An

from which Curtius 'has made the derivatives referred to above. In the same connection Fischer explained that a similar reaction follows with the anhydrides of alanine and leucine, from which alanylalanine and leucylleucine must result. To carry the process farther and obtain more complex groups proved practically difficult. other method was finally developed which may be illustrated by some of the simplest cases described by Fischer. On bringing together a halogen acid chloride, for example chloracetyl chloride, with an ester of glycylglycine, chloracetylglycylglycine ester results,

CICH CO. NHCH CO. NHCH,COOCH, which on saponification yields the acid. The latter in turn when treated with strong ammonia gives up chlorine for the amino group and diglycylglycine results. With a-brompropionyl bromide employed as the halogen compound, alanylglycylglycine is obtained, and with a-bromisocapronyl chloride leucylglycylglycine is secured in the same manner.

It will be seen that while the processes of Fischer and Curtius follow different lines they lead usually to the same ends. A considerable number of the Curtius investigations have been published in Vol. 70, N. F., 1904, of the Jour. prakt. Chem. under the title of 'Condensations of Amido Acids,' while the Fischer work has come out in recent volumes of the Berichte under the general title of 'Syntheses of the Polypeptides.' This work seems to be more directly concerned with the building up of bodies of physiological interest; the Curtius work is somewhat more general. Of many of the Fischer compounds it has been shown that ready hydrolysis with active pancreatic juice follows. The biuret reaction is also given in many cases, but apparently not always. Groups containing tyrosine, cystin, leucine, alanine, etc., have

been split by the ferments, and these, it will be remembered, are among the most important of the fractions secured by the hydrolysis of the true proteins. The method of producing these polypeptides seems to be without limit and doubtless much more complex aggregations will be secured. Molecular weights of over 500 have already been reached.

Closely related to the question of the synthesis of the polypeptides is that of the composition of the simplest proteins. The work of Kossel and others in this direction has furnished most interesting results. For several of the protamines and histones the content of hexone bases has been found with a fair degree of accuracy, and of many of the more complex proteins the amounts of both mono- and diamino acids present have been found. The numbers secured must be looked upon, however, as minimum values because of the practical difficulties in the way of quantitative separation and identification.

Several improved processes have been developed for the separation of amino acids from digestion or other mixtures. A method first suggested by Curtius for the production of ethyl esters of the amino acids, and which has been referred to above, has been perfected by Fischer. From mixtures the esters are distilled off under greatly reduced pressure. From the distillate some are separated by solvents, while others, after conversion to acids, are separated by fractional crystallization. It has been found that B-naphthalene sulphochloride combines with many of the amino acids to form compounds of very slight solubility and Fischer and Bergell have developed a method of separation based on this fact. Both general methods have been applied also in the detection and estimation of amino acids in urine which is likely to become a matter of considerable clinical in

terest, as these acids must represent degenerative or otherwise abnormal products having their origin in the liver and other organs.

Unquestionably one of the most important fields of effort in physiological chemistry at the present time is the study of the soluble ferments, and we have here for consideration not only certain newly discovered enzymes, but, perhaps, of more importance, a great advance in our knowledge of those already known. It was not many years ago that we considered the question of the gastric enzymes as practically settled. The presence of both pepsin and rennin no one could have doubted, but the work of Pawlow and his school in the last five years has thrown entirely new light on the subject and it would appear that one and the same ferment, working under different conditions, is responsible for both classes of observed phenomena. Pawlow has compared the digesting and milk curdling power of ferment secretions from the true pepsin and pyloric glands of the stomach, from the pancreas and from Brunner's glands, and has found them perfectly parallel under proper conditions of experiment; any cause which operates to destroy one power, destroys also the other according to Pawlow. But in any given extract or preparation the conditions must be properly chosen to show both effects. A commercial rennet, for example, may exhibit the milk curdling action very strongly, yet appear to be wholly inert toward fibrin. Pawlow holds that in all such cases simple dilution with very weak hydrochloric acid is all that is called for to show the peptic power. A valuable résumé of this work is given in a recent number of the Zeitschrift für physiologische Chem. (Vol. 42, p. 415, 1904)..

It is proper to say that the physiologists of the Hammarsten school do not admit the

claims of Pawlow, although the doctrines of the latter have been put in very strong light.

To Pawlow we owe, also, the discovery of a new group of ferments which he calls kinases, or activators. The most thoroughly studied of these is the enterokinase which converts the inactive pancreatic juice into an active ferment secretion. As to the value of the other kinases much less is known.

About four years ago Cohnheim described, under the name of erepsin, a peculiar ferment in the intestinal walls which has the power of splitting peptones and proteoses, but not albumins. This discov

ery grew out of an investigation to determine the fate of the peptone bodies of proteolysis, it being long known that no appreciable amount of these substances appears in the circulation after digestion. A theory grew up to the effect that in the intestinal walls, just before absorption, they were converted back into true albumins. According to the views now advanced by Cohnheim and others this can not be the case to any large extent. The peptones break down with liberation of the carbon and hydrogen excess, which serves as a source of energy, while the nitrogen fractions go over into the form of amino acids, to be further broken down by the liver. This coincides with the view that very little protein is actually needed by the body. On the other hand, it is held by several physiologists that the erepsin katabolism does not go so far, but merely to the production of amino compounds which are ready for a synthesis not yet understood.

