A review and update of an important topic

By William Parker and Rajendra A. Morey
Departments of Surgery (WP) and Psychiatry (RAM)
Duke University Medical Center, Durham, NC 27707

Historical Developments

The story of resolving immune dysfunction in Western society is one of uncovering a profound evolutionary mismatch. The story began 39 years ago when a parasitologist, John Turton, intentionally colonized himself with the human hookworm and eliminated his own hayfever [1].  Sadly, the story is littered with long pauses, and Turton’s observations went unappreciated for decades. The story took a new turn in the late 1980s when David Strachan pointed an accusing finger at some aspects of modern sanitation as being responsible for the plague of chronic immune disease affecting Western society [2]. Over the next 20 years, Strachan’s “hygiene hypothesis” evolved into “biome depletion theory” [3], as a large body of work identified the loss of biodiversity from the human body rather than hygiene, per se, as the underlying “evolutionary mismatch” [4, 5]. Graham Rook and others pointed toward the loss of eukaryotic symbionts in particular as being one of the most dramatic changes in the body’s ecosystem as a result of Westernization [6]. Further, a wide range of studies in animal models as well as a limited number of studies in humans pointed toward helminths as potential candidates for biological therapeutics that might alleviate the mismatch [6-8]. Given this information, a solution for chronic immune disease seemed apparent; enrich the depleted biome present in Westernized humans to eliminate pandemics of allergic, autoimmune, and other inflammatory-related diseases. The use of helminths appeared to be a very good place to start.

Recent Developments

In a conversation with Randy Nesse at the National Evolutionary Synthesis Center in 2010, Randy suggested that The Evolution and Medicine Review would be an excellent venue for discussing the idea that enriching biodiversity in the ecosystem of the human body is a necessary approach for preventing and even treating chronic immune disease. As a result, the first treatise, published in October of 2010, called for a paradigm shift in biomedical research, refocusing our efforts on finding appropriate organisms for biome enrichment rather than developing drugs to treat diseases that might have otherwise been prevented. (http://dev-evmedreview.pantheonsite.io/?p=457) In this manner, a fundamental evolutionary mismatch which causes disease could be alleviated, reducing the burden of dealing with the impact of that mismatch on human health.

The opinion piece in The Evolution and Medicine Review was followed by full length reviews, first in Medical Hypotheses  [7], then in Current Medical Research and Opinion [9], then in Evolution, Medicine, and Public Health [5]. These reviews were written with an ever widening list of collaborators in the fields of evolutionary biology (Jeffrey Ollerton, Gregory Wray), psychology (Staci Bilbo), anthropology (Michael Muehlenbein) and parasitology (Sarah Perkins). However, the opinion piece in The Evolution and Medicine Review took on a life of its own. Being widely available on the web and written in a concise style that was relatively devoid of technical jargon, it was noted by several prominent science writers, including Jim Thornton and Moises Valesquez-Manoff. These writers were interested in the practice of “self-treatment” with helminths, a practice that had evolved far beyond John Turton’s first published cure for hayfever.

Citizen Science and helminthic therapy

Perhaps in part due to the attention from science writers and their writing in popular magazines and books, the article in The Evolution and Medicine Review also came to the attention of individuals providing helminths for self-treatment. This, in turn, led to numerous conversations and discussions regarding helminthic therapy between one of the authors (WP) and those involved in self-experimentation with helminths. Understanding the richness of the experience of the self-treaters, in turn, led us and others [10] to appreciate the potential value of this “citizen science” for modern biomedical research. With this appreciation in mind, we worked with Janet Wilson, a social scientist at the University of Central Arkansas, and conducted a series of IRB-approved studies evaluating the practices and results of those self-treating with helminths. Several approaches were used, including interviews with providers of helminthic therapy, distribution of surveys to individuals self-treating with helminths, and compilation/examination of publically available information. The findings were numerous, and have led to new thinking in a variety of areas regarding biome enrichment [11]. The findings can be summarized as follows.

  1. Previous studies showing that helminths can halt the progression of multiple sclerosis [12] and effectively treat most cases of inflammatory bowel disease [13] were confirmed. Further, Turton’s report that helminths treat allergic disease in humans [1], an observation supported by numerous studies in animal models, was confirmed.
  2. Helminthic therapy was found to effectively treat migraine headaches, anxiety disorders, and major depressive disorder. Self-treaters reported effective treatment of bi-polar disorder, but subsequent psychiatric evaluation of their reported symptoms by co-author Morey indicates that these individuals probably had an episodic major depressive disorder that was self-misdiagnosed as bipolar disorder. Thus, the view that biome depletion strongly affects neurological function is strongly supported, and, more importantly, resolution of a variety of neuropsychiatric disorders may be within reach. Of great interest was the observation that helminths might effectively treat Parkinson’s disease, although the data supporting this view are very limited and need to be corroborated.

The idea that biome depletion affects neuropsychological function has been proposed by Graham Rook [14] and by us [7], but this study provided the first affirmation of this view in any biological system, animal or human.

