The Healthy Human Gets the Worm

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David Mack / Photo Researchers, Inc.

Back in the Stone Age, humans had to put up with all sorts of creepy crawlies. Parasites ran amok in people’s innards, freeloading on nutrient supplies. The parasites took a toll, but over the millennia, those that killed off their meal ticket too quickly didn’t make it. The survivors of this evolutionary shakeout include parasitic roundworms and flatworms, hitchhikers that allow their human hosts to live.

While this scenario might appear to be win-lose, with humans the clear losers, research now suggests that may not be the whole story. In their drive to make humans hospitable hosts, parasites have developed the ability to suppress inflammation aimed against them. And this, it turns out, isn’t necessarily a bad thing.

“They have evolutionarily adapted to this long-standing inter­action with their hosts–that’s us–and developed strategies to help the host dampen its immune response,” says Helmut Haas, an immunologist at the Research Center Borstel in Germany.

These strategies are not subtle. But humans have survived the effects and even adapted well to them: A toned-down immunity is, perhaps, the norm. A sober immune system might still defend against enemies while not overreacting to everyday substances in the environment, or otherwise going awry. Suddenly those prehistoric times don’t sound so bad–no Crohn’s disease, no multiple sclerosis, no asthma.

In a stroke of medical inspiration as bold as it is counterintuitive, scientists are now testing this theory by treating patients with live microscopic eggs or larvae of parasitic worms designed to quell these very afflictions. Several clinical research trials are under way and more are planned. Whether promising early results will lead to treatments for these known or suspected autoimmune conditions–and extend to allergies, type 1 diabetes, and other cases of immune revolt–remains to be seen.

Parasitic worms, or helminths, elicit a visceral response from people–in every sense. Worms don’t make for polite dinner conversation and, in industrialized countries, are considered a relic of days thankfully in the past. The notion that hel­minths are bad guys has been drummed into children of Western nations, as well as their doctors, for several generations. (The Latin name for one hookworm is Necator americanus, meaning “American killer.”)

But helminths have thrived in mammals for millions of years, fine-tuning the parasite act along the way. “These parasites do some harm to the host,” says immunophysiologist Derek McKay of the University of Calgary in Canada. “But if I’m [a parasite] inside a host, at the very least I want the host to reproduce and make more host babies.”

Besides, an all-out immune war on a helminth might damage the gut. “What we have instead is détente,” says David Elliott, a gastroenterologist at the University of Iowa Carver College of Medicine.

Only recently did the advent of better sanitation and potent drugs break up this marriage. Shoe-wearing put hookworms out of business in the United States. But the 20th century also ushered in asthma, allergies, and a host of autoimmune diseases that had been uncommon previously and remain so in less developed countries. All are marked by out-of-­control immunity. Vanquishing worm parasites in particular might have disrupted an equilibrium that kept humans healthy.

Of course, parasitic worms have not really gone away. Some estimates suggest that more than 1 billion people, mainly in the tropics, are infected, giving scientists a chance to study the link between immunity and parasites in context.

In 2003 researchers at the University of Nottingham in England and colleagues found that toddlers living in an Ethiopian city were twice as likely to wheeze–a symptom related to asthma–as kids living in less sanitary rural areas. Similarly, Ethiopian kids with roundworm infections were half as likely to wheeze as those free of parasitic worms.

At about that time in Argentina, physicians Jorge Correale and Mauricio Farez began a study that brought the helminth issue into sharp focus. Previous studies had shown that mice with a disease similar to multiple sclerosis, marked by damage to the fatty sheaths insulating nerves in the central nervous system, improved when they were infected with flatworms.

That prompted Correale and Farez to examine a group of MS patients and identify 12, average age 34, who had recently acquired a parasitic worm infection. Then the doctors found 12 other MS patients who matched the first group in age and other respects, but who didn’t have parasites. The rate of MS relapse had been similar in both groups.

As part of the study, which followed patients for an average of 4.6 years, those harboring parasites agreed not to be treated for them. Perhaps it’s just as well, because MS symptoms in this group became mild to nonexistent. Only three of the patients had a relapse–one apiece–during the study period. The other nine worm-
infected patients had none at all. In contrast, the MS patients without parasites had 56 relapses in all, about one per year each.

MRI scans showed 14 new or enlarged brain lesions in the worm-infected patients during the study and 164 in the other group. Mild anemia showed up in four people with worms, but the other eight had no serious ill effects from the parasites. The results appeared in the Annals of Neurology in 2007.

Despite the dramatic difference, the scientists acknowledged that such observational studies need to be borne out in trials in which scientists randomly assign patients to one of two groups with different courses of treatment.

Maria Yazdanbakhsh, an immune-parasitologist at Leiden University Medical Center in the Netherlands, and colleagues had done just that in Gabon in equatorial Africa. To assess whether a parasitic worm infection protects against allergies, the scientists enlisted 317 schoolchildren, ages 5 to 13, in a study. All of the kids had intestinal parasites, mainly roundworms, but none had an active allergy to house-dust mites. Then researchers randomly assigned half the children to get drugs ridding them of the parasites.

