People whose pupils change more dramatically during a visual perception task tend to score higher on a self-reported scale of autistic traits.
A father’s determination to help his son resulted in an experimental treatment for autism that uses roundworms to modulate inflammatory immune responses. Can the worms be used to treat other diseases?
February 1, 2011|
OVAMED In 2005 the Johnson family was at its breaking point. Lawrence, the family’s 13-year-old son, was diagnosed with autism at age two and a half, and his parents had valiantly coped with his illness for the ensuing decade.
Throughout his childhood, Lawrence’s disorder progressed along the typical path: he would not engage in pretend play like other children, he repeated himself incessantly, his interests were very restricted, and he was frequently agitated and anxious.
By his teenage years, Lawrence had veered into the dangerous realm of self abuse. He smashed his head against the wall dozens of times a day. He bit himself until he bled. He gouged at his eyes and tore at his face. A normal school experience was virtually impossible. He couldn’t walk a single block from the family’s Brooklyn brownstone without kicking and screaming when a traffic light changed at the wrong moment or streets were crossed in an unacceptable order. “If people haven’t actually experienced those symptoms of autism, they’re the killer,” says Stewart, Lawrence’s father. “They’re the things that destroy families.”
Over the years, the Johnsons tried several treatments to curb Lawrence’s violent and disruptive outbreaks. They started with applied behavior analysis when he was young, and attempted interventions ranging from dietary modifications to music therapy. Lawrence took every pharmaceutical that could potentially treat his problems—antiseizure medications, serotonin-reuptake inhibitors, atypical antipsychotics, lithium, and others in various combinations.
Some of these treatments offered the family momentary reprieves from what Stewart calls Lawrence’s “freak outs.” But any improvements in the boy’s behavior were usually short-lived. “Of all of them, the only one that gave us a brief respite was risperidone [a potent antipsychotic], and that actually did, for a brief window, stop his agitation and aggression,” Stewart recalls. But after a year or so, the drug stopped working. While still on risperidone, Lawrence began to gain weight rapidly and his daily bouts of violence and aggression returned.
When traditional pharmacotherapy failed, Stewart began to search outside the medical establishment for ways to help his son. “Lawrence was somebody who had had several trials of other medicines that have been well studied and really hadn’t gotten a therapeutic response,” says his doctor, Eric Hollander, then the head of Mount Sinai Medical Center’s Seaver Autism Center in New York City.
But Stewart, a portfolio manager in Manhattan, eschewed unproven and potentially dangerous alternative autism treatments, such as chelation therapy or intravenous hydrogen peroxide, to which some parents fall prey. Instead he employed a scientific approach, combing Web sites like PubMed and MedLine for published literature on promising treatments. “A large part of my free time and a lot of time I should have been sleeping was given over to researching what, if any, ways there are to try and get a handle on some of these symptoms,” Stewart notes. “I wasn’t looking to cure autism. I was looking for a way to make our lives bearable.”
His search would lead him to an idea that, on its face, might seem just as farfetched as some of the alternative autism treatments Stewart calls “junk science.” He discovered the work of a trio of physician/researchers at the University of Iowa who had successfully treated patients with Crohn’s disease and ulcerative colitis using a nematode parasite found in the intestines of pigs—Trichuris suis, the pig whipworm. Both are autoimmune disorders in which the immune system essentially attacks the intestinal walls. Stewart also found data that pointed to a link between some autism symptoms and inflated levels of proinflamma?tory cytokines, an apparent result of the immune system attacking glial cells in patients’ brains.[1. D.L. Vargas et al., “Neuroglial activation and neuroinflammation in the brain of patients with autism,” Annal Neurol, 57:67-81, 2005.] Putting these bits of information together, Stewart wrote a short review paper and presented it to Hollander. His central hypothesis was that parasitic worm infection would modulate Lawrence’s immune system and calm inflammation that was causing his disruptive behaviors.
“I had never heard of it before,” Hollander, now at the Montefiore Medical Center University Hospital of the Albert Einstein College of Medicine, admits. “It was a new thought. I looked into the literature and there did seem to be data supporting the basic hypothesis and some data in other conditions in terms of efficacy.” Hollander was impressed with Stewart’s research and agreed to help him obtain sterile, treatment-grade T. suis eggs that were being grown and tested in Europe by the German company OvaMed.
Stewart and Hollander were reassured by the behavior of T. suis in the human gut. Because they have evolved to infect the guts of pigs, the worms only colonize humans in a very limited fashion, are unable to reproduce, and are flushed out of the system after a couple of weeks. Like most internal parasites, T. suis cannot complete its entire life cycle in only one host, and in the environment the ova require a 3- to 6-week incubation in moist soil to mature, making inadvertent spread of the parasites to Stewart, his wife, or daughter unlikely.
