Paper - The development of the human pharynx
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- 1 The Development of the Human Pharynx
- 1.1 Introduction
- 1.2 Historical
- 1.3 Nomenclature
- 1.4 Material and Methods
- 1.5 Morphological Plan of the Pharynx
- 1.6 Developmental Transformations of the Human Pharynx
- 1.7 Thyreoid
- 1.8 Larynx
- 1.9 Pharyngeal Derivatives
- 1.10 Thymus
- 1.11 Parathyreoids
- 1.12 Thyreoid
- 1.13 Endocrine Organs
- 1.14 Literature Cited
- 1.15 Plates
The Development of the Human Pharynx
I. The Pharyngeal Derivatives
B. F. Kingsbury
From The Department Of Histology And Embryology, Cornell University, Ithaca, N. Y.
Thirty—Four Figures (Five Plates)
- The problem was suggested to the writer by the late Dr. Charles S. Minot, and was begun in his laboratory during a sabbatic leave in 1911. It is a pleasure to acknowledge the generous help from that laboratory, and particularly the kindly interest and suggestions of Dr. Minot and Dr. F. T. Lewis.
The following study began as an examination of the transformation of the second branchial or pharyngeal pouch} Of the branchial pouches that appear in the development of the embryonic pharynx" of man, the second, and the second alone, possesses rather negative characteristics. While the one cephalad of it, the ﬁrst or hyomandibular, develops into the middle ear and eustachian tube (tuba auditiva) and those caudad of it have the very interesting derivatiVes—thymus, parathyreoids, so-called lateral thyreoid, etc.— the second pouch leaves no clear and characteristic record in the bodily structure, save perhaps the palatine tonsils, which appear to mark its site and to whose appearance this branchial pocket may possibly bear some causal relation.
It is true that the second pharyngeal pouch gives rise to a thymus body in anurous amphibia, among ﬁshes, and according to de Meuron, (’86) Van Bemmeln (’86), and K. Peter (’O1), in the lizard; and that a parathyreoid or epithelial body is said by Van Bemmeln to develop from it in snakes; while Maurer’s claim from the conditions found by him in Echidna and Anura that the carotid body is, or represents, such an epithelial body II (parathyreoid II), is likewise a matter of record. Such ﬁndings in lower forms but naturally suggest the presence of at least potential thymus and parathyreoid elements in the second pouch as well as in the third (and fourth). Critical and careful examination of the abundant material in the way of human and higher mammal embryos in the past has failed to determine the presence of traces of such structures belonging to the second pouch (p. 360), and I may say at this point that careful examination by myself of the quite complete series of human embryos used in this study but conﬁrms the negative ﬁndings of other workers.
It would be but natural, however, in spite of negative evidence, to consider that these structures, as branchiomeric organs, were nevertheless potentially present. Particularly since the classical study by Verdun (’98) these organs are frequently thought of as branchiomeric organs, there being a thymus and a parathyreoid (epithelial body) component belonging to each branchial pouch. Such a conception would of necessityassume that these structures, as such, were in some way intrinsic in the cells of the pharyngeal entoderm metamerically arranged. Quite a different interpretation, however, is possible. The second pouch, unlike the ﬁrst, third and fourth, early becomes ‘spread out’ or ﬂattened out with but shallow depressions representing it (ﬁgures 18-21). This seems clearly to be due to the forward growth and widening of this portion of the pharynx associated with the growth of that portion of the head. It might therefore be possible that the ‘negative’ character of ‘the second pouch is a result of its growth relations; that what became of a pouch or what came out of it was largely a factor of its position; that the determining factors for the ‘branchiomeric’ organs might be extrinsic rather than intrinsic. My study had not proceeded far before it became evident that, when ultimately "interpreted, the entodermic pharynx and its derivatives would have to do considered in conjunction with the growth transformations of the entire region, taking full cognizance of the shiftings due to unequal growth.
One of the most alluring features of the region is its ancestral character, which is involved in the question of its interpretation and signiﬁcance. The fact that the mammalian embryo possesses gill clefts, pouches and arches, though never possessing branchial respiration, has been known since the first observations of the mammalian embryo; while the occurrence has been prominently cited as evidence of descent, as one of the most striking illustrations of the ‘Biogenetic law’ of Haeckel, of vestigial organs, etc. The present-day attitude, it is true, is inclined to be one of scepticism as to so-called vestigial organs; the recapitulation theory is pronounced a failure in furnishing broad interpretations, while the validity of the ‘law’ is questioned.
Sedgwick (’09) in an interesting essay challenges the validity of the ‘Recapitulation theory’:
The question at issue is: did the pharyngeal arches and clefts of mammalian embryos ever discharge a branchial function in an adult ancestor of the Mammalia? We cannot therefore without begging the question at issue in the grossest manner apply to them the term ‘gill-arches’ and ‘gill—clefts.’ That they are homologous with the ‘gill—arches’ and ‘gill-clefts’ of ﬁshes is true; but there is no evidence to show that they ever discharged a branchial function. The recapitulation theory originated as a deduction from the evolution theory and as a deduction it still remains. 3
Karl Peter (’10) critically examines the biogenetic law and seems to reject it. He explains the development and persistence of the branchial pouches as due to the middle ear and the ductless glands that develop out of them, but in Lacerta, which he chooses as an example, he is compelled to confess that this point of view hardly suffices as an explanation of the development of the fourth pouch, ﬁfth pouch, and the sixth pouch (his interpretation) on one side. Kranichfeld (’14) looks at the problem in a different way. His contention is that the embryonic pharynx is not a ‘vestigial’ structure but possesses throughout a function correlated with the embryo’s nutrition (metabolism) and hence it is but to be expected that glands having important metabolic functions should develop from it since their function is but a continuation of a primary one possessed by the entire pharyngeal epithelium. . These criticisms do not seem to me to -Weaken the general validity of the biogenetic law but rather -to strengthen it, inasmuch as they must of very necessity concede that the pharyngeal pouches, clefts and arches, do exist and are homologous with the gill pouches, clefts and arches of lower forms. It becomes possibly a matter of deﬁnition, as is so often the case. If interpreted to mean that there are in the development of the individual definite stages corresponding to deﬁnite ancestral type forms, the ‘law’ does not of course hold (Keibel ’98); but as the formulation of a fundamental element in the morphological pattern of development, which is only comprehensible in the light of descent, the biogenetic law cannot be escaped. It is, I believe, but a special aspect of a more fundamental principle of life processes, correlated with their cyclical character and including ‘heredity,’ which may be designated somewhat loosely and metaphorically perhaps as the ‘Principle of ancestral resemblance.’ It is not the intention to enter into a detailed discussion of the ‘biogenetic law,’ but as to disappointment that the biogenetic law has not afforded much in the way of explanation of biological facts, it may be stated that it stands for fact and is itself subject to explanation.
The fact remains that the morphology of a large part of the face and neck are comprehensible only on a clear comprehension of the transformations of this region, Whose morphology reﬁects its primitive character as a respiratory apparatus. For the skeletal elements of the region, the transformation history is nearly though not completely clear; for the nerves, largely so; for the musculature, less satisfactorily Worked out. As to the epithelial elements and the vascular elements, which are of course the dominant tissues in the branchial respiratory apparatus in lower forms, our knowledge is exceedingly crude; it covers only the simplest morphology, while more recondite characteristics that the constituent elements may possess are unknown.
From the references to the views of Peter and Kranichfeld in the foregoing brief comment on the branchial pharynx and the ‘biogenetic law,’ two views of the relation of embryonic pharynx and ‘pharyngeal derivative’ are apparent — association in development and fundamental genetic unity. It has been intimated in the preceding paragraphs of this article that a different interpretation may be advanced. This will be considered subsequently. At this point, I will venture to state only that the biological signiﬁcance and physiological effect of the pharyngeal derivatives — thyreoid, thymus, and parathyreoids — are wrapt up in the past history of the region and ultimately explicable only in the light of their origin. This postulate I conceive as applicable not merely to the structures in question, but to all organs and all development.
The general aspects of the problem of the embryonic pharynx as outlined above determined my attitude in the study of its developmental changes. I have furthermore, in attempting to follow the growth transformations and shiftings, endeavored to keep in mind, as far as possible, the original character of the region and the fact that as far as the branchial epithelium and vascular elements are concerned, it is a region whose primary adaptative value is lost.
While attention has been largely limited to the epithelium, it became apparent that the epithelium could not be interpreted entirely by itself; that its growth transformations were but a part of the growth changes in the region as a whole. It has ever been the aim to keep the ultimate explanation of the morphological transformations in mind, even where they cannot be directly analyzed, since only through an analysis of the developmental factors will the morphogenesis be ﬁnally comprehensible. Accordingly, it is felt that the emphasis should be ﬁxed differently from where it is ordinarily placed; not that organs develop in and from such and such places; but that organs owe their character to their origin. Expressed differently: that the body is not an aggregate of distinct organs, but that the body’ is a unit whose different portions are variously differentiated (as organs) the character of the differentiation depending upon the way the adaptation is met, determined by the past history.
So recently has the development of the human pharynx been considered in a general article (Grosser ’11 b) that a review of the literature dealing with the subject is unnecessary. The main framework of morphologic fact was then quite complete, due to the studies of His (’80—’85), Verdun (’98), Hammar (’0l), Sudler C02), Tandler (’09), Grosser (’11 a) and others; and it has been added to since then (Hammar ’11). Many details, however, remain. undetermined and the interpretational aspect of the development is still largelya controversial ﬁeld. In the last, the point of View is frequently a dominant factor, and hence the following study seemed quite appropriate. Conﬁrmation of previous work has also a distinct, Value, and in the main my results are conﬁrmatiory of those of Hammar and Grosser.
There exists by no means uniformity in the terminology of the pharyngeal region. This perhaps is to be expected in View of the great transformations that the region undergoes and the differences in interpretation. Hammar (’13) has speciﬁcally dealt with the question of the nomenclature of the region and his suggested terms are excellent, although some of them are clearly unsatisfactory, the term ductus being an example. Most of the terms here used are those employed by Grosser. Branchial is employed in preference to pharyngeal, pouch (sacculus) is used for the entodermic outpocketing; while cleft (ﬁssura) is employed to designate the ectodermal insinking. Each pouch cleft, arch, parathyreoid, thymus, etc., in the series, is designated by number (I—V). The term ‘Complex III’ includes the structures appearing in the transformation of the third pouch, while Complex IV or ‘caudal pharyngeal complex’ denotes the structures associated with the fourth pouch. As the complex, in the process of growth, becomes separated from the pharynx, the attenuated connection is designated as ‘ductus pharyngeobranchialis’ (III, IV), while the corresponding diminishing connection with the ectoderm is termed ‘ductus branchialis’ (II, IV), the ‘ductus cervicalis’ being the connection of the cervical vesicle with the ectoderm. ‘Parathyreoid’ is employed in preference to ‘epithelial body.’
Material and Methods
The study was begun in 1911 in the Department of Comparative Anatomy of the Harvard Medical School and continued at Ithaca, New York, and is based upon the human embryos in the embryological collection at the Harvard Medical School, supplemented by those in the collection at Cornell University, many of which were placed at my disposal by Prof. S. H. Gage, whose generous assistance I am glad to acknowledge. My studies were futher greatly assisted by the willingness of Prof. Minot and Prof. Lewis to loan me from time to time embryological series from the Harvard Collection. The list of embryos consulted is given in table 1. The ones more particularly studied include those modelled, namely, 3 mm, 5 mm, 7.5 mm, 9.4 mm, (2) 10.0 mm, 13.0 mm, 14.5 mm, 16.4 mm, 18.2 mm.
