Paper - A study of the causes underlying the origin of human monsters 4
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Mall FP. A study of the causes underlying the origin of human monsters. (1908) J Morphol. 19: 3-368.
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A Study Of The Causes Underlying The Origin Of Human Monsters
Experiments with Salts of Potassium and Changes or the Embryo Especially marked in the Heart
In case interference in the nutrition of the embryo is not too great the growth of part of the embryo, instead of all of it, may be retarded, with an additional destruction of tissue, thus producing the partial monsters in man, which, frequently develop to full term. However, there is every kind of gradation between total and partial monsters, the former often showing many indications of the latter and the latter are frequently multiple. A total monster may have spina biﬁda, hare-lip, anencephaly, club-foot, cyclopia, etc., and a partial monster may include several of these types. The primary affection which is to produce a pure spina biﬁda in man must be slight, must come at the right time, and subsequently the faulty implantation must be remedied so that the embryo may continue to grow. In order to make my standpoint clear I shall ﬁrst give some data regarding the frequency of some types of monsters as well as some experiments which show that the heart is extremely susceptible, its growth being easily retarded and often arrested after the embryo is well formed.
‘Von Winckel, Ueber die menschl. Missbildungen, Samml. klin. Vortréige, Leipzig, 1904.
Von Winckell has given us some data regarding 87 monsters obtained from 12,378 births in Dresden, that is, there was one monster in every 142 children born. He also states that there were 105 monsters in 20,000 births in Munich, or I to 190. The most marked deformity in each of the 87 Dresden cases number as follows:
Deformities of the head . . . . . . . . . . . . . . . . . . .. 23
Deformities of the face . . . . . . . . . . . . . . . . . . . . I2
Deformities of the neck . . . . . . . . . . . . . . . . . . . . 4
Deformities of the abdomen . . . . . . . . . . . . . . .. 7
Deformities of the back . . . . . . . . . . . . . . . . . . . . 3
Deformities of the upper extremity . . . . . . . . . . 9
Deformities of the lower extremity . . . . . . . . .. I7
Deformities of the skin . . . . . . . . . . . . . . . . . . . . II
Deformities of other organs . . . . . . . . . . . . . . .. I
I have compiled a similar table from Panum,2 who gives data obtained from Otto and from Meckel. It is as follows:
Total number Number of of monsters. cases.
Anencephalus . . . . . . . . . . . . . . . . .. 618 II9
Anencephalus (according to Bal lantyne . . . . . . . . . . . . . . . . . . . . . 325 46
Hydrocephalus . . . . . . . . . . . . . . . . .. 618 26
Hydrocephalocele . . . . . . . . . . . . . .. 618 93
Hare-lip . . . . . . . . . . . . . . . . . . . . . . . 618 77
Cyclopia . . . . . . . . . . . . . . . . . . . . . .. 618 I6
Eyes missing . . . . . . . . . . . . . . . . . .. 618 9
Deformed upper jaw . . . . . . . . . . . .. 618 3
Deformed extremities . . . . . . . . . . .. 618 II 5
Spina biﬁda . . . . . . . . . . . . . . . . . . . . 404 38
In my collections of I63 pathological embryos there are 48 which show deformities which can easily be recognized as similar or as being forerunners to foetal monsters. In 27 of the embryos this deformity is limited to a single part of the embryo, as indicated in the table, but in 21 of them two or more malformations are present. They are as follows. Total number of cases, 48.3
'Panum, L c.
Atrophichead.......... . . . . . . .
Malformed face and neck . . . . . . . . . . . . . . . . . . . I7
Displaced eyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Deformed extremities . . . . . . . . . . . . . . . . . . . . . . 18
Spinabiﬁda...... . . . . . . . . . . . . . . . . . . ......I2
Exomphaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
In a general way the deformities in these 48 malformed embryos correspond pretty well in per cent with the type of monsters as recorded by Von Winckel and Panum. As shown in the table on page 43, seven pregnancies out of every
‘In order to make it possible to look up the histories of the embryos
given in this table I add the numbers of "the specimens which are included under each heading:
Aggggic Fﬁqcgcind Eye. Extremities. Spina biﬁda. Exomphaly. 12 no 135 81 6 115 60 122 201 94 I2 162 69 124 285 122 54 166 81 132 124 94 244
104 201 I32 135 364 I32 212 13 5 182 135 226 142 189 I37 232 177 226 177 246 200 251 182 251 230 293 189 276 232 364 200 297 251 365 201 330 316
207 343 325
212 357 343
226 364 344
276 365 357
IOO give pathological ova of which but one-third give well formed embryo monsters, or two per cent of all pregnancies. The number of monsters which go on to full term is about .6 per cent, and it is just this group which has escaped me. The embryo and foetal monsters form, therefore, 2.6 per cent of all pregnancies, or, in other words, three well-formed monsters are aborted in the early months of pregnancy for every one which goes on to the end of pregnancy.