  1. There are several reasons why restoration or enrichment of the biome with helminths has not moved at a faster pace. Some reasons are apparent and were discussed in our first piece in The Evolution and Medicine Review. For example, modern biomedical research is not focused on evolutionary mismatch, but rather on molecular/genetic markers and pharmaceutical agents for treating the diseases that result from evolutionary mismatch. As another example, the field of research on the human biome has become dominated by detailed studies of the microbiome, the vast majority of which focus exclusively on microorganisms and exclude helminths. One especially large hurdle was brought to light during our work with self-treaters; finding the right helminth or helminths to incorporate back into Western society is not necessarily trivial. For example, the first helminth that was brought into use for FDA-approved trials, the porcine whipworm, was plagued by very high costs, with effective treatment initially costing more than $10,000 per year per person in most cases. Further, the helminth was apparently not packaged properly to maintain optimal function for clinical trials. In addition, broadly written patents cover the use of certain helminths (nematodes or roundworms) in therapy for autoimmune conditions, discouraged investment. Although individual investigators at medical centers could consider running small trials using less expensive helminths (the human hookworm and the human whipworm) that were in use by some self-treaters, these organisms are considered human pathogens, and obtaining these organisms in an approved manner would not be trivial. Further, information regarding the effective use of these organisms was not readily available. (This last problem was resolved by our comprehensive study of self-treatment practice. [11])
  2. All (100%) of the clinical trials in progress or completed as of 2014 utilized either too low a dose of helminth for effectiveness or used a helminth that was not packaged to maintain efficacy.
  3. Only within the last two years has a helminth, the rat tapeworm (a cestode or flatworm), been used that (a) is easily produced at low cost, and (b) is not considered a pathogen in humans. Human pathogens can be effective (non-pathogenic and beneficial) under the appropriate conditions, but they do tend to have more negative side effects than non pathogens.
  4. A number of helminth providers argue that exposure to domesticated helminths should be used as part of a healthy lifestyle to prevent disease rather than as a drug to treat disease. Other measures that ensure a healthy immune system include a good diet, adequate exercise, adequate supplementation with vitamin D if needed, maintenance of the microbiome, and avoidance of chronic psychological stress. At the same time, the human nature that drives us to view helminths as a drug that can be used in isolation to treat disease is commonplace in the current practice of self-treatment with helminthic therapy.
  5. Although self-treatment with helminths cannot be recommended by medical professionals due to a lack of blinded, placebo controlled trials, neither should it be discouraged since the available evidence suggests that it is beneficial in most cases when practiced by knowledgeable individuals.

The Future

Dramatic progress is being made in reconstituting the depleted biome to prevent immune disorders. Old questions centered on treating specific diseases that result from evolutionary mismatch will soon cease to hold value, and new questions will emerge regarding the most effective way to avoid the consequences of evolutionary mismatch. This new science will take into account the biology and maintenance of the ecosystem of the human body. Concerns regarding the function of effective helminths with low side effect profiles will become paramount to basic scientists, and new industries built on this new science will emerge which deal directly with evolutionary mismatches as a means of prevention. This change is unavoidable, as the very high burden of inflammatory-related disease in Western society rapidly drives this evolution in medicine to its tipping point.

 

 

References

 

  1. Turton, J.A., IgE, parasites, and allergy. Lancet, 1976. 2(7987): p. 686.
  2. Strachan, D.P., Hay fever, hygiene, and household size. British Medical Journal, 1989. 299: p. 1259-1260.
  3. Parker, W., The “hygiene hypothesis” for allergic disease is a misnomer. BMJ, 2014. 349: p. g5267.
  4. Rook, G.A.W., The hygiene hypothesis and the increasing prevalence of chronic inflammatory disorders. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2007. 101(11): p. 1072-1074.
  5. Parker, W. and J. Ollerton, Evolutionary biology and anthropology suggest biome reconstitution as a necessary approach toward dealing with immune disorders. Evolution, Medicine, and Public Health, 2013. 2013: p. 89–103.
  6. Rook, G.A.W., Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology, 2009. 126(1): p. 3-11.
  7. Bilbo, S.D., et al., Reconstitution of the human biome as the most reasonable solution for epidemics of allergic and autoimmune diseases. Medical Hypotheses, 2011. 77(4): p. 494-504.
  8. Elliott, D.E., R.W. Summers, and J.V. Weinstock, Helminths and the modulation of mucosal inflammation. Curr Opin Gastroenterol, 2005. 21(1): p. 51-8.
  9. Parker, W., et al., A prescription for clinical immunology: the pills are available and ready for testing. Current Medical Research and Opinion, 2012. 28: p. 1193-1202.
  10. Flowers, S. and M. Hopkins, Autoimmune disease: Patients self-treat with parasitic worms. Nature, 2013. 493(7431): p. 163.
  11. Cheng, A.M., et al., Overcoming evolutionary mismatch by self-treatment with helminths: current practices and experience. Journal of Evolutionary Medicine, 2015. 3: p. Article ID 235910.
  12. Correale, J. and M. Farez, Association between parasite infection and immune responses in multiple sclerosis. Annals of Neurology, 2007. 61(2): p. 97-108.
  13. Summers, R.W., et al., Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology, 2005. 128(4): p. 825-32.
  14. Rook, G.A.W. and C.A. Lowry, The hygiene hypothesis and affective and anxiety disorders, in Hygiene Hypothesis and Darwinian Medicine. 2009, Birkhauser Verlag Ag: Viadukstrasse 40-44, Po Box 133, Ch-4010 Basel, Switzerland. p. 189-220.