Within a year, 14 percent of the children treated for parasites had developed a dust mite allergy, skin-prick tests showed, compared with fewer than 7 percent of those who retained their parasites. The report appeared in the Journal of Infectious Diseases in 2004.

Some people beset by allergies, asthma, or autoimmune disease saw these early findings and took to stomping around in less-than-sanitary conditions in Central Africa in hopes of acquiring a parasite to cure ailments. Anecdotal evidence suggests it can work, but the approach is unverified and dangerous. Health risks from worm infections can range from mild (pinworm) to debilitating and sometimes lethal (schistosomiasis).

Others have resorted to buying unregulated parasite eggs on the Internet. They are available through an underground market with mixed results, says gastroenterologist Jonathan Terdiman of the University of California in San Francisco. He doesn’t endorse the approach, but he does regularly see patients with inflammatory bowel disease even if they are using it. “A lot of these patients are in great need,” Terdiman says. “The pharmaceutical approach has failed them.”

So controlled clinical trials are needed. To get a treatment trusted and cleared, scientists need to test it on people randomly assigned to get either the real thing or a placebo. This is the gold standard of medicine and, unlikely as it might have seemed a decade ago, it’s where parasitic worm therapy has now arrived.

Joel Weinstock had a perfectly good career as a parasitologist in the early 1990s when he and Elliott, then colleagues at the University of Iowa, noticed the lack of autoimmune diseases in the tropics. They knew about the hygiene hypothesis, which suggests that early exposure to germs is crucial for normal immune function later on. And the two knew about the rise of autoimmunity in the West.

“We asked, ‘What’s missing in developed countries?'” Elliott says. “We still had viruses and bacteria, but we were missing a whole class–helminths–which used to be universal.” Lab work and tests in animals soon convinced Elliott and Weinstock that helminth infection could quell inflammation. By 2000 they were speculating openly that failure to get parasitic infections might contribute to inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

The researchers found an innocuous gut parasite, the pig whipworm Trichuris suis, that didn’t cause disease in people. They asked patients with ulcerative colitis to drink a solution containing either a placebo or cleaned-up, microscopic
T. suis eggs every two weeks for 12 weeks. Roughly half the patients were randomly assigned to receive each. Of 30 people getting the helminth therapy, 13 improved substantially, compared with only 4 of 24 people on the placebo.

Two subsequent studies without placebo comparison groups found that helminth therapy could benefit people with Crohn’s disease. Of 29 Iowa volunteers who got T. suis eggs, 21 went into remission. A British-Australian research team injected hookworm larvae into nine volunteers who had Crohn’s disease. Most showed improvement, marked by less intestinal distress.

Despite the promising findings, helminth therapy isn’t a shoo-in. A placebo-­controlled trial in Denmark found no benefit from whipworm eggs given over three weeks for hay fever, scientists reported in January 2010 in the Journal of Allergy and Clinical Immunology. Another trial, at Nottingham, showed that very small doses of hookworm larvae proved no better than a placebo at controlling symptoms in 32 asthma patients. Those data appeared online in December 2009 in Clinical & Experimental Allergy.

But those results haven’t dimmed interest in the strategy. At the University of Wisconsin in Madison, neurologist John Fleming and his colleagues are testing pig whipworm eggs in MS patients, using what tastes like a sports drink to deliver the eggs. At Mount Sinai School of Medicine in New York City, scientists are recruiting participants to test the treatment against autism, which some people hypothesize has autoimmune links. In Boston, researchers at Beth Israel Deaconess Medical Center plan to try it for peanut allergy. A large Crohn’s disease trial is planned for Europe, Weinstock says, and Denmark will host an MS trial. For some trials, the German company Ovamed GmbH is providing live whipworm eggs that are free of bacteria and viruses and are of uniform size.

Purposely ingesting parasitic larvae or eggs “has an audacity about it,” says Fleming. “It doesn’t seem like mainstream science at first pass.”

Not everyone is sold on the approach. “The problem with giving people helminths is you’re introducing a foreign organism, and that has the specter of unforeseen consequences,” McKay says. Though the pig whipworm eggs currently used in clinical trials don’t cause disease in humans, even the idea is, for some, a bit hard to swallow.

Instead of using live organisms, some scientists propose figuring out and mimicking what parasites do to ratchet down inflammation. The trouble is, Fleming says, “Worms know more about the human immune system than we do.”

McKay and his team have studied the effects of helminth exposure by inducing colitis in rodents and then knocking out this inflammatory condition with a tapeworm infection. In response, the rodents produce more of the immune messenger protein interleukin-10. Other researchers are focusing on anti-inflammatory agents of the immune system called regulatory T cells, or T-regs. Also attracting attention: the inflammation-stopping protein TGF-beta and the immune protein interleukin-22.

These cells and proteins could be the active agents knocking back symptoms in people with autoimmunity who have benefited from helminth therapy, Elliott says. And they might all be necessary.

“It appears it’s a lot like getting a kid to clean his room,” he says. “You offer money, turn off the TV, hide the video games–then the room gets cleaned. Any one thing won’t do it.”

Excerpted from Science News (Jan. 29, 2011), an award-winning biweekly magazine published by the Society for Science & the Public. Reprinted with permission of Science

This article first appeared in the May-June 2011 issue of Utne Reader.

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