The Worm Returns Joel V

COMMENT HISTORY Centenary of the CONSERVATION Suburbanites’ BIOLOGY How life OBITUARY Keith Campbell, equation that launched conflicted relationship with turns random energy creator of Dolly the sheep, crystallography p.186 wild animals p.188 into useful work p.191 remembered p.193 JOEL WEINSTOCK LAB JOEL WEINSTOCK

The whipworm Trichuris suis is currently in trials for treating Crohn’s disease and ulcerative colitis. The worm returns Joel V. Weinstock explains why several clinical trials are deliberately infecting people with helminths to treat autoimmune diseases.

or as long as modern humans have a rapid increase in an entirely new set of to wait until the airport could get up and existed, they have carried parasitic diseases, such as inflammatory bowel running again. worms. That is around 200,000 years. disease (the focus of my research). These I was writing a review article at the time, FLike many bacteria, some roundworms and once-rare diseases, caused by autoimmun- on inflammatory bowel disease, and edit- flatworms (helminths) reside harmlessly in ity, have become relatively common in less ing a book about parasites. That day, I was the gut. Others can cause problems. than a century. Why? focusing on a chapter about how the ‘evil’ Before antibiotics and improvements This question was plaguing me as I properties of intestinal parasites are often in sanitation, gastrointestinal infections sat in a plane on the runway of Chicago’s overblown. Considering the vast number of — mostly with bacteria — killed perhaps O’Hare airport for five hours one day dur- people who have carried them throughout one in five children and many adults. ing the mid-1990s. I was on my way to a history, the occurrence of associated disease Now, thanks to clean food and water and grant-review session is surprisingly infrequent. I was reminded hygienic sanitation, it is rare for a child in for the Crohn’s and NATURE.COM of a classic teaching in parasitology, that a the Western world to die from such infec- Colitis Foundation of Treating multiple ‘good’ parasite imparts some advantage to tions. These advances in hygiene have also America when light- sclerosis using its host — because if the host dies, so does ‘dewormed’ much of the developed world. ning struck the con- helminths: the worm. Clearly, after thousands of years of Meanwhile, the twentieth century saw trol tower, forcing us http://doi.org/jnq co-evolution, the human immune system

PATH OF A PARASITE Infection with helminths prevents e ector T cells from triggering autoimmune reactions through three mechanisms: increasing the activity of regulatory T cells and stimulating cytokine release that dampens e ector T cells (left); turning on macrophages and regulatory dendritic cells that prevent e ector dendritic cells from activating T cells (right); and changing intestinal ora to boost ‘probiotic’ bacteria.

