Naturally, our main interest is to learn how we ourselves have once developed. How could information of the development of a mouse, or even of a frog or fly, help to understand human development?

The zoologist knows that human beings are members of the mammalian family of primates and, therefore, is not surprised to learn that early human embryogenesis exhibits considerable differences to that of mice, but shows only little differences to that of other primates. Self-evidently, disparities between the development of humans, frogs and flies are huge – in the final outcome. It is more astonishing that comparing embryonic development of forms such diverse as humans, frogs and flies discloses so many and fundamental commonalities. Modern molecular genetics has disclosed uncanny likeness and unexpected homologies. The common genetic basis will be dealt with in Chap. 12.

Experiments with model organisms introduced in the Chaps. 4 and 5 facilitated, or even enabled in the first place, the disclosure of many fundamental control mechanisms and genes involved also in human development. A pioneering finding was that many developmental malformations known to physicians since ancient times can be evoked in animal model organism experimentally. A classical historic example was the generation of “Siamese twins” in amphibians (see Fig. 13.​1). Further examples are the many known hereditary symptoms of diseases that in similar form can be evoked “in animal disease models” by targeted mutagenesis and genetic crosses.

Although laws, ethical and religious reservations forbid experimental interference, the development of man is the subject of morphological, histochemical, molecular and genetic investigations. For example, the pattern of gene expression can be studied with in-situ-hybridization (see Fig. 12.​5) in embryos lost from pregnant women. In addition to aborted embryos, living cells isolated from human teratocarcinomas are available for studies. The following description provides information on peculiarities of mammalian development in general and human development in particular, compared to traditional generalizing descriptions of animal development.

For a better understanding, the description of amphibian and avian development should be read first. On the morphological as well the molecular biological level many congruities have been found between mammals and amphibians, whose ancestors also gave rise to land vertebrates. And since a reptilian ancestor was inserted in the phylogenetic lineage leading from amphibian to mammalian ancestors, avian development can also confer information about our evolutionary heritage (zoologists conjoin reptiles and birds to a comprehensive taxon Sauropsida).

While still babies or embryos, girls store thousands of eggs which pause in meiotic prophase I for many years. Primordial germ cells (oogonia) destined to give rise to the next generation are generated and laid aside early in embryo development; they can be identified in the pre-natal female embryo in the 3rd week of development. By this time, the primordial germ cells immigrate from the yolk sac by amoeboid movements into the gonadal ridges (see Figs. 8.​3f and 15.​2). In the 5th month of pregnancy the female embryo harbours some seven million oogonia in her ovaries. By the 7th month of development the majority have perished. The surviving 0.7–2 million oogonia stop mitotic multiplication and become primary oocytes. These enter the prophase of meiosis I (Fig. 6.1) but pause at diplotene (Figs. 6.1 and 8.​4). There follows an interval lasting 12–40 years, in which lampbrush chromosomes and multiple nucleoli (Fig. 8.​5) may be present in oocyte nuclei (not firmly established for human oocytes). Much transcription takes place, many ribosomes are produced, and the oocyte is fed with yolk material by the surrounding follicle cells. Even the relatively small human oocyte undergoes a 500-fold increase in volume.

During childhood, many more oocytes perish. At puberty some 40,000 are left; they are enveloped by nourishing primordial follicles. Stimulated by the pituitary gonadotropin follicle-stimulating hormone (FSH), 5–12 oocytes begin to mature in each ovarian cycle. Later, the follicles are exposed to another gonadotropin, the luteinizing hormone LH (Fig. 6.2). These hormones signal the egg to resume meiosis and to initiate the events culminating in the release of the mature egg from the ovary. As a rule, in one ovarian cycle, which lasts some 28–30 days, only one (or up to three) of the follicles attains the state of a mature Graafian follicle. In the middle of the menstrual cycle, about 14 days after the last menses, one of the oocytes finishes the first meiotic division by extruding the first polar body, and the egg is released from the ovary (ovulation). In mammals including man the second polar body is not constricted off until the egg is fertilized.

Before fertilization takes place, the egg is caught at the mouth of the oviduct. If not, a fertilized egg that falls into the abdominal cavity dies or may give rise to a malformation exhibiting tumour-like features, called a teratocarcinoma.

The time point of ovulation, the short window of 6–12 h in which the egg can be fertilized, and the short, at the maximum 3 days, life span of the sperm, restrict the conceptive period in the cycle of a women to about 4 days in the middle of the menstrual cycle (Fig. 6.2b). Physicians assume the optimal time point for conception to be the day before ovulation.

