Paper - The potency of the pharyngeal entoderm (1932)
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|endoderm. This early paper was attempting to understand the developmental mechanisms involving induction from specific tissues. Note the historic term for endoderm was entoderm.
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The Potency of the Pharyngeal Entoderm
By H. H. Woollard
Department of Anatomy, St Bartholomew’s Hospital Medical College
The pharyngeal entoderm has long been famous as the seat of formation of the branchial arches and their derivatives. These structures remind us of our origin from water-breathing forms, and are always quoted as one of the best anatomical proofs of evolution, and as a striking proof of the biogenetic law that each organism repeats, albeit in a compressed and abbreviated manner, the history of its origin. This region is of course also the seat of some of the more spectacular ductless glands.
Early Morphogenesis of the Pharyngeal Entoderm
A scientific morphology can be based on only two lines of enquiry, viz. an investigation of the history of the structure and a knowledge of the functions it performs.
Descriptive and experimental embryology has established the fact that the body of the vertebrate embryo is laid down in a definite order due to the successive activity of three great centres of growth. In the course of its development the embryo reaches a stage when it becomes a bilaminar slightly elongated body enclosing a central cavity, the archenteron. The place where the two laminae are conjoined is known as the blastopore. The margins of this blastopore, owing to the proliferation of the cells which compose it, adds further to the length and volume of this original cavity. The portion so added is called the deutenteron. In the formation of the axial organs of the embryo these two parts behave very differently.
The archenteric region builds up the apical extremity of the body; actually the parts in front of the notochord, a line which in the human body passes obliquely through the posterior wall of the pituitary fossa. This region includes the fore-brain vesicle, i.e. the cerebrum and diencephalon or thalamic region, sense organs like the optic and olfactory, the front wall of the pharynx and the buccal cavity.
The cells of the blastopore itself multiply and add to its volume by interstitial growth. This interstitial growth constitutes the second region of growth, and it produces the head region of comparative anatomy. The head in comparative anatomy means the zone which is bounded in front by the origin of the trigeminal nerve and behind by the caudal limit of the vagus. This cephalic region includes pre-eminently the branchial region.
Around the lateral part and caudal to the remains of the blastopore there is a zone of appositional growth, an area in which increase in size is due to the addition of cells from the neighbouring parts. This zone of appositional growth forms the third growth centre, and from it the trunk and tail are formed. It is the seat of the alimentary, the locomotive, and the genito-urinary apparatus. The nervous system is simple without important differentiations. The peripheral nerves merely repeat themselves, and there are no organs of special sense and no branchial windows.
These three great stages succeed each other, though indeed there is some overriding, and it is certain that they occur in all vertebrate embryos. The head is not a transformed trunk but a primary ontogenetic product, while the trunk and tail are secondary diversities.
Implications of this Mode of Development
These facts of development must be explained by the origin and evolution of the vertebrates, though all inferences must be checked by observation and experiment wherever possible.
Fig. 1. Sagittal section through a frog embryo showing the zones of differentiation. a. archenteron; an. anus; cn. neurenteric canal; d. deutenteron; h. hypoblast; m. mesoblast; n. central nervous system; z. zone of apposition. (Brachet, Traité d’Embryologie des Vertebrés, 1921.)
This general account of morphogenesis is implicit in the work of Gaskell on the origin of the vertebrates. He recognised the fore-brain as the oldest region of the vertebrate body. Gaskell has been criticised for the excessive ingenuity with which he derived the vertebrate from an already highly specialised form represented more or less by the still existing king crab. At the moment there is an increasing reluctance among some anatomists to admit the derivation of higher forms from types obviously akin but already specialised in some way. The idea of succession is dropping out of evolution, and with the departure of the notion of sequence the term evolution becomes almost meaningless. Some would deny the closeness of the chimpanzee-gorilla stock to Man and seek for his origin in more remote and more generalised types. The same way of thinking affects conceptions of the origin of the vertebrates. Nevertheless the insight embryology has given us of the order of development shows that Gaskell cannot have been very far from the truth, and we need not be so frightened of the idea of sequence in evolution. As for generalised types, it is to be asserted that some degree of specialisation is a condition of existence at all.
