The Role of Helminths in the Recent Evolution of the Human Immune System

 

Introduction

            One of the most intriguing new areas of study in both the biological and medical sciences began with the simple, nearly universal observation that as a society becomes more industrialized—and begins to take advantage of the social benefits that come along with it, such as improved hygiene and cleaner, less crowded living conditions—the rate of allergic and inflammatory diseases within that society skyrockets.  This phenomenon, which became more and more prevalent as the 20th century moved along, seemed to be counterintuitive to fundamental epidemiological principles and puzzled scientists for decades.  The understanding of this topic was changed significantly in 1989, when David Strachan first proposed what has come to be known as the “hygiene hypothesis.”  In his original essay, Strachan (1989) looked at the relationship between hay fever, hygiene, and household size, and finds that smaller, cleaner, and better-off families tend to have a higher incidence of allergic diseases.  This, he suggests, is due to the fact that children who grow up in these conditions are not fully exposed to infectious agents early in their life, and as a result do not build up an immunity to them. This type of occurrence creates the possibility of a much more serious infection later on in life, which is why allergic diseases such as hay fever appear much more frequently in these individuals.

 

            In the almost 25 years since this article was published, much clarification of the initial observations has been achieved yet many questions regarding the hygiene hypothesis still remain. Strachan’s initial notion of “immunity” as the mechanism for the observations he made has been fine-tuned into the concept that the lack of exposure to these infectious agents as a result of an increasingly clean world may actually cause a deficiency in the way the human immune system develops, though the details remain unclear (Sironi & Clerici 2010).  Biochemical and genetic evidence supporting this streamlined hypothesis seem to suggest that exposure to certain infectious agents, such as viruses, protozoans, and, most importantly, helminths (i.e. parasitic worms), early in a child’s life may actually have more of a positive effect on his or her long-term health than a negative one.  Helminths, including nematodes, trematodes, and cestodes, have long been known to reside within the human gut and were among the organisms most affected by the widespread sterilization of the industrialized world in terms of direct human contact (Rook 2009).  These observations have led scientists of many fields to wonder whether these tiny worms do more than simply parasitize our intestines, as they have long been accused of.  The length of time over which humans and helminths have co-existed has led many to speculate that some type of symbiosis has co-evolved between the two groups of organisms, though the potential benefit to humans has never been totally clear. 

 

           All this reasoning has led to one simple question within the realm of evolutionary biology: do humans need helminths within their bodies in order to prevent certain genetic diseases?  In this paper, I will summarize co-evolutionary theories, explore biochemical mechanisms, and examine experimental evidence in an attempt to answer this crucial, intriguing question regarding the human relationship with the oft-disparaged “old friends” known as helminths—an answer that could have resounding effects on the future of public health on a societal (and potentially global) level.

 

The Unique Evolutionary Conditions of the Immune System

           The agricultural revolution represented not only a significant cultural turning point in the history of human progress but a biological one as well.  In settling down into larger communities and beginning to domesticate certain crops and animals, humans became exposed to both new types of infectious agents as well as novel opportunities for inter-individual transmission (Rook 2009).  From that point, nearly 10,000 years ago, onward, the human body—and especially its immune system, whose job it is to contain these invaders—has had to adapt to the varying and sometimes intense pressure that these microorganisms applied.  The most unique aspect about the evolution of the human immune system is that the main pressures which cause its adaption are themselves constantly evolving; the biotic forces that challenge immune function in humans are more dynamic than the typical environment and as a result the immune system may be subject to much more rapid, drastic evolution than any other part of the human body.  As Sironi & Clerici (2010) noted in their summary, these features of a co-evolutionary arms race between infectious organisms and the immune system may result in a type of selection that favors “novel” genes to remain present in humans as a tool to fight off these ever-changing biological invaders.

 

           Fumagalli et al. (2009) tested this hypothesis experimentally by sequencing human immune genes and conducting population genetics analyses, and have shown that some of these genes have been subject to balancing selection—a process that serves to maintain genetic diversity in humans.  This high diversity, they argue, is advantageous because it allows the immune system flexibility in responding to the various types of foreign invaders while also permitting it to seek a balance in terms of effectiveness in fighting infectious agents and toleration of harmless allergens, such as pollen.  In short, specific genes in the immune system that allow for this sensitive equilibrium seem to have been evolving at a rate much rapider than other genes in humans in response to specific, consistent biotic threats that have been present for thousands of years.  So why is the sudden removal of these threats from the environment causing such a noticeable negative reaction in human immunoregulatory function?  That’s where the specific biochemistry and genetic structure of helminths comes in.

