Presentation Speech by Professor C. Sundberg, Vice-Chairman of the Nobel Committee for Physiology or Medicine of the Royal Caroline Institute, on December 10, 1913
Your Majesty, Your Royal Highnesses, Ladies and Gentlemen.
The Nobel Prize for the year 1913 for Physiology or Medicine has been awarded by the Staff of Professors of the Caroline Institute, to Charles Richet, Professor of Physiology in the Medical Faculty, Paris, «for his work on anaphylaxis».
It has long been known that certain infections do leave behind an immunity, that is to say, diminished susceptibility or non-susceptibility regarding a renewal of infection of the same kind. With the introduction by Jenner of vaccination against smallpox, we learned how to ensure immunity by artificial means. Since the first preventive inoculations against live infectious agents carried out by Pasteur around 1880, artificial immunization has maintained constant progress. It now covers protein toxins of bacterial, vegetable and animal origin, such as the diphtheria toxin, snake venom, etc. Immunization in these instances is carried out on the following general principles: first, inoculation of attenuated virus or, with respect to toxins, of a toxin dosage diluted to the point of being harmless; then, inoculation of stronger viruses or increased dosage of toxin, until immunity is effected. After the first inoculation, susceptibility to a second inoculation of virus or toxin is, by and large, visibly less. It is not uncommon for one treatment to suffice in giving immunity, as far as microbial virus is concerned. On the other hand, toxin injections do have to be repeated many times and the dose increased to get this result.
In the course of the numerous immunizations that have been carried out in all countries, with the aim of finding different serums apt for medical usage, certain effects have been observed from time to time, which did not fit in with the general rule of diminished susceptibility. Thus, Robert Koch, in his research to find an anti-tuberculous serum, was able to show that the tuberculin prepared by him had a stronger effect when the injection was administered to tuberculous subjects, than when injected into subjects not suffering from tuberculosis. Von Behring in his work observed that, in certain isolated cases, a horse that had long been non-susceptible to very strong doses of diphtheria toxin, when under injection to obtain the diphtheria serum, could suddenly – and with no forewarning – succumb to a new dose of the toxin that was no stronger than those that had already been administered, and that had been tolerated quite easily by other horses from the same stable, treated in the same way, and with the same toxin. Richet, who with his co-worker Héricourt had found that eel blood-serum was toxic to dogs, confirmed that this serum caused a more violent reaction at the second or third injection than at the first.
These cases of increased rather than diminished susceptibility were however taken to be accidental exceptions. They were explained in two ways: at the time of a fresh injection, the toxin was added to the amount already absorbed by the body, and thus had a heightened effect (Koch, Richet); or else certain subjects were occasionally and paradoxically hypersensitive, and this, as it were, by a kind of surfeit caused by repeated doses of the toxin (Behring).
Richet has lifted this problem of hypersensitivity to toxins on to a new plane. In 1902 he published, in collaboration with Portier, the first work on this subject. Later, in a series of studies collected in the monograph L’Anaphylaxie of 1912, Richet – unaided – confirmed and expanded this discovery.
He experimented with several protein toxins, of animal and vegetable origin. If one of these toxins is injected beneath the skin of the test animals, in such a small dose that the subjects do not react, and if the injection is repeated after an interval of two or three weeks with an equally weak dose, this is almost always followed, sometimes even during the second injection, by the most violent toxic symptoms. These can cause the death of the animal in a few minutes, or else the animal is seen to recover completely and with equal rapidity. The toxic state in this case is nearly always markedly transitory.
This violent reaction, similar to shock, is in no way due to the second dose being added to possible toxic traces of a former dosage. It was quite simple to prove that such was not the case. If the two doses are given at one session, or at a brief interval, or even four or five days apart, there are no toxic effects. There must always be a certain preparation, a period of incubation before the toxin injected has time to cause hypersensitivity in the organism.
This hypersensitivity that Richet found does not correspond with the sporadic cases of hypersensitivity found by Behring in horses immunized against diphtheria. The hypersensitivity of Richet is not fortuitous; it is constant and produced with the same regularity as diminished susceptibility produced by immunization. Richet calls this hypersensitivity with regard to toxins, anaphylaxis, in contrast to phylaxis or prophylaxis, meaning protection.
