Paper - Early Stages of Human Development

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Hamilton WJ. Early stages of human development. (1949) Ann R Coll Surg Engl. 4(5): 281-94. PMID 18121228 PMC2238331

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This 1949 historic paper by Hamilton describes the earliest stages of development following fertilisation.

Also by this author: Hamilton WJ. Boyd JD. and Mossman HW. Human Embryology. (1945) Cambridge: Heffers.

Modern Notes:

Week 1 Links: stage 1 | stage 2 | stage 3 | menstrual cycle | fertilization | zygote | morula | blastocyst | Lecture - Fertilization | meiosis | mitosis | Lecture - Week 1 and 2 | menstrual cycle | oocyte | spermatozoa | twinning | Genetic risk maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | hydatidiform mole | GA week 3

Week 2 Links: stage 4 | stage 5 | stage 6 | Lecture - Week 1 and 2 | implantation | trophoblast | human chorionic gonadotropin | pregnancy test | twinning | Category:Week 2 | GA week 4

Stage 1 Links: Zygote | Week 1 | Oocyte | Spermatozoa | Zona pellucida | Mitosis | Genetics | Human Genome | Mitochondrial Genome | Lecture | Medicine Practical | Science Practical | Stage 2
Historic Papers  
1919 Human Ovum | 1944 Ova Maturation | 1944 In vitro fertilization | 1949 Early Ova | 1966 Pronuclear Stage | 1986 human oocytes in vitro

Stage 2 Links: Week 1 | Morula | Blastocyst | Mitosis | Zona pellucida | Lecture | Medicine Practical | Science Practical | Next Stage 3
  Historic Papers: 1956

Stage 3 Links: Week 1 | zona pellucida | blastocyst | trophoblast | mitosis | Lecture | Medicine Practical | Science Practical | Blastocyst Day 3-6 Movie | Next Stage 4
  Historic Papers: 1954 | 1956

Carnegie Embryo - 8663, 8794

Stage 4 Links: Week 2 | Implantation | | Trophoblast | Human Chorionic Gonadotropin | Lecture | Practical | Category:Carnegie Stage 4 | Next Stage 5
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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Early Stages of Human Development

William James Hamilton (1903-1975)
William James Hamilton (1903-1975)

Professor W. J. Hamilton, M.D., B.Sc., F.R.S.Ed.

Anatomy Department, Charing Cross Hospital Medical School.

Lecture delivered at the Royal College of Surgeons of England on 31st July, 1947.


In 1899 Peters described an early human ovum in which the vili were in the process of formation but the primitive streak had not yet appeared. The specimen was estimated by Peters to be about 3-4 days old. This estimate is obviously incorrect in the light of present-day knowledge; it is now considered to be about 13 days old. At the time of its discovery it represented the youngest known stage of human development.

In 1906 Leopold described a specimen which was younger than the Peters ovum, but no embryonic rudiment was present. Later stages of development were described by Beneke (1904) and Jung (1908); these stages confirmed the appearances in the Peters ovum but did not amplify our knowledge of early human development. Bryce and Teacher (1908) described the early development and implantation of a human ovum (T.B. 1). They estimated that the ovum was 13-14 days old (more probably11days). The detailed structure of this ovum is well known (see Bryce,1924, and Teacher,1924). It is now recognised by many embryologists as being pathological. At the time (1908) when first described it was considered to make a definite contribution to our knowledge of human embryology. In 1913 Miller gave a brief description of an early human embryo found in fragments of the endometrium after curettage for the relief of dysmenorrhcea. Unfortunately, only five sections were preserved. A fuller description of this ovum was given by Streeter in 1926. The histological preservation was good and the embryo was estimated to be about 11 days old. For details of other ova previous to this date, reference should be made to the monographs of Bryce (1924) and Streeter (1926).

