycline had other benefits too. In parts of central Africa, it is incredibly hard to treat people with river blindness, because they also carry a second filarial nematode called Loa loa—the so-called “eyeworm.” If you kill the species that causes river blindness, the eyeworms die too, and their larvae are so large that they can block blood vessels and cause brain damage. Go after one nematode, and the other could kill the patient in its death throes. But since the eyeworm doesn’t have Wolbachia, doxycycline won’t harm it. This drug can attack the parasites behind river blindness without inflicting heavy collateral damage.
But like ivermectin, doxycyline has its own weaknesses. Pregnant women can’t take it, nor can children. It also acts slowly, so people need to take several courses over many weeks. In rural, remote communities, it can be hard to get the drug to people over that whole period, much less persuade them to complete their course.
To find a better drug, Taylor set up an international team called A-WOL—the Anti-Wolbachia Consortium—in 2007. With $23 million of funding from the Bill and Melinda Gates Foundation, their mission is to find new drugs that kill filarial nematodes by targeting their Wolbachia symbionts. They have already screened thousands of potential chemicals and found one promising lead—minocycline. It proved to be 50 percent more potent than doxycycline, and the team immediately ushered it into trials in Ghana and Cameroon.
Minocycline is still inaccessible to kids and pregnant women, and is several times more expensive than doxycycline. But A-WOL has since screened another 60,000 compounds and identified dozens more promising candidates. “There’s always the valley of death in drug discovery,” says Taylor. “Things hit one problem or another, but we think we have enough candidates to overcome that.”
The idea is ambitious and the stakes are high. If A-WOL can break this partnership between worms and bacteria, which has been around for 100 million years, he could improve some 150 million lives.
This article has been adapted from Ed Yong’s forthcoming book, I Contain Multitudes.
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