Once caught by the mouth of the oviduct, the egg awaits the sperm with reservation: it is surrounded by a tough envelope, called the zona pellucida, and by a corona of mucous material, called the corona radiata. Both these envelopes have been produced by the ovarian follicle, and must be penetrated by the sperm.

From 200 to 300 million sperm released into the vagina in each ejaculation about 1 % advance to reach the egg. On their long journey through the vagina, uterus and oviduct the sperm cells undergo capacitation, that is, they acquire the competence or capacity to fertilize through the influence of female secretory products. Only one sperm succeeds in entering the egg cell. The other sperm may help to dissolve the egg’s envelopes by releasing acrosomal enzymes (Chap. 3).

Whether in humans pregnancy can occur naturally without the contribution of a male individual (parthenogenesis) is discussed in Box 6.2.

Pre-implantation development (Fig. 6.3). Because the embryo will be provided with nutrients by the mother early, the egg can be void of yolk, and it is in fact almost free of yolk. The human egg is amazingly small, just 0.1 mm in diameter and thus not larger than the egg of sea urchins, and considerably smaller than the egg of the small fruitfly. The egg and early embryo can sit enthroned on the tip of a needle (Fig. 6.3).

Although the mammalian egg lacks significant quantities of yolk and has reverted to holoblastic cleavage, cleavage in mammals is extremely slow. This apparently retarded development is correlated with an early start of transcription of zygotic genes; no midblastula transition as it occurs in amphibians (and other animals) is known from mammals. Not until the third day is the 12–16 cell stage of the morula reached. By the 6–7th day the blastocyst stage is attained. The blastocyst looks just like a blastula, but it isn’t a blastula that would proceed to form an archenteron through invagination as do the true blastulae of sea urchins and amphibians. Rather, the cellular wall of the blastocysts undergoes differentiation to become the trophoblast (trophectoderm). This is an ‘extra-embryonic’ organ destined to invade the wall of the maternal uterus, absorb maternal nutrients, and dispose of waste. After implantation the trophectoderm undergoes several rounds of endoreplication and develops polyploid giant cells. Part of the trophoblast will eventually give rise to the placenta, a foetal organ formed to optimize all of these functions (Sect. 6.4). The trophoblast encloses a cavity and the inner cell mass, also called the embryoblast because those cells, which remain diploid, eventually will generate the embryo proper. The inner cell mass is a group of cells eccentrically concentrated at a location beneath the ‘polar’ trophoblast. The blastocyst hatches, attaches to the uterine wall and sinks into it, a process known as implantation or nidation.

If the mouth of the oviduct fails to catch the egg, and the blastocyst settles down in the abdominal cavity (ectopic abdominal pregnancy) the embryo dies or develops to a tumour-like teratoma, a risk a woman has to bear; a teratoma eventually must be surgically removed.

After extracorporeal fertilization the fertilized egg can, appropriate culture media provided, develop in vitro up to the blastocyst stage. Then, according to the current state of reproductive medicine, further development must take place in the uterus.

Post-implantation development (Figs. 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.10, 6.11, and 6.12). The hatched blastocyst attaches with its polar trophoblast to the wall of the uterus. Entry is facilitated by lytic enzymes released from the trophoblast. The outer layer of the trophoblast proliferates into the uterine tissue. While doing so it transforms into a multinucleated syncytial trophoblast; the inner layer of the trophoblast, called the cytotrophoblast (Figs. 6.4 and 6.5), remains cellular and encloses the blastocoel. Later the wall of the blastocyst is supplemented by an inner layer, called the parietal mesoderm. The cavity of the blastocyst will not be enclosed in the embryo and is therefore called the exocoel or chorionic cavity.

The invasive syncytial trophoblast prepares the space into which the embryo can grow. The solid epithelial cytotrophoblast becomes reinforced and supplemented by mesodermal cells that immigrate from the embryo: the whole organ is known as the chorion. From its outer surface primary chorionic villi (Fig. 6.5) project and extend through the loose syncytiotrophoblast to establish contact with the surrounding maternal uterine tissue. With these chorionic villi the embryo takes up nutrients and O₂ from maternal blood lacunae of the decidua (layer of the uterus surrounding the germ). In human embryological illustrations the term trophoblast usually is now replaced by the term chorion. The nutritive organ of the chorionic villi is designated extra-embryonic, meaning that the villi are not organs of the embryo proper; this does not yet exist at this stage. The chorionic villi are the functional precursors of the much larger villi that are later formed by the placenta.