In 1930 Allen et al. succeeded in obtaining five unsegmented ova by reverse irrigation of the uterine tube from the uterus. Since that date a number of investigators have obtained unsegmented living tubal ova. For details and literature the reader is referred to the publications of Hamilton (1944) and Rock and Menkin (1944) and Rock and Hertig (1948).

A well-preserved embryo, aged about 11days, was described by Stieve (1936) and an almost complete embryo was described by Dible and West in 1941. However, the outstanding contribution to our knowledge of human development from 74-16 days has been made by the researches of Hertig and Rock (1941, 1944 and 1945) and Rock and Hertig (1942, 1944 and 1948). Other early human embryos have recently been described by Hamilton etal.(1945), Davies (1944), Marchetti (1945) and Heuser et al. (1945).

Unsegmented Eggs

Soon after ovulation the ovum with its surrounding corona radiata passes into the uterine (Fallopian) tube. (Fig.1.)

A number of unsegmented ova at this stage have been described (see Hamilton, 1944, Rock and Hertig, 1944, for literature). The corona cells are loosely applied to the zona pellucida. In the living egg the zona has a homogeneous appearance and is closely applied to the vitelus. After fixation and staining, the zona undergoes a contraction and appears bluish-pink when stained with haematoxylin and eosin (Stain - Haematoxylin Eosin). The vitellus in the recently ovulated living egg is yellowish in colour, uniformly granular, and does not have a polar distribution as occurs in some other mammalian eggs. In ova which are undergoing degenerative changes coarse and fine granular zones become evident in the vitellus (see Rock and Hertig,1944). In the living human ovum the nucleus is not visible by transmitted light. By the time of ovulation the nucleus is at the stage of the second maturation division and can be seen in sectioned material. (Fig.2.) It cannot be stated at present whether the second maturation division is completed in the absence of fertilization, but it is probable that this division is not complete in the absence of fertilization and in this respect the human ovum agrees with what is known to occur in most mammalian eggs.

Fertilized Ova

An ovum at an early stage of fertilization was described by me in1944. It shows sperms passing through the zona pelucida. (Fig.3.) A second ovum with pronuclei was recovered on April3,1944. It was found on the 17th day of the menstrual cycle. (Fig. 4.) In vitro fertilized 2-3 cell stages were described by Rock and Menkin (194). When these ova were examined after incubation two blastomeres of" fairly uniform size and appearance" were found in two specimens and three blastomeres in a third. From the examination of one of the sectioned ova it is evident that the cells are undergoing degenerative changes. An abnormal segmenting ovum was discovered by me on January 1, 1944, after flushing the uterine tube on the 18th day of the menstrual cycle. It consists of a group of small cells (?) in one half of the zonal cavity and a large cell in the other half. (Fig.5.) When sectioned and stained it was evident that the small cells(?) had undoubtedly been derived from one of the first blastomeres by fragmentation. The other blastomere was also undergoing degenerative changes. Rock and Hertig (1948) have recovered three segmenting ova, one consisting of eight blastomeres and assumed to be about 72 hours old; another consisting of nine blastomeres is probably 84 hours old and may be abnormal; the third has 12 blastomeres and is probably normal, but no details have yet been published about this egg. It is deduced from this material that the duration of cleavage in the human ovum occupies 72 hours. Stages between that of the 12-blastomere stage and the 7.5-day partially implanted embryo described by Hertig and Rock (1945) are unknown.

Implanting Ova

It is estimated that the human blastocyst becomes attached to the endometrium on the sixth day after ovulation. The youngest stage of implantation yet described (Rock and Hertig, 1942, 1945) is superficially implanted and is only partially covered by maternal endometrium. The blastocyst consists of the trophoblast and embryonic (inner cell) mass.

