Introduced bee on a native ʻōhiʻa flower. Photo by Flickr user Zesuri As most of my friends on the mainland don longer sleeves and more layers, it's hard not to be a little smug about living in paradise. While, in their neighborhoods, leaves are falling off of trees and icy winds threaten to bring snow, I can throw on a T-shirt and shorts, grab a picnic basket, and hike to a scenic overlook for lunch. But Hawaii's ever-sunny weather comes with one side-effect that can be deadly serious: year-round, Hawaii has bees. Don't get me wrong—bees are wonderful insects, even though most species are not native here in Hawaii. When the first Hawaiians arrived on the shores of these stunning isles, only the yellow-faced bees buzzed around. Honey bees were introduced in the 1850s, and have since become indispensable, wedging their way into the Hawaiian economy and filling the shoes of native pollinators that have become scarce. They're economically and ecologically vital, not just here in Hawaii, but throughout the US—according to the U.S. Department of Agriculture, these busy bugs pollinate 80% of our flowering crops, and are thus essential for the production of 1/3 of our food. Worldwide, the economic contribution of pollination alone has been valued at over $200 billion. But for more than 2 million Americans, bees are a dangerous threat. Somewhere between 1% and 7% of human beings are allergic to insect venoms, with their symptoms ranging from mild overreactions to full-blown anaphylactic shock. For those with bee allergies, even the slightest sting can lead to a fight for life. Even more troubling is that, in half of all fatal sting allergy cases, victims had no previous major reactions to venom. Nearly 100 Americans die every year from bee stings, and many more experience severe reactions that require immediate medical treatment.

The allergic response to a bee sting. From What To Do About Allergies Allergies are defined as 'hypersensitive immune responses'—or, in colloquial terms, odd moments when our immune systems flip out. Anaphylaxis is the whole-body manifestation of an allergy, which can range from something as minor as hives to sharp drops in blood pressure and even cardiac arrest. You don't have an allergic reaction the first time you come in contact with an allergen; instead, like with viruses or other potential invaders, your body takes an immunological picture so it can remember the allergen later. This is what is known as the adaptive immune response, and it's usually a good thing—when you get the chicken pox, for example, your adaptive immune system remembers what the disease looks like, and can find and kill it should you ever be re-exposed. But when it comes to allergies, the adaptive immune system goes too far. The next time it detects allergens, it sends out hordes of IgE antibodies to destroy them. These IgE antibodies wreak havoc in our bodies—through cascading immunological pathways, IgE antibodies cause the release of histamine and other inflammatory compounds and can lead to anaphylaxis. In fact, IgE antibodies are so damaging, scientists struggle to understand why—from an evolutionary standpoint—our bodies produce them in the first place. After all, without modern medicine like Epi-Pens, people with severe allergies would most likely die from their condition. Genetic conditions that cause swift death, especially as a child, tend to be weeded out because they prevent individuals from passing along their genes. So how have allergies persisted so long? For a long time, scientists have viewed allergies as 'immunological anomalies'—physiological accidents, if you will—genetic disorders in which the body produces IgE antibodies when it shouldn't. But this view of allergies doesn't explain why IgE antibodies are found in our genomes in the first place. Given the conservative nature of evolution, it doesn't make sense for a whole class of destructive antibodies to arise that are never used except by people with a genetic disorder. They have to have some purpose–or, at least, have had one in the past. One group of scientists thinks that IgE antibodies are meant to fight against parasites, making allergies still the unfortunate side-effect of a different body action. Yet even this is unsatisfying—the vast majority of allergens are pollens, foods, drugs, venoms, and metals. Is our parasite defense system really so poorly fashioned that it makes so many mistakes? It was an incongruity that Margie Profet simply couldn't accept. Profet isn't exactly your classic evolutionary biologist. She received degrees in physics, math and philosophy, but not a single one in biology. Yet her grasp of the evolutionary mechanics of allergies is profound. "The specialized mechanisms that collectively constitute the allergic response appear to manifest adaptive design in the precision, economy, efficiency, and complexity with which they achieve the goal of producing allergy," she wrote. In 1991, Profet proposed a radical explanation for allergies: IgE antibodies, and the allergic reactions they cause, were meant to save our lives from toxins. Profet laid out four main arguments, which she coined the "toxin hypothesis" for allergies. First, that toxins are ubiquitous and cause acute damage. Thus it would make sense for our bodies to have developed defenses against them. Second, the types of physiological activities that toxins perform—covalent binding to serum proteins, for example—are known to trigger allergic reactions. Third, most allergens are either themselves toxic substances or carrier proteins that bind to smaller toxic substances. Lastly, allergic symptoms could be construed as helpful in the case of envenomation or poisoning, as allergies cause behaviors like vomiting, sneezing and coughing, which could expel toxins, and drops in blood pressure, which could slow the speed at which a toxin moves through the body. While her ideas won Profet a McArthur Genius Grant in 1993, given her background and the controversial nature of her suggestion, the scientific community was not instantly convinced. Most of her detractors focused on one simple detail: a lack of any experimental evidence. If allergic responses are adaptive, they said, show us. Decades passed with little evidence to support Profet's radical explanation. Then, in 2012, Cornell University researchers Paul and Janet Shellman-Sherman connected Profet's toxin hypothesis to a strange medical phenomenon: people with allergies have lower risks of certain cancers. It's possible, the team told Psychology Today, that allergies serve to combat potential carcinogens. It was a suggestion made by Profet herself—she noted that the most cancer-causing heavy metals also were the most allergenic, and aflatoxins from fungi that grow on the bane of many allergy sufferers—hay—are some of the most carinogenic substances known to man. If allergies protect the body against such substances, people with them would be less likely to expose themselves to these mutagenic toxins that can cause cancer. Others think the correlation is simpler: the highly overactive immune system of allergic people attacks all invaders, foreign and domestic, and is thus hyper-vigilant against cancer. With so much uncertainty, the connection between allergies, toxins, and cancer remains philosophical. Today, a paper in the journal Immunity provides even stronger evidence to support Profet's toxin hypothesis. In it, Stanford University School of Medicine scientists show that small doses of venom and the subsequent allergic pathways triggered serve to protect mice against fatal doses of venom later on. The team was interested in how adaptive immune responses help in the case of venomous stings and bites. Statements made by postdoc Philipp Starkl, co-first author or co-leader of the study, echoed Profet's original reasoning: "It was kind of a dogma that most IgE-related responses are detrimental," he said. "We and others speculated that there should be some very positive evolutionary pressure to keep these cells and these antibodies, because if they were just bad and deleterious, they would have been eliminated." Bee stings, in particular, are known for their allergic potential. So, the team designed an experiment using a mouse model to see if allergic responses were beneficial in the case of bee stings. They first injected one group of mice with small amounts of bee venom, equivalent to one or two stings, and another with saline. Then, three weeks later, they injected both groups with a potentially lethal dose of bee venom, and watched to see how the two groups responded. The mice previously injected with venom fared significantly better. They were three times more likely to survive, had less severe sublethal reactions, and—most importantly—did not develop the anaphylactic reactions characteristic of allergies. But to really see if an allergic pathway explained this difference, the team ran the same test on three different kinds of mice: mice without IgE, mice without IgE receptors on a special type of immune cell called mast cells (which amplify allergic responses), and mice without those mast cells altogether. Unlike the normal mice, these three mutant mice types—without the key components of allergic reactions—did not benefit from pre-exposure to venom. "That was pretty exciting for us," said Thomas Marichal, lead author. "It was the first time we could see a beneficial function for these IgE antibodies."

