by Fernanda Ferreira

figures by Krissy Lyon

The young, scaly creature bursts from the torso of its doomed host in a mix of guts and blood and stares blinkingly at its new environment.

For most people the sentence above describes a famous scene from Ridley Scott’s Alien, but for many insects it’s a daily reality.

The inspiration for H.R. Giger’s nightmarish alien comes from one of nature’s most ingenious predators: parasitoid wasps. These wasps lay their eggs in other insects or their larvae, transforming their prey into a living incubator that feeds and protects the growing wasp larvae. This behavior is present in many wasp species, and their prey includes a diverse array of insects and arachnids [9]. In Alien, Sigourney Weaver saves herself and the last member of the spaceship Nostromo from the alien, but if you can’t count on Warrant Officer Ripley to save the day, how do you protect yourself and your kin from a parasitoid wasp?

What is Self-Medication?

While in the human world giving your baby alcohol would probably be considered a form of child endangerment, fruit flies do this as a form of self-medication. For humans, the term “self-medication” refers to any instance in which someone uses a substance to treat a self-diagnosed illness [8], but it is commonly associated with substance abuse.

In the animal world self-medication is also referred to as “zoopharmacognosy,” and it involves the ingestion or application of substances by non-human animals to prevent or treat illnesses [10]. Within self-medication, there are many subdivisions (Table 1), depending on whether the use of the substance is therapeutic (for healing a current disease) or prophylactic (for preventing a disease) and who is benefitted by the substance [3].

Self-medication was long thought to be a learned behavior, which one acquires through experience, rather than an innate behavior [11]. The first examples of self-medication came from primates [10], so it was assumed that it could only occur in animals that could observe and learn [3]. However, scientists have observed various instances of innate self-medication in insects, demonstrating that this behavior does not always have to be learned.

Before self-medication, an insect has two lines of defense: first, their cuticle works as a barrier to keep pathogens out and, second, should a pathogen penetrate this layer, their immune systems can fight the infection [1]. When neither of these defense systems works, an insect can turn to its environment to find substances that will help it deal with pathogens. Like the alcohol in the fruit-flies case, the majority of these protective substances are plant-derived and studying the growing number of insect self-medication examples may give us new organic compound targets for drug discovery.

Fruit flies: taking alcohol as a medicine

One of the best-studied examples of self-medication in insects, involving both therapeutic self-medication and prophylactic transgenerational medication, comes from fruit flies, which were heavily researched by Dr. Todd Schlenke and colleagues. Like all insects, fruit flies have a series of innate immune mechanisms that fight pathogens, but at times the fruit fly must resort to self-medication to combat specific predators, such as parasitoid wasps.

A fruit fly’s choice of medicine is foods with a certain alcohol percentage, particularly rotten fruit. Healthy fruit flies that consume diets with a high alcohol content tend to have a lower fitness. That is, when we compare the survival rates of healthy fruit flies that are fed food with a high alcohol content to those that are fed food with no alcohol, the teetotaler (a.k.a., sober) flies live longer than their alcoholic brethren (Figure 1, upper panel)[7].

When fruit flies are parasitized by wasps, however, this relationship flips: the survival rates of fruit flies with high alcohol diets are two to four times higher than those with no alcohol in their diets (Figure 1, lower panel). The alcohol protects the fruit flies by disturbing the development, and therefore causing the death, of the wasp larvae [7].

Parasitoid wasps also target the larvae of fruit flies, and female fruit flies have evolved to recognize female wasps and to respond to the risk of infection these wasps represent to their offspring. In a series of elegant experiments, Schlenke [6] demonstrated that when female fruit flies saw female wasps they changed their oviposition, or egg-laying, preferences. Fruit flies lay their eggs in locations with plenty of food for their growing larvae, and they normally choose locations without any alcohol (Figure 2a). However, once a female wasp has been sighted, flies start to lay their eggs on food that contains alcohol. Flies do not change their egg-laying when shown male files, meaning that female flies have evolved the ability to not only recognize wasps and respond accordingly, but to also discern between the innocuous male wasps and the dangerous, parasitic larvae-laying female wasps [6].

Social insects and socialized medicine

With the fruit fly example it already becomes clear that “self-medication” includes examples of medication that are not restricted to “self”: female fruit flies medicate both themselves and their offspring. This makes sense from an evolutionary perspective because the fruit fly’s offspring represents a way for the female fruit fly’s DNA to live on once she’s died. Social insects, such as bees and ants, push the definition of “self-medication” even further [5].