(Fig. 6.) The trophoblast varies from a thick proliferating disc of syncytioblast and cytotrophoblast adjacent to the embryonic mass and a thin mesothelial-like layer at the abembryonic pole. This latter layer has not yet penetrated into the endometrium and so depicts the structure of the wall of the blastocyst before implantation. The mesothelial-like layer is collapsed and applied to the surface of the embryonic mass. Trophoblastic cells at the edges of the proliferating disc and in contact withthe maternal tissue are hypertrophied but with the cell boundaries distinct. The cells over the embryonic mass are differentiating into " primitive" cytotrophoblast and syncytiotrophoblast, but lacune formation has not yet begun. The embryonic mass consists of a layer of polyhedral ectodermal cells and a layer of vesicular endodermal cells. Between the ectodermal cells and the trophoblast there are two clefts which represent the primordium of the amniotic cavity. Amniogenic cells are being delaminated from the cytotrophoblast in the region of the embryonic mass.

The next known stage of human development is shown by the Hertig and Rock embryo (No. Wi 8004) which is estimated to be about 91 days after ovulation. The blastocystismorethantwo-thirdsimplanted intotheendometrium. The entire trophoblastic wall has undergone proliferative changes; these, however, are more prominent on the embryonic than abembryonic wall. (Fig.7.)

Numerous and irregular slit-like lacune are developing in the deeper parts of the syncytiotrophoblast. Many of the lacune contain maternal blood and intercommunicate and thus constitute the beginning of an intervillous circulation. The junction between the syncytiotrophoblast and the maternal tissue has an irregular contour, due to the invasion of the later by pseudo-podial outgrowths from the former. The embryonic mass is composed of a bilaminar disc of columnar ectodermal cells and a cap of endodermal cells. The amniotic cavity is beginning to form. Mesodermal cells are differentiating from the inner aspect of the cytotrophoblast.

During the next three days (10, 11 and 12) the ovum becomes almost completely surrounded by the maternal endometrium. The defect in the uterine epithelium, caused by its penetration by the ovum, is gradually closed by a coagulum of fibrin and by the proliferation of the adjacent endometrial epithelium over the fibrin. A number of well-preserved ova have been described which show this stage of development (see Hertig and Rock, 1941 and 1945) and Hamilton etal.(1945) for literature. The syncytiotrophoblast, especially in the deeper parts, continues to proliferate rapidly and forms approximately three-fourths of the trophoblastic covering of the ovum. The peripheral part of the syncytiotrophoblast invades and absorbs the oedematous endometrial tissue and extravasated blood to make room for the enlarging ovum. The blood and maternal tissue so absorbed is a source of nutrition for the embryo and the membranes. Maternal capillaries are invaded by the advancing trophoblast so that maternal blood can readily flow into the enlarging lacune. The cytotrophoblast forms about one-quarter of the trophoblastic wall and for the greater part of its extent is made up of a single layer of cuboidal cells.

The embryo at this stage is composed of a bilaminar disc of opposing ectoderm and endoderm and is aproximately circular in outline. The longitudinal axis of the embryo is not yet apparent. The ectoderm is composed of columnar cells which are vertically arranged in respect to the horizontal axis of the embryo. At the edge of the embryonic disc they are continuous with the flattened amniotic cells. (Figs. 8 and 9.) Amniogenic cells are in the process of differentiating from the cytotrophoblast. The endodermal cells are of approximately the same extent as the ectodermal cells. Their relations vary considerably in the different embryos described. In the Hertig and Rock embryo No.7699 they form a mass of from one to three layers thick (Fig. 8), but in the Hertig and Rock embryo No.7700 they form a single layer.(Fig.8.) In the Barnes embryo (Hamilton et al., 1943) they are heaped up to form a layer several cells thick at one side of the embryonic disc.(Fig. 10.)

Hamilton1949 fig10.jpg

Fig.10. A general low-power view of the Barnes embryo stimated to be about 10.5 days old. The extent of the syncytio- and cytotrophoblast in the different parts of the vesicle is shown. The embryonic rudiment has differentiated into columnar ectoderm and embryonic endoderm, the latter is continuous with Heuser's membrane. The extra-embryonic mesoblast has been artificialy separated from the cytotrophoblast. X.C.

