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

It is not without emotion that I address this assembly on the experiments that have brought me, through the most gracious favour of the Caroline Institute, the highest reward that a scientist has the right to hope for. I ask your indulgence in speaking of my own research, as I must do, and in setting out the findings that have given anaphylaxis a leading place in general pathology over the last decade.
First I feel I must explain and indeed justify the use of the word itself, for it may seem somewhat barbarous at first glance. This neologism I invented twelve years ago on the assumption, which I think is still valid, that a new idea calls for a new word in the name of scientific precision of language.
Phylaxis, a word seldom used, stands in the Greek for protection. Anaphylaxis will thus stand for the opposite. Anaphylaxis, from its Greek etymological source, therefore means that state of an organism in which it is rendered hypersensitive, instead of being protected.

Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
……we will consider the example of a subject that has received a poison.  Let us suppose the dosage to be moderate and that after a few days the subject is, or at least appears to be, normal. If, at this point, a further injection is given of the same dosage of the same poison, what will happen?  There are three possibilities.

• The first and simplest is that there has been no change in the organism and that in receiving the same dosage as one month previously, exactly the same phenomena will result, in exactly the same conditions. Naturally this is what happens most of the time. Specialists and doctors work on this assumption when they repeat the intoxication at one month intervals.
• The second possibility is that the subject has become less sensitive. In other words, the preceding intoxication has produced a certain condition of tolerance or non-sensitivity. This will mean that a stronger dose is necessary at the second injection to give the same results. This is the case of (relative) immunization or, as it is sometimes called, of mithridatism. The most remarkable case of this tolerance is to be seen when opium or morphine are used. People who take morphine injections need stronger and stronger doses for the morphine to take effect. Some unhappy morphine addicts get to the point of standing a dose of 20 grams, whereas one decigram is dangerous in a normal subject. It has been known for persons to drink one litre of laudanum per day [sic], while one drop of laudanum produces already some effect.

These two cases, of unchanged sensitivity or stability, and of diminished sensitivity or habituation, have been known since long. Now I have shown that there is a third possibility, frequently to be observed in certain conditions which I have specified: this is of heightened sensitivity. The first injection, instead of protecting the organism, renders it more fragile and more susceptible. This is anaphylaxis.

Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
Anaphylactic symptoms vary to a great extent, although the differences are marked rather according to the nature of the experimental animal than according to the nature of the poison used. It is indeed worthy of note to find that the phenomena are constant, whatever the poison used.. I have made especial study of anaphylaxis in dogs, which permits of greater accuracy in specifying symptoms than in experiments with the guinea-pig. In the dog, four degrees of anaphylaxis may be distinguished, according to intensity.

• In the lightest form, the main symptom is prurience or itching. The animal, let loose, sneezes and gives various shakes of the head as if there was something inconvenient in his ears. The dog scratches his head and sides with his paws, sometimes frantically. Sometimes he rubs his muzzle against the ground and rolls over.
• The next stage in anaphylactic intensity is characterized by itching again, but this time more violent. This is followed almost immediately by various symptoms; more rapid breathing, lowered arterial pressure, faster heart-beat, vomiting, blood diarrhoea and rectal tenesmus.
• At the third degree, depression of the nervous system is such that the itching has gone or almost gone. The animal has no strength to vomit, diarrhoea is marked while the fluid passed from the rectum is often almost wholly blood. The nervous symptoms often develop so suddenly and violently that there is no time for colic and diarrhoea. Ataxia follows at once. The animal reels as if drunk, the pupils are dilated, the eyes haggard and after heart-rending cries, the animal falls to the ground, urinating and defecating underneath himself, unconscious, no longer reacting to the excitations and in complete mind-blindness. Breathing is laboured and agonized. The heart beats are so faint as to be barely perceptible: blood pressure hardly reaches the one or two centimetre mercury level. To sum up, all the symptoms point to the central nervous system being the seat of severe and sudden intoxication. This brutal assault of the poison on the nervous system has been called anaphylactic shock.
• There is a fourth degree of anaphylaxis, it may be said, which is more serious still: when all the symptoms, instead of passing off, worsen so that within a quarter or a half hour the subject is dead.