It is clear that those cases in which the embryo is markedly deformed or is absent altogether, as is the case in about 100 of my specimens, cannot possibly develop for any great length of time, for without either heart or form they cannot exist. However, the second group of forty—eight embryo monsters show within themselves such radical changes that they also could not have existed much longer. In nearly all of them the heart is markedly changed, is atrophic or is wanting altogether. There are also many other changes, especially in the central nervous system, which makes it probable that they have lived as long as they could and were then ﬁnally aborted. In general, I think that the form of the monsters and their classiﬁcation show clearly that they are practically identical with those that grow into foetuses and then to full term, differing only in the degree of their changes. These are so radical in the embryo monsters that their lives are destroyed.
Teratologists have long ago observed that the heart must be affected more or less in monsters on account of the frequent oedematous condition of the tissues and of the excessive accumulation of ﬂuids in the serous cavities and in the amnion. In fact, a large per cent of monsters have hydrocephalus and hydramnios. These conditions are seen in many of my specimens and have been observed by experimental teratologists like Panum and Dareste. However, we now have some good experiments which throw some light upon this subject.
In 1893 Loeb made the brilliant discovery that the heart beat could be arrested in Fundulus by placing the eggs in a I. 5 per cent aqueous solution of potassium chloride shortly after fertilization. He found that the eggs develop in a pretty normal fashion with the exception that though the heart develops it does not beat at all. The blood-vessels develop properly as regards their course and division, but their lumina are irregular, like a chain of beads, which Loeb believes to be due to a lack of normal blood-pressure. Similar pictures may be seen in pathological human embryos, that is, only part of the vascular system is present, or the heart is atrophic but some of the blood-vessels are present, or the whole vascular system of the body is absent, with remnants of vessels in the yolk sac and in the chorion. In the last instance the vessels of the body may have been present at one time, for they should not have reached the chorion without passing ﬁrst through the body. The embryos in Loeb’s experiments rarely hatched, and all of them died before the sixteenth day, due to heart poisoning. Loeb thought that all of the organs-— brain, eye, ear and myotomes—developed without any marked anomalies, but I do not think that his experiments were extensive enough to test this point thoroughly. However, he states that the pigmentation of the yolk sac was aifected decidedly by the absence of the circulation. Under normal conditions the pigment, which is at ﬁrst evenly scattered over the yolk, wanders to the blood-vessels as soon as the circulation begins and stays there, forming pictures which correspond with the branching vessels. In potassium embryos where the blood does no.t circulate the pigment cells are not attracted to the blood-vessels, but remain scattered evenly over the yolk.
By extirpating the heart anlage from very young frog embryos Knower obtained a similar arrest in the development, but his experiments show that absence of the heart or early defects in its action produces marked abnormalities in the development of the embryos. While the earlier stages of the development of these frog embryos is normal, the later changes are arrested and strikingly abnormal. These embryos grow in an irregular fashion, become oedematous and the lymph vessels, blood-vessels and serous cavities are distended. Especially is the pronephros thus affected and the glomerulus distorted. The vascular system is much distended and very irregular, the chief vessels being laid down, though incomplete. The aorta and pronephric sinuses open into a mesenteric sac. The capillary system is imperfect or absent, blood corpuscles are relatively few and apt to be collected in the enlarged sinuses. Remarkable also is the role the lymph hearts play in such specimens. They continue to beat and pump the lymph containing some blood into the veins, and from their periphery it must pass again into the tissues. In connection with arrest in the development of organs the coiling of the intestines is limited to :1 single loop, the pancreas and liver are not normal, the subdivisions of the brain do not acquire their speciﬁc size and shape, the eyes are much aborted and the musculature is vacuolated. Knower obtained similar results from frog embryos developed in acetone chloroform, which inhibits the heart action from its earliest stages.
The recent experiment of Bardeen, in which he produced toad monsters by subjecting the sperm to the inﬂuence of X-rays before fertilization, may also bear upon the question of the importance of the heart in early development. “The eggs develop at ﬁrst apparently normally or even better than the control, but beyond the gastrula stage the development begins to become retarded, and at the time of hatching, as the tail begins to grow out, marked deformities begin to appear in the larvae.” The change takes place at the time the heart begins to function, for the vascular system was barely developed in any of the embryos experimented upon. The heart is rudimentary and may have no continuous lumen. The chief arteries and veins are incompletely developed. There are but few blood corpuscles in any of the embryos, and Bardeen‘ states that it is uncertain whether the blood had circulated at all in any of the embryos. In all of ‘them the spaces in the tissues indicate that there is a marked oedema. The mesenchyme is increased in amount, the cells being spread apart by the ﬂuids between them. Unfortunately for my purpose, Bardeen has not examined early stages of his monsters, nor has Loeb examined with sufficient care the later stages. If we keep Knower’s experiments in mind, we may think for the present that the changes in circulation in Bardeen’s experiments are primary, and the other changes, like irregular development of the nervous system, dropsy and hydrocephalus, are secondary, that is, due to the absence of the circulation. At any rate, Bardeen’s description of his “X—ray toads” corresponds in many respects with those I have given of pathological human embryos in earlier publications and in Part III of this publication.