After obtaining permission to administer the treatment from the US Food and Drug Administration (FDA) under “compassionate use” rules, Stewart and Hollander navigated customs protocols to import OvaMed’s formulation of T. suis ova, called TSO. They had Lawrence drink a solution containing 1,000 of the roundworm eggs every two weeks for 5 months beginning in early 2006.
The results were beyond disappointing. Lawrence’s aggressive and agitated behaviors abated for just four days during the entire 20-week treatment period. “There were only those four days,” Stewart recalls. “Each day subsequent, he went right back to his old self.”
Stewart started looking at residential schools where Lawrence could live under the constant supervision of healthcare professionals. “We couldn’t live like that anymore. We were at our wit’s end,” he says.
But when Stewart contacted OvaMed’s president Detlev Goj to inform him of the dispiriting results, his hope was renewed. Goj told him that Lawrence’s response to the low dose of worm eggs—1,000 ova every two weeks as opposed to 2,500 in the promising Crohn’s and ulcerative colitis trials—actually fit the profile of a potential responder. He recommended that they give Lawrence 2,500 eggs every two weeks for a period and see what happened. Stewart relayed the information to Hollander, and they prepared to conduct another trial, this time at the full dose.
The research that initially stoked Stewart’s hopes for treating his son using parasitic worms was conducted a few years earlier in the University of Iowa lab of Joel Weinstock, who is now head of gastroenterology at Tufts University in Boston. Weinstock, along with his colleagues Robert Summers and David Elliot, hit upon the idea of treating inflammatory bowel diseases by infecting patients with roundworms after finding epidemiological evidence linking worms and autoimmune diseases.
The Iowa researchers knew that when people moved from less developed to more developed countries, the rates of autoimmune diseases rose in the immigrant population. For example, in populations moving in the 1970s and 1980s from India, a country with high incidences of worm infection, to the United Kingdom, where such infections are rarer, the incidence of Crohn’s disease increased rapidly.[2. V. Jayanthi et al., “Epidemiology of Crohn’s disease in Indian migrants and the indigenous population in Leicestershire,” Q J Med 82:125-38, 1992.] And in the 1930s and 1940s epidemiologists had found virtually no occurrence of bowel disorders in children living in the rural southern states of the United States. Because pig farming was done on a regional basis and many rural dwellers lived in close proximity to their livestock, worm infections were much more common outside urban areas. As nationwide programs were launched to tamp down worm infections among rural populations and migration to urban areas increased, autoimmune diseases became more prevalent.
Weinstock and his colleagues hypothesized that rather than the presence of some environmental factor leading to the uptick in certain autoimmune disease, perhaps the absence of something was to blame. Maybe steering clear of worm infections was also robbing individuals living in industrialized nations or developed urban centers of crucial immune-system modulation that had arisen through millennia of coevolution with these parasites, they reasoned. “This could be a reason why, if people are infected naturally in a developing country, they might not develop inflammatory bowel disease or other immune diseases,” says Robert Summers.
They settled on the porcine whipworm to test their hypothesis, and administered the helminths to a group of Crohn’s disease and ulcerative colitis patients.
In an open-label pilot study, four patients with Crohn’s disease and three with ulcerative colitis ingested T. suis ova. Symptoms improved in all seven patients.[3. R.W. Summers et al., “Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease,” Am J Gastroenterol, 98:2034-41, 2003.]In a larger trial in 2005, nearly 80 percent of 29 patients suffering from Crohn’s disease reported significant alleviation of their symptoms after 24 weeks of treatment.[4. R.W. Summers et al., “Trichuris suis therapy in Crohn’s disease,” Gut, 54:87-90, 2005. Free F1000 Evaluation] The team reported more modest but still promising results in a study testing the treatment on patients with ulcerative colitis.[5. R.W. Summers et al., “Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial,” Gastroenterology, 128:825-832, 2005.]
The Iowa team suspected that their research would be ridiculed, discounted, or followed up on by their colleagues. “We knew that it could be totally ignored, or it may get some real conversation, because anything new makes people talk,” remembers Weinstock.
Though scientists were indeed intrigued by the Iowa research, it took Stewart Johnson’s happening upon the findings and applying them to the treatment of his autistic son for helminthic therapy to really sprout wings.
The Johnson family anxiously awaited the effects of the full dose of TSO on Lawrence’s violent behavior. Within 10 weeks of the higher-dose treatment, the autistic boy stopped smashing his head against walls. He stopped gouging at his eyes. The paralysis and frustration that held him and his family prisoners in their own home lifted. The freak outs ceased. “It wasn’t gradations,” remembers Stewart, who had always kept meticulous notes on Lawrence’s disorder and the interventions they had attempted. “It just went away. All these behaviors just disappeared.” Elated, Stewart called Lawrence’s doctor, Eric Hollander. “He was stunned, because all of that behavior set was gone,” Stewart says. “He was speechless, as I was.”