If time permitted I should like to go into the question of enzymes in other directions, especially with reference to the work in the liver and the action of the so-called autolytic ferments, the behavior and general importance of which are still very ob

A

scure. A large and interesting literature has grown up around the discussion. word must be said, however, about the important discussion started two years ago by Cohnheim when he announced the relation of two distinct ferments to the oxidation of carbohydrates in the body. The bearing of this on the question of diabetes was immediately recognized and numerous investigations were launched to throw more light on the subject. According to Cohnheim the pancreas furnishes one of these enzymes and the muscle substance the other. One may serve as a kinase or activator for the other and the effect of the two is to facilitate oxidation in the muscles. The subject is immensely important, but the latest studies do not seem to fully confirm all the Cohnheim statements.

In connection with the subject of enzymes reference must be made to the considerable number of papers which have appeared in the last few years on the question of the relation of the ferments to the simple inorganic katalytic agents. Beginning with the work of Tammann published in the Zeitschrift für physikalische Chemie many attempts have been made to express the velocity of enzyme reactions by equations analogous to those suggested by Wilhelmy for the inversion of sugar. The extended investigations of Tammann led in general to formulas which were more complicated than those corresponding to the simple logarithmic curve. Some of the more recent work, especially that of Henri, has led to more definite results. This whole discussion has been well reviewed by Bredig in volume 1 of the Ergebnisse der Physiologie.

One of the most interesting developments in recent physiological chemistry is in the discussion of theories of immunity and the relations of toxins and antitoxins. As first presented by Buchner, Bordet, Ehrlich,

Pfeiffer and others, these doctrines appeared from the chemical standpoint wholly visionary and intangible, but in the last few years a great change has followed in the attitude of chemists and now some of the phrases of the immunity theory of Ehrlich have become part of the language of organic chemistry.

It was early recognized that toxins and antitoxins act on each other in a manner suggesting combinations in definite chemical proportions, and attempts were soon made to work out the laws of the union. The earlier Ehrlich experiments seemed to point to simple combinations like those between an acid and a base, the union following to complete saturation. It was recognized later, however, in many cases, that the reaction is not complete and that the saturation curve is far from being a straight line. These observations led to various speculations. Ehrlich assumed that in the ordinary toxin mixtures we have certain modified forms known now as toxoids and toxons, which, while non-toxic, have saturating power resembling that of the toxins. Hence the amount of antitoxin added to a toxin solution to destroy its toxicity would have to be sufficient to combine, not only with the real toxin, but with any toxoid or toxon present also; just as in neutralizing free sulphuric acid by sodium carbonate the amount of the latter necessary would have to be increased if some salt decomposable by sodium carbonate, such as alum, is likewise present. the one case as in the other the simplicity of the reaction would be obscured by complexity of the mixture.

Arrhenius and Madsen, and others following them, have been led also to study these extremely important phenomena and have given a different interpretation. cording to the notions of the physical chemists these reactions are more or less per

Ac

fectly reversible, which certain experiments seemed to prove, and resemble somewhat the union of an alcohol and an acid which combine to reach a condition of equilibrium. They assume for the toxin-antitoxin reaction the perfect applicability of the Guldberg-Waage mass action formulas, and for a number of relations have calculated the value of the constant k. It is interesting to note that a number of the leading physical chemists have taken part in the discussion. About a year ago Michaelis reviewed the subject in a long article in the Biochemisches Centralblatt and this has recently appeared in expanded book form under the title, 'Die Bindungsgesetze von Toxin und Antitoxin.' Michaelis does not accept the Arrhenius work as satisfactory or convincing, and points out several conditions necessary for the applicability of the mass action laws which do not obtain in the cases in question; for. example, the mixtures are not homogeneous and the degree of reversibility is extremely limited, if it really exists.

On the other hand, the doctrine of the toxoids and toxons appears to explain the apparent discrepancies and in certain mixtures secured in the experiments of Keyes and Sachs, known to be free from these bodies, the toxin and antitoxin combination followed in proportions represented by an almost perfect straight line.

It remains to add that this whole discussion can not fail to have an important influence on the attitude of medical men to the rapidly developing physiological chemistry. The Arrhenius theory seemed to simplify the question somewhat and make it one of analogy with other well-known phenomena. The facts more recently adduced by the Ehrlich workers do not seem to permit this theoretically preferable solution. The toxoid and toxon hypotheses are necessarily chemical, however, and for the

present may better serve in the advance of investigation. J. H. LONG. NORTHWESTERN UNIVERSITY MEDICAL SCHOOL, CHICAGO, ILL.