During particularly bad flu seasons a common piece of advice from the Center for Disease Control (CDC) is to avoid crowded areas in order to both protect yourself and others from getting infected. Social insects live in colonies comprised of thousands or millions of individual insects, which is much akin to the CDC’s “crowded spaces”, and, as the CDC warns, the high population density of the colony increases the chance of infection. But the same way colonial life has its dangers, the colony can also work together to prevent an infection from happening or to limit its spread in the colony. Both ants and bees do this by collecting resins with antimicrobial or antifungal properties that protect their colony from harmful bacteria and fungi, respectively.

While resin-collection is a behavior shared by both bees and ants, the timing of the collection differs between them. Ants participate in social prophylaxis, collecting resin with antimicrobial properties from conifers in order to prevent the presence of bacteria in the colony, but they don’t start collecting more resin when the colony becomes infected [3]. Bees on the other hand perform social therapeutic medication: they constantly gather resin, but following infection by a fungal pathogen, they begin to collect more resin[12].

Why should we care about self-medicating insects?

In the quest for new drugs, scientists have looked at everything from traditional native remedies to marine bacteria. It’s therefore not a great leap to expand the search for novel natural compounds to examples of self-medication in insects [4]. Despite the innumerous differences between humans and insects, there have already been cases in which compounds present in human drugs have also been used by insects.

The monarch butterfly is targeted by the protozoan parasite Oprhyocystis elektroscirrha, which covers the outside of the butterflies decreasing their ability to fly and ultimately killing them. Furthermore, female butterflies accidently spread the parasite to their offspring when they lay eggs. In order to defend their larvae from these parasites, monarch butterflies lay their eggs on medicinal milkweed species [2]. Milkweed is the food of choice for monarch butterfly larvae and there are various species of milkweed, both medicinal and non-medicinal. The medicinal types of milkweed contain cardenolides, a class of compounds that have been used in both anticancer drugs and to treat heart failure.

Our observation of self-medication in animals can also teach us about the best ways to rear certain species. For instance, during the domestication of honeybees, beekeepers have selected for bees that collect less resin because large quantities of resin make the harvesting of honey more difficult [12]. Given the delicate nature of beehives and the propensity of colonies to disease, beekeepers may want to alter their stance on resin.

With antibiotic resistance on the rise, we are always in need of new avenues of drug discovery. Maybe the next big treatment for Methicillin-resistant Staphylococcus aureus (MRSA) or tuberculosis is already being used by some of our favorite insect zoopharmacognosists.

Fernanda Ferreira is a PhD student in the Virology PhD program.

References

1. Abbott, J. (2014). Self-medication in insects: current evidence and future perspectives. Ecological Entomology 39, 273-280.

2. Do monarch butterflies use drugs? (Emory Report) http://www.emory.edu/EMORY_REPORT/stories/2010/09/13/monarch_butterflys_may_use_drugs.html

3. De Roode, J.C.; Lefèvre, T.; & Hunter, M.D. (2013). Self-Medication in Animals. Science 340, 150-151.

4. How butterflies self-medicate. (TEDYouth) https://www.ted.com/talks/jaap_de_roode_how_butterflies_self_medicate?language=en#t-15374

5. Ants self-medicate: are even cooler than Ant-Man made them look. (SITN Waves) http://sitn.hms.harvard.edu/waves/2015/ants-self-medicate-are-even-cooler-than-ant-man-made-them-look/

6. Kacsoh, BZ.; Lynch, ZR.; Mortimer, NT.; & Schlenke, TA. (2013). Fruit Flies Medicate Offspring After Seeing Parasites. Science 339: 947-950.

7. Milan, NF.; Kacsoh, BZ.; & Schlenke, TA. (2012). Alcohol Consumption as Self-Medication against Blood-Borne Parasites in the Fruit Fly. Current Biology 22: 488-493.

8. Ruiz, ME. (2010). Risks of self-medication practices. Current Drug Safety 5(4): 315-323.

9. Parasitoid wasps may be the most diverse animal group. (BBC Earth) http://www.bbc.com/earth/story/20150522-the-wasps-that-rule-the-world

10. Shurkin, J. (2014). News Feature: Animals that self-medicate. PNAS 111(49): 17339-17341.

11. Operant Conditioning: Innate vs. Learned Behaviors. (Khan Academy Medicine) https://www.khanacademy.org/test-prep/mcat/behavior/learning-slug/v/operant-conditioning-innate-vs-learned-behaviors



12. Bee’s ‘Self-Medicate’ With Propolis to Fight Infection, Study Says. (Huffington Post: Science) http://www.huffingtonpost.com/2012/04/02/bees-self-medicate-propolis_n_1396401.html