Morphological Plan of the Pharynx
In considering the developmental changes in such a region as the pharynx, from the viewpoint of its ancestral character as a branchial chamber, it is of obvious importance to obtain a clear conception of the fundamental morphology of the region; the primitive and typical plan which is more or less modified and departed from in the particular form considered. In the case of the human pharynx the attempt at once carries the investigator into controverted ground and brings him face to face with the problem of primitive chordate types and the ‘Ancestry of the vertebrates.’ In the search for the primitive type of pharynx one must pass over the higher forms and teleostomes to the elasmobranchs, cyclostomata (larval lamprey), Amphioxus and-the ascidians, which for a number of reasons must be considered the more primitive of living chordate forms. There We find, in addition to the lateral branchial region with the gill pouches, well-deﬁnied hypobranchial and epibranchial (hyperbranchial) longitudinal zones, each with characteristic ciliated grooves—(or ridges)——the hypobranchial and epibranchial grooves (Acanthias, larval lamprey)—which again are comparable with the corresponding grooves of Amphioxus and the ascidians. I shall therefore consider the primitive pharynx as consisting morphologically of four zones: the hypobranchial region or zone, the ‘ﬂoor’; the epi (hyper) branchial region or zone (the roof), and the lateral wall or branchial region proper. As to the number of branchial pockets which the primitive pharynx possessed, there is no way of estimating, nor is the point important in the present connection; there would seem to have been at least eight. While the terms ‘hypobranchial’ and ‘epibranchial’ are subject to criticism, particularly the latter, they nevertheless are defensible and the former has long been used—as, hypobranchial groove, hypobranchial skeleton, hypobranchial musculature, etc. In considering the fundamental morphological relations of the region We encounter also considerable difficulty in their precise determination. In the ﬁrst instance, this applies to an exact delimitation of the pharynx caudally, Where the pharynx passes more or less insensibly into the esophagus. In the hypobranchial region the fundamental plan of the vascular relations is quite characteristic. While the heart appears in all cases to occupy a position caudad of the pharyngeal region (infra-pharyngeal), the truncus aorticus is hypobranchial and its bifurcation Well forward~as judged by the characteristic relation to the thryeoid gland, at the level of the second arch, although from comparative observations it is clear that the position of the bifurcation may vary considerably in the adult. While the heart seems infrapharyngeal, the pericardial mesothelium is joined to the mesodermal cords of the branchial arches, Within which branchial coelomic cavities may exist in a number of vertebrates (e.g., elastobranchs, turtles) and may appear occasionally in mammals (Froriep, Zimmermann, myself). In some instances these branchial coelomic cavities are actually or potentially in communication with the pericardial coelom.
|MEASUREMENT IN COLLECTION|
|MEASUREMENT COLLECTION MILLIMETERS NO: IN MILLIMETERS NO. 3 .0 Cornell 31 19 .0 Cornell 3 4 .0 Harvard 714 19 .3 Harvard 1597 5 .0 Cornell 5 19 .7 Cornell 30 6.25 Harvard 1918 21 .0 Harvard 744 7 .5 256 22 .0 851 8.3 Cornell 59 22 .8 737 9.2 Harvard 734 22 .8 871 8.0 817 23 .0 181 9 .4 529 23 .0 Cornell 48 9 .4 1005 25 .0 29 9.6 1001 25 .0 64 10 .0 1000 25 .6 12 10 .0 1919 28 .8 Harvard 1598 10.2 736 29 .0 914 13.0 Cornell 26 30.0 913 11 .5 Harvard 189 31 .0 1706 12 .0 816 31.5 Cornell 62 12 .0 Cornell 34 32 .0 63 13.5 52 35.0 Bdall 2§‘3* 13 .6 Harvard 939 35 .0 Cornell 44 14.5 1003 36 .0 61 15 .0 Cornell 53 37 .0 Harvard 820 15 .0 12 40.0 1917 16 . 0 Harvard 1322 41 .0 Mall 21! 1* 16.0 1128 42 .0 Cornell 58 16 .4 1707 44.0 49 18.0 Cornell 57 44.0 Mall 2?! 2* 18 .2 Harvard 1913 44.3 Harvard 1611 19 .0 819 48 .0 Cornell 13 19 .0 828|
|Three embryos that had been loaned to Prof. S. H. Gage by Prof. F. P. Mall were kindly placed at my disposal as well. They were examined for the stage of development of the thyreoid and number and position of the parathyreoids, and are therefore included in the above list.|
In man and mammals, a number of developmental features serve to modify the more primitive relations of the pharyngeal region. The precocious development of the lungs thus profoundly alters the developmental pattern by arising early in the development of .the region. If not infrapharyngeal (postpharyngeal) from their mode of development in the amphibia, they represent the most caudal (7th ?) branchial pouches. Due to the precocity of their development, the ‘intrusion’ of the tracheo-pulmonary anlage Within the floor of the pharynx is a most marked feature. The early and marked development of the heart correlated with the placental circulation may also be mentioned as altering seemingly in a mechanical way the simpler morphological relations of the region.
A third factor which modiﬁes the plan of development of the mammalian pharynx is the tongue. Despite the recent statement by Lewis (’10) that the hypoglossal musculature develops from mesenchyme in situ, it seems highly probable although not yet actually demonstrated~—that the myoblasts are directly derived from the first three (or four) myotomes and occupy secondarily‘ the hypobranchial region; differently put, that the pharyngeal region is primarily cephalad of this musculature and in its developmental differentiation and expansion caudally there is a mutual shifting which brings about the characteristic intrusion of the hypoglossal musculature and the development of the tongue. The course and relations of the hypoglassal nerve have thus a marked morphological Value. Inasmuch as a hypobranchial musculature is present throughout vertebrates, beginning with the elasmobranchs—the morphological relations in the cyclostomes being somewhat problematic———it is clear that in this respect other vertebrates as well as mammals illustrate a departure from the primitive pharynx morphology. However interpreted, the tongue early complicates the development of the pharynx.
Finally there must be mentioned the evident and marked modiﬁcation of the dorsal region (epi-hyperbranchial) of the pharynx by the growth of that portion of the head as epitomized by the brain—tube, whose growth in length and bendings has clearly been accompanied by corresponding effects on the adjacent pharyngeal structures. The expansion dorsally, as contrasted with the ventral restriction of the pharyngeal region, is expressed in the arrangment and relations of the external gill clefts, as illustrated in any typical lateral View of a mammalian embryo.
Developmental Transformations of the Human Pharynx
From the above brief considerations it will be apparent that the pharynx of mammals (and man) departs widely from the primitive conditions and relations that the region must have presented in the vertebrate ancestor. In the examination of the growth transformations and shiftings it has thus been necessary to keep in mind the fundamental morphology of the region, since it constitutes the basis to which the growth transformations must be referred. .
The different growth relations of the cephalic portion of the pharynx and the caudal portion of the pharynx (well illustrated in the ﬁgures of plates 1 to 4, particularly 14, 15 and 21), the former being characterized by its expansion and participation in the growth of the head, the latter by its concentration and Ventro—caudal growth, soon differentiates the pharynx into two fairly well deﬁned regions, for which Mayr (’12) has proposed the names of ‘propharynx’ and ‘metapharynx’ (‘laryngopharynx’) respectively. The investigation of the growth shiftings in the domain of the pharynx thus falls quite naturally into three parts: (1) that of the dorsal wall and cephalic portion, including the ﬁrst (and second) branchial arches and the ﬁrst and second pouches; (2) that of the tongue and the corresponding portions of the pharyngeal ﬂoor; (3) the caudal and ventral portions including the third and fourth pouches and clefts and the second cleft, together with the thyreoid gland. It is mainly the last section of the pharynx development which is considered in the present paper. While it is the author’s plan to consider at a subsequent time some of the growth changes in the territory ﬁrst mentioned, no attempt is contemplated to add to the knowledge or interpretation of the tongue, inasmuch as it is felt that there is not a great deal to add to the published work of Kallius and others, save in the earliest transformations, material for which is not at hand or at present easily available.
Closely interwoven with the developmental changes which the lower portion of the pharynx undergoes, are (1) the development of the lungs (larynx and trachea) and (2) the development of the heart and aortic arches, mentioned above as of modifying inﬂuence in the development of the pharynx. To these should be added a third modiﬁcatory factor, the epibrancial placodes; while the neck-bend as an expression of cranial growth relationships and similarly, to a certain degree, thedifferent postpharyngeal growth tendencies, affect the morphogenesis of the region.
The precocity in the development of the lungs has already been referred to. In a 2.5 mm. embryo (Robert Meyer, No. 300) Grosser (’11 a, ’11 b) has described its ﬁrst appearance as well caudad or the branchial region at a stage in which the laryngo-tracheal groove extends to the caudal limit of the ‘mesobranchial ﬁeld.’ With the subsequent development of the glottideal opening and of the branchial region, the laryngo-tracheal groove is described by Grosser (p. 463) as “extending farther into the mesobranchial ﬁeld between the medial ends of the fourth and (later) even the third branchial arches.” This intrusion of the laryngeal opening into the branchial region of the pharynx might, I believe, be better described as essentially a ‘telescoping’ or intussusception, due to the expansive cephalocaudal differential growth of the branchial pharynx and the precocious development of the lungs (trachea and larynx), in the nature of a heterochronia. The attendant alteration in the morphology of the region may be illustrated by means of the accompanying simple diagrams (schema A). Such an interpretation was essentially set forth by His (’85), as would appear from his well-known view of the origin of the so-called ‘lateral thyreoid.’ However one is inclined to interpret the origin of the lungs——as primarily developed out of and representing branchial pouches and hence primitively double in origin, or as arising caudad of the branchial region and appearing as a medial ventral outpocketing of the pharyngeal entoderm caudad of the branchial region—its morphological position is caudal to the branchial portion of the pharynx as developed in the higher vertebrates. The position of the laryngeal opening in the pharynx is in the nature of an intrusion, due in part, as has already been stated, to its precocious appearance, affecting thus markedly the essential morphology of the developing pharynx. It is not, I believe, going too far to interpret the ‘furcula’ described by His (’85) and shown in his well-known and often reproduced ﬁgures (40) as itself but a fold due to the interrelated growth of glottideal lips and branchial pharynx and in itself, therefore, of no intrinsic morphologic significance.
How early the tracheo-pulmonary outpocketing makes its appearance it is difﬁcult to determine. Grosser’s (’11) account is the most satisfactory, although clearly other embryos of about this stage (Robert Meyer embryo No. 300) and earlier should be examined. With the mid—ventral groove (ventral pharyngeal furrow by Grosser) ﬁgured by him before the deﬁnite appearance of the thyreoid outpocketing (in embryo Keb., N. T. No. 3) it apparently has nothing to do. This groove, which appears thus early extending caudally from the thyreoid whose early anlage it includes, may tentatively be regarded as a hypobranchial groove, in its cephalic part at least. Subsequently with the expansion of the pharynx and the growth of the neighboring heart and pericardium, itbecomes obliterated.
With the expansive development of the heart within the pricardium, the branchial arches and truncus aorticus, begin the important and characteristic transformations of the pharynx, ending only with the assumption of its adult morphology. It is generally assumed that the branchial pouches possess ventral and dorsal extensions or diverticula. Ventral diverticula are shown for several of the pouches in ﬁgures 12, and 13, while small dorsal projections exist in the 7.5 mm. embryo (ﬁgure 14). Although these are usually considered as branchial extensions of intrinsic signiﬁcance, careful study of their relations indicates that in their shape and extent they are also a partial expression of the growth relations of the region and are affected by the adjacent arches whose size and direction they in a degree indicate; this readily appears in models such as those represented in ﬁgures 12, 13 and 14, in which the impressions of the arches, as negative pictures, are shown in the molding of the epithelium.
In ﬁgures 12 and 13, which might be compared with similar ﬁgures, such as ﬁgure 22 of Grosser (’11 a) and ﬁgure 7 of Ingalls (’07) and ﬁgure 6 of Coulter (’09) for the eat, there is shown the ‘thyreoidipetal’ direction of the ventral branchial diverticula I, II, III and IV. This direction of the pockets of course is also in conformity with that of the arches. As important constituents of the arches are the branchial aortic arches, which arise from the truncus aorticus, so that the region Where the axes of these ventral branchial diverticula center might be described with equal propriety as being that of the truncus aorticus or its bifurcation (cf. also ﬁgures 1, 2. 3). In front of (cephalad of) the bifurcatio trunci aortici and in close apposition to it is the thyreoid gland. In embryos of 5 to 7 mm. length the branchial pharynx attains its most marked development. The transformations that speedily succeed are marked by the growth shiftings, whose most striking and central features center around about the descent of the heart? the inﬂuence of which on the subsequent development of the pharynxis striking.
