It may be well to enumerate some of the cases in which the influence of specific substances circulating in the blood upon phenomena of growth has been proven. One of the most striking observa­tions in this direc­tion is the one made by Gudernatsch on the growth of the legs of tadpoles of frogs and toads.[145] The young tadpoles have no legs, but the mesenchyme cells from which the legs are to grow out later are present at an early stage. From four months to a year or more may elapse before the legs begin to grow. Gudernatsch found that legs can be induced to grow in tadpoles at any time, even in very young specimens, by feeding them with the thyroid gland (no matter from what animal). No other material seems to have such an effect. The thyroid contains iodine, and Morse[146] states that if instead of the gland, iodized amino acids are fed to the tadpole the same result can be produced. We must, therefore, draw the conclusion that the normal outgrowth of legs in a tadpole is due to the presence in the body of substances similar to the thyroid in their action (it may possibly be thyroid substance) which are either formed in the body or taken up in the food.

Thus we see that the mesenchyme cells giving rise to legs may lie dormant for months or a year but will grow out when a certain type of substances, e. g., thyroid, circulates in the blood. There may exist an analogy between the activating effect of the thyroid substance and the activating effect of the spermato­zoön or butyric acid (or other partheno­genetic agencies) upon the egg, but we cannot state that the thyroid substance activates the mesenchyme cells by altering their cortical layer.

The fact that the substance of the thyroid may induce general growth in the human is too well known to require more than an allusion in this connec­tion. When growth stops in children as a consequence of a degenera­tion of the thyroid, feeding of the patient with thyroid again induces growth. It may also suffice merely to call atten­tion to the connec­tion between acromegaly and the hypophysis.

It was formerly believed that the nervous system acted as a regulator of the phenomena of metamorphosis in animals, but it was possible to show by simple experi­ments that the central nervous system does not play this rôle and that the regulator must be the blood or substances contained therein. In the metamorphosis of the Amblystoma larva the gills at the head and tail undergo changes simultaneously, the gills being absorbed completely. The writer showed that in larvæ in which the spinal cord was cut in two, no matter at which level,—the sympathetic nerves were in all probability also cut—the two organs continued to undergo metamorphosis simultaneously.[147] Uhlenhuth found that if the eye of a salamander larva is transplanted into another larva the transplanted eye undergoes its metamorphosis into the typical eye of the adult form, simultaneously with the normal eyes of the individual into which it was transplanted.[148] These and other observa­tions of a similar character leave no doubt that substances circulating in the blood and not the central nervous system are responsible for the phenomena of growth and metamorphosis.

An interesting observa­tion on the rôle of internal secre­tion in growth was made by Leo Loeb.[149] When the fertilized ovum comes in contact with the wall of the uterus it calls forth a growth there, namely the forma­tion of the maternal placenta (decidua). This author showed that the corpus luteum of the ovary gives off a substance to the blood which alters the tissues in the uterus in such a way that contact with any foreign body induces this deciduoma forma­tion. The case is of interest since it indicates that the substance given off by the corpus luteum does not induce growth directly, but that it allows mechanical contact with a foreign body to do so while without the interven­tion of the corpus luteum substance no such effect of the mechanical stimulus would be observable. The action of the substance of the corpus luteum is independent of the nervous system, since in a uterus which has been cut out and retransplanted the same phenomenon can be observed.

Bouin and Ancel[150] have shown that the corpus luteum, which in the case of pregnancy continues to exist for a long time, is responsible for the changes in the mammary gland in the first half of pregnancy, when an active cell prolifera­tion takes place in the gland. This process can be interrupted by destroying the corpus luteum artificially. During the second half of gravidity no further cell prolifera­tion takes place, but the cells begin to secrete milk while during the period of cell prolifera­tion such secre­tions do not occur.

Claude Bernard and Vitzou had shown that the period of growth and moulting of the higher crustacea is accompanied by a heaping up of glycogen in the liver and subdermal connective tissue. Smith[151] found that during the period between two moultings, when there is no growth, the storage cells are seen to be filled with large and numerous fat globules instead of with glycogen. He also found that in the Cladocera “the period of active growth is accompanied by glycogen—as opposed to fat—metabolism.” He observed, moreover, that if Cladocera are crowded at a low temperature the fat metabolism (with inhibi­tion to growth) is favoured, while at high temperatures and with no crowding of individuals the glycogen metabolism is favoured. In the latter case a purely partheno­genetic mode of propaga­tion is observed, while in the former sexual reproduc­tion takes place. The effect of crowding of individuals is possibly due to products of excre­tion, which then act on growth and reproduc­tion indirectly by changing the “glycogen metabolism” to “fat metabolism.”

All these cases agree in this, that apparently specific substances induce or favour growth, not in the whole body, but in special parts of the body. Sachs suggested that there must be in each organism as many specific organ-forming substances as there are organs in the body.

We will now show that the assump­tion of the existence of such “organ-forming” substances (which may or may not be specific) and of their flow in definite channels explains the inhibitory influence of the whole on the parts as well as the unbridled regenera­tion of the isolated parts.