The Unexpected Discovery of Anaphylaxis

How the sting of the Portuguese man-of-war led to one of the most significant medical advances rooted in oceanographic work.

Published October 31, 2016

The turn of the 20th century was a heady time for science. New fields from immunology to oceanography were opening up, attracting interest and investment from individuals eager to be involved. Prince Albert of Monaco, a dedicated patron of oceanography, regularly invited scientists to conduct research in the labs aboard his royal yachts.

In 1901, Prince Albert welcomed physiologists Charles Richet and Paul Portier aboard the Princesse Alice II to study the sting of the Portuguese man-of-war (Physalia physalis). The sting is extremely painful, and Prince Albert asked Richet and Portier to investigate the properties of the venom. With a lab stocked with unfortunate animals destined to be test subjects, the yacht headed into the Atlantic toward Cape Verde to gather the jellyfish-like creatures.

The scientists’ shipboard experiments were designed only to test the effects of the venom, but their results were sufficiently interesting that they continued their work in Paris after the cruise. Physalia venom was not readily available on shore, so Richet and Portier used sea anemone venom, which was more accessible and similar in composition and effect.

The physiologists looked at the effect of multiple sublethal doses on dogs, and Portier expected that small doses of venom would serve as a sort of immunization to protect the dogs from future exposures. Unexpectedly, they found the opposite: the dogs that had recovered from an initial dose of venom exhibited dramatic symptoms and often died after being injected with a second dose of venom, regardless of the size of the second dose. Richet initially termed this “aphylaxis” (the opposite of the “phylaxis” or prophylaxis they were searching for), and later added the “an” as he thought the extra syllable sounded better.

Richet and Portier found that the secondary dosage had very little effect on the dogs’ reactions: after the first dose primed the animals’ system, even a minuscule second dose following an incubation period of a few weeks would induce acute symptoms. They determined that anaphylaxis was an immune response, and although the notion of an allergy would be described two years after Richet and Portier’s discovery, their results were the first concrete evidence that immune reactions could have adverse effects. Their discovery was announced in two papers published in Comptes Rendus de la Société de Biologie in 1902.

While Richet continued to research anaphylaxis for several years, Portier returned to his work as a lab assistant at the Sorbonne not long after the papers were published. Richet was awarded the Nobel Prize in Physiology or Medicine in 1913 in recognition of his work on anaphylaxis; Portier was not included in the award, but expressed no resentment and remained on friendly terms with Richet until his death. Monaco commemorated the discovery and Richet’s award with a series of three stamps in 1953. The stamps, all featuring the same imagery, contain three grand mustaches, but also a significant error: the yacht pictured is not the Princesse Alice II.

Decades of research have followed Richet and Portier’s groundbreaking work. We now know that anaphylaxis is usually triggered by an allergen, though there are non-allergic mechanisms that result in similar symptoms. Food, drug, insect, and latex allergies are the most common allergies associated with anaphylaxis, and as rates of food allergies increase in Western nations, more people are at risk of an anaphylactic reaction. Anaphylaxis can manifest in a wide range of symptoms, from minor hives to life-threatening asphyxiation, and it can be difficult to predict the severity of a reaction following exposure to an allergen.

Richet and Portier were searching for a prophylactic treatment, but for food, drug, and latex allergies, the only known way to protect against anaphylaxis is to avoid exposure. (Insect sting allergies can be treated with venom immunotherapy.) The only proven treatment to reverse anaphylaxis is injectable epinephrine (EpiPen), and both demand and price in the United States have risen sharply in recent years. There is significant public pressure to make the life-saving drug more accessible, as carrying an EpiPen at all times is the single best way to mitigate the risk of anaphylaxis.