The precedence of the brain in evolution of vertebrates has already infected neurology and our way of thinking about behaviour. A theory of behaviour founded on the spinal reflex must be an abstraction, for the brain is not a modified spinal cord. General impressions and total responses precede individual and local responses.
Fig. 2. A. Frog gastrula looked at from the lower pole. In this non-pigmented area, the grey crescent, the blastopore has formed and is shaped like a horseshoe. (Brachet.) B. This is a schematic representation of the manner in which the blastopore closes. (Morgan.) C. The short black mark indicates the position of blastopore when almost closed. The elevated margin labelled 2 is the transverse medullary fold, and the area between this cerebral fold and the blastopore will become the medullary tube. (After Hertwig.)
The order of events outlined above also affects the vegetative nervous system. As a matter of.expectation from the above and also as a matter of observation the system is comparatively more recent, and the order of origin and development is vagal, sacral and lastly thoracolumbar.
Differentiation as an Induced Process
Thus far we have been led to conclude that the front end of the pharynx belongs to the oldest and first-formed part of the vertebrate body, while the branchial region occurs in the deutenteric region, the second portion to be laid down by interstitial growth in the vicinity of the blastopore.
Recent investigations in the field of experimental embryology have revealed how development in some part at any rate depends on the action of certain inducing structures. We know from the work of Brachet that the formative materials out of which the later organs will be formed reside in the cytoplasm of the ovum and become definitely localised when the ovum is penetrated by the sperm.
With the entrance of the sperm several major events are decided. Firstly, there is the contribution of paternal chromosomes; secondly, the stimulus to cell division; thirdly, the inception of a definite localisation of the developmental factors; and, fourthly, a coincidence between the point of entry and the plane of the first division of the ovum which corresponds to the axial symmetry of the right and left halves of the body.
Fig. 3. The “organiser” from the dorsal lip of the blastopore has been implanted from one species of amphibian into another. Fig. a on the left shows a secondary embryo developing on the left side of the host. The secondary embryo consists of medullary tube, somites, otocyst and tail. b. The same embryo seen in section. On the left the axial organs of the host are seen; on the right the medullary tube and otocyst of the secondary embryo. (Spemann.)
In the fertilised frog’s egg there develops an area free from pigment known as the grey crescent. This by observation and experiment is known to outline the future blastopore of the embryo. The cranial lip of the blastopore occupies the greater part of the crescent, while its lateral lips follow the horns of the crescent.
The margins of the blastopore approach each other by an eccentric growth, and all the dorsal organs of the embryo come to occupy the area in front of the blastopore constituting what is known as the dorsal plate. It is here that the medullary tube, the notochord, and the somites which become the myotomes will be differentiated. Just in front of this area the transverse cerebral fold out of which will be formed the prechordal head region, the first growth area, appears.
These localisations are now known for many organisms, and may, with some minor variations, be regarded as occurring in all amphibians. With a knowledge of the localisation of developmental factors the way is open for further investigation. So far it seems certain that the development factors reside in the ovum and have nothing to do with the sperm. The order of localisation and the time sequence are still obscure and nothing is known of their physicochemical nature.
The dorsal organs, medullary plate, notochord, somites, etc., do not undergo spontaneous development. They are induced by what Spemann has called the “organiser.”” Spemann used this term organiser to indicate that part of the cranial lip of the blastopore which acts as a morphogenetic centre inducing the development of these dorsal organs. Spemann’s experiments are many, but amongst the most decisive are those in which it was shown that material, which, if left in its own position in the embryo, would have become, say, ventral abdominal wall, is changed when brought into proximity with the organiser into nervous system, notochord, muscle, etc. Or, conversely, when the organiser is implanted into some other region of the embryo where these dorsal structures are not found, their formation is immediately excited. Most striking of all was the induction of these dorsal organs by the organiser when it was transplanted into another embryo of a different species. The embryos chosen were differently pigmented, so that the events could be easily followed. A double embryo was formed with two sets of dorsal organs. That the organiser actually changed cells of the host into these structures could be seen easily, for the difference in pigment made identification of host and transplant evident.
