Living helminths are better than helminth-inspired drugs

In many laboratories around the world, researchers are busy trying to identify helminth-derived molecules that could potentially be utilised in pharmaceutical products to treat immune-related disorders. When interviewed, these scientists will typically make a point of dismissing the idea of using living worms as a therapy, referring to it in negative terms, as unethical, unappealing to patients, or even dangerous.  

Infecting someone directly with nematodes isn't an appealing idea. [1]

Giving people worms belongs in the trash bin. [2]

However, other researchers advise that no drug will ever match the effects of living worms, given that helminths each excrete/secrete hundreds of molecules (TSO, for example, produces at least 350 different proteins [3]) and that host/helminth interactions have been developed over hundreds of millions of years of coexistence and coevolution.

It's hard if not impossible to believe we could restore the immune system to 'normal' using a pharmaceutical directed at one cog in the immune apparatus, when in fact the entire apparatus is out of sync with nature. (William Parker, Duke University. [4])

It is like a three-legged stool - the microbes, worms and immune system regulate each other. The worms have been with us throughout our evolution and their presence, along with bacteria, in the ecosystem of the gut is important in the development of a functional immune system. (Ian Roberts, Manchester University. [5])

The learned thinking pattern for medical professionals and biomedical researchers is to envision isolation and characterization of the individual components produced by helminths, with the goal of creating new helminth-inspired drugs to treat disease. On the one hand, this approach is consistent with the general practice of modern medicine and the common approach used to find new drugs today. On the other hand, recapitulating the effects of an integral member or members of the biome using a single or even a handful of pharmaceuticals may prove extremely difficult. Indeed, given the complex and continuous nature of the interactions between host and helminth that have evolved over hundreds of millions of years, the design of therapeutics to entirely and effectively recapitulate this interaction may prove impossible. (William Parker, Duke University. [6])

Helminth-derived pharmaceuticals might offer an alternative to biome reconstitution, but given what is already known about the complex and multi-faceted nature of helminth–host interactions, pharmaceuticals which effectively mimic the effects of helminths might prove extremely difficult and expensive to develop and utilize. Further, the low costs, high efficacy, and very low rate of side effects that are expected to be associated with biome reconstitution make this approach extremely appealing. (Bilbo, et al. [7]) See below for a full exposition of this team's thinking on the question of biota reconstitution versus helminth-inspired pharmaceuticals.

When you give someone a live worm, it’s like giving them the factory that makes the products and letting the factory do what it needs to do… Evolution has already created this thing. (David Elliott, University of Iowa. [8])

… efforts to develop helminth-derived drugs are misguided. Our view is that exquisitely complex interactions between two biological systems cannot be recapitulated by pharmaceutical intervention. Helminth-derived molecules with specific biochemical targets may in some cases work as an immunosuppressive drug, perhaps attenuating the symptoms of a particular disease. However, no drug can train and modulate immune function as do host-symbiont interactions. Thus, it is our view that even ideal results from attempts to develop helminth-derived drugs will be disappointing compared to results that can be obtained using intact organisms. Further, as we and others have maintained, humankind eventually needs to move beyond the idea that helminths are best used as a drug or a therapy. Rather, we need to embrace the view that helminths are a necessary component of the ecosystem of a healthy body, and that helminths should be cultivated for population-wide biota restoration. Attempts to develop helminth-derived drugs are, by intent, designed to treat disease, not to restore health to the population. As such, efforts to produce helminth-derived drugs will not help achieve the long-term goals of disease prevention, and may indeed provide a distraction from such goals as they divert resources that could be used for biota-based restoration and maintenance. (Villeneuve, et al. [9])

Here we examine the notion that, because of the complexity of biological symbiosis, intact helminths rather than helminth-derived products are likely to prove more useful for clinical purposes. (Sobotková, et al. [10])

There is also a possibility that helminth-derived immunomodulatory drugs may trigger allergic reactions to parasite allergens. [11]

Biota reconstitution v helminth-inspired drugs

(From Bilbo, et al, 2011)

To reconstitute the biome or to develop helminth-inspired drugs that mimic a reconstituted biome?