In the dog such death at the onset is rare. In most instances, following the anaphylactic shock, the dog revives. After fifteen or thirty minutes, he gets to his feet, staggering a bit, regains feeling and consciousness and is left with only blood diarrhoea still persisting from the anaphylaxis. Often death takes place during the night following the injection; but constantly after a period of apparent recovery.
In the rabbit, according to Arthus, respiration becomes polypneuic. The animal falls on its side, throws its head back, makes running movements with the legs and then suddenly breathing stops. Heart failure is systolic and death ensues within a couple of minutes.
Arthus also observed some interesting local effects of anaphylaxis in the rabbit. The second injection being given in the same ear as the initial injection, ulcers and gangrene appear, although there are almost no general symptoms. This local effect of anaphylaxis is often called the "Arthus phenomenon".
The guinea-pig is extremely sensitive to anaphylaxis. If the anaphylaxis is slight, only symptoms of itching, excitation and heightened breathing appear. Often the animal falls on its side, sometimes in violent convulsions, sometimes on the contrary paralysed and powerless. In both of these cases, death takes place fast and it is almost a matter of seconds between the injection and the final failure of the heart.

Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
…. the effects of anaphylaxis in mankind are very well known. Two doctors from Vienna, Pirquet and Schick, have studied the matter with the greatest care. They have described serum-sickness ("Serum-Krankheit") in children subjected to injections of diphtheria serum and they saw that it was in most cases an anaphylactic phenomenon. It is only in the rarest cases that the first injection is productive of immediate reaction. When it comes to the second injection, an immediate reaction follows for 90% of the cases, that is to say when the period between the first and second injection is from ten to thirty days.

The symptoms to be observed are very close to symptoms observed in animal subjects: urticaria, erythema, pangs of pain, itching and in the worst cases demi-syncope, with nausea, vomiting, hyperthermia, edema over the whole skin area and general urticaria.

Thus by comparison of anaphylactic effects in man and the animals, it will be seen that they are akin. It is as if poison had been produced, which reacts upon the nervous system, especially on the vaso-motor nerves or the trophic nerves of the skin……

Anaphylaxis has caused death in certain instances. …..Some years back I was in Brazil and I heard the story of a doctor who had given himself a preventive injection of anti-plague serum. The next year a new outbreak of plague was feared so he persuaded his students to have a preventive injection of the same serum. He set the example by giving himself another one. This was however an unleashing injection and his body had been affected by the first. The second injection was fatal and within two hours he was dead.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It is relevant here to indicate the relationship I have been able to establish between leucocytosis and anaphylaxis, a relationship that is hard to grasp without elaborate techniques and prolonged observations. All my experiments have been conducted on dogs, with the help of my friend P. Lassablière who did the calculations.

The number of white corpuscles or leucocytes in the normal dog is 100 per hundredth of a millimeter cubic on average, varying from 70 to 130. In animals, now, that have been anaphylactized, even after a considerable time-lag of say six months, when they appear to be completely normal and in perfect health, the number of leucocytes reaches and often exceeds 200.

An initial injection which makes the body anaphylactic, therefore, induces a marked leucocytosis and this is the only symptom that can be observed.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It has long been known that some people are sensitive to cheese or to strawberries or to fish or to shellfish or to eggs or even to milk. Now the symptoms to be seen in such individuals on ingesting such and such foods are analogous to the effects of anaphylaxis: acute stomach pains, vomiting, diarrhoea, colic, erythema, urticaria, severe itching and sometimes cardiac troubles and fever. We know now that these are anaphylactic phenomena; this has become a pathological commonplace.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It is now opportune to examine the substances apt to develop the anaphylactic state. They can be defined very simply, by using a fairly arbitrary system of classification, which groups substances in colloids on the one hand and crystalloids on the other.

Crystalloids are on the whole non-active. I am not aware of any successful attempt to induce anaphylaxis by one crystallizable salt or by any alkaloid. On the other hand all the proteins without exception produce anaphylaxis: one has seen this with all sera, milks, organic extracts whatsoever, all vegetable extracts, microbial proteinotoxins, yeast cells, dead microbial bodies. It would be of more interest now to find a protein which does not produce anaphylaxis than to find one that does.

To date, all experiments mentioned above have been carried out by parenteral injections, that is to say that the substance introduced into the blood was introduced by other means than the digestion, and namely by means of subcutaneous, intravenous, intraspinal and peritoneal injections.