E ector dendritic cells

E ector T cells Regulatory T cells

Change intestinal ora

Macrophage

Helminthic exposures Regulatory dendritic cells Cytokines induce and macrophages

has evolved to handle the presence of blood to the lungs. Humans then cough up One of the last US groups to present with most parasitic worms, which have, in turn, and swallow the larvae, which grow into Crohn’s disease was African Americans4, developed adaptations that enable them to adult worms in the gastrointestinal tract. who are, on average, poorer than their live for years in a human host. Other helminths have even more complex white counterparts. Similarly, in Europe, Was it possible that improved hygiene, life cycles. autoimmune diseases are more common by ridding our bodies of parasitic worms Today, most helminths are found in in the richer Western Europe than in and beneficial bacteria alike, made way for developing countries in which poor sanita- Eastern Europe. the newer problem of immune-mediated tion contaminates water and soil. In Europe Today, Native American reservations, diseases? And could reintroducing para- and the United States such infections are which have relatively high rates of infection sitic worms protect people against those rare, but as recently as the 1930s and 1940s, with parasitic worms, also have lower rates diseases? up to 70% of children in some rural parts of inflammatory bowel disease. Latinos That brainstorm in the middle of a light- of the southern United States carried born and raised in South America rarely ning storm has turned into an active area helminths2. develop this gut disorder. If their children of research. Several ongoing clinical trials, At the time of my insight on the O’Hare are born in the United States, where condi- in which patients with inflammatory bowel tarmac, I had been researching intestinal tions are often more sanitary, they have a disease or multiple sclerosis are colonized parasites for many years. Different species much higher risk of the disease. with an intestinal worm, have produced of worm cause a variety of effects. Some, early evidence that the treatment may be such as Schistosoma, TESTING A THEORY safe and effective. can impair the liver “The first When I returned to my laboratory (then This counterintuitive hypothesis has or bladder. Biliary patient eagerly at the University of Iowa in Iowa City), I captured the imagination of the popu- flukes and some consumed the told my colleagues about my theory. Some lar press, and drawn the opprobrium of species of schisto- 2,500 nearly of them were intrigued and wanted to start sceptics. The World Health Organization some can predispose microscopic experiments. Others thought I was joking. 1 estimates that nearly 50 million chil- people to biliary eggs.” We had access to parasitic worms — dren under the age of five were treated for and bladder cancer, already a focus of our research — and to parasitic worms in 2006. Some of these respectively. Heavy acute infections with mouse models of inflammatory bowel dis- parasites can damage the liver, bladder or some helminths can cause diarrhoea and ease. Sure enough, when we gave the mice eyes. How could such an infection actually nausea. Hookworm can cause iron-defi- enteric worms such as Heligmosomoides improve health? ciency anaemia in heavily infected, suscep- bakeri or Trichuris muris by feeding tube5, tible hosts. or schistosome eggs by injection6, the ani- TOO CLEAN Despite the potential dangers of some mals were protected from autoimmune Helminths, being parasitic, evolved inde- helminths, when I proposed the connection disease. pendently of the ‘worms’ people often between the decrease in parasitic infections To test the therapy in humans, we think of, such as earthworms. Some take and the rise of autoimmunity, I had some selected Trichuris suis, a whipworm that up residence in the gut after the host swal- historical facts on my side. In the United typically infects pigs but can survive for a lows their eggs in contaminated water or States and Europe, Crohn’s disease first few months in people. Evidence suggested food. Even gardening in contaminated soil emerged in affluent populations living in that this was a safe choice — if swallowed, or playing in the mud can cause an infec- hygienic conditions in the more northerly the worm remains in the gut and does not tion. Others, such as hookworm, burrow latitudes, where colder temperatures are pass into the bloodstream, and pig farm- into the body through the skin and ride the less hospitable to soil-borne helminths3. ers are commonly exposed to it without