The essential elements in the organiser reside in the entodermal cells. The overlying ectoderm has no effect. This cannot be without significance, for the endocrines of the pharynx are mainly entodermal in origin. The mode of action of the organiser is still under investigation, but it is to be noted that it is not preformed in the ovum but is formed during development, and secondly that its action is only effective at a certain time in development.
It is the body of the embryo that comes into being in this manner, the branchial region and the trunk, while the first area, the prechordal region, seems to arise in an altogether autonomous manner.
One other observation may be mentioned for its future clinical interest. Brachet found that if the lateral part of the grey crescent in the frog’s egg (this corresponds to the region of Spemann’s organiser) be injured by a heated needle, then cell proliferation might follow but no differentiation. Such an embryo lives for only a limited period. Investigations in this manner have shown that the size of the organs which will be formed from a particular region depends on the amount of organising substance they have received, and that organs which have been reduced in size in this manner never regain later what they earlier lost.
At the moment we cannot piece the many facts gathered from experimental embryology into an ordered account of development. The genes of the chromosomes must be in some way parallel to the organisers. Then other organs, so far as we know, proceed with their development without induction, such as the prechordal head. For all the stages later than gastrulation we know of no other morphogenetic organs until we come to the ductless glands. There is perhaps one sort of exception to this. Some organs which themselves may have been induced may acquire the property of inducing secondarily others. The relation of the optic cup to the overlying ectoderm seems a case in point. For experiment shows that the cup has the power in some cases of inducing the overlying ectoderm, normal or transplanted, to form a lens.
Fig. 4. A representation of the pharyngeal derivatives.
The Development of the Branchial Region
Perhaps we may regard the pharyngeal entoderm as a secondary organising region. It will be necessary first to discuss its development before we can examine this idea further.
Though the number is greater in the more primitive vertebrates only four branchial arches, five depressions and six aortic arches have been recognised in Man. The branchial depressions immediately succeed the corresponding arches, the fifth depression being rudimentary. In those animals with branchial respiration the depressions become clefts, but in all Mammals the entoderm remains in apposition with the ectoderm, a cleft only appearing occasionally in the second.
The external form of the néck is affected mainly by the first and second arches, for these rapidly increase in size and so expanding come to overlie the remaining arches and thus bound a depression known as the cervical sinus. Within this sinus there will be the external depressions from the second to the fifth, while its prominent upper margin will be formed by the second arch. The caudal boundary is formed by the thorax towards which the second arch has grown.
Internally the entodermal depressions increase in what corresponds to the lateral wall of the Template:Pharynx. Here the depressions become drawn out into narrow ducts whose blind ends are in apposition with the ectoderm, and in the case of the second to the fifth the place of apposition is in the upper part and floor of the cervical sinus. These ducts soon lose their connection with the pharynx, this process starting caudally and then later involving the third and second pharyngeal ducts. With the loss of the pharyngeal connections buds of entoderm are left enmeshed in the mesenchyme of the neck. At the same time the second arch fuses with the thorax and the ectoderm lining the cervical sinus disappears. These changes are completed by the end of the first month of intrauterine life.
Fig. 5. A schematic representation of the gill arches (vertical hatching), the branchial depressions (clear slits with dotted margins), the relations of the nerves (solid black). V.C. is the. cervical sinus, and the scheme shows its connections with the entodermal depressions. (After Moatti.)
From these discrete entodermal remnants organs of great interest are formed. The tonsil arises from the extremity of the second duct. The blind end of the third forms a dorsal and a ventral part. The dorsal part becomes one pair of parathyroids while the ventral becomes thymus. The fourth behaves in a similar manner, but in Man the ventral contribution to the thymus seems to have dropped out.
The apex of the first depression is found in the middle ear at the tympanic membrane. The last forms the ultimo-branchial body and can be traced for some time in the lateral lobe of the thyroid gland, from which it can always be distinguished. It disappears finally without forming any part of the thyroid.