It is also clear that the necrotic changes in the central nervous system of these larvae, as well as those in pathological human embryos, can be due to deﬁcient nutrition, but in order to produce a ﬁnished monster the nutrition must not be impaired too much. The heart may be poisoned somewhat, which in turn may aﬁect the central nervous system, causing histolysis and dissociation there, and the general development may be retarded and the embryo deformed, but as soon as the heart ceases to function all growth ceases and the embryos gradually disintegrate, as has been the case in about Ioo specimens out of my 169.
In very rare instances human embryos continue to develop to the end of pregnancy without a heart. Such a specimen must be one embryo of duplicate twins, with a common umbilical cord through which it may receive nourishment from its healthy brother. Quite early in development its circulation must be reversed in the descending aorta, for as soon as its heart stops blood enters the body through the umbilical arteries, which passes in a reversed direction up the descending aorta. Under these conditions all kinds of curious monsters develop, ranging from a single head without a body to a kind of teratoma known sometimes as a placental parasite. Of course, a “rescue” like this is out of the question in nearly all cases, and the life of the embryo is of short duration after its heart has ceased to beat.
Specimens similar to Bardeen’s and mine have often been found in chicks by Dareste and by Panum. Panum describes quite extensively the changes which take place in chick monsters. He recognizes in his classiﬁcation that ﬂattened monsters are of two kinds: (1) Anaemic ones, in which no blood is found, and (2) those in which red blood had been found but most of the vessels are retained in the area vasculosa. In these probably the vascular anlage was destroyed very early or it began in the area vasculosa and did not develop into the embryo. The result is similar to that obtained by Bardeen, Knower and myself.
It is clear, I hope, that certain parts of the embryo are more susceptible to insults than others, and thismust be admitted in order to explain why potassium stops the heart, lithium affects in a peculiar way the movement of the protoplasm in the blastomeres, and sodium produces spina biﬁda by arresting the movements which close the spinal canal. In order to analyze the situation we must concern ourselves mostly with simple reactions in their early stages, for they are not under way long before they become very complex and beyond our reach. Mesenchyme is less susceptible than nerve tissue, and the brain is more susceptible than the spinal cord; and so on. A susceptible tissue when affected undergoes certain morphological changes well recognized by Panum. Panum pictured to himself a kind of inﬂammation of the tissues, tparenchymatous, due to disturbances in the nutrition of the part, but it is by no means clear that anything like inflammation in the healing of wounds takes place in embryos or in the various tissues after they have become partly necrotic. Often it is noticed that cells accumulate in portions of the embryo, and His thought that they wandered out from the blood-vessels. In my former publications I spoke of these cells as the wandering cells of His. Hertwig and Bardeen speak of necrosis, and there is every evidence that destructive and not constructive processes are present in parts of the embryo which are becoming deformed. As this question is being investigated more and more it is clear that we must build up a pathology of our own based upon observations upon normal healing of wounds} etc., in embryos, just as Morgan was compelled to study anew the development of the frog in order to interpret properly the various malformed eggs he had under consideration.
I am quite certain that in the human embryo the cells may spread from the blood-vessels into the surrounding tissues after the heart has stopped, and I am also certain that mesenchyme cells may separate and segregate, and that the cells of the central nervous system may become necrotic in part, dissolve their connections and gradually ﬁll the central canal. It matters little what we call this process, it probably includes a series of processes, but for the present I shall apply to it the term dissociation. In doing this I do not commit myself as to the origin of a group of cells. In order to describe my human embryos properly I must also use the term maceration, and by it I mean that the process has taken place after the death of the part. When cells dissociate they are still alive, but they are on the way to meet their fate. As the tissues continue to grow their sharp borders are broken and they gradually become hopelessly confused. For the present the terms dissociation and maceration will do; in a short time it will be necessary to displace them, for experimental teratology will continue to be a fruitful ﬁeld of research.
- Loeb, Pfluiger’s Archiv, LIV, 1893.
- Knower, Anatomical Record, Amer. Jour. Anat., VII, 1907.
- ‘Bardeen, Jour. Ex. Zoolf, Baltimore, 1907.