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The Good Worms

Not all intestinal parasites are bad. In fact, some may be essential to a healthy immune system, a Tufts gastroenterologist argues

Parasitic intestinal worms and human beings have been inseparable since the Garden of Eden. Calcified worm eggs have been found in the internal organs of mummies dating from 1200 B.C., and Egyptian medicine contains descriptions of what are almost certainly parasitic infections long before that. Worms love dirt and thrive in dirty places. Lucky for the worms, human beings have generally been a messy lot. As Joel Weinstock, professor of gastroenterology and immunology at the School of Medicine and chief of the Division of Gastroenterology at Tufts-New England Medical Center, puts it, “Most people have lived in filth.”

For a homegrown example, he asks us to imagine a boy living in small-town America in the 19th century. The boy runs outside to play in the street, a repository for horse droppings and raw sewage. He cuts through a field barefoot to reach a friend’s house. Worms lie in wait along the earthen path. He races home for lunch. His sandwich and water, unscreened by any health agency or government office, are likely rife with parasites. which causes blindness in Africa and parts of South America, where they are transmitted by sand flies.

Worms have lost ground lately. Starting in the 20th century, it has been taken as a general rule among public health officials in industrialized nations that eradicating the parasites through better hygiene is a smart move. Worms have suffered from bad press forever, and you can understand why. They creep people out, and every so often, they make people retching sick. But, according to Weinstock, the prevailing bias against worms was never really based on hard evidence. It was more of a cultural habit of revulsion carried on unthinkingly.

He snatches a textbook off a shelf and flips to a densely printed chapter that discusses intestinal worms in entirely negative terms. “There,” he says. “Look at that,” indicating the three or four brief citations at the chapter’s end. “There’s not much data behind those assertions.” Not that it ever mattered much to public health activists. “The consensus has been, ‘these things are awful—we’ve got to get rid of them,’ ” says Weinstock, who grew up in Michigan and retains a certain Midwestern openness, a willingness to be surprised, on his features.

And so, with the best of intentions, we as a society have roared down that antiseptic path. Beginning with immense public works projects that encircled American cities around 1900, but even more emphatically since the hygiene craze of the 1950s, when household germs in suburban kitchens were viewed as a threat akin to communism, our water has been filtered, our food purified, and our sanitation improved dramatically. The operating room of modern life has been scrubbed clean.

Many infectious diseases have been drastically reduced or altogether wiped out along the way. That’s the good news. But in a hypothesis that is at once counterintuitive and queasily unexpected, Weinstock argues that we may have gone too far with our cleanup efforts. In the process of ridding ourselves of stubbornly resistant, even deadly pathogens, he says, we have also eliminated a batch of naturally occurring agents that regulate the health of our immune systems. In the words of one of Weinstock’s collaborators, “We seem to have thrown the baby out with the bathwater.”

Lack of Exposure
The background here is ominous. For whatever reason, something is clearly out of whack with immune response in the industrialized world.

Rates of asthma, Type I diabetes, multiple sclerosis, and inflammatory bowel disease—the Big Four diseases that involve a malfunctioning immune system—have risen sharply in industrialized nations over the past half-century. “They’ve gone up like this,” says Weinstock, flicking a thumb toward the ceiling. At the same time, the Big Four remain rare in the developing world.

Trends in asthma are particularly intriguing. The incidence of the disease among British children climbed from less than 5 percent in 1964 to more than 25 percent in 2001. By late 2004, asthma was touching one in five households in the U.K.—one of the highest rates in the world—and killing a British citizen, on average, every seven hours. Meanwhile, the condition remains practically nonexistent in underdeveloped countries with poor sanitary conditions.

Why the upsurge in autoimmune diseases? People often finger environmental causes—chemical exposure of some kind, or more dust in the air, or the greater use of vaccines. But Weinstock, in a moment of inspiration that resembled a comic book lightning flash, turned this idea on its head.

Back in the early 1990s, he happened to be working on two book projects at the same time. One book concerned parasitic worms; the other, inflammatory bowel disease. Weinstock noticed that the first had declined in number as the other rose. “Deworming and the rise in IBD are directly related,” he said. In contrast to what practically everyone in the world believed, the missing worms seemed to be having a deleterious effect on human health.