Anaphylaxis is analogous in several ways to the phenomenon of immunity. Both are specific, in that they apply only to the toxin used for the previous dose. Both require a period of incubation. They are both constant to a certain point, and last as a characteristic feature of the organism for a considerable time.
In 1888 – in other words well before serum treatment, which is now so generally used in the fight against different contagious diseases, was known – Richet had proved that immunity could be transferred experimentally from one animal to another not so far immunized by injecting blood serum of the first into the second, in other words by passive immunization. Richet’s next step was to find out whether these findings on passive immunization were equally applicable to anaphylaxis, and in fact he demonstrated that anaphylactic hypersensitivity could be transferred from one animal to another by the injection of blood serum from the animal anaphylactized. This fact could serve as a basis for methods aimed at ascertaining, e.g., in man, if an ailment suspected of being anaphylactic was in fact so or not. As to the bearing of anaphylaxis on pathology, it was naturally of prime importance.
One feature of anaphylactic intoxication is that the symptoms are almost identical in all cases of anaphylaxis whatever the toxic agent and, up to a certain point, whatever the animal treated. The symptoms always show certain general characteristics: lowered blood pressure, paralysis of the higher brain functions, dyspnoea, low temperature, etc. The subject who survives a severe anaphylactic shock acquires by so doing diminished susceptibility: he is immunized. These last two points have led to theoretic research of vast scope, which is not yet completed.
It is as a physiological research worker that Richet discovered the phenomenon of anaphylaxis. If it is true that any knowledge of a new principle underlying the phenomena of life brings us a step nearer to understanding organic life itself, then Richet – by his original contribution just outlined – has rendered biology sterling service and deserves the highest recognition.
Anaphylaxis has already been carried into the field of medical practice. The materials that can be used to induce anaphylaxis are very numerous. I shall confine myself to enumerating the different forms of proteins of alien origin to the subject and of inoffensive appearance (called proteins alien to the species), such as colouring matter of the blood, milk, white of egg, fish protein, oysters, tumour cells, vegetable protein (for example of the pollen that causes hay fever), microbial extracts, etc.
On the basis of the discovery of anaphylaxis, a series of investigations, very important for the knowledge of diseases, has been inaugurated on what is called the idiosyncrasies or the individual reactions pertaining to each subject towards certain protein foodstuffs. Richet himself has taken part in this work, particularly in respect of different meats. In this sphere, research is still only in its infancy and it would be premature to make any pronouncement on these questions. It may however be said that Richet’s discovery has revealed the first of these phenomena which has been clearly proved and plainly understood. This is one of the central discoveries of medical science, physiology and pathology, in recent times.
Professor Richet. In one of your numerous works, which have embraced so many branches of human culture, you uttered the stimulating exhortation: «Laboremus». The diligence with which you have followed your maxim has won for you above all a reputation in medical science; it is to this science that you have devoted the greater part of your unremitting labours, and you have enriched it with ideas and new knowledge. Your greatest success has been the discovery of anaphylaxis, an outstanding scientific achievement.
In an age in which the leading members of the medical profession tend to concentrate on innumerable experiments demonstrating the growing immunity of the organism towards poisons already resisted successfully once, you, Sir, have found that in certain cases a completely opposite result is produced. You did not restrict yourself to this isolated observation: studied in depth by you, it has become the foundation on which you have based the evidence of a reaction that is sometimes just as regular as the phenomenon of immunity. We are not concerned solely with specific prophylaxis; thanks to you, we are now aware of a specific anaphylaxis.
We do not discount the work of those who, following your lead, have observed similar phenomena, but to you goes the honour of having established the basis of a new biological reaction, anaphylaxis, and of having been the first to demonstrate it clearly. Thereby you have opened up to medical science an enormous field of study as yet unexplored. The Staff of Professors of the Caroline Institute wishes to reward you for this achievement by conferring on you the prize instituted by our compatriot Alfred Nobel for those «who have made the most important discovery in the field of physiology or medicine».
Please accept the warm congratulations of the Institute and myself, together with the wish of us all that success will continue to crown your devoted work.