The Eustachian tube is supposed to represent the first cleft, the supratonsillar fossa a remnant of the second, the piriform sinus the third above the superior laryngeal, and the fourth below this nerve.
The thyroid arises from the median entoderm of the pharyngeal floor anteriorly just behind the stomodeal membrane on a level with the first arch, and grows ventrally and caudally. In its growth it undergoes some caudal displacement, and from being ventral and in front of the hyoid arch it comes to lie dorsal to this, thus bringing the thyroglossal tract dorsal to the hyoid bone. From the blind extremity of the tract epithelial cords are first produced. Then these become broken up and colloid appears in the columns which become transformed into vesicles.
The Neural Crest and the Branchial Region
This presentation of the development of the branchial region has followed orthodox lines, but there are a number of facts and observations to be mentioned which should convince us that the whole of the truth is not to be compressed — into any merely schematic arrangement. Useful such may be for making a complicated process intelligible, useful in giving a general idea of the anatomy of the anomalies of this region, but it leaves out the more dynamic aspects of pharyngeal growth and development.
There are a large number of observations on lower vertebrates, on the monotremes, and on Mammals and Man which have drawn attention to the relatively enormous mass of neural crest tissue which is proliferated in the region of the hind-brain, to the extensions and migrations which this undergoes, and its apparent metaplasia into a form resembling mesoderm. For this reason it is termed mesectoderm. The suspicion that this tissue of ectodermal origin took some part in the formation of the branchial region was put to experimental test. Excisions of this material in the Amphibia and a study of the resulting defects in growth have shown quite clearly that the branchial skeleton is derived from material which belong to the neural crest.
This applies to the lateral portions of the branchial skeleton. The median part of the neck has a different origin. This part of the neck is derived from tissue belonging to the pericardial region. This has recently been confirmed by Fraser in the study of the human embryo, for he has traced the origin of the middle line of the neck from the epicardial tissues. As a matter of fact, only the first and second arches approach the middle line of the neck, the third and fourth are displaced laterally: i.e. the part of the neck most affected by the branchial arches is in the submandibular region. It is possible that this metaplasia and differentiation of ectodermal tissue into a cartilaginous skeleton is due to induction by pharyngeal entoderm.
Fig. 6. A sagittal section of a rabbit embryo illustrating how the median tissues of the neck are formed from a prepericardial (p.th.) lamina that extends up to the cervico-facial angle (a.c.v.). (After Vialleton.)
Fig. 7. A is a drawing of the state of the branchial cartilages from a specimen in which nearly the whole of the neural crest had been removed eighteen days previously. Only three small cartilages appear on the operated side. B is a section of a similar specimen at the level of the optic vesicles showing the relative sizes of the quadrate when the neural crest is removed onone side. (L. 8. Stone.)
Further Remarks on the Branchial Development
The branchial region is a very fleeting affair. While the more caudal arches are being formed the more cranial ones are disappearing. Their very existence is evanescent, for the invasion of mesodermic tissues soon makes them unrecognisable. The coincidence between the internal and external depressions is soon lost, and the arches as such have disappeared before the cartilaginous skeleton has appeared. The aortic arches are never definite vessels in the human embryo. They form only a capillary net in which the blood flow through them is made difficult by other factors. Again these vascular arches are never present simultaneously, the cranial ones having gone before the caudal ones have appeared.
The temporary nature of these arches and depressions, the quick changes induced by the invasion of mesoderm make difficult the precise interpretation of the later events in the anatomy of the neck. Fraser has drawn attention to the inaccuracy of the orthodox description that limits the Eustachian tube to the first cleft. Further, he has shown that the cervical sinus is a much more restricted affair than is usually supposed. The pillars of the fauces and the supratonsillar fossa usually regarded as parts of the second arch, the second entodermal depression, and the third arch are regarded by some as altogether secondary and not truly related to the branchial system.