“What if,” he asked recently as he sought to replay his thinking from 10 or 15 years ago, “the increase we see in autoimmune disease is due to a lack of exposure? What if it’s caused by something that we’re no longer exposed to that we should be exposed to? Let’s start from scratch. Can something affect the immune system because you’re not exposed to it?”

Weinstock’s question took the scientific inquiry in a whole new direction. The mental leap involved had the effect of rendering a negative print of a familiar scene, whereby black goes white and white black, reversing the figure and ground.

Weinstock needed some hard numbers to buttress or refute his working hypothesis that people and worms historically have enjoyed what he calls a “good parasitic relationship.” To gather evidence, he pored through public health data gathered across the American South in the 1930s that showed that as many as 70 percent of the residents carried worms without any ill effect. During this period, only about 400 people had died from parasitic infections—mostly from trichinosis—out of a rural population of millions.

“That’s a pretty small number, given the sample size,” Weinstock points out. “So just how dangerous were these worms?”

Safety Circuits
Consider the lowly parasite. This is a mini-creature—could be a flea, a tick, or a nematode—that attaches itself to a host and relies on that host for survival. Although in general parlance we put the parasite in a lower box than the host, and utter the word in a derogatory tone, nature doesn’t really work that way. The relationship between the two is symbiotic. As Weinstock explains, “The first law of parasitology says that the parasite must impart a survival advantage to the host.” And this makes perfect sense, because evolution has nothing judgmental about it.

Any worm that gets into the body faces a huge, immediate problem. How can the intruder survive when the body’s immune system is poised to destroy it? One tactic is to hide. “Through co-evolution,” Weinstock suggests, “the worm has learned our immune system better than we know, and it modulates our immune system to make itself essentially invisible.” The hypothesis is that this modulation stems from a cellular network of “regulatory pathways” that the worm triggers within the host. In effect, the pathways put a lid on the immune system’s tendency to flare up over infection, holding the response in check.

“We’re better off having these pathways,” Weinstock says. “Everything has to be kept in balance with the immune system or it will destroy you.” David Elliott, a former colleague of Weinstock’s at the University of Iowa who has co-authored a number of articles with him, concurs. The role of worms in the host’s body, he says, is to supply “safety circuits that prevent the immune system from going haywire.” The host’s survival advantage lies right there, in the implications of that last, loaded word. By being intimately involved with each other, both the parasite and the host have improved their odds of living to see another day.

It’s a classic win-win. “The parasite down-regulates the immune system for its own benefit,” explains Rick Maizels, an immunologist at the University of Edinburgh in Scotland who is familiar with Weinstock’s work. “But doing so has wider ramifications, because it also dampens unrelated immune responses such as allergic responses.” Scientists have determined that parasitic worms can suppress allergy by inducing a class of immune cells known as regulatory T cells, which interact with inflammatory cells by sending them “off” signals.

“These regulatory T cells may exist naturally to prevent us from suffering autoimmune disease,” Maizels told a British reporter recently. “We think the mechanism that is protecting us from our immune system is also protecting the parasite from our immune system.”

It’s not all theoretical. Doctors in Brazil have noticed that a group of children began suffering from asthma once they had been removed from their parasite-rich environment and purged of worms. When the children returned home and were once more exposed to the processes of their fecund natural milieu, the asthma went away.

Many gastroenterologists have followed Weinstock’s work with keen interest. J. Thomas Lamont, for one, sounds willing to be persuaded. “I think it’s a very original and unique idea he has,” says Lamont, who is chief of gastroenterology at Beth Israel Deaconess Medical Center in Boston and an associate editor of The New England Journal of Medicine. “If this idea has legs, it’s going to be a breakthrough.”