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

....the second experiment to be adduced against the specificity of anaphylaxis I conducted with two kinds of toxalbumin, extracted from the Actinia, a substance which I named congestin, as its property is to bring on grave congestion of the circulatory system in the intestines and stomach. Two congestins may be prepared at some pains: yellow congestin, soluble in a fluid containing 50% alcohol, and black congestin, completely insoluble in a fluid containing 25% alcohol. Now I was able to show that black congestin is not unleashing, but is better as the preparatory injection than the yellow congestin. This gives us authority for thinking that the sensitizing (or preparatory) property and the unleashing property can belong to allied protein groups, but not identical ones. Biological chemistry will no doubt unravel these two substances. In practice the two substances, preparatory and unleashing, are almost always lined up together, so that we have a near right to pronounce on strict specificity.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
Another experiment of prime importance is this, for it shows the very nature of the anaphylactic process. In April 1907 I showed that the injection of serum from an anaphylactized dog induced an anaphylactic state in untreated dogs, as if this serum contained the toxic substance which activates the unleashing injection.
With actino-congestin, the experiment is clear-cut. Almost harmless doses cause death within a matter of hours in dogs that had not been anaphylactized, but had had injections of serum from anaphylactized animals. This is what is known as passive anaphylaxis.
At about the same time, in May and June 1907, Gay and Southard in America, and Otto in Germany, also showed quite clearly that passive anaphylaxis exists. It has become one of the classic tenets of anaphylaxis.

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
To evaluate this reaction, we must mention a valuable experiment of Claude Bernard carried out long ago. Bitter almonds contain two substances: amygdalin which is harmless and emulsin which is harmless too. Animal subjects survive an injection of either amygdalin or emulsin. But emulsin is a diastase and has the property of breaking up amygdalin, liberating hydrocyanic acid, which is one of the most virulent toxic gases known. Thus if an animal that has been given amygdalin is then injected with emulsin, hydrocyanic acid will be formed in the blood stream and death will take place at once. Yet injected separately, neither the amygdalin nor the emulsin has any effect.

 

 Charles Robert Richet - Nobel Lecture - December 11, 1913 on Anaphylaxis
It does indeed seem absurd that an organic disposition should make beings more fragile, more susceptible to poisons, for in most cases everything in living beings seems disposed to assure them a greater power of resistance.

But some reflection on the final aim of anaphylaxis will give the answer.

It is in fact important that animal species are of determined chemical entity. If, following the hazard of ingestion or injection, alien proteins were found in the cellular juices as part of our humours, then the chemical make-up of beings would be modified and consequently perverted. Crystalloids dialyse through membranes and are speedily eliminated. In a few days, even in a few hours, they are completely gone. Colloids however, that no dialysis can eliminate, do not disappear once they have penetrated to the blood. They fix on cellules and end up by being integral to them.

Grave danger would thus face the animal species, were they not nicely balanced in their hereditary chemical make-up. If heterogenous substances got fixed into our cellules and definitely intermingled with our humours, that would be the end of the chemical constitution of each animal species, which is the fruit of slow evolution down the generations, and all the progress that has been achieved through selection and heredity would be lost.

It does not matter much that the individual becomes more vulnerable in this regard. There is something more important than the salvation of the person and that is integral preservation of the race.

In other words, to formulate the hypothesis in somewhat abstract terms but clear ones all the same: the life of the individual is less important than the stability of the species.

Anaphylaxis, perhaps a sorry matter for the individual, is necessary to the species, often to the detriment of the individual. The individual may perish, it does not matter. The species must at any time keep its organic integrity intact. Anaphylaxis defends the species against the peril of adulteration.

We are so constituted that we can never receive other proteins into the blood than those that have been modified by digestive juices. Every time alien protein penetrates by effraction, the organism suffers and becomes resistant. This resistance lies in increased sensitivity, a sort of revolt against the second parenteral injection which would be fatal. At the first injection, the organism was taken by surprise and did not resist. At the second injection, the organism mans its defences and answers by the anaphylactic shock.

Seen in these terms, anaphylaxis is an universal defence mechanism against the penetration of heterogenous substances in the blood, whence they can not be eliminated.