Hollander and Stewart recognized the potential importance of Lawrence’s reaction to TSO, and after a year or so of closely monitoring the boy’s progress, the researcher asked Stewart to present their findings to his colleagues at the Seaver Autism Center during its annual conference in 2007. Stewart did so, and the team at the research facility, one of the most prominent in the nation, was intrigued. “They were very impressed,” Stewart recalls. “It was very well received.”
The Seaver Center researchers were so impressed, in fact, that they agreed to use the case of Lawrence Johnson as the basis to apply for a more formal clinical trial testing TSO in other autistic patients with severely disruptive and aggressive behaviors. With Stewart’s help, the team submitted an Investigational New Drug (IND) application to the FDA to import and administer TSO for 16 weeks to 10 adult autistic patients with symptoms similar to Lawrence’s.
According to Alex Kolevzon, clinical director of the Seaver Center and the lead researcher of the TSO study, it took some convincing both at the FDA and within the Seaver Center’s own review board to launch the trial. “What I had to convince them of was that we were going to be very safe with using this medicine,” he says. “Everybody who encountered this held it up to a lot of scrutiny.”
Recently, the FDA and Mount Sinai’s internal review board were persuaded to allow the trial on adults to go forward, and Kolevzon and his colleagues are now recruiting 10 patients with the right behavioral profile for the study. Hopes are high for TSO’s potential and for the study’s ability to shed light on the role of immune system functioning in autism. While it may be that TSO will be a benefit, Kolevzon says, “the broader hope is that we’re going to learn something about how the immune system responds to TSO that may lead to other, more targeted treatments.”
Kolevzon’s group at the Seaver Center isn’t the only team of researchers pursuing the treatment approach that Weinstock and his Iowa colleagues launched—and autism isn’t the only disease that scientists are now targeting with the use of parasitic worms. John Fleming, a University of Wisconsin neurologist, is investigating TSO’s safety in multiple sclerosis (MS) patients, testing the treatment as an IND under FDA’s supervision. Fleming was, in fact, the first researcher to start the IND application process, and Kolevzon credits him for laying the groundwork with the FDA that made it possible to get the autism trial started. But Fleming, like Kolevzon, says that getting the FDA to allow him to proceed with the studies was no small task. Fleming’s study, which will treat 18 MS patients with the helminth ova, was approved in a grant from the MS Society in 2004. It wasn’t until last year that the FDA finally allowed him to proceed with the trial under IND rules. “We spent long years in a regulatory wilderness until we got FDA approval,” Fleming says.
Fleming himself needed some convincing when he initially came across the idea. “When I first heard of this I thought it implausible,” he admits. “The evidence from the people in Iowa and thinking about the science behind what they did gradually had an impact on me, and I said, ‘This is plausible and it ought to be tested.’”
While he was awaiting the FDA’s approval to proceed with the helminth studies, Fleming learned of a study in Argentina in which 12 MS patients with naturally occurring helminth infections who were followed for four and a half years showed significantly less neurological damage when compared to 12 MS patients without infections.[6. J. Correale, M. Farez, “Association between parasite infection and immune responses in multiple sclerosis,” Ann Neurol, 61:97-108, 2007.] That study “certainly gave at least some hope that the helminth treatment in inflammatory bowel diseases could be applied in multiple sclerosis as well,” according to Fleming. He adds that he is still recruiting patients for the phase I trial.
Another researcher, Harvard pathologist Marie-Hélène Jouvin, has also convinced the FDA to allow her to proceed with trials of TSO, in her case testing its safety in five patients who suffer from severe food allergies, which are caused by overzealous inflammatory responses to particular environmental triggers. Like her colleagues working with autism and MS, Jouvin holds hope that helminth infection will eventually open new treatment options for people with food allergies as well as a host of other diseases. “From what we know from epidemiological studies with helminth infections and from animal studies and from the clinical studies done by Joel Weinstock,” she says, “it is clear that there is a good chance that TSO could fine tune or modulate inflammation/immunity in many diseases where it is now clear that inflammation/immunity plays a critical role.” Also like her colleagues, Jouvin is still in the process of recruiting patients. As of last November, she had recruited only one.