In addition to the embryonic mass the chorionic cavity is filled to a varying extent with primitive mesoblast, magma reticulare. This tissue is composed of stellate cells in the form of a network. The innermost layer of the mesoblast becomes condensed to form a mesothelial membrane or Heuser's membrane. At the edge of the embryonic disc this membrane is continuous with the endoderm. The space enclosed by the endoderm and mesothelial membrane is the primary yolk sac. (Fig. 11.) It will be seen that these cells lining the primary yolk sac have two distinct origins, cuboidal endodermal cells derived from the embryonic mass and mesothelial cells derived from the mesoblast. Within this primary yolk sac is a granular eosinophilic precipitate.

Hamilton1949 fig11.jpg

Fig. 11. Diagram to show the development of the amniotic cavity and primary yolk sac

There has been much speculation and conjecture concerning the origin of the primitive mesoblast. Hill (1932) and Florian (1933) were of the opinion that this mesoblast is precociously developed allantoic mesoblast, as in Tarsius, and that it arises from amniotic ectoderm posterior to the site of the future cloacal membrane. Inthehuman subjectitdevelops before the appearance of the primitive streak. The extensive investigations of Hertig (1935) Wislocki and Streeter (1938), Heuser and Streeter (1941), Hertig and Rock (1941 and 1945), seem to point to its origin from the inner aspect of the cytotrophoblast. At the abembryonic pole where the trophoblast is least differentiated the cytotrophoblastic cells are unevenly arranged and appear to be intimately connected with the delaminating mesoblast. In many places the processes of the peripherally placed stellate mesoblastic cells are continuous with the cytotrophoblast.

During the next few days a number of important changes occur in the chorion and embryo. The syncytiotrophoblast lining the lacunar spaces and covering the cytotrophoblast now forms the greater, part of the chorion. Syncytial streamers from the trophoblast pass into the endometrium. Outgrowths of the cytotrophoblast occur and form the primary vili. These vili later form the cytotrophoblastic columns. Soon a core of mesoblast appears in each primary villus to convert it into a secondary vilus. The chorionic mesoblast which is increasing in amount is soon separated into somatopleure and splanchnopleuric layers by the appear- ance of the extra-embryonic ccelom. (Fig. 12.) The splanchnopleuric layer forms the outer layer of this secondary yolk sac. In the Marchetti embryo, estimated to be about 13 days old, the extra-embryonic coelom has not yet appeared, while it is well formed in the Carnegie embryo No. 7801 (Heuser et al.) estimated to be about 13+ days old.

Hamilton1949 fig12.jpg

Fig.12. Diagram to show the development of the secondary yolk sac, extra-embryonic coelom and remnant of the primary yolk sac

As a result of axial differentiation the embryonic disc becomes oval in outline,the long axis being in the antero-posterior axis of the embryo. The axial differentiation is due to the appearance of the primitive streak at the caudal part of the disc. (Fig. 13.) Cells from the primitive streak proliferate as a down growth between the ectoderm and endoderm. At the anterior end of the primitive streak Hensen's node soon differentiates and gives origin to the head process. The amniotic cavity increases in size and is now composed of a layer of flattened cells covered by coat of mesoblast. The primary yolk sac of the earliest stage becomes transformed into a secondary yolk sac as the result of the appearance of an inner layer. The secondary yolk sac is relatively smaller than the primary yolk sac. The cells of this inner layer resemble those of the embryonic endoderm and are continuous with it; whether these cells are derived from the embryonic endoderm by migration or by differentiation from the mesothelial cells of Heuser's membrane is still in doubt. The distal part of the primary yolk sac may become detached from the proximal part with the expansion of the extra-embryonic coelom and in many embryos forms an isolated vesicle in the extra-embryonic ccelom. (See Bryce, 1924, and Heuser et al., 1945, for literature.)


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Hamilton WJ. Early stages of human development. (1949) Ann R Coll Surg Engl. 4(5): 281-94. PMID 18121228 PMC2238331

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