In the 3 mm embryo—the youngest of the series studied— the thyreoid gland is present as a median outpocketing, still broadly in communication with the caudal limb of the ﬁrst branchial pouch and in immediate contact with the truncus aorticus. The ﬁrst (mandibular) aortic arch is disappearing, the second and third continuous to the dorsal aorta, while the fourth (apparently) has not yet become completely developed. In the 5 mm. embryo the thyreoid is somewhat elongated transversely and is close to the aortic trunk bifurcation, which has ‘moved’ caudally somewhat in the process of growth. The bifurcation has now a somewhat different morphological value as compared with the earlier stage. _ The second aortic arch has ‘moved out’ along the third arch, while the first arch has apparently ‘moved out’ along the second, the ﬁrst arch seemingly having lost its connection with the dorsal aorta. As at some points these Vessels were collapsed, it was somewhat difﬁcult to determine their exact extent. The condition appears very similar to that in the His embryo R (ﬁgure 120). The apparent migrations of the ﬁrst and second arches are undoubtedly correlated with the growth of the region as a whole. The anterior portion of the pharynx, including the ﬁrst and second arches, expands in a ‘cephalic’ direction, and the growth of these bilateral moieties carries the arches with them, forming thus the so—called ventral aortae.’ The median structures (thyreoid, truncus, heart, and the pericardial cavity) do not share in the forward growth, and there is thus instituted the ‘descent of the heart.’ The neck and thoracic wall, in completely burying the heart and blood vessels, gives to the ‘descent’ of the heart somewhat the character of a growth funnel or eddy. This analogy is not without its force in comprehending the growth transformations of the branchial region, as will be seen subsequently.
- 2 In the following pages the term ‘descent of the heart’ is, for convenience, frequently used and represents a growth shifting that has, of course, many sides. It is used without the intention of giving this side of it undue emphasis.
The vessels which have appeared in the process of growth that has carried the second arch forward may even at this stage be considered as the common carotid arteries, while the common trunk for the ﬁrst and second arches is the external carotid. At this stage the common carotid artery springs rather directly from the aortic trunk forming the bifurcation. Diagrams 1 and 2 in the accompanying schema B may illustrate the general morphological relations of thyreoid and arches at this stage. Continuance of lateral growth, together with relative caudal displacement of the truncus, increases the length of the common carotid artery and causes it in its turn to move out along the fourth aortic arch to its permanent position.
The thyreoid gland in its expansion shares in the lateral ‘upward’ growth and median ‘down sinking,’ it then becomes transformed into a U, already marking out the lateral lobes and isthmus of the adult organ, the isthmic portion still being close to the aortic bifurcation, while the lateral lobes are molded about the common carotid arteries upon their medial and ventral sides, as they have plastically followed, them in their lengthening (ﬁgs. 2, 4, 6, 7, 15, 18). With the lateral growth of the thyreoid the descent of the gland as a whole becomes arrested; it lags behind the heart and truncus, altering its relative position but little in subsequent development. The growth of the ventral neck material, and of the larynx particularly, soon removes the thyreoid from the intimate contact with the carotid arteries (18.2 mm.). Its adult morphology is then speedily assumed. Diagram 3 of schema B may illustrate the third stage in its growth transformation, based on the conditions in the 13. mm embryo (fig. 20), and comparable with the well-known ﬁgures of Verdun (’98, pl. 1). Complex III
The above paragraphs clearly show the inﬂuence of the unequal growth and growth movements summed up as the descent of the heart on the development of the thyroid, which from its ﬁrst appearance follows the aortic bifurcation. The third branchial pouch is also drawn into the ‘growth eddy’ caused by the descent of the heart.
As has just been said, the branchial pouches are directed toward the aortic bifurcation (ﬁgs. 12-13), this arrangement being clearly due to the arrangement of the branchial arches. From their mode of appearance——each pouch following in development the one cephalad of it and therefore lagging behind it in extent and size——the more cephalic pouches and arches tend to overlap those more caudally located unless the relations are disturbed by unequal growth. This arrangement appears in ﬁgures 12, 13, and 1, 2. In the case of the ﬁrst two pouches this relation is inappreciable, or speedily lost. In the growth of the head the propharynx including these pouches is carried forward away from the mid-ventral or cardiac region. The third pouch is thus not only morphologically cephalad of, but also laterad to, the fourth pouch. It also occupies a position of peculiar interest in the series of branchial pouches in its relation between the third and fourth arches, it is at ﬁrst (morphologically) caudad to the common carotid artery. As the aortic truncus and the thyreoid descend the third pouch soon becomes lateral to these structures as they move by, and to the common carotid. This position is shown in ﬁgures 4, 7, 8, 15 and 20.
As the truncus descends the third pouch follows it in its growth movement. Drawn, so to speak, into the heart eddy, growing as the heart descends, the epithelial tube representing the ventral diverticulum of the third pouch becomes more ventral in position, the material from the pouches of the two sides ﬁnally meeting upon the ventral side of the vascular funnel, where cephalad of the pericardium in the anterior mediastinum it becomes the thymus gland (so—called) which will be considered subsequently. For illustration of the above, ﬁgures 15, 18, 20 and 22 may be consulted, as well as ﬁgures 1, 2, 4, 6, 7 and 8, which will give the relative location of the third pouch territory in succeeding stages.
Hammar (’11) has already given an excellent description of the growth and morphological differentiation of the thymus and the Complex III, so that it is necessary to offer only a few comments upon the transformations of the pouch as awhole, in its connection with the growth shiftings accompanying the descent of the heart. As is well known from the work of Hammar and others, the growth of the third pouch that accompanies the descent does not keep pace with it, with the results: (a) that the complex as a whole moves down and the epithelial connection with the remainder of the pharyngeal epithelium becomes drawn into a tube or cord (ductus pharyngeo-branchialis III) and broken (in embryos of about 14 mm. length). The proximal (cephalic) end—the so—called thymus nodule or head, now com Figs. 1-8 Were drawn by means of an Edinger projection apparatus, x 40. The wall of arteries (e.g., carotid) is shown in heavy black line, pharyngeal epithelium and surface ectoderm in solid black, the pharyngeal derivatives in oblique cross line, the parathyreoid IV (fig. 8) being stippled. In some instances only are muscles and nerves outlined; ‘territories’ are frequently indicated by interrupted lines.
Figs. 1, 2 and 3 Outline drawings of sections 143, 147 and 155, respectively, from a 7.5 mm. human embryo (No. 256, Harvard collection). X 20.
Figs. 4 and 5 Outline drawings of sections #229 and #239, respectively, from the 9.4 mm. human embryo (No. 1005, Harvard collection). X 10.
Fig. 6 Outline drawing of section #288, 10 mm. human embryo (No. 1000, Harvard Collection). X 10.
Fig. 7 Outline drawing of section #228, 14.5 mm. human embryo (No. 1003, Harvard Collection). X 10.
Fig. 8 Outline drawing of section #457, 16.4 mm. human embryo, (No. 1707, Harvard Collection). X 10.
posed largely of parathyreoid III moves down, for a time, although more slowly, until the parathyreoid III has considerably passed the parathyreoid IV. (b) The intermediary epithelial cord (thymic cord of Hammar) joining the caudal portion (thymus) to the cephalic portion (parathyreoid III) becomes attenuated and ruptures (in embryos of about 35 mm. 2 length). The parathyreoid III, as a result of small growth shiftings and largely through the expansion of the thyreoid, comes to occupy its adult position as the inferior parathyreoid.
The ventral pocket of the third pouch is from the beginning quite close to the pericardium and retains this intimate association throughout the descent (ﬁgs. 23-24) so that the statement of Hammar (’11, p. 217) that “after entering the thoracic cavity the thymus comes into relation with . . . the pericardium” hardly, I think, conveys the correct impression of the topographical relation of thymus to pericardium in the course of development. The small amount of mesenchyme between the branchial epithelium and the pericardial mesothelium does, in fact, bebecome thinned out, doubtless due in part to the expansive growth of both structures.
Critical and careful examination of the series of sections of embryos of progressively advanced stages has convinced me that the mesenchyme surrounding the third pouch participates in the down—growth accompanying the heart’s descent, so that it is not only the branchial epithelium but the material of the region as a whole that suffers the growth displacement which is so characteristic of it. What signiﬁcance this may have in the later thymic transformation can only be inferred (vide s1_1bseq.). The parathyreoid III and the thymus, which remain as ‘derivatives’ of the transformation of the Complex III, will be discussed subsequently.
The transformations undergone by the fourth pouch and associated epithelium comprised under the name of ‘caudal pharyngeal complex,’ or Complex IV, have already been brieﬂy discussed by me (Kingsbury ’14 b) from a somewhat different point of view, so that it is only necessary to supplement somewhat what was then said and with more particular reference to the growth transformations of the region as a whole.
The Complex IV from the method of its development occupies a position not only morphologically caudad to the third pouch, but also from its later development and growth is almost imediately medial and dorsal to it, the fourth arch intervening (ﬁgs. 1-3, 12, 13). It therefore is not so intimately involved in the descent of the heart as is the third pouch complex. Growth continuing after the establishment of the fourth pouch, there is formed the so-called ultimobranchial body, which, however, I do not ﬁnd extending to or toward the ectoderm, and hence hardly to be given the value of a ﬁfth or of a sixth pouch. The question of the signiﬁcance of this body has already been discussed in the earlier paper. The so-called ultimobranchial body lies next the laryngeal mesoderm and between it and the fourth (ﬁfth) arch. At this stage (5-7 mm.) the Complex IV consists of the so-called thymus IV—the ventral diverticulum of the pouch, the portion making contact with the ectoderm and the so-called ultimobranchial body. The form and position of the complex is shown, not quite satisfactorily, for the 5 mm. embryo in ﬁgure 12, while ﬁgures 13 and 14 show the corresponding structures in the 7 .5 mm. embryo. Figure 3 is a section through the ventral diverticulum IV. These regions of the Complex IV speedily become lost in the transformations which it undergoes, and a fourth portion is differentiated-—the parathyreoid IV—— already well indicated at 8.3 mm. (ﬁgure 30) although not recognizable in the 7.5 mm. embryo.
In order to understand the part that the descent of the heart plays in these transformations and growth shiftings, it is essential to keep in mind the relative movements of the third and fourth arches. The third arch has become the common carotid artery, and in its ‘migration’ out upon the fourth arch it becomes relatively more dorsally located. The head of the third pouch complex, at ﬁrst morphologically caudad to it, moves thus around to its ventral side, becoming soon more widely separated from it (ﬁgs. 20, 21,22). The parathyreoid III thus rotates from a lateral position upon the dorsal aspect of the pouch to a more ventral one (Hammar ’11, p. 207). The dorsal position of the Complex III shares thus the ventral movement so pronounced in the growth of its ventral moiety. The Complex vIV——which, as seen, is more deeply located—comes less under the ‘inﬂuence’ of the descent and grows and shifts caudally more slowly and to a less degree. The ventral diverticulum (IV), like the ventral pocket of the third pouch, at ﬁrst as it lies between the fourth branchial aortic arch and the pulmonary arch is well marked and directed like that of the third pouch toward the bifurcation of the aortic trunk (ﬁgs. 12, 13, 3). It does not, however, like the third pouch, follow the caudal movement of the truncus but is soon withdrawn into the complex and is thenceforward indistinguishable.
A caudal movement of the complex as a whole also takes place, although more slowly than the fourth aortic arch. The broad communication of the Complex IV with the pharynx, on the one hand (ductus pharyngeo-branchialis IV), and its connection with the cervical sinus (ductus branchialis IV), on the other, are speedily stretched to slender cords or tubes and ruptured, the latter ﬁrst in embryos of 10 to 13 mm. length, (ﬁgs. 15, 17, 20), the latter somewhat later, in embryos of ca. 14 mm. length (ﬁgs. 21, 22). With the rupture of the ductus branchialis IV, in the 10 mm. embryo (ﬁg. 17) already thinned and bowed, the fourth aortic arch passes it by in the descent upon the outer side. As this occurs the complex follows it by a rotation whereby the parathyreoid IV moves from a position upon the lateral aspect (ﬁg. 15) in the dorsal portion (morphologically) of the complex to a dorsal one (ﬁgs. 20-21), rotating thus roughly through ninety degrees, as does the parathyreoid III, but in an opposite direction.
After the rupture of the ductus pharyngeo—branchialis IV, a somewhat more rapid movement of the caudal portion of the body of the complex causes the appearance of a more attenuated portion (neck) to appear, whereby it is joined to a head consisting mainly of parathyreoid IV (ﬁg. 8). Subsequent rupture and disappearance of the neck separates the two portions, leaving the parathyreoid—at this time near the upper pole of the thyreoid lobe—upon its dorsal side, in the interval between esophagus and trachea, therefore near the position which it typically occupies as the superior parathyreoid.
