Hookworms are among the oldest life forms on Earth, and when they sink their teeth into our blood vessels, they cause nausea, anemia, cramping, and more. Ancient Egyptians referred to the symptoms in a 3500-year-old papyrus, and Hippocrates may have described miners infected by them. In the early 1900s, an intensive campaign eliminated the worms from the intestines of U.S. schoolchildren and spawned the formation of the U.S. Public Health Service.
Now, after years of viewing hookworms as the enemy, scientists are beginning to wonder whether these tiny critters, shorter than the width of a human fingernail, could also be an ally. Buried in the creatures, many believe, are molecules with healing powers. Scattered studies in diseases like Crohn’s and celiac, as well as self-treatment by patients, suggest the worms might alleviate symptoms of autoimmune conditions—the exact ailments that have become more and more prevalent as hookworms have faded from our lives and general cleanliness has prevailed.
Severine Navarro, an immunologist at James Cook University in Cairns, Australia, is among those on the hunt for these magic molecules, and she believes she has found one: anti-inflammatory protein-2 (AIP-2). In mice with asthma, AIP-2 suppresses airway inflammation, Navarro and her colleagues report, and the protein also appears to damp down the proliferation of some immune cells in the blood of people with allergies.
“It’s a clear demonstration that a single product from a parasite can have sweeping systemic changes that are very favorable,” says Rick Maizels, a parasite immunologist at the University of Glasgow in the United Kingdom, who wasn’t involved in the research.
The work, published today in Science Translational Medicine, reflects a shift in the field, from examining hookworms’ immune effects to identifying the molecules that drive them. The ultimate goal is new drugs based on these prized molecules.
One reason for the shift from worms to molecules they produce is the “yuck” factor—not everyone wants parasites as their medical treatment. “They’d much prefer to swallow a pill,” says William Harnett, a molecular immunologist at the University of Strathclyde in Glasgow. Another is that the parasites are, well, parasites, with all the health downsides that accompany them.
For Navarro, an important development came when she and others in the lab, which is led by molecular parasitologist Alex Loukas, found that it wasn’t the worms themselves that were key, but rather the molecules they were secreting. Whenever lab members got their hands on hookworms, they plopped them in a petri dish. Later they would freeze the worms and, separately, freeze the liquid they had been swimming in. The worms could then be crushed and injected into animal models of different autoimmune diseases, and so could the “soup.”
“When you take the soup it works much better” than the worms, Navarro says. One of her students demonstrated this on a model of ulcerative colitis, a form of inflammatory bowel disease. Navarro tried it in a mouse model of asthma. “It was just pure research, you put your cowboy hat on and go for it,” she says. And “it worked amazingly” well at treating mice with the condition.
In the new work, Navarro, Loukas, and their colleagues built on the lab’s “soup” analysis. Proteomics researchers had found about 100 proteins in the soup, and among the most abundant was AIP-2. So Navarro and the others decided to test it first. Because the worms are hard to come by, they retrieved the protein’s sequence and created more of it. Then they injected it into mice with a version of asthma. The rodents were given a battery of tests measuring lung and immune function, similar to what’s done in human patients.
The treated animals had “almost a complete reversal of disease,” Navarro says. The researchers also found that AIP-2 shifted the balance of different immune cells, including T cells and dendritic cells, which seemed to help suppress harmful immune reactions in the lung. AIP-2 also suppressed the proliferation of T cells in blood from five patients allergic to dust mites—a small clue that the hopeful effects in mice might stretch to people.
Researchers still have a long way to go. Some species of parasitic worm secrete several hundred molecules, says Harnett, who like Maizels and others is hunting for the ones that might target disease. “Some people look at it very positively—it’s like Christmas where you get lots of different things you can analyze.” Although studying some members of this constellation himself, Maizels is also curious to learn more about AIP-2, including exactly how it works.
Meanwhile, Navarro, Loukas, and their colleagues are pushing ahead. The group is hunting for a company to support a clinical trial. The end goal: getting the benefits of the parasites without having to live with them.