A comparison with the lower animals shows that proliferation takes place when all but three of the factors considered in connection with hypertrophy and regeneration in the higher forms have been eliminated. These are, first, the action of substances that act either directly or as counteracting some substance already present, as Ziegler suggests; second, an innate tendency in the organism to complete itself; and, third, the use of the organ. It is impossible that the second factor enters into the problem of hypertrophy. In those cases in which regeneration takes place when a part of an organ is removed, as in the case of the liver, for example, the result may possibly also involve the second of the two factors, for the process is much like that of morphallaxis in the lower animals. If it be granted that the growth in a hypertrophied organ is brought about by some substance that increases the function of that organ, can we suppose the phenomenon of regeneration to be due to similar factors? In other words, can we reduce both phenomena to the same principle? The case is complicated by two facts that may be illustrated by concrete examples. If a piece is cut from the middle of the body of lumbriculus new cells are produced at both ends of the piece. If we suppose the proliferation is brought about by the accumulation of certain substances in the piece, we must still invoke other factors to account for the differentiation of the proliferated material, since a head forms at one end and a tail at the other. All the hypothesis can do in itself is to account for a proliferation, not for the differentiation, and, both in the case of hypertrophy and in that of regeneration, it is the formation of new structures that we are chiefly concerned with, rather than the simple act of growth or of proliferation. If a piece of a hydra is cut off, the whole piece changes into the typical hydra form. Here there is no extensive process of proliferation, and the change is in the old part. It seems highly improbable that the production of substances in the piece could account for its change of form. These examples will suffice to show that in the process of regeneration it is very improbable that the change is brought about by special substances that may develop or be present in the part. We must suppose that during regeneration the formation of the typical form is not the result of a stimulus originating in a chemical substance acting upon the living material, but due to changes brought about directly in the living part itself. We must conclude, therefore, that despite the apparently close connection between the phenomena of hypertrophy of uninjured organs and of regeneration, they may often involve different factors.