At the same time that the Complex IV is more slowly descending in a more dorsal position and more deeply placed, and the Complex III is descending by growth more rapidly in a more ventral and superﬁcial position (ﬁgs. 20, 21) the thyreoid is rapidly extending in the intermediate interval between these materials, following the carotid artery as it shifts relatively more dorsally (ﬁgs. 4, 6,,'7., 8). The body of the complex is thus enveloped by ‘the expanding thyreoid lobe, is brought in contact with its medial dorsal edge and fuses with it (ﬁg. 8). Nothing further relative to its fate can be added to the discussion already published.
Considerable variability characterizes the morphological transformations of the Complex IV, which is particulary apparent in the models from the 13.0 mm., 14.5 mm., and 18.2 mm. embryos, in which the two structures upon the two sides are markedly different. Differences between the two sides are evident in most of the embryos of about this size or larger. In the 18.2 mm. and 31.0 mm. (1) specimens, tubular epithelial prolongations from the complex occur in the mesenchyme upon the dorsolateral aspect of the thyreoid, while in the 32 mm. embryo a thymus IV is present outside the thyreoid. These variations in the form of the complex clearly indicate differences in the conditions that determine its growth and in which altered environment in undoubtedly a factor.
Aside from the early differentiated area that becomes the parathyreoid IV, it is impossible to distinguish and follow, in the transformations which the complex undergoes, any regions of speciﬁc structural value, such as a thymus IV, or a corpus ultimobranchiale as a deﬁnite organ of however ‘vestigial’ a character, and it may be asserted that the evidence of the existence of such structures as intrinsically branchiomeric organs is exceedingly meager. The occasional occurrence of thymus bodies or persistent epithelioid structures developed from this complex is subject to a quite different interpretation, as has been previously stated, and this will be considered again subsequently.
Thus the downward movement of material in the shiftings as a result of unequal growth, usually summed up under the descent of the heart, involves the branchial region as well. The thyreoid follows the aortic trunk, but expanding laterally its descent is arrested, as has been described. The third pouch complex, from its peculiar position in relation to the forward growth of the propharynx and to the truncus and 'aortic arches, becomes peculiarly involved, being drawn in ventrally, the Ventral prolongation (diverticulum) following by growth the pericardium throughout the descent. The entire pouch complex, however, moves down and becomes differentiated into a head (embodying the parathyreoid III), body (thymus) _and intermediary portion, which in man becomes attenuated .and ruptures. Likewise and to a less degree, the more deeply located caudal pharyngeal complex or Complex IV participates in the movement and undergoes a comparable differentiation, the initial complexity and the ultimate fusion with the thyreoid differentiating it from the Complex III. The following diagrams may crudely schematize the movement of these three pharyngeal componants~—thyroid, Complex III and Complex IV. In schema C the arrows serve to indicate the general line of movement for (a) the thyroid, (b) Complex III, and (c) Complex IV, in horizontal and sagittal projection, while in ﬁgure D successive positions for each of these three pharyngeal derivatives are superimposed. Figure D is purely ‘schematic, but ﬁgures 23 and 24 and the ﬁgures of plates 1 to 4 may be consulted in comparison, as also the text ﬁgures 1 to 8.
The descent movement is accompanied by rotation, most obviously shown in the case of the parathyreoids, as already described. As the" ventral portion of Complex III is drawn into the ‘heart eddy,’ a rolling or rotation upon its long axis gives to it a slight spiral twist (18.2 mm.) which is rendered obvious by the growth furrows in the beginning expansion, as well as by the shifting of the thicker epithelium of the tube from a dorso— lateral position higher, to a Ventrolateral position lower down. The latter of these features has been commented on by Hammar (’11). I
The prevalent asymmetry in the adult relations seems clearly due to a corresponding asymmetry in the descent. Thus the right parathyreoid III is usually lower than the left, while the pyramidal lobe of the thyreoid, when present, is in the majority of cases asymmetrically placed, to the left. Inasmuch as the pyramidal lobe unquestionably, I believe, marks the line of descent of the thyreoid, both its more. usual excentric position, as well as the generally lower position, of the right parathyreoid III indicates a more extensive descent tendency upon theiright side, probably associated with the asymmetry in the aortic arches (IV), or is due to the asymmetrical position of the common carotid arteries upon the right and left sides, associated therewith. Decisive proof of this would be difficult to secure.
The epibranchial placodes
While the growth shiftings in the cephalo-caudal growth in head and neck produce the effects upon the branchial pharynx just described, these are modiﬁed and correspondingly inﬂuenced by the growth and expansion in the transverse dimensions. In this connection it will be necessary to call attention to the effects produced by the expansion of the branchial arches II, III and IV, particularly the second arch, which through its growth, together with that of the postbranchial and epibranchial regions, outlines a roughly triangular depression and determined its transformation into the sinus cervicalis, into which the second, third and fourth clefts open. It would be entirely superﬂuous to describe, in repetition of others, the further transformation of the sinus cervicalis into the ductus branchialis II and the vesicula cervicalis, save in so far as it is necessary to emphasize the fact that they are formed in the increase in thickness as a result of a growth whose relations, direction and degree they express, and to call attention to the inﬂuence which the epibranchial placodes have in their formation.
These last named structures have until recently received small recognition and little emphasis in texts of embryology when it is considered how long their occurrence has been described. Since von Wijhe (’82) described them in the elasmobranch, and Froriep (’85), under the name of ‘Schlundspaltenorgane,’ in the mammal, they have been described in elasmobranchs (Froriep ’91), the lamprey (V. Kupffer ’91), teleosts and ganoids (Landacre ’12), amphibia (Landacre and McLellan ’12; Driiner ’043), reptiles (Lucy W. Smith4), birds4 (Kastschenko ’87, ’10), and in man (Streeter ’11, Hammar ’11). In all instances they bear a relation as epibranchial thickenings to clefts I to IV (or more), while the‘ ventral (caudal) portions of the respective ganglia \VII, IX, X) are intimately fused with them. In the lower forms ganglia seem to be derived from them (Landacre, V. Kupffer, Froriep). In higher forms this is less clearly shown. The intimate association of neural crest ganglion and placodal ectoderm, however, is clearly of marked significance.
- 3 Druner clearly describes the epibranchial placodes in the axolotl and recog nized that they contributed to the ganglia of the VIIth,IXth and Xth, although he described them as ‘ectthymus’ (p. 552).
- 4 From unpublished observations made in the laboratory by Miss Lucy W. Smith, in the turtle, Chyrsemys marginata, and Miss M. E. Goudge, in the chick.
Epibranchial placode I — which, as in the territory of the propharynx, lies outside the scope of the present study—~has in the 7.5 mm. embryo apparently severed_its connection with the ganglion VII (geniculatum) with which it was doubtless conﬂuent at an earlier stage. In a 6.2 mm. cat embryo (Harvard Embryol. Coll. No. 380) placode and ganglion (N. VII) are intimately associated.
In contrast with the placode I, placodes II, III and IV maintain their close association with their corresponding nerves and ganglia, and clearly play a part in the development of theductus branchialis II and cervical vesicle, as will subsequently appear. In the 7.5 mm. embryo, placode II is a thickening of the entoderm lining, a depression behind the upper end of the second branchial cleft, in intimate Contact with the glossopharyngeal nerve at the lower end of the ganglion (petrosum; ﬁg. 25). Corresponding thickenings and depressions behind the upper ends of the third and fourth clefts, as placodes III and IV, (ﬁgs. 27, 28) are in close relation to the ganglion of the vagus nerve. With the increase in thickness of the arches and the consequent removal of the “ganglion petrosum of the IX and ganglion nodosum of the Xth nerve from a more superﬁcial position, the placodal ectoderm remains closely associated with the corresponding ganglia, while there are produced the ectodermal insinkings of the ductus branchialis II and cervical vesicle respectively.
In the 9.4 mm. embryo (ﬁg. 19) ductus branchialis II has become quite prolonged, while the cervical sinus has deepened and narrowed, but both open to the exterior into the outer portion of the cervical sinus by separate apertures (ﬁg. 10). By further growth, in the 10 mm. embryo the cervical vesicle and ductus branchialis II now communicate with the exterior through a common tubular opening (ﬁgs. 15-17). Figure 17 in particular shows the marked and rapidly acquired effect growth has produced in the wide separation of structures closely adjacent in the 7 mm. embryo. The ectoderm associated with the ganglion petrosum is now prolonged into a long tube extending to the lower pole of the ganglion.’ The crest of the sinus cervicalis (representing the vagal placodal ectoderm) is imbedded in the lower end of the ganglion nodosum, which has been removed to reveal it. The connection of the Complex IV with the cervical vesicle, close at 9.4 mm. (ﬁg. 19) has now by growth and descent become drawn out (ﬁg. 17) to a slender tubular cord (D. branchialis IV), soon to be ruptured, as in the 13 mm. embryo, where on the left it is ruptured and no longer recognizable, on the right, just ruptured (ﬁg. 20). The connection of the indrawn ectoderm, as the D. branchialis II and cervical sinus (through the ductus cervicalis) with the superﬁcial ectoderm, becomes speedily severed and for some time (ﬁgs. 20, 22) the upper portion of the ductus persists as a dwindling vesicle close to the lower pole of the ganglion petrosum; while the cervical vesicle remains in intimate contact with the ganglion nodosum, where it gradually disappears, apparently without trace.
By growth of the surrounding structures the sinus cervicalis may thus be described as becoming divided into external5 and internal portions, the latter again including the ductus branchialis II and the cervical sinus. These two structures obviously owe their existence and form relations in part to the intimate connection of the ganglia petrosum and nodosum respectively, with the epibranchial ectoderm and the persistence of such connection, under the expansive growth of the region. It is likewise clear that the name, ductus branchialis I.I, is not appropriate, since it clearly owes its existence to the persistence of a connection of nerve and epibranchial ectoderm. In its development, it is true, the second cleft becomes in part incorporated, so that the second pouch adjoins it in a characteristic manner (ﬁg. 15), but the ‘duct’ projects beyond it toward the ganglion of theglossopharyngeal nerve (ﬁgs. 15, 17, 19). Thisiconclusion is further borne out by the fact that in a 9.2 mm. embryo (Harvard Embryol. C011. No. 734) this ductus branchialis opens independently of the second cleft upon the ectoderm behind the cleft, i.e., at the point characteristic for" the epibrachial placode II. Similar epithelial prolongations in continuity with the ectoderm in the territory of the second cleft have been described in other mammals, e.g., in the rabbit by Piersol, (’88) in the pig by Zottermann (’11) and Badertscher (’15), in the guineapig by H. Rabl (’13), under the name of ductus branchialis. It is not quite clear, however, what the morphological value in these cases may be, and inasmuch as it is an expression of persistent ectodermic attachment under growth expansion, its value may well vary in different forms.
- 5 Sulcus cervicalis, or sulcus precervicalis, of Hammar. DEVELOPMENT or HUMAN PHARYNX 357
Whether or not that portion of the ductus branchialis II that adjoins the second pouch persists so that ectodermal cells become incorporated with the entodermal cells, was not determined but exists as a possibility. In the same manner, the fate of the cells of the vesicles that maintain their association with the ganglion petrosum and ganglion nodosum is problematic. The connection of the vesicle derived from the ductus branchialis II with its ganglion (vesicula branchialis II, ﬁgs. 21-22) seems not so intimate as does the connection of the cervical vesicle with the ganglion nodosum, where the epithelium merges with the ganglion without sharp boundary and all appearance of a close fusion. Whether the characteristic elements of the gangilon, neuronal or other, receive from the placode or subsequently from the vesicle, augmentations, could not be deﬁnitely determined, although the histological appearances and relations suggest strongly that such may be the case——a conclusion similar to that reached by Hammar, and independently formed. Whether a deﬁnite group of neurones, the gustatory, have this placodal origin, from the epibranchial placodes———as Landacre concludes from. his interesting study of the developmental relations in Lepidosteus.and Amiurus——can of course be still less determined from the material and methods of the kind used in this investigation; it is a study quite apart from that of the pharynx and its derivatives.
The cervical vesicle is not only partly imbedded in the lower end of the ganglion nodosum, but in the mechanics of growth remains closely joined to the third pouch so that as long as it persists, it is a "component of the head of the Complex III. My observations, however, conﬁrm those of previous investigators that in man it contributes nothing to the pharyngeal derivatives, whereas in some mammals it unquestionably undergoes thymic transformation, as will be commented on subsequently. Its position and relations in the Complex III are shown in ﬁgures 20, 21 and 22.