 

Evolution of the Human-Helminth “Superorganism”

            Parasitic worms, which tend to thrive in the gut of mammals, have likely been a common component of the human superorganism since at least the domestication of large animals, indicating that these two groups of organisms have had a long time to co-evolve in an effort to optimize their interaction (Rook 2009).  Helminths are unique amongst other parasitic pathogens in that their rate of evolution is relatively slow and they tend to engage in steady, sustained infections of a population without becoming overly-virulent (Sironi & Clerici 2010).  These features allow for long-term interactions of these worms with a population of humans, who are thus able to steadily adapt to the moderate threat posed by the parasites without having to wipe them out completely to survive.  As a result, many researchers, including Fumagalli et al. (2009) have been able to show that helminths have had a significant impact on the structure of several genes (and possibly thousands of loci) that are crucial for the regulation of the immune system.  The long-term effect of helminths on these genes has likely been much more significant than that of highly pathogenic parasites, such as viruses or protozoans, that may at times provide a more intense selective pressure but one that is not able to be sustained for long.  Thus, the uniquely benign host-parasite relationship between humans and helminths that has been present for thousands of years has likely allowed for a targeted co-evolution between the two organisms that has resulted in a mutual dependence on one another for proper development and/or survival.

 

            The benefits of this relationship for the worms are pretty clear; these tiny organisms must be able to reach and stick in the gut of humans or other mammals without being killed off by the immune system of the host in order to complete their life cycle and reproduce.  Therefore, a trend towards benignity and ultimately peaceful symbiosis with the human body would confer a clear advantage—an assertion supported by the fact that the most common parasite in the United States, the nematode Necator americanus, causes no clinical symptoms in human beings (Pritchard & Brown 2001).  Scientists have long been puzzled, however, about what exactly humans get out of this relationship.

 

           According to the hygiene hypothesis, the advantage to humans is that the presence of these “old friends” within the body will provoke only a mild response by the immune system, a response that, if activated continually, will condition immune response to optimize its balance between fighting pathogenic invaders and ignoring innocuous ones (Sironi & Clerici 2010).  It is important to note, however, that human generation time is much longer than that of most helminths; consequently, it follows that the degree to which humans have adapted to fit this symbiotic model will be less than how well the worms have adapted.  In other words, the genes upon which the selective force of this relationship has acted are likely far from perfectly suited to elicit the desired expression in a wide variety of environments.  For this reason, researchers have predicted that the genes that have been pressured to change by the parasites may contain a significant number of deleterious alleles contributing to chronic allergic diseases—alleles that are only exposed in the absence of supplemental contributions from our old friends.  This model is similar to the one J.B.S. Haldane (1949) described in the mid-20th century regarding resistance to malaria in sub-Saharan Africa.  In an environment where there is a real risk of acquiring the Plasmodium parasite which ultimately causes malaria, heterozygotes for sickle-cell anemia have a significant competitive advantage.  In the absence of this risk, the heterozygote has a disadvantage in terms of biological fitness—they are merely carrying the allele for a disease that confers no advantage in their particular environment.  Similarly, in the absence of helminths, the effects of deleterious alleles leading to allergic diseases may become more pronounced in a population of humans. 

 

           To summarize, the relatively benign host-parasite relationship between humans and helminths has likely led to a situation where both organisms have evolved, at least partly, a dependence upon one another for proper development and function. When the two are forcibly separated, which is happening increasingly often in the sterilized industrial world, the human superorganism loses a key component of itself and may be exposed to harmful expression of its own genes as a result.  Decades of development of this evolutionary theory seem to indicate that humans do indeed require certain helminth contributions in order to develop in a healthy manner, and these theories are simple enough to test on a large-scale basis—even if many questions about the functioning of this mechanism remain.

 

Biochemical and Clinical Evidence; Reunited with our Old Friends

            The first step in confirming the predications of the hygiene hypothesis involved eliciting the biochemical mechanism by which helminths “activate” the immune system to reach its proper state of regulation and function.  In a summary paper on the implications of the hygiene hypothesis, Rook (2009) described the advances in physiochemical knowledge of human immune regulation that help to explain this multi-step process.  Specific antigens on the surface of helminths and other parasites are recognized by several types of specialized immune cells located in the human gut, including crucial ones known as dendritic cells (DC).  This recognition causes maturation of the DC into regulatory cells that in turn activate regulatory T cells (Treg) that carry out the ultimate intended responses of the immune system to foreign invaders.  The continuous stimulation of this process (summarized in Figure 1) results in an intense conditioning of this part of the immune system so that it is quick to recognize and react to pathogens without over-reacting to the benign invaders that lead to allergic diseases.  In the absence of helminthic antigens, however, the DC cells fail to mature and thus leave the Treg cells inactivated.  This process leads to a poorly conditioned, over-active immune system that reacts to innocuous agents and occasionally its own cells as well as foreign invaders, leading to many types of allergic diseases.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