SCIENTIFIC BOOKS.

New

The Evolution of Man. By ERNST HAECKEL. Translated from the fifth German edition by JOSEPH MCCABE. 2 vols., 8vo. York, G. P. Putnam's Sons. 1905. In the two stately and richly illustrated volumes before us we have a translation of the fifth edition of Haeckel's 'Anthropogenie,' and coming as they do from the pen of one who may now be regarded as a Nestor of zoology and the most vigorous exponent of the historical method of investigation, they present not a little interest. They profess to give in their course of some nine hundred pages an account of the embryological and comparative anatomical evidence bearing on the origin of man, a subject of perennial interest not only to the laity, but also to professional zoologists, since it involves the problem of the origin of the vertebrates.

The work opens with a chapter upon the biogenetic law, or, as it is termed, 'the fundamental law of organic evolution,' and then follow five especially interesting chapters devoted to a history of the development of embryology and phylogeny. To these succeed an extended account of the principal embryological stages of the vertebrates and a discussion of their significance, in which the germ cells, segmentation, gastrulation, the germ layers, metamerism, the fetal membranes and the development of the general form of the body, are all considered from the standpoint of their bearings on the ancestral history. This completed, the author passes on to a consideration of the recent representatives of the ancestral stages and concludes with several chapters devoted to the phylogeny of the various organs of the human body.

It would require much space to consider adequately the entire contents of the volumes, and the purpose of this review will, perhaps, be best served by indicating briefly the line of descent which Haeckel advocates. It is essentially the same as that presented in earlier

editions, of which the third has appeared in an English translation, but differs in the greater detail and precision with which the various stages are defined.

It starts with the Monera, non-nucleated masses of protoplasm which 'stand exactly at the limit between the organic and the inorganic worlds' and have originated by spontaneous generation. Of these, two varieties existed, differing in their physiological activities; the one group, the phytomonera, being plasmodomous, building up protoplasm from unorganized material, and the other, the zoomonera, being plasmophagous, finding their nutrition in already organized material. The phytomonera were the more primitive of the two, the zoomonera arising from them by metasitism or metatrophy, the reversal of the mode of nutrition, a process which may have occurred several times independently and among cytodes as well as moners. Hence not only have zoomonera been derived from phytomonera, but nucleated unicellular plasmophags have arisen from similar plasmodomes, and so Haeckel takes as his second stage of the ancestry the Algaria, represented to-day by such unicellular algæ as the Palmellaceæ. From these he derives the third stage, that of the Lobosa, represented by Amoeba and having corresponding to it the ovum stage of ontogeny.

The line of descent is then traced through the moræa, blastæa and gastræa, familiar to all readers of Haeckel's writings, and then passes to the Platodaria and Platodinia, two groups of turbellarian worms represented today by the so-called Acola and the Rhabdocœla. The ninth stage is that of the Provermalia, represented by such recent forms as the Rotatoria and Gastrotricha, and presenting an advance upon preceding stages in the possession of a body cavity and an anal aperture; and to these succeed the Frontonia, a group which many will regard as decidedly heterogeneous, since both the Nemerteans and the Enteropneusta are regarded as being its modern representatives. Then follows the Prochordonia stage, characterized by the possession of a definite notochord and branchial

slits and by the absence of a well-defined metamerism; its nearest representatives among recent forms are the copelate ascidians and the appendicularia larvæ.

Haeckel thus omits metamerism as a fundamental and primitive condition whose existence in several groups of animals implies a community of descent; for him it is merely a mode of growth and as such has been independently acquired in different phyla. He regards the metamerism of the annelids and arthropods as something quite different both structurally and phylogenetically from the metamerism of the vertebrates, and consequently excludes the annelids from the line of descent.

The next stage ushers in the vertebrate phylum and is that of the Prospondylia, which finds its modern representative in the larval Amphioxus, and then succeeds a stage corresponding to the adult Amphioxus, then the Archicrania, represented by the Ammocates larva, and then a stage corresponding to the adult cyclostome. The line then passes through the Proselachii, Proganoidea and Palædipneusta, thence through the stegocephalous Amphibia to the Proreptilia represented most nearly by the modern Hatteria, and so to the Monotremes, which represent the Promammalian stage. Then follows the Prodidelphian stage and then that of the Prochoriata or Mallotheria, represented by an extinct group of placental mammals which included the stem-forms of the rodents, ungulates, carnivores and primates and, perhaps, finds its nearest recent representatives among the Insectivora. From the older Mallotheria the Prosimiæ are descended and of these Haeckel recognizes two ancestral stages, the Lemuravida and the Lemurogona, both belonging to Eocene times. From these the Simiæ with a true discoidal placenta are descended, but a discrepancy occurs between the general text, which is identical with the earlier edition in passing directly to the catarrhine forms, and the table given on p. 551, in which the line of descent is taken through primitive platyrrhines and thence through the Cynopitheca. However, the