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Some science behind the scenes

Anaphylaxis - discovery of

Dr Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis

These are the circumstances under which I first observed this phenomenon. You will allow me to go into some details on the origins. You will find that it is by no means the result of profound thought but a simple observation, almost a fortuitous one; so that my merit has only been in letting myself see the facts which were plain before me.

In tropical waters, Coelenterata are to be found floating on the surface, also known as Physalia (Portuguese galleys). The basic structure of these creatures is a pocket filled with air so that they can float like a bladder. A bucco-anal cavity is subjoined to this pocket, with very long tentacles which hang in the water. These feelers sometimes run to two or three meters long and are equipped with small devices which adhere like sucking cups to objects encountered. Within each of these innumerable suction-cups is a pin-point which drives into the foreign body that is being touched. At the same time, this pin-point causes penetration of a subtle but strong poison, which is contained in the tentacles, so that contact with a feeler of the Physalia is tantamount to a multiple injection of poison. On touching a Physalia an acute sensation of pain is felt immediately, due to the penetration of this liquid venom. This is similar in relative intensity to a swimmer's mishap when he bumps into a jelly-fish in the water.

During a cruise on the yacht of Prince Albert of Monaco, the Prince advised me to study Physalia poison, together with our friends Georges Richard and Paul Portier. We found that it is easily dissolved in glycerol and that by injecting this glycerol solution, the symptoms of Physalia poisoning are reproduced.

When I came back to France and had no more Physalia to study, I hit upon the idea of making a comparative study of the tentacles of the Actinia (Actinia eqnina, Anemone sulcata) which can be obtained in large quantities, for Actinia abound on all the rocky shores of Europe.

Now Actinia tentacles, treated with glycerol, give off their poison into the glycerol and the extract is toxic. I therefore set about finding how toxic it was, with Portier. This was quite difficult to do, as it is a slowly acting poison and three or four days must elapse before it can be known if the dose be fatal or not. I was using a solution of one kilo of glycerol to one kilo of tentacles. The lethal dose was of the order of 0.1 liquid per kilo live weight of subject.

But certain of the dogs survived, either because the dose was not strong enough or for some other reason. At the end of two, three or four weeks, as they seemed normal, I made use of them for a new experiment.

An unexpected phenomenon arose, which we thought extraordinary. A dog when injected previously even with the smallest dose, say of 0.005 liquid per kilo, immediately showed serious symptoms : vomiting, blood diarrhoea, syncope, unconsciousness, asphyxia and death. This basic experiment was repeated at various times and by 1902 we were able to state three main factors which are the corner-stone of the history of anaphylaxis: (1) a subject that had a previous injection is far more sensitive than a new subject; (2) that the symptoms characteristic of the second injection, namely swift and total depression of the nervous system, do not in any way resemble the symptoms characterizing the first injection; (3) a three or four week period must elapse before the anaphylactic state results. This is the period of incubation.

Once these first factors in anaphylaxis were well grounded, the field opened right up, thanks to the skilled and fruitful research of many investigators.

In 1903 Arthus, in Lausanne, showed that a first intravenous injection of serum on a rabbit causes anaphylaxis, i.e. three weeks after the first injection the rabbit is hypersensitive to the second injection. The phenomenon of anaphylaxis was becoming of general application. Instead of applying only to toxins and toxalbumins, it held good for all proteins, whether toxic at the first injection or not.

Two years later Rosenau and Anderson, two American physiologists, demonstrated in a noteworthy piece of work that the phenomenon of anaphylaxis occurs after every injection of serum, even when the injection is minute, for example of 0.00001 ml which is an infinitely small amount but nevertheless sufficient to anaphylactize an animal. They quoted examples of anaphylaxis from all organic liquids: milk, serum, egg, muscle extract. They specified the reaction and clearly showed that of all the subjects, the guinea-pig appeared the most sensitive in anaphylactic terms.

In 1907 I conducted an experiment which shed much light on the pathogeny of anaphylaxis. An anaphylactic state is produced by taking the blood of an anaphylactized animal and injecting it into a normal animal subject. The anaphylactogen poison is therefore a chemical substance contained in the blood.

Such are, I think, the main stages through which our knowledge has passed. I pass now to particular points I wish to stress.

The incubation period varies according to the poison used rather than according to the type of animal subject. There is however a minimum period of one week (in the guinea pig, following the injection of milk). With mytilin extracted from the common mussel (Mytilus edulis), the incubation period is a fortnight. With the dog, using crepitin extract from Hura crepitans, the period is longer, of some four weeks. With the guinea-pig, following the injection of serum - on an exhaustive series of experiments - the incubation period is of some eleven days and the reaction symptoms reach their peak at the fourteenth day, always allowing for considerable variation according to subject.

But it is a much harder task to state when the anaphylactic period has actually passed. Most writers incline to the view (and I myself would think them correct in their view) that the anaphylactic state never passes. In other words, once a subject has been anaphylactized and consequently modified in his chemical constitution, then the subject can never go back to his former state. Return to normal is not possible. Subjects have been known who even after four years from the date of the first serum injection, were still sensitive to the unleashing reaction.

Let me add in passing that it is an extraordinary phenomenon that so insignificant a quantity of poison can modify the organism to the extent that the succeeding days down long years can not eradicate this indelible modification. Unfortunately minute researches on just this point are still lacking. But it certainly looks as though considerable differences will be found in the duration of anaphylactization.