            If the findings summarized by Rook (2009) are indeed correct, then it appears that a relatively simple solution exists concerning the negative health effects of living in an industrialized society: reuniting the human body with our old friends.  If the absence of helminthic antigens within the intestines is the primary cause of most allergic and inflammatory diseases in the modern world, re-introducing them into the body of affected individuals should be all that it takes to spur the proper development of regulatory immune function.  Weinstock & Elliot (2014) chronicled researchers who have tested this logic over the past decade by allowing individuals with certain types of chronic allergic or inflammatory diseases (e.g. Crohn’s or inflammatory bowel disease) to ingest the eggs of certain helminths in an effort to have them colonize the intestines and thus provide this consistent activation of dendritic cells.  Though variations in the types of diseases studied and the species of helminths used exists, the limited number of human clinical trials approved by the FDA have shown signs of success.  One study in particular, which involved the treatment of 29 Crohn’s disease patients with the ova of Trichuris suis (the pig whipworm) resulted in full remission of the disease in 66% of patients and an improvement of symptoms in others—all results occurring with no observable side-effects (Weinstock & Elliot 2014).  As experimental results such as these become more common, public outcry for broad access to helminthic therapy has grown and as a result the FDA has begun fast-tracking the research of certain methods in an effort to make them accessible as modes of treatment for individuals suffering from chronic allergic diseases.  However, there are several aspects of helminthic therapy that seriously complicate this process and are contributing to stall its widespread availability as a treatment option.

 

            As previously mentioned, helminths have traditionally been stigmatized as nothing more than vile parasites that need to be stamped out of the human body in order to achieve health; while contemporary research on the hygiene hypothesis has shown this stereotype to be false, there is a reason why it existed in the first place.  Beneficial effects towards the development of the immune system notwithstanding, many species of helminths can have pathogenic potential within humans and can lead to a variety of diseases with very ugly symptoms.  Even though researchers have isolated two uniquely benign species of helminths, T. suis and N. americanus (the new world hookworm), for use in testing the predictions of the hygiene hypothesis, the very nature of using a living human parasite as a method of treatment can result in serious complications that scientists may never be able to fully predict.  For instance, unanswered questions regarding the ability of T. suis to travel outside of the immune system once ingested exist, as well as a lack of clarity regarding the long-term effects of N. americanus infections—symptoms such as chronic diarrhea and anemia have been observed, though infrequently (Weinstock & Elliot 2014).  Additionally, the unpredictability of helminth reproduction and life span is troubling to medical researchers who are trying to pinpoint appropriate doses (both in terms of amount and frequency).  Jouvin & Kinet (2012) asked whether avoiding the worms altogether and researching simply how to inject the antigens into humans might be the better course of action.  In short, although early clinical trials of helminthic therapy have proved promising in terms of treating diseases associated with a poorly conditioned immune system, the unpredictable nature of utilizing a live parasite makes the process of developing it as a treatment very complicated and unpredictable.  It is likely that many more years of thorough research will be required to answer the myriad questions that prevent helminthic therapy from being available to the public.

 

Conclusion

            In the two-and-a-half decades since David Strachan opened the door for the study of the relationship between exposure to certain parasites and the prevalence of allergic disease in human society with his introduction of the hygiene hypothesis, an explosion of research has resulted in a tremendous advancement of knowledge regarding this topic.  Scientists now better understand the unique evolutionary conditions of the human immune system that can lead to very rapid changes in certain genes as well as the important role of parasitic helminths in shaping this adaption due to the nature of their chronic, typically benign infections of human populations.  Additionally, clarification of the details of the intimate relationship between humans and helminths has revealed that the human body may depend on the presence of specific helminthic antigens for the correct expression of genes that are critical to the development of the immune system.  A sterilized world in which helminth infection is relatively rare represents an environment much different than the one that the immune system has been adapting to for thousands of years, and as a result certain harmful alleles are more likely to be expressed, leading to improper regulation of the immune system that causes many types of allergic and inflammatory diseases.

 

            The development of these evolutionary theories had led to the elicitation of specific biochemical mechanisms by which helminths may facilitate the proper activation of the immune system.  These proposed mechanisms have been supported by clinical evidence showing that individuals suffering from such diseases as Crohn’s or inflammatory bowel showed marked improvement in their symptoms upon ingesting certain helminths in a treatment method known as “helminthic therapy.”  Despite these promising initial results, a number of complications associated with the use of a parasitic worm as a treatment prevent the widespread usage of helminthic therapy at this time, and it seems that a significant amount of research still needs to be conducted in order to answer the many questions that remain before full FDA approval can even be an option.

 

            Research and experimentation on the hygiene hypothesis has taught the scientific and medical communities a number of important lessons, perhaps the most crucial of which entails the need to consider the conditions of human evolution when designing systems meant to improve or optimize human health.  Since the acceptance of the germ theory in the early 20th century, public health officials have relentlessly promulgated an all-out war against dirt and microbes.  What these officials failed to consider, however, is that some of these filthy enemies are actually old friends, without whom the healthy human body is not fully complete.  The findings associated with the hygiene hypothesis have exposed the irony of this battle, as some of the very methods employed in an attempt to improve human health have actually resulted in an explosion of specific types of diseases associated with the human body attacking itself.  Though most of the advances in public health and sanitation over the past century have been beneficial for overall human well being, this paper highlights a reason why a general “cleansing” of the world may not be the best approach to ensure better health.  Drastic changes to the environment in which human populations have lived and adapted to for thousands of years can have unintended consequences, and thus the approach to such changes must be meticulous and well-researched lest more crucial elements of the human superorganism are lost.