Fig. 9 Lateral (surface) View of the ectodermal pharyngeal surface, in a 7.5 mm. human embryo (No. 256, Harvard Embryological Collection), as modelled with the entoderm (shown in ﬁgures 13 and 14).
Fig. 10 Surface (lateral) view of the branchial arches and clefts in a 9.4 mm. human embryo, as shown in a model, the posterior aspect of which is given in ﬁgure 19.
Fig. 11 Surface view, from the left side, of the branchial region in a 10 mm. human embryo (No. 1000, Harvard Embryological Collection), from a model of the ectoderm. Other aspects of the model are shown in ﬁgures 15, 16 and 17 S.C., indicates the external portion of the cervical sinus (sulcus cervicalis).
The external portion of the cervical sinus owes its existence more to the growth of the postbranchial territory, together with the precocious and marked growth of the second arch, which as an- operculum encroaches upon the boundaries of the sinus and ﬁnally causes its obliteration. The rather deep insinkings of ectoderm along the lines of the branchial clefts in the precervical region appear to be withdrawn with the growth of the mesoderm, although the inclusion and degeneration of portions cannot be excluded (ﬁgs. 9-11).
Although the pharyngeal transformations that determine the development of the larynx and its related structures are but a part of the growth of the entire region and are affected by the shiftings in the lower pharynx, they are omitted from the present paper, since the points of interest still undetermined relate more to the mesodermic arches than to the epithelium and its derivatives, whose explanation is the question considered in the present paper.
In the foregoing paragraphs I have attempted to describe in a concise way the morphological transformations of the branchial epithelium, entoderm and related ectoderm, as but the expression of one side of the growth of the region with its varied stresses and strains and shiftings, which in their totality produce the anatomical relations of the adult. But a moment’s reflection is necessary to establish the conclusion that it could not be otherwise, and the criticism may perhaps be offered that any morphological analysis of the regional growth is superﬂuous, as it can only establish conclusions that are self-obvious and which might be arrived at from a priori reasoning; that is, it is simply a description of changes that inevitably follow from the relations of parts in the region which can establish nothing in the way of explanation or build a foundation on which the explanations may be subsequently worked out. Such a criticism, however, in the speciﬁc instance in hand, has weight only on the assumption that there are certain pharyngeal organs predetermined in development, ‘pharyngeal organs’ whose growth 360 B. F. KINGSBURY
and evolution follow inevitably in the growth of the body from intrinsic causes not analyzable in the present stage of our knowledge. As soon as it is recognized that the existence of these organs is itself a subject of scrutiny and analysis, the determination of the developmental conditions and growth transformations becomes a matter of considerable importance, and—not to minimize in the least the ultimate importance of other sides of the problem—a correct interpretation of the morphogenesis and histogenesis remains a fundamental prerequisite for the adequate interpretation of the signiﬁcance of these structures as bodily organs.
In the case of the thymus, the prevailing tendency at the present time is to View it as an ‘epithelial organ’ the factors for whose appearance are intrinsic in certain cell groups in the third branchial pouch, where, in the ventral diverticulum the thymus anlage as early as 5 or 6 mm. embryos is indicated by the thicker character of the epithelium that by its growth produces the thymus body or gland. So universally have recent investigators supported this localization that it is necessary to cite speciﬁc references or quote passages; Verdun C98), Maurer (’O6), and Grosser (’11 b) have crystallized the common interpretation in their comprehensive articles on the pharyngeal derivatives. Localization of a thymus anlage in the ventral diverticulum of the third pouch, under the sway of the ‘branchiomeric organs’ conception leads naturally to the homologization of the comparable pockets in the second and fourth pouches (ﬁg. 12-13) as thymus bodies II and IV. Thus Groschuff C96) and Tandler C09) term the ventral pocket of the fourth complex a ‘thymus IV,’ and Griinwald (’10) derives the palatine tonsil from the Ventral pocket of thesecond pouch and regards it therefore as a thymus metamer. The fact that thymus bodies are unquestionably developed from the Complex IV, in man occasionally, and in certain mammals (e.g., eat) more constantly, is regarded as supporting the homology, especially since thymus bodies are developed in connection with a number of branchial pouches in certain lower vertebrates. Kolliker (’79), Piersol (’88) and Verdun (’98) described a thymus from the second pouch in the rabbit. Hanson (’11) has more recently shown that no thymus body is derived from the second pouch in this mammal.
Despite the prevailing opinion and the evidence presented therefor, when critically examined, it is found to offer no support for the localization of thymus anlages in the branchial epithelium. As to the thicker character of the epithelium of the ventral pocket of the third pouch, it may be stated that growing epithelium tends to be thicker and that simple mechanical stresses and _strains have clearly a marked effect in causing thinning or thickening of an epithelium, numerous illustrations of which might be given. The thickness of the epithelium can: not in itself, therefore, be taken as a criterion of homology; nevertheless, the tendency to do so is strong; witness the suggestion of Hammar (’11) that the thicker character of the epithelium on one side of the tubular Complex III in man may mark the localization of the thymus anlage in the epithelium and thus bridge the gap between the condition in mammals and that in lower forms. This fact just alluded to—that in mammals the thymus comes out of the ventral portion of the pouch (so interpreted) while in forms below mammals it develops from the dorsal portion of the pouch, on the assumption of a deﬁnite localization of a thymus anlage in the branchial epithelium— is confessedly an objection to the homology of the thymus bodies throughout the vertebrate series, as has been recognized by Maurer (’06), Grosser (’11 b), Hammar (’11), and others. It is only, however, on the assumption of such epithelial localization that this different mode of origin necessarily opposessuch homology, whereas it does give evidence against a primary thymus-forming group of cells in the branchial epithelium.
The evidence against a‘ distinct thymus anlage becomes markedly stronger when the development of the thymus in different mammals is considered. In man—-—as previously stated and as is also well known; conﬁrmed in the work of Hammar already cited—-the Complex III in the process of growth and the accompanying growth shiftings, becomes markedly prolonged and regionally differentiated into (1) a head containing the parathyreoid III and the branchial remnant (Hammar), closely joined to the cervical vesicle; (2) a neck or intermediary portion or cord (thymic cord, Hammar) ; and (3) a body, the ventral free end or apical portion of the pouch which coming to be located within the thorax undergoes thymic transformation, extending up a varying distance into and beyond the thoracic aperture. The remaining portions of the complex including the cervical vesicle degenerate and disappear, with the exception of the parathyreoid. In the pig, the entire complex—head, neck (intermediary cord, mid cervical segment, cervicothoracic cord) and body (thoracic segment), always excepting the para-thyreoid—undergoes thymic transformation, as Zottermann and Badertscher particularly have shown, although their results are in full accord in this respect with the less extensive studies of earlier investigators. In the guinea-pig, it is equally clear that the entire third complex, excepting the parathyreoid—forming portion, becomes transformed into thymus (H. Rabl ’13, Ruben ’11). The Ventral pocket or prolongation “remains very weakly developed” (Ruben) or is apparently lacking, according to the description of H. Rabl, and the complex remains purely cervical. In this form, somewhat different conditions of unequal growth, with different grouping of mechanical shiftings, may be in part responsible for the cervical position. Furthermore, the cervical vesicle becomes thymus, as Badertscher and Zottermann have shown in the case of the pig, and Ruben in the guinea-pig.
It is unnecessary further to multiply illustrations of the variability in extent of development or in position, by considering the results of investigators in the development of the thymus in other mammals (sheep, mole, cat, mouse, etc.) since the well established facts above stated——whi1e they do indicate, as do the numerous observations on lower vertebrates, a marked and extensive tendency to form thymus bodies inherent in the branchial region—do not afford any support to the acceptance of a speciﬁc and intrinsic anlage for the thymus in the branchial epithelium, which would have to include therefore—to limit the consideration to the mammalian thymus and the third pouch— the entire branchial entoderm and that portion of the adjacent ectoderm which becomes cervical vesicle.
It is necessary, therefore, to ﬁnd some basis for understanding the development of the thymus other than the assumption that it is a representative of branchiomeric organs whose anlages are deﬁnitely located in one or more of the branchial pouches and potentially in all. Such a basis for its interpretation is found in the recognition that it is a structure whose appearance is determined by extrinsic factors of relation and position and not intrinsic factors located in any particular group of cells. In support of such an interpretation and giving us, I believe, a better comprehension of its morphologic signiﬁcance, we have the fundamental plan of its histogenesis.
The histogenesis of the thymus, it is true, has been a mooted question, there being six different interpretations in two rather natural groups. The results of recent workers, including the extensive work of Maximow (’09—) and Hammar (’O7—) and his pupils, supplented by that of Pappenheimer (’13), Badertscher (’15 b), Hartmann (’14), and others (e.g., Jolly, ’11, Hart ’12) show quite conclusively, I think, that the thymus is formed by extensive inﬁltration of the epithelium by cells from outside with the characteristics and potentialities of lymphocytes, which there proliferate. These cells are derived, according to Maximow, Badertscher and Hartmann, from the connective tissue (mesenchyme) while Hammar (’11) still recognizes the possibility or‘ probability that they come from the blood. I believe that the correct interpretation is that of Maximow,’ Hartmann and Badertscher—the work of the last named having been closely followed by me. Brieﬂy stated, and in somewhat general terms and with the attempt to emphasize the fundamental in the process: The epithelium of the third pouch complex due to its peculiar location, by growth and the attending growth shiftings, as has been described above, becomes transformed into an elongated epithelial tube. The caudal portion which becomes the thymus lobe (in man) grows extensively (ﬁg. 24) but in a manner not in the least typical of an epithelium. The lumen is lost and with it all surface relation for the epithelium, which from this time grows loosely, forming the cyto-reticulum or syncytium so characteristic of it, growth occurring particularly and irregularly in the basal layers (next the mesenchyme). The growth is further attended by an accompanying diffuse degeneration. In its relation to the underlying (surrounding) mesenchyme also the relations are atypical. The growth co-ordination of these two tissue forms would typically determine the appearance of a (connective tissue) membrana basalis. In the case in point, mesenchynal elements (so—called large lymphocytes, primary wandering cells, leucoblasts) become free and invade the cyto-reticulum, there proliferating rapidly, forming the characteristic small cells with scanty cytoplasm (the lymphocytes, small lymphocytes), the proliferation occurring mainly in the peripheral growing zone—next themesenchyme—— leading to the well known differentiation into cortex and medulla. This peculiar relation of growth and proliferation continues, in general coextensive with the presexual growth of the body, then ceases and a more or less rapid involution of the structure succeeds. Hassal’s corpuscles are clearly phenomena of degeneration—cytoconglomerates—more marked and larger during the period of involution.
The thymus, from this point of view, may be regarded as an expression of a persistent and atypical growth of a non-adaptative epithelium, this being accompanied by an altered epitheliomesenchymal relation whose characteristic feature is the inﬁltration of the epithelial (epithelioid) mass. The epithelial growth is attended by an accompanying degeneration which becomes more profound in the later period (involution). The tliymus transformation may thus be thought of as a reaction of degeneration, prolonged and given its characteristic features by the attendant growth. Such an interpretation at once raises a number of important questions of marked biological and morphological interest, both theoretical and practical, and for the consideration of most of them the basis in fact is still insufficient. The far—reaching signiﬁcance of the interpretation and the point of view it represents will be apparent from even the scant consideration that follows.
If the thymus represents a form of ‘reaction of degeneration’ as outlined above, other instances of similar nature should occur, as indeed is the case. Jolly particularly has created a group of “lyrnpho-epithelial organs” in which he has grouped Peyer’s patches, tonsils, esophageal lymphoid organs of birds, the follicles of the bursa Fabricii of birds of prey, the lymphoid papillae of anal glands, placoid thymus of teleosts, bursa Fabricii (of other birds), and the thymus of most vertebrates. To these might be added a number of others, such as the amphibian tonsils (Kingsbury ’12), Kiemenreste of Anura, the tubal tonsils of birds, and others will doubtless be added as the ﬁeld of in— vestigation is extended. In all these cases there is illustrated a more or less intimate reaction of epithelium and lymphoid cells (lymphocytes). In View of what seems to the writer strong and convincing evidence of the mesenchymal origin of such lymphatic cells (lymphocytes) and with the acceptance of this origin, these structures illustrate a reaction of epithelium and mesenchyme (connective tissue) characterized by free proliferation of the cells of the latter with an invasion and inﬁltration of the former. An essentially regressive character of the epithelial structure in many of the instances is not clearly apparent, and awaits more light on the biological signiﬁcance of the part, as in the case of the bursa Fabricii of birds. In other cases the degenerative element is clear, as in the case of glands (e.g., tubal tonsils of birds) where the lymphatic cells inﬁltrate and replace the gland, entirely or in part.
