Author: Ibon Cancio, UPV/EHU Associated Professor in Cell Biology; researcher in the ‘Cell Biology & Environmental Toxicology’ (CBET) research group of the Plentzia Marine Station (PiE-UPV/EHU); Spanish scientific representative in the EMBRC Committee of Nodes

Have you ever been stung by a jellyfish, an anemone or a Portuguese man-of-war? Even worse, have you ever repeated the experience? Believe me, it’s painful!! I turn into ‘The Hulk’ after each new sting, but with a reddish colour like a Northern European under the sun in the Mediterranean. Richet explained to us why a second sting is that bad between 1881 and 1913.

Professor Charles Robert Richet (born in Paris, 25 August 1850, and deceased on 4 December 1935) was a physiologist at the Collège de France in Paris. His broad work in physiology touched different aspects of digestion, thermal regulation, respiratory control, diuresis, fever, pain, heart rate, and toxicity of metals on bacteria. But it was his interest in poisons that lead him to ‘accidentally’ become a marine scientist. This was an accident that would lead him to win the Nobel Prize in Medicine and Physiology in 1913 ‘in recognition of his work on anaphylaxis’. 

Anaphylaxis (ana from ava=without, phylaxis=protection), a term coined by Richet, is an immune response, where a small exposure to a toxin or foreign substance results in a severe reaction to later exposure, even if subtle. It is a very severe allergic reaction that although it is often associated with insect bites, food or medications, was first described in relation to marine toxins. 

Richet’s work on anaphylaxis was initiated aboard the yacht ‘Princess Alice II’ in July 1901 while working with the venom in the tentacles of the Portuguese man-of-war, Physalia physalis. The ship belonged to Prince Albert of Monaco who headed the cruise, that would carry the crew and a group of scientist from Toulon to Cape Verde and Azores for 2½ months. 
Richet was invited on-board to work with Paul Portier (1866-1962). Their goal during the cruise was to analyse the toxic effects of Physalia venom on small animals like frogs, guinea pigs, ducks, and pigeons carried on board. They all became paralysed under a clear central nervous system depressing effect when injected with venom-infused glycerol, so Richet and Porter coined the term ‘hypnotoxin’ for the ‘poison’.

Allergic skin reaction arm
The arm of the poor marine biologist that has authored this text:
after yet another sting turning into 'The Hulk'. Photo by Ibon Cancio.

Upon their return, Richet and Portier decided to continue their work on the effects of venom but using bigger animals (like dogs) for the injections. Physalia are not that easy to obtain but sea anemones (Anemonia sulcata) can be easily harvested in large quantities on the coast of Brittany. Lacaze-Duthiers, director of the Station Biologique de Roscoff (an EMBRC France marine station), was instrumental in the earlier carrier decisions of Portier towards marine biological research and the supply of anemones from Roscoff was guaranteed. 

The hypothesis of Richet and Portier was that small injections of venom might immunise dogs against later inoculations, as was beginning to emerge from recent bacteriological and vaccination research. In 1888, Richet personally adapted pioneering concepts of Pasteur in vaccine production and effectively immunised dogs and rabbits with attenuated cultures of staphylococci and avian and human strains of bacilli causative of tuberculosis. Coming back to ‘actinotoxin’ and after identifying its lethal dose (0,15 ml/kg), Richet and Porter performed their first sublethal experiments with eight dogs, but they all died in an experiment that was not well monitored. So they decided to carry out one last experiment with only two dogs (statistically not very sound, we would say today). The dogs endured a first inoculation of 0,05 ml/kg, apparently without any effect, but died 30 minutes upon a second injection of only 0,01 ml/kg, delivered 27 days apart. By the way, the name of one of the dogs was ‘Neptune’, God of freshwater and the sea. 

Richet was intellectually and scientifically trained to understand such a contradictory observation, the same way as Pasteur was for his serendipitous discovery of penicillin. He interpreted that the extreme response resulted from factors produced by a challenged body system and not by the injected foreign agent itself. Becoming aware of this provided the clues to understand hypersensitivity as an immune phenomenon. Realisation of its relevance to human disease followed instantly. Richet's, and let us not forget Porter's, work in anaphylaxis helped to elucidate diseases such as hay fever, asthma as well as others that arise from massive allergic reactions.

Portrait of Charles Richet
Portrait of Charles Richet (public domain)

Later, further analysis by other researchers demonstrated the reasons for the dual toxic effects of actinotoxin, immunogenic and hypersensitising at the same time. Actinotoxin is a cocktail of molecules. Together with large-molecular-weight proteins, we can find urticariogenic agents, and mediators of inflammation in a mixture containing biogenic amines (histamine, serotonin, dopamine), prostaglandins, polypeptide neurotoxins and cardiotoxins, proteinase inhibitors and haemolytic and cardiotoxic enzymes. Much later, actinoporin would be isolated from sea anemones, a toxin with pore-forming, haemolytic, cytotoxic, and heart stimulatory activities. In the 1980s, physalitoxin was isolated from the man-of-war. This is a potent haemolytic and neurotoxic toxin that induces insulin secretion in the pancreas and that increases Ca2+ cell concentrations.

Good stories require epilogues. Prince Albert-I of Monaco was pivotal for the development of oceanography and marine biological research in the end of the 19th century. Portier, who was appointed professor and first director of the Institut Oceanographique in Paris founded by Prince Albert in 1906, became professor of comparative physiology in a chair especially established for him at the Faculté des Sciences in Paris in 1923. 

As to our marine scientist of today, Richet, we need to say that scientists are humans and thus they have their lights but also their shadows. Professor Charles R. Richet was a brilliant scientist but at the same time he was dazzled by paranormal and spiritualist phenomena, and became a credulous parapsychologist. A pacifist and man of wide culture and intellect with interests spanning from poetry to aeronautics, he was at the same time a defender of eugenics and white supremacy. By all means, even as marine scientists, we are not perfect!!

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