Just as the morphological results of branchial development fit uneasily into our teaching schemes, so also is its potency for developing organs not so focal as these schemes suggest. Not only is there aberrant tissue associated with the usual organs derived from the entoderm, as indeed there is with all organ development of the body, but an appeal to comparative anatomy shows a wide variation in the origin of the various derivatives. The pituitary is generally regarded as being of ectodermal origin starting immediately in front of the dorsal attachment of the membrane that separates the mouth from the pharynx, but in marsupials and other species Watson found that it was, in part at any rate, of entodermal origin, and this variation is common in lower vertebrates.
In some of the lowest vertebrates (Petromyzon) every branchial depression forms a thymus, and throughout the vertebrates there is the greatest variation in its mode of origin. In Reptiles and Birds, for instance, it comes from the dorsal element of the thymopharyngeal duct, while in Mammals it comes from the ventral.
These variations are to be interpreted as evidence of the general potency of the pharyngeal entoderm.
The complicated method of development which occurs in the neck affords a strong presumption that inclusions of entoderm and less commonly of ectoderm in unusual positions would be a common matter. In addition to the processes already alluded to, the migration of premuscle tissue and the constricting effect of the loop around the arches formed by the hypoglossal nerve afford additional causes for displacement.
The estimation of the frequency of displaced elements entails a laborious investigation, and the few attempts which have been made give discordant results. Some have claimed that heterotopia is no more frequent in the neck than elsewhere, while another has recorded the frequency of such inclusions as twenty-six in fifty-five investigations.
In addition to such inclusions and displacements of embryonic material, there exists also in the neck vestigial organs like the ultimobranchial bodies. The proper fate of this body is to disappear about the seventh month of intra-uterine life, but observations have been published in which it is stated that this organ persists and forms cysts containing a colloid-like substance and also assembling tissue about it with a structure like that of the thymus.
Clinical experience encounters not only fistulae but also cysts which may become papilliferous and invasive and in which colloid may be found and also lymph nodes and Hassall’s corpuscles, and even cartilage may occur.
Histological investigation has disclosed the fact that displacement, persistence, and metaplasia are not infrequent associations of the developmental process in all parts of the body. There seems to be some evidence that these events are common enough in the neck, but no reason for believing that they are more likely to persist or become invasive here than elsewhere in the body. This seems to suggest that the control of the behaviour of these heterotopic tissues resides elsewhere than in the displaced tissues. The frequent presence of lymph nodes and Hassall’s corpuscles has suggested to some that it is always thymic tissue that is displaced. This kind of metaplasia is so frequent wherever entoderm interacts with mesenchyme that it should be regarded as a general phenomenon and not a specific attribution of the thymus.
It seems at the moment that any portion of the pharyngeal entoderm may be the source of an aberrant entodermal inclusion, and any such inclusion, if it grows, is likely to assume a cystic papilliferous form and excite a lymphoepithelial reaction. This again we would attribute to the special quality of the entoderm of the pharynx.
Possible Functions of the Pharyngeal Entoderm During Early Embryonic Life
In addition to furnishing several well-known ductless glands, the suggestion has been hinted occasionally that perhaps the pharyngeal entoderm has some inducing action during the early development of the embryo. No proof can be advanced at the present moment, but perhaps the idea is worth investigation.
At any rate it is unwise to regard the transformations of the branchial region as being merely of historical interest. A branchial region occurs in all vertebrates, but only in the Icthyopsida (the Fishes, and Amphibia) do they function as respiratory organs. Some have gone so far as to deny their evolutionary significance if they function only in such a small fraction of the vertebrate kingdom. Kranichfeld has suggested that some embryonic functions reside in the pharyngeal region. He brings some general arguments, but specifically suggests that the so-called epibranchial placodes may be such embryonic organs. These are cell accumulations occurring along the dorsal extremities of the arches in association with the seventh, ninth and tenth nerves. It is generally supposed they form the lower of the two ganglia to be found on these two nerves, but their precise origin and function have not yet been determined.
Pende has described a series of epithelial structures found in the neck tissues. of later embryos and distinct from the known glands of the neck. His histological studies of these organs led him to suggest that they might function as embryonic organs. His anatomical observations have not, however, been confirmed by anybody. It is, however, true that one does encounter organs of an epithelial nature in the neck in later embryos which are distinct from the known glands, which have all the appearances of active structures and not those of degenerating ones.