The three phase I clinical trials underway in the United States using helminth eggs are, by regulation, designed as safety studies, simply testing the suitability of introducing the parasites into the guts of patients. But given the anecdotal evidence that T. suis infestations in humans have virtually no negative side effects, the underlying scientific push is to understand exactly how the worms are acting to modulate immune responses that lie at the root of certain autism symptoms, inflammatory bowel diseases, and food allergies, among other autoimmune diseases.
Science is uncovering more of the intricacies of the human immune system every day. Ten years ago, prevailing thought on adaptive or acquired immunity held that two types of T helper cells—Th1 and Th2—maintained an equilibrium in the body: Th1 cells spur the bactericidal tendencies of macrophages and ramp up cellular immunity against bacteria and viruses, while Th2 cells induce immune system changes that target parasites, toxins, and allergens. From this model scientists predicted that if parasites like intestinal worms could activate a Th2-type response, the Th1 response, which is usually implicated in autoimmune diseases, would be suppressed. In recent years, however, this simplistic model has fallen out of favor.
As more is learned about the complexity of immune responses and more lymphocyte subpopulations come to light, recent theories point to a modulation of T regulatory cells—which function to suppress activation of the immune system and prevent it from attacking the body’s own tissues—by worm infection. “The thought is that the helminth can induce T regulatory cells initially in the gut,” says John Fleming, speaking about the worm’s potential effect in MS patients, “but somehow this changes the whole inflammatory milieu and this translates to less inflammation in the brain.” He cautions, however, that other possible mechanisms could be at play.
Clues to the mysterious mechanism behind the ability of parasitic worms to seemingly calm the immune system also come in the form of case reports from patients with concomitant worm infections and autoimmune diseases. For example, a team of researchers from New York and San Francisco recently found elevated levels of T helper (Th2) cells in the intestinal epithelium of an ulcerative colitis patient who had infected himself with Trichuris trichiura, the human whipworm. At spots in his intestine where the colitis was clearing up, T helper cells initiated the production of a protein called interleukin-22, a cytokine involved in mucosal healing, while genes involved in carbohydrate and lipid metabolism were upregulated.[7. M.J. Broadhurst et al., “IL-22+ CD4+ T cells are associated with therapeutic Trichuris trichiura infection in an ulcerative colitis patient,” Sci Transl Med 2:60ra88, 2010.]
Working with mice, Joel Weinstock and colleagues at Tufts have found a tantalizing new piece of the puzzle. In a recent study using a mouse model of colitis, they found that dendritic cells, which process and present antigens to other immune cells and in this case were functioning in innate immunity, may be just as important as T cells—the principle agents of adaptive immunity—in driving the autoimmune attack on intestinal tissues that is characteristic of colitis. The researchers found that infection with the helminth Heligmosomoides polygyrus could reverse colitis by interacting with dendritic cells to influence pathogenic T cells.[8. L. Hang et al., “Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity,” J Immunol, 185:3184-89, 2010.]
While the complicated mechanisms behind the effect of worm infections on the human immune system will come to light only after many years of careful study, the fact that the FDA has sanctioned preliminary trials is something of a watershed moment. The three ongoing clinical trials with TSO represent the first time that the FDA has allowed studies of a whole-organism therapeutic agent.
Although the FDA cannot legally comment on unapproved products, an agency spokesperson did write that, “The FDA does recognize the potential importance of alternative therapies, including certain intestinal worms,” in an e-mail to The Scientist.
Meanwhile, Lawrence Johnson, now 20 years old, continues to respond positively to treatment with T. suis eggs. Because the parasites are flushed from his system regularly, he takes a dose of TSO as his father sees the need, roughly every two weeks. Though this costs Stewart and his family about 600 Euros a month, he says the treatment has changed their lives and that it’s well worth the price. “There’re no words to describe it. It’s like giving me my son back,” he says. “Or in many ways, like giving me a son that I didn’t ever have.”
Since seeing the positive effects of TSO on Lawrence’s worst behaviors, Stewart has launched a Web site, autismtso.com, to share his family’s experience and inform other parents of current research and the progress of the clinical trial at the Seaver Center. He also wrote a chapter about his experience with TSO treatment in the recently published Textbook of Autism Spectrum Disorders.[9. Textbook of Autism Spectrum Disorders, E. Hollander, A. Kolevzon, J.T. Coyle, eds, Arlington, VA: American Psychiatric Publishing, 2010.]
Even given the remarkable contributions he’s made in the field of helminthic therapy, Stewart remains realistic about his continued contribution. “Am I the one who’s going to find out the underlying mechanism by which helminths interact with the immune system?” he asks. “No. I am definitely not that person. But I got us to this point, and now hopefully others can figure that out, and hopefully there is a connection and this will help other people.”
Correction (2nd February): When originally posted, this article conflated irritable bowel syndrome with inflammatory bowel diseases. The Scientist regrets the error.