Biomedical researchers often envision isolation and characterization of the individual components produced by helminths that modulate the immune system, with the goal of creating new helminth-inspired drugs to treat disease. On the one hand, this type of approach with other organisms has proven instrumental in the progress of modern medicine, giving us antibiotics and some important vaccines. Further, repeated injection of helminth-derived extracts or proteins in animal models of disease has already proven useful in alleviating such conditions as collagen-induced arthritis [12] and experimentally induced colitis [13], among others [14] [15]. On the other hand, several factors are likely to limit the general use of this approach as a substitute for biome reconstitution.

First, it is difficult to imagine a single pharmaceutical or even a collection of pharmaceuticals that could recapitulate the vast complexity of the interaction between helminths and the host immune system. While pharmaceuticals are generally directed at one component in the immune apparatus, a single helminth species produces dozens if not more molecules that each target specific components of host immunity. The likely possibility that more than one species may be required to effectively reconstitute the biome adds a level of complexity that seems staggering to anyone interested in replicating the natural state using pharmaceuticals. Perhaps more importantly, our understanding of helminth immunoregulation is far from complete, with many gaps in our knowledge [16]. For example, many proteins secreted by helminths in low abundance may not have been identified, but yet may have important biological activity. Further, the biological role of some proteins secreted by helminths in high abundance, such as the glycolytic enzyme triose phosphate isomerase, remains poorly understood [17]. Thus, our present level of understanding of the vastly complex interactions between helminths and their hosts potentially adds a substantial hurdle to the design of therapeutics which will mimic those interactions.

Not only is the helminth/host interface vastly complex, it requires continuous input from the helminth. Helminths actively maintain a state of immunosuppression, and removal of helminths results in a loss of that regulation [18], suggesting that any pharmaceutical substitute would also need to be maintained at a relatively constant level for maximum efficacy. Such continuous maintenance is potentially difficult and costly to maintain using traditional pharmaceuticals, and regular injections of helminth-in- spired drugs, even if effective, might prove burdensome and expensive. Further, the mechanism of delivery of helminth-derived immunoregulatory molecules by living helminths may be important for their function, and it is possible that new drug delivery technologies may need to be devised which mimic the delivery of a living helminth. In other words, given the long coevolution of immune systems and helminths, it seems reasonable that the immune system may be adapted to and indeed dependent upon the nature, dose, and delivery method used by living helminths.

Probably it is the field of evolutionary biology that most strongly argues for living helminths and biome reconstitution in favor of pharmaceutical substitutes. Helminths represent a potential therapeutic that has been fine-tuned by hundreds of millions of years of natural selection not to encumber a healthy host. Consistent with this idea, several helminths are known to cause few if any symptoms in most cases [19] [20]. The bovine tapeworm (Taenia saginata), for example, has been labeled a ‘‘commensal’’ rather than a parasite in humans. To achieve this balance, natural selection has tested countless billions of combinations of molecular tools over millions of years, selecting those that are most effective for both helminth and host survival. Quite obviously, no pharmaceutical has ever been developed to match that record.

Another advantage that living helminths have over pharmaceuticals is their potential cost effectiveness. Helminths are typically long-term therapeutics if used in their natural host species, with a single dose lasting for years if not decades. Thus, costs will be limited by the long-term effectiveness of a single treatment. Further, the prospects for new technologies that facilitate cost effective and safe production of helminths in sufficient numbers for widespread use seem almost unlimited. Biotechnology involving in vitro culture of helminths or cultivation of human specific helminths in genetically modified mice (e.g., humanized or immuno-suppressed mice) are two examples of such biotechnologies which remain untapped. The technology and clinical implementation of biome reconstitution may eventually prove no more complex than that utilized for vaccinations, with biome reconstitution and maintenance being a routine part of a typical checkup at the doctor’s office.

One potential advantage of living helminths as a therapeutic is that they might be genetically altered to enhance their beneficial nature. Currently available organisms can hypothetically be modified by selective breeding to enhance their beneficial nature, or may be modified in the laboratory to create specifically altered organisms, including transgenic helminths. In this manner, genetically modified helminths could be used as an effective drug delivery agent (vector) to treat a potentially unlimited variety of medical conditions. Helminths offer a number of advantages over viral or bacterial vectors for certain applications because of their long life span, built in resistance to destruction by the immune system, and, since they do not complete their life cycle in the host, a low propensity to mutate or evolve once introduced into the host.

