A single kind of red cell is supposed to have an enormous number of different substances on it, and in the same way there are substances in the serum to react with many different animal cells. In addition, the substances which match each kind of cell are different in each kind of serum. The number of hypothetical different substances postulated makes this conception so uneconomical that the question must be asked whether it is the only one possible. ... We ourselves hold that another, simpler, explanation is possible.

According to the older view, for every single effect of a serum, there was a separate substance, or at least a particular chemical group... A normal serum contained as many different haemagglutinins as it agglutinated different cells. The situation was undoubtedly made much simpler if, to use the Ehrlich terminology... the separate haptophore groups can combine with an extremely large number of receptors in stepwise differing quantities as a stain does with different animal tissues, though not always with the same intensity. A normal serum would therefore visibly affect such a large number of different blood cells... not because it contained countless special substances, but because of the colloids of the serum, and therefore of the agglutinins by reason of their chemical constitution and the electrochemical properties resulting from it. That this manner of representation is a considerable simplification is clear; it also opens the way to direct experimental testing by the methods of structural chemistry.

I have recently observed and stated that the serum of normal people is capable of clumping the red cells of other healthy individuals... As commonly expressed, it can be said that in these cases at least two different kinds of agglutinins exist, one kind in A, the other in B, both together in C. The cells are naturally insensitive to the agglutinins in their own serum.

On the whole, at least in the author's experience, the preparation of species-specific antiserum fractions and the differentiation of closely related species with precipitin sera for serum proteins does not succeed so regularly as with agglutinins and lysins for blood cells. This may be due to the fact that in the evolutional scale the proteins undergo continuous variations whereas cell antigens are subject to sudden changes not linked by intermediary stages.

The morphological characteristics of plant and animal species form the chief subject of the descriptive natural sciences and are the criteria for their classification. But not until recently has it been recognized that in living organisms, as in the realm of crystals, chemical differences parallel the variation in structure.

The reactions follow a pattern, which is valid for the blood of all humans... Basically, in fact, there are four different types of human blood, the so-called blood groups. The number of the groups follows from the fact that the erythrocytes evidently contain substances (iso-agglutinogens) with two different structures, of which both may be absent, or one or both present, in the erythrocytes of a person. This alone would still not explain the reactions; the active substances of the sera, the iso-agglutinins, must also be present in a specific distribution. This is actually the case, since every serum contains those agglutinins which react with the agglutinogens not present in the cells—a remarkable phenomenon, the cause of which is not yet known for certain.

There is no sharp boundary line separating the reactions of the immune bodies from chemical processes between crystalloids, just as in nature there exists every stage between crystalloid and colloid. The nearer the colloid particle approximates to the normal electrolyte, the nearer its compounds must obviously come to conforming to the law of simple stoichiometric proportions, and the compounds themselves to simple chemical compounds. At this point, it should be recalled that Arrhenius has shown that the quantitative relationship between toxin and antitoxin is very similar to that between acid and base.

During the time that [Karl] Landsteiner gave me an education in the field of imununology, I discovered that he and I were thinking about the serologic problem in very different ways. He would ask, What do these experiments force us to believe about the nature of the world? I would ask, What is the most. simple and general picture of the world that we can formulate that is not ruled by these experiments? I realized that medical and biological investigators were not attacking their problems the same way that theoretical physicists do, the way I had been in the habit of doing.