Have Some Eggs
It didn’t take long for Weinstock to stir up excitement among his colleagues at the University of Iowa. In the mid-1990s he and several Iowa collaborators set out to test his hypothesis. Studies on mice and pigs proved encouraging. The logical next step was human testing, which required approaching the Food and Drug Administration and winning the agency’s approval through normal channels. One can only imagine some poor FDA administrator sitting at his or her desk and muttering, “You want to do what with these worms?”—but eventually the agency said yes, and the studies began. In 1999, six patients with either Crohn’s disease or ulcerative colitis (two principal forms of inflammatory bowel disease) who had not responded to conventional treatment volunteered to participate in an experiment at the Iowa lab. They were asked to swallow capsules containing the microscopic eggs of a helminth known as a whipworm. The whipworm was chosen for its benign characteristics: it could not penetrate the skin or multiply within the body, and had the capacity to colonize for several weeks at most. The hatched eggs were shed harmlessly in the stool.

Researchers found that the Crohn’s disease got better in all six patients. For five patients, the disease went into remission for up to five months, while in the sixth, the condition “improved substantially but did not obtain clinical remission,” according to Weinstock. The patients experienced no negative side effects from ingesting the worm eggs, and after about three weeks, when the patients gradually relapsed, their symptoms did not appear to be any worse than before the experiment.

More recently, the University of Iowa team asked a group of 29 Crohn’s patients to swallow whipworm eggs every three weeks for six months. Once again, these were patients for whom standard treatments had failed. Results were just as impressive as before. By the end of the study, all but one of the patients had shown improvement, with 21 reporting no symptoms at all. The results were published in the gastroenterological journal Gut in 2004.

For anyone who can’t imagine anything more repulsive than popping a vial of whipworm eggs into your mouth, bear in mind that these are patients under duress. Common symptoms of Crohn’s include abdominal pain, bloating, fever, persistent diarrhea, and rectal bleeding, among other torments. “It was almost never a problem” convincing patients to swallow the worm egg capsules because of how desperate they were for relief, according to Robert Summers, director of clinical programs for the gastroenterology division at the University of Iowa and a frequent past collaborator with Weinstock. “They would say, ‘Well, if it has a chance, I’ll do it.’ ”

A double-blind study published in Nature Clinical Practice Gastroenterology & Hepatology in 2005 further confirmed the merit of the Iowa team’s approach. In this study, which involved 60 patients suffering from ulcerative colitis, those treated with whipworm eggs fared demonstrably better than those who took placebos. Summers, who believes that Weinstock’s hypothesis “may have important implications for other autoimmune diseases not related to gastroenterology,” is more convinced than ever of the gold that lies inside the mountain. Over the past decade, he has seen more than 100 Iowa patients treated effectively with helminth eggs without experiencing side effects of any kind. Asked if he knows of any refutation of the team’s hypothesis from experiments done anywhere, he answers simply: “Not really.”

The world is waking up to the news. Maizels, the Scottish immunologist, has been a true believer since he came across Weinstock’s papers on the topic of helminths and immune regulation a few years ago. Maizels calls Weinstock, whom he has invited to speak at the University of Edinburgh, “a leading force” in the emerging field. The two men joined to organize the first international conference on the topic last year, attracting 150 scientists to Germany, where the groundswell of excitement was palpable, according to Maizels. Could worms have a healing effect comparable to what they have already demonstrated in the treatment of Crohn’s disease and ulcerative colitis on other autoimmune disorders such as asthma, Type I diabetes, and multiple sclerosis? For now, that’s only one of many questions looming over the field. Gastroenterological treatments based on Weinstock’s research are currently in development.

In an expansive moment in his office, Weinstock suggests that worm therapy stands a chance to reduce autoimmune disease in Western societies significantly. “It’s not time to open the champagne yet,” he cautions, “but it’s not too early to say, ‘Yeah, these puppies have an effect, and they could play a role in the treatment of disease.’ ”

Elliott, his Iowa colleague, rings the victory bell more forcefully, like some-one calling the world’s doctors and scientists to dinner from the farmhouse porch. “You’ve got all these diseases of developed countries, all these illnesses of development. Why?” he asks rhetorically. “Ours is the strongest explanation. It’s the helminths, guys.”

BRUCE MORGAN came east from Ohio to attend college in 1968, and calculates that he has lost about 14,000 hours of daylight since then. He is editor of Tufts Medicine, the award-winning alumni magazine of Tufts School of Medicine and the Sackler School of Graduate Biomedical Sciences.

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