On general grounds it might be supposed that the higher vertebrates would base their more complicated development on a larger series of inducing organs than the simpler vertebrates, and the pharyngeal entoderm is the most likely place to look for them.
The Function of the Pharyngeal Entoderm in Later Embryonic Life
Dependence of foetus on its own ductless glands
The anatomist naturally wishes to formulate some general notion of the significance of the endocrine organs derived from the pharyngeal entoderm.
The activities of the endocrine glands have been classified in various ways, but broadly they can be considered as either morphogenetic or physiological. At the very outset one is confronted with the difficulty that it is not always possible to distinguish structurally those elements which form morphogenetic secretions and those which have regulatory functions, and indeed it is possible that one and the same substance may do both.
In trying to get some idea of the réle of the morphogenetic secretions in determining the growth and form we can appeal to the order and mode of the development of the vertebrate body as outlined above. Further, we can apply Child’s law of gradients, for development does pursue a cranio-caudal progression and there is some evidence that the physiological gradient slopes in the same way.
The pituitary belongs to the prechordal region which we have seen is the oldest part of the vertebrate body and the first to be developed, and since this has an inductive effect on the later growth centres and indeed gives rise to an organiser that induces the formation of notochord, medullary plate, somites, pronephros, etc., we might expect to find that the pituitary plays a dominant réle both in regard to its morphogenetic action and its control of the later ductless glands. Therefore the order of appearance of these glands and the inception of their activity become of some interest.
It might seem at first sight that amongst placentals the embryo would have no need to invoke its own ductless glands, for the maternal circulation would supply these secretions if necessary to development, and indeed there is some clinical evidence that insulin passes from the foetus to a diabetic mother. Also the sporadic cretin or, perhaps better, infantile myxoedema, the athyreotic type, which appears not earlier than three months after birth, might be regarded as having subsisted on the secretion of the maternal thyroid before birth.
Nevertheless we have the broad fact that endocrine organs are peculiar to a fragment of the animal kingdom, namely the vertebrates. Their existence amongst the invertebrates has never been proved and all the evidence is to the contrary. In the group of vertebrates it is only amongst the Mammals the possibility of interchange of these secretions occurs. In the Fishes, the Amphibia, the Reptiles and the Birds, the development of the embryos must proceed in the absence of maternal hormones. Experimentally McCleod has found no evidence in dogs that insulin passes from the foetus to the mother. Furthermore, these secretions are non-specific, and the fact that a sample from any vertebrate will affect any other vertebrate suggests that their developmental réle would be the same in them all. On general grounds an interchange seems improbable, for it would be necessary to imagine a mechanism that let through some and not others, that regulated the amount passed through, and became active at only the appropriate time. Despite the difference in the degree of response to thyroid treatment between the endemic and sporadic cretin, yet in both the thyroid defect is the most important fact and endemic cretinism arises in utero. Sporadic cretinism is better understood by regarding the term athyreotic as relative and not absolute, and the time of onset as being indicative of the degree of anaplasia. Finally we might urge that if the foetus receives its hormones from the mother there would be reason to suppose that they might not develop at all, for a resected thyroid does not hypertrophy if the hormone be administered. Thus we would conclude that the foetus does not receive its hormones from the mother.
Activity of Ductless Glands During Development
It is not altogether certain that the endocrine organs assume their activity during foetal life. The pituitary comes into being as an embryological structure when the embryo is 2-5 mm. in length, while the evagination of the floor of the third ventricle appears at 10-5 mm. (the seventh week). According to Erdheim, eosinophile cells appear in the embryo when 29 cm. in length, and basophile cells just before or after birth. Hammar has placed the appearance of eosinophile cells as early as the 20 to 25 mm. stage, but this needs confirmation.
The thyroid appears very early when the embryo is between 2 or 8 mm. in length. The degeneration of the thyroglossal duct, the formation of follicles and the appearance of colloid have all been followed. Colloid appears when the embryo has reached a length between 25 and 40 em.