medical reports of associated illness. on the task of developing T. suis eggs Third, worms seem to alter the bacterial We began with a dose of 2,500 eggs — as a drug. Both the US Food and Drug composition of intestinal flora. Research one investigator in an earlier study had Administration and the European Medi- in mice suggests that helminths promote given themselves a similar dose to prove cines Agency have formally approved the the growth of gut microorganisms typically that this organism could colonize the manufacturing process and allowed fur- considered to be ‘probiotic’, which help to human intestine, and reported no clinical ther testing. maintain intestinal health. symptoms7. We infected pigs with T. suis At present, a multi-centre trial in Europe The more we learn about the changes that eggs, then isolated adult worms from conducted by drug firm Dr Falk Pharma, helminths induce, the more we will under- the infected animals and cultured them based in Freiburg, Germany, is enrolling stand about how autoimmunity develops and in vitro. The worms survived long enough nearly 300 patients with Crohn’s disease; be able to devise more therapies — consisting to produce eggs that could be harvested an interim analysis of the data suggests the of either helminths or agents that mimic their and cleaned for clinical use. treatment is safe. Coronado Biosciences, a actions in the gut. Our institutional review committee gave firm based in Burlington, Massachusetts, “Worms seem For me, the project us permission to try a dose in one patient. and for which I am a consultant, is running to have three has generated the It was not hard to find a volunteer; many a similar multi-centre, double-blind trial major effects gamut of emotions patients with inflammatory disease do not for Crohn’s disease. There are trials under on the immune for nearly 20 years do well on conventional therapy and read- way in multiple sclerosis and autism, and system.” now. The scientific ily seek alternative approaches. The first others set to begin in ulcerative colitis, pso- and medical com- patient in the study had untreatable Crohn’s riasis, type 1 diabetes and other immune- munity initially received the hypothesis disease, and he eagerly consumed the 2,500 mediated diseases. with a mixture of fascination and vocal nearly microscopic eggs, which we gave to Some investigators worry that helminths scepticism. Thankfully, this research him in a popular sports drink. We held our could weaken patients’ immune systems eventually obtained funding from the US breaths. and leave them more vulnerable to some National Institutes of Health and support After six weeks — the time it takes for types of infectious disease, even under from organizations such as the Crohn’s and T. suis eggs to mature into adult worms — careful medical supervision. But as long Colitis Foundation of America. Most of my he reported no adverse events and showed as society maintains its current modern colleagues took a neutral stance, waiting for improvement in disease symptoms that hygienic standards, I consider this risk to more data. Today, studying the effects of lasted for several months. In another trial, be negligible. Given the lack of side effects alterations to intestinal flora and fauna on three more patients with Crohn’s and from helminth therapy, morbidity from health and disease is one of the hottest areas another three with ulcerative colitis all immune-mediated diseases and the toxici- in medical research, and investigations of reported substantial improvements (or ties of modern therapies for them almost the impact of helminths are increasing. complete remission), with no side effects. certainly exceed the risk from helminthic The public-hygiene measures and vac- Eventually, we administered live eggs exposure. cine programmes to eliminate enteric every two weeks for 24 weeks to 29 patients and other types of infections have vastly with Crohn’s disease. By week 24, nearly HOW IT WORKS improved quality of life during the past 80% of them reported a decrease Worms seem to have three major effects 100 years, with many more lives saved in symptoms, and 72% were in on the immune system (see ‘Path of a para- than taken. The goal now is to reintroduce remission — more than one site’). First, they seem to cause changes organisms into people in a controlled and would expect from a placebo that activate regulatory T cells such as predictable way, to prevent immune-medi- effect. None reported side Treg. These cells dampen immune ated disease without increasing the risk of effects8. In another trial of responses and curb autoimmun- serious infection. ■ JOEL WEINSTOCK LAB JOEL WEINSTOCK 54 patients with ulcera- ity — by, for example, ramping tive colitis, about half of up the production of regula- Joel V. Weinstock is a professor at Tufts whom were given placebo, tory molecules such as inter- University and is chief of the Division of 43% of helminth-treated leukin-10 and transforming Gastroenterology and Hepatology at Tufts patients improved after growth factor-β. Medical Center, Boston, Massachusetts 12 weeks, compared with Second, helminths seem 02111, USA. only 17% of those given a to act on other cells — regu- e-mail: [email protected] placebo9. latory dendritic cells and 1. Partners for Parasite Control. Action Against Several pharmaceutical macrophages. These prevent Worms 8 (World Health Organization, 2007). companies have since taken the switching on of danger- 2. Weinstock, J. V., Summers, R. & Elliott, D. E. Gut ous effector T cells, which 53, 7–9 (2004). 3. Shivananda, S. et al. Gut 39, 690–697 (1996). normally leads to inflamma- 4. Sonnenberg, A., McCarty, D. J. & Jacobsen, S. J. tion and disease. Gastroenterology 100, 143–149 (1991). Both of these effects seem to 5. Elliott, D. E., Urban, J. F. Jr, Argo, C. K. & Weinstock, J. V. FASEB J. 14, 1848–1855 (2000). protect from autoimmunity in a 6. Elliott, D. E. et al. Am. J. Physiol. 284, G385–G391 redundant fashion. My colleagues (2003). and I have found that when we block 7. Beer, R. J. Res. Vet. Sci. 20, 47–54 (1976). 8. Summers, R. W., Elliott, D. E., Urban, J. F. Jr, regulatory T cells or regulatory dendritic Thompson, R. & Weinstock, J. V. Gut 54, 87–90 cells in helminth-infected mice, the ani- (2005). mals are still protected from developing 9. Summers, R. W., Elliott, D. E., Urban, J. F. Jr, 10 Thompson, R. A. & Weinstock, J. V. colitis — either type of cell is sufficient Gastroenterology 128, 825–832 (2005). in its own right to protect the mice. This 10. Blum, A. M. et al. J. Immunol. 189, 2512–2520 redundancy may be one of the reasons (2012). Several pharmaceutical firms are developing why helminths are so effective in control- Competing financial interests declared; see eggs of the pig parasite Trichuris suis as a drug. ling these immune-mediated diseases. tinyurl.com/blhntgo for details.