One potential objection to the use of mutualistic helminths for biome reconstitution is that the introduction of organisms possessing ‘‘vastly complex and uncharacterized elements’’ into the human body might have unforeseen consequences. This argument is easily turned on its head, however, when we ask how it is rational to eliminate our coevolutionary partners that possess vastly complex and uncharacterized elements without expecting dire consequences. Indeed, many of the factors proven to be important for human survival, including the microbiome and even the food we eat, contain vastly complex and uncharacterized elements. Thus, complexity and a lack of understanding of that complexity do not rule out the importance of an element of the normal human biome for health. Further, many pharmaceuticals, molecules with substantially less complexity than helminths, cause exceedingly complex reactions within the human body, often with consequences that remain poorly understood. Thus, the relative simplicity of a drug at the molecular level does not necessarily lead to a complete understanding of that drug’s effects, and certainly does not impart safety for patients. Finally, the idea of biome reconstitution is not to modify human biology in a new way, but to restore the ecology of the post-industrial human biome to harmony with the way that our genes have evolved to function. In a nutshell, comfort with the idea of biome reconstitution requires only an understanding that natural selection has shaped our genes so that they are compatible with the environment. It does not require a complete and total understanding of that environment or how that environment interacts with the human body.

Another potential objection to the concept of biome reconstitution is the fact that helminths extract a horrible toll of suffering and death in developing countries [21]. Given this potential to cause harm, it could be argued that these organisms should not be reintroduced into post-industrial cultures. This argument, however, is entirely undermined by a consideration of the nature of parasitic disease in developing countries. In developing countries, at least one of the following three conditions are necessary ingredients for morbidity and mortality associated with helminth infection:

1. The widespread occurrence of starvation and malnourishment, conditions which add risk to colonization by helminths.
2. The absence of water treatment facilities and sewer systems, allowing uncontrolled infections and potentially high burdens of helminths.
3. The presence of helminths that are not well adapted to the host (e.g., parasites that are harmful to even a healthy host, such as Dracunculus medinensis, which causes dracunculiasis, Taenia solium, which causes cysticercosis, and Loa loa, which causes Loa loa filariasis).

Not one of these factors presents a difficult hurdle when considering the reintroduction of helminths into post-industrial societies, which generally enjoy over-nourishment rather than malnourishment. Given a proper selection of helminths for colonization, uncontrolled infections are impossible in the face of modern sewer systems and water treatment facilities. Further, modern medicine makes it possible to easily identify individuals with pre-existing conditions that could be contraindications for helminth therapy (e.g., anemia, malnutrition, immune deficiencies, coagulopathies, advanced aging, etc.). In addition, modern clinical research practices can readily be utilized to ensure that adverse side effects are reduced to far below acceptable levels prior to widespread therapeutic application. Thus, post-industrial cultures have the luxury of selecting controlled colonization with helminths, not pathologic infection. In essence, post-industrial society will have domesticated helminths. No restoration of the natural ecology of helminths is expected or even suggested, with the survival of the domesticated helminths being strictly dependent on the medical community. To maintain a reconstituted biome, patients would need periodic evaluation and maintenance, since natural transmission of therapeutic helminths would be non-existent given the proper selection of helminths and the sewer systems of postindustrial culture. Further, given the effectiveness of anti-helminthic drugs, therapy will be readily reversible should particular patients develop a condition in which the helminths are no longer warranted.

The loss of evolutionary partners leading to disease is not unique to the helminth/hyper-immune condition. The historically omnipresent struggle against predators and for food resources have left our bodies addicted to particular diets and a degree of exercise. The loss of predators and the loss of any challenge in finding food in post-industrial cultures have led to epidemics of obesity, type 2 diabetes, and other complications associated with a rich diet and little exercise. However, just as post-industrial societies do not need to face predation and possible starvation to avoid obesity and heart disease; neither do post-industrial cultures need to face the specter of helminth-associated disease in order to avoid allergy and autoimmune disease. Just as we have the option of safely utilizing proper diet and exercise regimens to give our cardiovascular system what it has evolved to require, it is expected that, far more effortlessly, we can safely utilize selected organisms to give our immune system what it has evolved to require.