Stohr in 1891, in dealing with the development of the palatine tonsils, concluded with a general discussion containing the following pertinent paragraph (translation): It is probable that most of those leucocytes that occur outside the lymphatic nodes (lymph glands) and outside of lymph and blood vessels are the agents of resorption processes whether the same occur in the service of digestive processes or are for the purpose of removing bodily structures which have entered upon a. partial or complete regression. As proof of the latter, one may point to the frequent occurrence of collections of leucocytes in degenerating organs, for example, in the pronephros of lower vertebrates, the gills of anura, thymus, processus vermiformis; also such a possibility may not be at once rejected in the case of the tonsils (residuum of a visceral cleft) and the socalled trachomal glands (degeneration, of the nictitating membrane?). Certain of the groups of leucocytes found in the mucous membranes are in direct relation to the degeneration of glands (p. 547).
In most places in the above quotation lymphocyte might be substituted for leuocyte for greater precision. As is of course well known, Stohr (’06) subsequently altered his interpretation of the thymus, coming to regard the “small round cells” as of epithelial origin and a cell type sui generis, not to be confounded with small lymphocytes. The recent work has not, however, conﬁrmed his second interpretation but rather the former one; with some difference of opinion, however, as to the local or general (blood) origin or source of the invading cells. The comparison to which Stohr here refers~that of the thymus and tonsillar structures (Whether palatine, lingual, pharyngeal, esophageal, coecal, conjunctival, or elsewhere occurring), as well as the comparable collections of lymphatic tissue in mucous membranes such as Peyer’s patches, solitary nodules, etc. is involved in the interpretation of the thymus insisted on in this paper, and is an important one. Inasmuch as the discussion would require going into the matter in greater detail than is desirable here, and as it is the purpose of the writer to supplement later the preliminary brief paper already published by him (Kingsbury ’12), he will only add that, as in the case of the thymus, so in tonsillar structures, the primary local or general origin of the ’lymphocytes’ requires further consideration, as well as the relation they bear to regressive epithelial structures (glands). In this connection I quote the comment of Stohr in a footnote to the same article quoted from above, apropos the invasion and inﬁltration of epithelia so characteristic of tonsils, that: In the case of the thymus the immigration has the purpose of removing the organ that is of no further use. The leucocytes wander into the epithelium of the tonsils; this is not, however, ‘removed since the crypts of the tonsil are hollow so that the leucocytes so commissioned with its removal suddenly come out on a free surface and reach the mouth cavity without having fulﬁlled their duty.
In this connection the writer, on his part, desires to offer the comment that the intrusion of a teleology, While in many instances in biological work apparently justiﬁable as an avoidance of complex paraphrasing and explanation, is in such instances as the above quite unnecessary. Before leaving the question of a ‘lymphocytopoietic’ reaction of mesenchyme (connective tissue) in the presence of regressive structures I wish to mention some other aspects. First, every histologist is familiar with the circumscribed small mononuclear cell (lymphocytic) accumulations, more or less compact, occasionally encountered in glands of the most diverse character~—kidney, (thyreoid) lachrymal gland, salivary glands, as well as in minor glands of the respiratory and digestive systems—attended by the degeneration and inﬁltration of a certain number of the epithelial acini.
In the transplantation of tissues, where in some instances they ‘take’ and grow, and in other cases (as in most homoitransplants, Loeb) they fail to do so and undergo regressive change and disappear, peculiar opportunity is given for the examination of the relation of regressive structure to its environment. The statement of Leo Loeb (’15) in summing up the results of many years of investigation in this ﬁeld are so pertinent that I venture to quote in some detail:
A certain metabolic activity on the part of parenchyrna of various organs determines the attitude of lymphocytes and of fibroblasts toward the parenchyma. If the activity is normal, lymphocytes do not or only to a slight extent enter the parenchyma. The connective tissue is held in a deﬁnite state of activity (p. 728). . . . . While the vitality of the tisscs has not been essentially impaired after homoiotransplantation, and they may even grow, ‘and the metabolic changes they underwent in the different chemical environment did not therefore markedly interfere with their power to live or even propagate, these metabolic changes lead to a new -condition in the host tissue, which secondarily brings about a destruction of the transplanted piece, namely, these metabolic changes cause (a) an increased activity on the part of small monocuclear cells (probably lymphocytes) and (b) a destructive activity on the part of the connective tissue of the host. The mononuclear cells collect around the transplanted tissue, penetrate into it and destroy its cells. . . . We may conclude therefore that the metabolic changes taking place in tissues after homoiotransp1anta— tion stimulate the activity of the lymphocytes and cause the altered function of the fibroblasts‘ which now produce ﬁbrous tissue in large quantity. . . . The activity of lymphocytes and of connective tissue is to some extent independent of each other; while in many cases the two act together, in some cases the one prevails, in other cases the other (p. 727). . . . Connective tissue and lymphocytes may therefore be regarded as organs of attack, lying quiescent under ordinary conditions, but exerting their efforts as soon as within given limits certain pathologic changes take place (p. 728).
Might it not well be that lymphocyte inﬁltration and connective tissue invasion represent two sides of a fundamental mesenchymal reaction?
Finally, I desire to call attention to Metchnikoff’s conception of senescence (“In senile atrophy there is always present the atrophy of the higher and speciﬁc cells of a tissue and their replacement by hypertrophied connective tissue”) and to his accompanying well-known View of the frequent destruction in old age of epithelia (as in the kidney) by phagocytes——leucocytes from the blood. Without stopping to comment on his recognition of two ‘distinct’ reactions, the connections that the interpretation here discussed has with pathology is sufficiently obvious.
It is also recognized that the interpretation of the thymus involves the biological and morphological interpretation of the lymphatic nodes (including hemolymphatic nodes) as well as the simpler or more complex accumulations of lymphatic tissue in mucous membranes and glands. From this aspect the lymphatic nodes have scarcely been considered as yet. Furthermore, the thymus problem is a part of the larger problem of the blood cells and hematopoiesis in general. The unitary character of the group of the blood cells, while not established beyond controversy, has been made highly probable through the work of Maximow and of Weidenreich particularly.
It is customary to express it*in terms of cell lineage, and to designate it as the ‘monophyletic’ mode of origin of the blood cells. It is a conception compatible with the acceptance of either the derivation of the primary blood cells from the entoderm, in accordance with the angioblast theory of His, or a derivation from and development out of the mesoderm, although the evidence, as the writer sees it, mainly supports the latter interpretation. It is possible, however, to look at the unity in origin of the blood cells as an expression of a fundamental unity of conditions. While this view would not necessarily oppose the monophyletic interpretation under either an angioblastic or mesen— chymal origin, it would not, on the other hand, necessarily presuppose it. One of the characteristic features of hematopoiesis is the ever-shifting setting of the scene, the succession of regions in which blood—cell formation occurs :—blood islands (yolk sac), liver, par- and preaxial mesenchyme (?), mesonephros (some forms), spleen, lymphatic tissue, thymus, bone marrow~ as well doubtless as other places. There may well be a common metabolic feature that determines the appearance of bloodcell formation successively or simultaneously in these different places. That ‘absorption’—frequently~of products of regressive change may be an element is suggested, as illustrated, for example, by the tendency of blood—cell formation to follow bone (or cartilage) absorption even when it occurs in very unusual localities (Maximow ’07 b). On the other hand, it is possible that the blood-forming regions are characterized by a continued growth tendency in the mesenchyme, associated with a lack or loss of the adaptive connective tissue differentiation, such as occurs in other places such as, for example, the formation of skeletal connective tissue membranes in correlation with epithelia, etc., and that this covers factors that determine hematopoiesis. Our knowledge as yet is clearly neither detailed enough nor extensive enough to permit any comprehensive conclusions. In the case of the thymus, however, not only lymphocyte formation but also the formation of granular leucocytes (including eosinophile cells) and red blood corpuscles incontestably occur, although I question whether many of the last named ﬁnd their way into the general circulation (cf. Badert— scher ’15, b). It should also be noted that formation of granular cells and red blood corpuscles occurs in the cervical vesicle (ectodermic) portion of the thymus in the pig (thymus superﬁcialis), as well as in the entodermic thymus.
To return to the morphological interpretation of the thymus: It is obvious that an explanation from the point of view set forth above removes many of the difficulties that beset the interpretation of the thymus as a branchiomeric organ deﬁnitely located in the branchial epithelium. 'Recognizing that the thymus-forming factors are not intrinsic but extrinsic, i.e., partly a function of position and relation, it is no longer necessary directly or completely to homologize thymus bodies in different forms, since it is obvious that different growth conditions may determine the thymus development from quite different portions of the branchial epithelium, and portions that in one form may persist and undergo thymus transformation, in others may degenerate and disappear without the characteristic reaction appearing. It is only for convenience, and in view.of the ﬁnal result, that the purely epithelial stage may be termed ‘thymus’ or ‘thymus anlage.’
Turning now to the question of a ‘thymus IV anlagez’ In the human embryo it is clear that there is no reason for serially homologizing the ventral diverticulum IV with the thymus III. The thymus IV is variable (as indeed is thymus III) and inconstant. It has never been shown that it is distinctively or exclusively derived from this portion of the branchial epithelium. The ventral pocket is clearly but an expression of the early and temporary morphological growth relations and speedily disappears as such (Kingsbury ’14 b). It is altogetherprobable that the thymus transformation may befall any portion of the epithelium of the Complex IV (caudal pharyngeal complex) which may persist in the mesenchyme.
It may be said in closing this consideration of the thymus that at most it may be stated that there is a wide-spread tendency to thymus-formation in the branchial region, characterized by a persistence and growth of epithelium with a characteristic (though not peculiar) reaction with the adjacent tissues, under conditions that are not yet fully analyzable. What these conditions are and what determines the development of a thymus or thymus bodies is unknown, and any attempt to determine them awaits further analysis of the growth conditions of the region, particularly in lower forms. I desire to call attention to an entirely similar point of view regarding the homologization of tonsils in lower and higher forms (Kingsbury ’12).
The characteristic number of four parathyreoids III and IV on the two sides appears in man to be quite constantly present. In the series of 60 embryos examined, many of them attaining beyond the period of differentiation of these structures from the other portions of the pharyngeal epithelium (ca 20 mm.), in but two instances were accessory parathyreoids noted. In the 40 mm. embryo, there were four parathyreoids on the right side, the two extra bodies, from their position, being undoubtedly derived from both III and IV. In the 18 mm. embryo there was a small accessory parathyroid III on the left. But little has been added to the known mode of development of these structures in man, as set forth by Grosser (’11 b) and more recently by Hammar (’11). It has been possible, however, to follow them a little farther back in development, to emphasize their fundamental morphological relations and to offer a suggestion as to their morphological significance.
They develop, as already described (Hammar ’11), as a thickening of the branchial epithelium in the dorsal portion of the third and fourth branchial pouches respectively, upon their lateral, and to a slight extent (morphologically), cephalic aspects. The thickening is attended by and at ﬁrst in large part at least due to a peculiar loosening or reticulation of the epithelium. Parathyreoid III was ﬁrst clearly recognizable (ﬁg. 18; also ﬁg. 17) in the 7.5 mm. embryo, while the parathyreoids IV were not yet distinctly recognizable. In the subsequent growth their characteristic appearance is maintained. The thickening of the epithelium continues and with the (typical) degeneration and disappearance of the contiguous branchial epithelium they remain as subspherical-oval bodies in the adjacent mesenchyme. How far their increase in size in the early period of growth is due to extension of the parathyreoid-forming‘ process to the adjacent epithelium, and to what extent it is due to only enlargement of the original anlage, it is diﬂicult to determine. A careful study of their histogenesis in suitable material is much needed. It seems to be quite unnecessary to introduce ﬁgures in illustration of their position and general development in addition to those already published (cf. Grosser ’11 and Hammar ’11). It may be permitted, however, to call attention to the evident mistake in lettering in the otherwise typical ﬁgure published by Grosser (’10) and subsequently reproduced in the Keibel and Mall Handbook (vol. 2, ﬁg. 330.) On the left, epithelial body III should obviously be epithelial body IV, and vice versa; the position is in itself characteristic. At this place I also desire to mention an error in the description of ﬁgures 1 and 2 in my earlier article (’14 b): Th. = thyreoid, thy. = thymus.