A Russell's viper, one of the most dangerous snakes in the world. From Wikipedia user Shyamal But for the hypothesis to hold up, IgE responses would have to be beneficial for much more than just bee stings. So, the team tried the same experiment with venom from Russell's vipers. Russell's vipers cause more snakebite incidents and deaths than any venomous snake in the world, and are one of the "big four" snakes of high concern in India. Again, pre-exposure to the venom protected the mice. "Our findings support the hypothesis that this kind of venom-specific, IgE-associated, adaptive immune response developed, at least in evolutionary terms, to protect the host against potentially toxic amounts of venom, such as would happen if the animal encountered a whole nest of bees, or in the event of a snakebite," affirmed co-author Stephen Galli. "This is the first evidence, that we know of, indicating that IgE-associated 'allergic-type' immune responses can actually reduce the toxicity of naturally occurring venoms." The connection between toxins and allergies may have gone unnoticed because, in modern times, the substances that cause allergies have become less threatening in our daily lives. "We experience allergies in a much cleaner world, where we don't have the same threats of venomous creatures and potentially toxic food that existed for much of our evolutionary history," said Galli. "So we're left with this residual type of reactivity that seems completely mysterious and pointless and harmful." If allergies are supposed to be helpful, though, why are some people so prone to anaphylaxis? "Anaphylaxis probably represents the extreme end of a spectrum of IgE-associated reactivity," said Galli, "which in some unfortunate individuals is either poorly regulated or excessively robust, so the reaction itself can become dangerous." Further research is needed to see if the pattern holds with the diversity of toxins that cause allergies. But if it does, it says something very interesting about our evolutionary past. For such a dangerous defense system to have evolved, the threat of deadly toxins—like those from venomous animals—must have created a strong selective pressure. Lynne Isbell once proposed that fear of venomous snakes drove the evolution of primate eyes and brains, tying the very elements that make us human to these infamous animals. If IgE antibodies, too, are a defense against venoms, it would further suggest a very intimate relationship between our ancestors and dangerous animals. Perhaps the biblical tale connecting early humans to snakes is much closer to reality than we thought. Citation:

Marichal T., Starkl P., Reber L., Kalesnikoff J., Oettgen H., Tsai M., Metz M. & Galli S. (2013). A Beneficial Role for Immunoglobulin E in Host Defense against Honeybee Venom, Immunity, DOI: 10.1016/j.immuni.2013.10.005