The histological evidence of activity has been supplemented by experimental enquiry. An extract of the glands has been obtained by rubbing up the glands from foetal pigs and testing this on tadpoles. The results obtained by this and similar methods have been somewhat discordant. Hogben and Crew’s results agreed well enough with the histological evidence, and they concluded that these glands became active during the second half of pregnancy—at four months in the calf and at the third month in the sheep.
Fig. 8. A drawing of a median section of the amphibian larva to show the position of the pituitary anlage (black) and the site of the incision for its removal (dotted line).
Dominance of Pituitary
The evidence obtained from experiments on the Amphibia is far more satisfactory and conclusive. Ablation experiments on amphibian larvae show definitely that even the earliest stages of development of the pituitary are essential for the development of the thyroid gland. The secretion of the anterior lobe of the pituitary must be present in the blood or development of thyroid docs not take place. The buccal outgrowth of the pituitary includes the pars anterior, the pars intermedia and the pars tuberalis. The operation does not touch the pars nervosa. This does appear when the buccal anlage is removed, but its development is abnormal and retarded compared with the normal. Should, however, any part of the pars buccalis be left by the operation, then the development of the pars nervosa becomes normal. Thus we conclude the development of the pars nervosa depends on the pars buccalis.
The effect on the thyroid of removal of the buccal outgrowth is to reduce its size to about one-sixth of the normal and it does not form or store colloid. Further, the metamorphosis does not occur in the absence of the buccal outgrowth. Such tadpoles can be got to metamorphose in two ways, one by feeding them with thyroid preparations or implanting the pars anterior. The pars intermedia has no effect and the pars tuberalis has not been tried. With the implantation of the pars anterior the power of the thyroid to store its colloid is regained. The hypophysis without the thyroid is powerless to induce metamorphosis. It is therefore concluded that, whatever be the réle of the hypophysis, the secretion it forms works in co-operation with the thyroid and induces metamorphosis. The mode of co-operation is not a nervous one.
It is to be noted that amongst other effects induced by ablation of the buccal anlage is retardation of growth. Thyroid ablation does not stop the growth of tadpoles though metamorphosis does not occur. Evans got thyroidectomised ' rats to grow by giving them intraperitoneal injections of pars anterior, and concluded that cretinism in rats was due to a dysfunction of the hypophysis and thyroid. This point may be of clinical interest. Growth in tadpoles can be induced by the pars anterior in the absence of the thyroid.
From these amphibian studies it can be concluded that the pituitary and the thyroid are responsible for the continuance of development from a certain point onwards, this point being characteristic of each species.
These studies at any rate suggest that the dominant endocrine is the pituitary and not the thyroid as is generally asserted, and that the inference from its situation in the prechordal growth centre is not without significance in interpreting its rdéle in development.
The Relationship Between the Morphogenetic and the Physiological Secretion
The pars anterior with its eosinophile cells is the seat of the growth hormone of the pituitary, and at the same time it exerts an inducing effect on the pars nervosa, At the moment we need not discuss the problem as to whether it is the hypothalamus or the pars nervosa that exert the physiological effects of this region. Suffice it to say that comparative anatomy is in full accord with the present ideas centring round the hypothalamus. We can agree that the pars anterior is the growth-promoting element and the inducer of the thyroid activity, that the pars intermedia both on histological and experimental grounds is probably inactive. Nothing is known about the pars tuberalis at the moment.
The idea suggests itself that the vertebrate in adopting the hormonic method of growth first began with the morphogenetic elements and then met the physiological demands so engendered by the development of necessary catalytic and stimulating hormones. In some way like this the warm-blooded vertebrates came into being. The twofold réle seems clear enough in the case of the pituitary, but it is not easy to understand in the case of the thyroid.
It is true that the idea of a double secretion in the case of the thyroid has occurred to several. It is not difficult to imagine, though as yet impossible to prove, that the colloid is the morphogenetic secretion, while the follicular cells directly secrete into the blood stream the substance that elevates the metabolic rate. Histological evidence of this twofold activity has been presented by Bensley. There is some clinical evidence that exophthalmic and myxoedematous symptoms may occur in the same patients.