In facing the problem of the morphological signiﬁcance of the parathyreoid. bodies, the investigator——as in the case of the thymus—encounters the two alternative interpretations of intrinsic branchiorneric organs whose anlage is located in deﬁnite regions of the branchial pouch, and the interpretation that their development is a factor of their relative position and relations, and hence extrinsic, to a marked degree. The former is the generally accepted view, and their development from an epithelial area of deﬁnite location, seems to conﬁrm its soundness. I am inclined to believe, however, that further investigation will support the alternative. In the early development of both parathyreoids III and IV, in embryos of (7.5 mm.) 8.3 mm. to 10 mm. the epithelium undergoing the ‘parathyreoid trasformation’ is that immediately adjoining the corresponding aortic arches III and IV, respectively. These arches here pass close to and in intimate contact with the branchial epithelium upon the anterior and dorso-lateral aspects of the respective pouches. It is -here that the parathyreoids are being differentiated, and the mesenchyme between the two structures, vascular endothelium and branchial epithelium (parathyreoid anlage) is scanty or lacking. (ﬁgs. 26, 29, 30). If this correlation possess morphological signiﬁcance, it will be found in other mammals, and whether or not this is the case has not been ascertained. The existence of such an association is man in presented, therefore, merely as a suggestion that has several sides: (1) that possibly herein lies the signiﬁcance of the fact that the third and fourth pouches are the only ones that develop parathyreoids, the third and fourth arches alone persisting; (2) the parathyreoids may thus more closely represent the primary branchial epithelium and more truly deserve the name of branchial remnants than other branchial derivatives; (3) Maurer’s contention that the carotid body (in amphibia, and other forms?) represents an epithelial body II (parathyreoid II) may herein ﬁnd support and conﬁrmation. In any event, a reexamination of the origin of the epithelial bodies and their vascular relations in amphibia, as well as those forms in which the development of an epithelial body (parathyreoid) II has been described, is called for. However interpreted as to its primary signiﬁcance, the association of parathyreoid and corresponding arch persists for some time (ﬁg. 20), and the parathyreoid follows the growth shiftings of the corresponding blood vessel, the parathyroid IV rotating toward the dorsal side, the parathyreoid III toward the ventral side of the corresponding pouch complex, as above described. Ultimately, of course, the vascular arch moves away from the parathyreoid, which remains stranded in the midst of the mesenchyme by the degeneration of the associated branchial epithelium.
This derivative has received but little attention in this study, aside from its form changes already considered. The separation from the pharynx is early and complete, so that a thyreoglossal duct—in no sense a duct, any more than‘ are the other so-called pharyngeal ducts—does not at any time normally exist, or has only a brief existence. The point of separation from the pharynx, while always recognizable from the first as a shallow depression, is only deepened subsequently (13 to 14.5 mm.) apparently mainly by growth of the adjacent mesoderm. The beginnings of a pyramidal lobe, clearly a growth of cells in the line of descent, was ﬁrst found at 14.5 mm. The cavity of the thyroid is speedily lost (5 mm.) and the period of expansion begun by the peripheral growth of thyreoid cell cords. The vascularization seems to take place rather gradually, being marked in embryos of 32 to 40 mm. Lumina (follicular cavities) within the cell cords appear at about this period (32 mm.) and at ﬁrst contain no demonstrable colloid. In the 40 mm. embryo some of the follicles contain colloid, although not much is present in the oldest embryo (48 mm.). At 10 cm. the colloid-containing follicles are numerous.
Ultimobrcmchial body, postbrcmchial body, or lateral thyreoid
The writer desires to add nothing to the discussion of this structure already published (Kingsbury 14 b). The view then taken was that this derivative gives no good evidence of being a ‘vestigial gland,’ which in lower forms possesses a duct opening into branchial pouch or pharynx. Its origin, form and fate appear to be due to a persistence of a growth tendency in the branchial epithelium, as molded by the attending growth conditions and movements, but without any characteristics that mark it out as an ‘organ’—~of past or present usefulness—or as an externally or internally secreting gland. Its fate appears to be a degeneration within the thyreoid, although it must be confessed that this has not yet been deﬁnitely proved.
In view of the very large amount of work, experimental and observational, being done at the present time on the endocrine organs, by both the physiologists and clinicians, it may seem somewhat presumptuous for a morphologist to venture upon a discussion of their interpretation and signiﬁcance, particularly as discordant evidence indicates—as has been insisted on by others—that the time is not yet ripe and a much greater body of facts must be accumulated before broad interpretations may be drawn. The embryologist cannot escape, however, a consideration. of certain aspects of the problem; what an organ becomes is a function of its origin and development, and its activity in the adult is determined by its origin and ancestral history.
Thus to the embryologist falls the duty of contributing a respectable portion of the facts, while the character of his problems gives him a peculiar interest in certain sides of the general inter pretations.
In the group of the endocrine or ‘internally secreting glands’— so—called—two things stand out strongly: (a) The close correlation between them on the physiological side, showing particularly in their pathological derangement, so that hypertrophy or abnormal growth in the one is in some way correlated with abnormal changes in other endocrine organs. The organs thus particularly linked are“ thyreoid, hypophysis, suprarenal; thyreoid, hypophysis, thymus, gonad; parathyreoid, thryoid; parathyreoid, gonad (?); thymus, thyreoid; thymus, gonad, lymphatic organs; thymus, suprarenal (?) ; suprarenal (medulla), pancreas (islands of Langerhans ?); suprarenal (cortex), gonad; suprarenal cortex and medulla; hypophysis, gonad; hypophysis, thyreoid; pineal body, gonad, hypophysis. The evidence that these structures are bonded by either a ‘functional interdependence’ or vicarious or reciprocal functioning is, it would seem, very slight or lacking; the physiological characteristics that they possess in common clearly lie deeper. (b) The second peculiarity of the group of endocrine organs contrasts, it would seem, with their common metabolic features and is at variance with the rule that organs which may be grouped in a natural physiological system also show a unity in development, so that parallel embryologic systems exist. In the case of the structures under consideration, the greatest diversity of origin prevails; their characteristic parenchyma is from all the germ layers and parts of the embryonic body regionally remote and unrelated, while material of quite distinct sources may become associated—as in the case of the hypophysis and suprarenal body. Several of them come out of the embryonic pharynx -or its immediate neighborhood—hypophysis, thyreoid, para ° The writer makes no claim to ﬁrst-hand information in this complicated physiological ﬁeld. The grouping here given is based mainly on Biedl: “Die Innere Sekretion.” My colleague, Dr. S. Simpson, kindly examined the above list. thyreoids, thymus—and this it is that causes the inclusion of the problem of the endocrine organ group as a subject of discussion in this paper. The common origin of these organs from the pharynx led Kranichfeld to assume that the pharyngeal epithelium is from the beginning and primitively ‘internally secreting’ (which it may well be) and that its epithelial derivatives but continue an activity that was common to them while still a part of the embryonic pharynx. He brings in support of this view no evidence, direct or indirect, and several objections might be raised in criticism. I believe it is possible, however, to view the pharyngeal derivatives, in common with the other endocrine organs, quite differently.
It is, of course, a matter of history that many of these organs have been frequently regarded as vestigial structures remnants of organs of past usefulness, but now obsolete and without ‘function.’ With the increase in knowledge of internal secretion, the pendulum swung the other way and there is frequently met a tendency to deny altogether the existence of anything ‘vestigial,’ or without function, in the body. It becomes, however, largely a matter of deﬁnition of ‘vestigial’ and ‘function.’ As far as the endocrine organs are concerned, it is quite possible that both views are correct; that they are, in a sense and from one point of view, vestigial structures and that they are peculiarly ‘internally secreting;’ further, even that they owe their signiﬁcance as endocrine organs to their quasi vestigial nature. In the case of many of them it is clear that they arose either in the individual or in the race, out of structures morphologically quite different and physiologically of a distinct adaptative value, while the designation as organ or gland frequently becomes difficult.
The corpus luteum arises out of the wall of the Graaﬁan follicle after its collapse, by what might be called a reaction of degeneration accompanied by growth; has, it would seem, an unquestioned inﬂuence, particularly upon the uterus through its metabolism; it ﬁnally degenerates. It might be termed a ‘gland,’ periodically developed and disappearing Within the individual lifetime. The pineal body or gland develops out of the epiphysis, grows for a time, approximately during adolescence, and then undergoes degenerative changes. The epiphysis, however, is an encephalic evagination, primitively developing an optic evagination, forming a parietal eye in certain lower forms. The thymus I have just presented reasons for considering as formed out of the branchial epithelium by a kind of reaction of degeneration attended by growth. The parathyreoids are likewise formed out of the embryonic branchial epithelium in its growth transformation. They are not encountered in forms breathing through gills. The thyreoid of the lamprey—‘which is the only form in which we obtain a glimpse of its origin—arises out of the endostyle organ, when it degenerates at transformation (Marine ’13). It is customary, it is true, for zoologists to designate the endostyle organ as thyreoid. It may be pointed out, however, that the endostyle organ corresponds in no respect to the thyreoid that arises from it, in its morphology, and there is, as far as I am aware, no evidence that the endostyle organ— or, as a matter of fact, the thyreoid derived from it—possesses the inﬂuence on growth characteristic of the thyreoid of mammals. There is thus no more~nor as much—justification of speaking of the endostyle organ as thyreoid than there would be of speaking of the Graafian follicle as corpus luteum. It develops very early in the mammal and is clearly an old organ. The colloid vesicles, however, so characteristic of it, are more comprehensible, according to Dohrn’s view of the colloid as stagnated and condensed secretion, primarily mucous, rather than as exhibiting any adaptative feature correlated with its inﬂuence on the bodily growth metabolism.
The hypophysis is of more obscure genetic signiﬁcance. We have the attempts to interpret it as some form of ancestral mouth (Owen, Beard, Dohrn, Kupffer); as primitively a sense organ, possibly for the detection of changes in the sea—water (Sajous) ; as preoral branchial clefts (Dohrn); as a gland (neural gland); while the possibility is large that it may owe its development at the end of the primitive growth axis and its curious correlation with growth, to the more general growth conditions of the region, rather than to any more speciﬁc phylogenetic tendency in its ontogeny. In connection with the last view, its development as an expression of the growth of the entire prechordal region requires investigation.
The morphological signiﬁcance of the suprarenal body is equally obscure. However, while there are, as far as I have been able to ascertain, no facts available that give any suggestion as to why the cortex (or interrenal system) arises from the coelornic epithelium and in a place medial to the gonadal anlage, the derivation of the medulla cells from the embryonic sympathetic system affords a basis for further analysis and investigation of the suggestion that they are, essentially and primarily, undifferentiated sympathetic neurones. The type of cell is widely distributed in the sympathetic system, and is characterized by its strong reducing power, which is responsible, for its ready impregnation with oxydizing salts such as chromates (and dichromates), potassium permanganate, osmium tetroxid etc., and is responsible for the incorrect (Kingsbury ’11) and misleading names of chromafﬁn cell, system and reaction, so commonly employed. It is quite in accord with this mode of origin that the suprarenal medulla cells contain a chemical substance possessing the same general effect as that of the neuronal system from which they were derived.
It is also premature to attempt an explanation of the genetic signiﬁcance of the islands of Langerhans of the pancreas. We know only that they arise out of the same anlage as the rest of the pancreas parenchyma and still retain a connection with the epithelium of the duct system by cell cords (Bensley ’11); but whether they represent undeveloped acini, regressive acini, or ‘exhausted’ acini, and what the conditions that determinedor determine~their appearance, cannot be surmised. The ancestral history of the pancreas is itself obscure.
As to the ovary (aside from the corpora lutea) and testis, there is, I believe, no evidence of the existence in either of them of endocrine glands, in the morphological sense, nor suﬁicient evidence of a speciﬁc gland, in the physiological sense. To the so—called interstitial cells in both instances is usually ascribed the importance of a gland. In the case of the ovary I have myself (Kingsbury ’14 a) made, from the morphological side, a critical study of these cells and the conditions that determine their appearance, with results opposing the use of the term ‘interstitial gland.’ We are compelled, I think, to look to the general metabolic processes of the organ for the basis of the effect on general bodily growth and metabolism, and it is quite suggestive that regressive change is constantly an accompaniment of the growth processes therein proceeding.
Disregarding the ovary and testis, in which no distinct morphological gland is recognizable and in which regressive change is constantly present, in all the other glands grouped together as endocrine glands——even to a degree in those whose genetic signiﬁcance is still obscure—there is found one feature in common. In the midst of the heterogeneity and atypicality of their origins, as apparently the one embryologic bond paralleling the physiological community that they evince, is the fact that they arise or have evolved out of structures quite different. This is most clearly shown in organs Whose history is better known (corpus luteum, pineal body, thyreoid, thymus, parathyreoids). They appear by a process of metamorphosis and their persistence is attended by a ‘metaphysiosis’—if one might coin the word—to which is due their inﬂuence on bodily metabolism and growth. Their activity and its peculiar effects would thus be a function of their origin, in its peculiarity. Nor could the analysis stop here; their physiological community, it would seem to me, must have its basis in the general bodily metabolism and the relation they bear to it in virtue of their unique genetic qualities. The acceptance of such a point of view would mean, however, a marked reversal of what is, I believe, the accepted interpretation, and a transference of emphasis from the organ to general bodily metabolism; from the body as a collection of organs to the body as a metabolic unit. More speciﬁcally, in the case, for example, of exophthalmic goiter, cretinismus, status thymico-lymphaticus, giantismus and acromegaly, dystrophia adiposogenitalis, or Addison’s disease~I must confess it is difﬁcult for me to conceive of the primary cause lying in thyreoid, thymus, hypophysis, gonad or suprarenal, but in the general metabolism, particularly ‘growth metabolism’ as centering in the development of the reproductive phase.
In this origin out of structures of a different adaptative value, in all cases where we may follow it and where the genetic signiﬁcance is not still too obscure, there appears to be an element of regressive change present; differentiations of one character, either in the individual or in the race, have disappeared and are replaced by the endocrine organs, and herein lies possibly the hint of a reason for the peculiar correlation of the structures so derived (i.e., the endocrine organs) with the general bodily growth and metabolism. As I have said elsewhere in discussing the question of the signiﬁcance of the interstitial cells (Kingsbury ’14, p. 81): “The assumption that the end-products of metabolism may stimulate growth (and metabolism) is not I believe opposed to the facts of general physiology, but rather the reverse. As applied to the endocrine organs in general, the suggestion has three sides; (a) that the end—products of their metabolism have a marked stimulatory effect on bodily growth (and metabolism) ; this would seem more or less a restatement that they are endocrine organs; (b) that the end—products of growth metabolism should peculiarly affect their growth; and (c) as a correlary of (b) that abnormal bodily metabolism should be associated with an abnormality of growth in these structures.
That the suggestion conveyed is, in its bearings, broader than the more speciﬁc problem of the endocrine organs is obvious on the face of it. In an earlier portion of this paper there is brieﬂy discussed the question of a possible correlation with regressive change of the connective tissue and of the blood-forming cells. On the pathological side, the problems of the nature of the inflammatory reaction, the healing of wounds, abnormal growths, etc., are inevitably included.
To return to the primary question of the genetic interpretation of the endocrine organs: It was to be expected that the ‘ductless glands’ had been looked at by others from the point-of view here developed. Dohrn in 1875 formulated the following “Principle of change of function:”
Through a succession of functions whose bearer remains one and the same organ, is accomplished the Transformation of Organs. Each function is a resultant of several components of which one constitutes the chief or primary function while the others represent accessory or secondary functions. The subsidence of the chief function and the rise of an accessory function alters the total function. The total function becomes a different one and a result of the transformation is the Transformation of the Organ (p. 60).
Dohrn at this time did not apply his principle to the pharyngeal derivatives. He subsequently, however, in his “Studies of the development of the lower vertebrates,” stated his conclusions (a) that the thyreoid represents a pair of branchial pockets located between the first and second in the present series (Studies VII, VIII); (b) that the hypophysis is developed from a preoral pair of branchial clefts (Study II); and (c) that the thymus (in sharks) is developed out of dorsal portions of the gill pouches which form gill lamellae, but, being overlaid by dorsal branchial musculature, become cut off and grow to form the thymus (Study IV). The ﬁrst two interpretations are, I think of purely historical interest at the present day.
Willey in his interesting book on “Amphioxus and the ancestry of the vertebrates” clearly faces the question of the interpretation of the glands, which his central theme brings in for comparison, namely, the thyreoid (p. 169), the thymus (p. 29) and the hypophysis (p. 283); and as clearly recognized the principle of the “change of function.” In the case of the thyreoid, the regressive element is recognized in that the “ductless gland” (the thyreoid) is a “Vestige of the very actively functional endostyle or hypobranehial groove of the Ascidians, Amphioxus and Ammocoetes.” He does not propound any ‘principle,’ however, nor does he discuss the matter in detail or more broadly.
Wiedersheim (’03), on the other hand, in a paper on“The aging of organs in the race history of man and its inﬂuence in disease processes,” clearly recognizes a genetic principle involved and its broad signiﬁcance for pathology. The endocrine organs are considered, but only as having their place in a larger conception. I desire to translate two passages: I turn now to those organs of man which as their comparative anatomy and embryology teach, in the course of phylogeny have given up their original physiological duty and undergone a change of function. I have primarily in mind the thyreoid, thymus gland, pineal gland, pituitary body (hypophysis cerebri), the so-called glandula carotica, the suprarenal, and a certain territory within the nasal cavities. Many of these organs follow the gland type in their development and are primarily connected with the place of origin by means of a duct. This disappears later however so that from this time on the secretion that is formed is passed directly into the surrounding lymph or blood vessels (inner secretion). (p. 12). A typical change of function can hardly be thought of ; and when we ponder it and consider what profound processes of change have taken place both anatomically and physiologically, in the thyreoid gland, for example; or, in other words, how the organ just mentioned has given up a prior clearly highly specialized function in order to enter into very important physiological relations to the entire organism, the question becomes quite pertinent, I think, as to whether the unusual and frequent variations in form and size, as also the very marked tendency to pathological alterations of different character, are not due ﬁrst of all in large measure to the storm and stress period in its phylogeny. (p. 14).
Finally, general biologists have recognized a principle of “retrogression with change of function” (cf. Needham ’10, p. 253), ﬁnding illustration in the plant and animal world. In the above quotations the word function has been repeatedly employed. It is not, however, I believe through a search for speciﬁc ‘function’ that a clearer comprehension of the ‘internally secreting glands’ is to be gained. While the adaptative aspects of the growth pattern cannot be ignored, of course, it will be through the analysis of the growth metabolism of the entire organism and the determination of the fundamental characteristics of growth that there will be established a correct basis for the understanding of this group of structures in its morphological, physiological and pathological aspects.
In conclusion, I desire again to emphasize that it is clearly due to no accident of development or chance circumstance that the branchial pharynx in its regressive metamorphosis gives rise to structures of such profound metabolic signiﬁcance. DEVELOPMENT or HUMAN PHARYNX 383
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Figures 9-11, 13~19, 21 and 22 were drawn by Miss Herford in the Department of Comparative Anatomy of the Harvard Medical School, from models by the author.
The remaining ﬁgures were drawn by Miss Whitman, Cornell University.
A.A.III, third aortic arch
A.A.IV, fourth aortic arch
A.C., carotid artery
CJII, complex III
CJV, complex IV
C'.P., pericardial cavity
D.br.II, ductus branchialis II D.br.IV, ductus branchialis IV D.ph—br. III, ductus pharynge0—bran chialis III D.ph-br. IV, ductus pharyngeo-branchialis IV
D.C., ductus cervicalis
D.thyr., ductus thyreoglossus
D.v.II, diverticulum ventrale II D.v.III, diverticulum ventrale III D.v.IV, diverticulum ventrale IV
E;m'.II, epibranchial placode II Ep1’.III, epibranchial placode III
Epi.IV, epibranchial placode IV
F.br.I, ﬁssura branchialis I (cleft I)
F.br.II, ﬁssure. branchialis II (cleft II)
F.br.III, ﬁssura branchialis III (cleft III)
F.br.IV, ﬁssura branchialis IV
G.IX, ganglion petrosum (IX)
G.X, ganglion nodosum (X)
N.IX, ncrvus glossopharyngeus (IX) N .X , nervus vagus (X)
N.XII, nervus hypoglossus (XII) N.symp., nervus sympatheticus
P.III, parathyreoid III
P.IV, parathyreoid IV
S.br.I, sacculus branchialis I (pouch I) S.br.II, sacculus branchialis II (pouch
II) S.br.III, sacculus (pouch III) S,br,IV, sacculus branchialis IV (pouch IV)
S.C., sinus cervicalis
T.A., truncus aorticus
U, corpus ultimobranchiale
V.br.II, vesicula branchialis II
V.C., vesicula cervicalis
V.J., vena. jugularis
12 Ventral View of a model of the epithelium of the pharynx in a 5 mm. human embryo (Buxton embryo, No. 5, Gage Collection). X 50. Upon the right, the ectoderm is shown in position. cut surfaces are indicated by cross lining.
13 Ventral View of a model of the pharyngeal epithelium in a 7.5 mm. human embryo (No. 256, Harvard Embryological Collection ). X 60. Only the left half was modelled in the anterior portion of the pharynx.
14 Lateral View of the same model. The ectoderm is removed, and the surfaces of contact are indicated by line shading, as in figure 12. X 60.
15 Lateral View of a model of the pharyngeal entoderm from a 10 mm. human embryo (No. 1000, Harvard Embryological Collection). X 50. The left half of the anterior portion of the pharynx only is shown in the model. Cut surfaces are indicated by lines, in this and ﬁgure 16.
16 Ventral View of the same. X 50.
17 View of the same model from the aspect that is toward the right in figure 15; that is, from the dorsal aspect as referred to the embryo’s body. X 50.
18 Ventral View of the model of the pharyngeal epithelium in a 14.5 mm. human embryo (No. 1003, Harvard Ernbryological Collection). X 40.
19 Dorsal (posterior) view—as referred to the embryo’s body—of a model of the pharyngeal epithelium in a 9.4 mm. human embryo (No. 1005, Harvard Embryological Collection). One—ha1f of the pharynx only is shown. The ectoderm upon the left side is included in the model, the inner surface being here revealed. X 50; reduced 1/3.
20 Lateral view of the caudal portion (met-apharnyx) of a model of the pharyngeal epithelium in a 13 mm. human embryo (No. 26, Cornell University Collection). X 75.
21 Lateral View of a model of the pharyngeal epithelium in a 14.5 mm. human embryo (No. 1003, Harvard Embryological Collection). X 40. Other aspects are shown in ﬁgures 18 and 22.
22 Dorsal (posterior) View of the same model. X 40.
23 Photograph of section No. 317 from a 12 mm. human embryo (No.816, Harvard Embryological Collection), showing the Complex III cut longitudinally on both sides. Upon the left side, parathyreoid III and the lumen of the complex, as well as the ductus pharyngeo—branchialis III, are particularly well shown. Note the relation of the ventral diverticulum (epithelial thymus) to the pericardium. X 50; reduced 1/4.
24 Photograph of section No. 417 from a 19 mm. human embryo (No. 828, Harvard Embryological Collection), showing the Complex III cut nearly longitudinally on both sides. Upon the left, parathyreoid III is particularly well shown. X 30.
25 From section No. 127, 7.5 mm. human embryo (No. 256, Harvard Embryological Collection), showing the epibranchial placode II, and the fusion with it of the lower end of the ninth cranial ganglion (petrosum). X 100.
26 From section No. 125, of the same embryo, showing the parathyreoid III in its first appearance and its relation to the third aortic arch. X 100.
27 From section No. 134, of the same embryo, showing the epibranchial placode III and its relation to the Vagus nerve. X 100.
28 From section No. 143, of the same embryo, showing epibranchial placode IV and its relation to the vagus nerve and ganglion. X 100.
29 Photograph of a section of a 8.3 mm. human embryo (No. 59 Cornell University Collection), showing the development of the parathyreoid III and its position in relation to the third aortic arch. X 120.
30 Photograph of a section in the same embryo on the same side, 11 sections (110 ,U.) intervening, to show the developing parathyreoid IV and its position in relation to the fourth aortic arch. X 120.
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