There is also the extremely interesting fact that thyroid preparations have no effect on the adult frog. There is some evidence of a rise in metabolic rate during metamorphosis, but after this event no effect can be discerned. We must suppose that the metabolic effect is acquired later in evolution presumably amongst the extinct Mammal-like Reptiles.
I would say nothing about the parathyroid, as its réle seems to be primarily physiological—acting as a stimulant of the osteoclast. From the work of Dott and Fraser we can assign a place to these several glands in accordance with their relation to the cells of bone. They observed that the cartilage cells were unable to maintain themselves in the absence of the pituitary, while if the thyroid was removed the cartilage cells persisted but did not multiply. The parathyroid comes into bone formation at a later stage, that of modelling. Thus the craniocaudal situation of these organs has a corresponding sequence in their action on bone formation.
The Lympho-Epithelial Elements
The tonsil and the thymus both represent an interaction in which entodermal activity induces secondarily a local or immigrant accumulation of lymphocytes.
These are so often absent or developed so variously in position, and this applies particularly to the thymus, that no phylogenetic significance can be attached to them.
All experimental evidence, whether derived from high or low vertebrates, fails to attach any specific function to them. The very behaviour of the entoderm, viz. its tendency to form Hassall’s corpuscles (and these are found occasionally in the tonsil) does not afford any ground for expecting secretory activity.
The role of the lymphocyte is obscure. In allocating a defensive reaction to them the behaviour of lymphatic endothelium and of the reticulo-endothelial elements associated with them is often forgotten. It would seem that all lymphocytes, whether belonging to the haemolymph system or to the lymphoglandular or the epithelio-lymphatic, are the same morphologically and physiologically. They do not put out pseudopodia, they are not phagocytic, they contain no special granules and liberate no ferments as do the granular cells of the blood. On the other hand, they are all extremely sensitive to irradiation and respond quickly to slight changes such as dietetic defects. They can accumulate in any organ.of the body that undergoes atrophy or regression even if this be the usual fate of the organ. They, of course, accumulate at the periphery of carcinomata, disappearing where they have been surrounded by the growth. In experimental transplantation lymphocytes accumulate about the transplant if its constitution is the same or very nearly the same as that of the host. On the other hand, if the two be widely different then the polymorphonuclears accumulate.
They are generally supposed to be protective and resistive, but the evidence seems equivocal and might just as well be interpreted in the opposite sense. Morphologically, being composed almost entirely of nucleoproteid, they resemble in this the heads of the sperm. That they might produce trephones or growthpromoting substances was suggested by Carrel. By analogy it might be suggested that they promote cell division. At present nothing is really known about their functions.
We have attempted in this essay to set forth briefly a theory of development which is founded on the study of comparative embryology. Such comparative studies have shown that the vertebrate body is laid down in three growth centres which succeed each other both chronologically and topographically. The antecedent centre is in general dominant over and exerts an inducing or organising effect on the region which follows it.
The pharyngeal entoderm lies at the junction of the first and second growth centres and it plays a large rdle in the induction process. This is the real meaning of the complicated series of changes that it undergoes. It is suggested that it functions as an organising region in the early stages of development, and that this may be the meaning of some of the structures developed there which have only a transient existence. Its functions in the later stages of development are made manifest by the ductless glands which arise from it.
Since the pituitary belongs to the first growth centre and the thyroid to the second it follows from this theory of the mode of growth of the embryo that the pituitary should be dominant over the thyroid. The evidence obtained from the comparative physiology of the ductless glands is used to show that this is so, and that the thyroid fails to function without the co-operation of the pituitary.
The allotment of such an important part in development to the pharyngeal entoderm endows its cells with special potencies, and in the course of this essay the manifestation of these potencies on the development of the neck, on the transformations of the neural crest in the hind-brain region, and on the pathology of the growths of this region and the behaviour of aberrant tissues are mentioned.
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