From this point on, generation of the actual embryo follows the path paved by our non-mammalian ancestors.

Gastrulation, germ layer formation, and neurulation are similar in many ways to avian embryo development (Figs. 6.5 and 6.6; compare Fig. 5.​25). In gastrulation, epiblast cells move to a primitive groove and pass through it, colonizing the cleft between the epiblast and the hypoblast. In front of the groove, a primitive streak appears. Underneath, the invading cells give rise to the mesoderm, and perhaps contribute also to the endoderm which essentially derives from the hypoblast. The mesoderm subdivides itself in the traditional manner giving rise to notochord, somites, and lateral plates. Atop the notochord the epiblast forms neural folds that close to form the neural tube (Fig. 6.6). Thus, gastrulation (through a primitive groove), neurulation, and formation of notochord and mesodermal primordia, follow traditional basic patterns of vertebrate development.

There are, however, mammalian-specific peculiarities. The anterior part of the notochord, known as the “head process” pushes anteriorly and contacts a prechordal plate which will give rise to head muscles and to the pharyngeal membrane. Initially and temporarily, the notochord is hollow. The chordal canal begins with an open pore in the primitive groove close to the node and ends with another open pore in the yolk sac. A similar chordal canal (canalis neurentericus) is found in reptiles and some birds.

When the neural folds merge above the notochord to form the neural tube, this tube also remains open at its anterior and posterior ends. Both the anterior and posterior neuropores connect the neural canal with the amniotic cavity. The pores are closed when the majority of the somites, the optic vesicles, the ear placodes and the pharyngeal pouches (“gill arches”, Figs. 6.7, 6.8, 6.10, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16, 6.17, 6.18, 6.19, 6.20, and 6.21) are visible, and the heart beats.

By the 28th day of development the blood vessels have proliferated and spread inside and outside the embryo; embryonic circulation is connected to the placenta through the umbilical cord (Figs. 6.5, 6.6, 6.10, and 6.11).

In human development embryologists find unique features compared to other mammals. One peculiarity of the human embryo is the extremely slow cleavage. Compared to other vertebrates cleavage is slow in all mammalian species. The germ commences transcription of its (zygotic) genes shortly upon fertilization, a first wave starting at the two-cell stage. Transcription takes time. In subsequent development the mammalian human passes stages that can be understood only owing to its evolutionary past. Also in the outward appearance (Fig. 6.7) such traits become apparent, for instance gill pouches (Figs. 6.6, 6.7, 6.8, and 6.21), eyes positioned at lateral sides and for long time uncovered by a lid, arms and legs laterally protruding like in amphibians and reptiles, tail and milk lines (Fig. 6.9d).

A further, significant feature is the enormous growth of the cerebral hemispheres (Fig. 6.9), which for their part expand the still malleable head enormously. The diameter of the head, which principally increases in the frontal region, sets limits to length of time the child can stay in the womb of the mother. The birth canal cannot be expanded to any width, and it is indeed rather often too narrow, compelling surgical intervention (Caesarian delivery).

Another peculiarity occurs on the side of the mother. Especially in human mothers, in the uterus wall-less lacunae are formed, filled with maternal blood, that facilitate the exchange of substances between the mother and the child (see following section).

The developing child lies within a double-layered cyst. Both layers are of embryonic origin: the inner layer is the wall of the amniotic cavity and the outer layer is the chorion, largely a derivative of the trophoblast (Fig. 6.5 and 6.10).

In a region of the chorion, now called the placenta, the tiny primary chorionic villi are replaced by larger secondary villi, and eventually by tertiary villi. The branching, tree-shaped villi grow into cavities inside the uterine wall. The villi become vascularized: Two arteries (umbilical arteries) leave the body of the foetal child at the point of the future navel, traverse the amniotic cavity inside the umbilical cord, enter the villi, ramify and re-join to form the umbilical vein, which returns to the embryo to supply it with nutrients and oxygen. In exchange for maternal nutrients and oxygen, waste products such as CO₂ and urea are transferred to the mother across the villi.

All this is of benefit to the child, indeed the mother has to pay a blood price because in birth the lacunae are not immediately closed. When a mother gives birth (Fig. 6.12) maternal blood gets lost. In other mammalian species, especially in non-primates, birth is not accompanied with much blood loss, and appears to be less painful.

From a pure biological view, and disregarding all joyful anticipation, the human embryo like any viviparous embryo might be considered a parasite that has to overcome the host’s defence. In fact, the removal of tissue barriers between mother and child is not entirely beneficial. The fetus comes into dangerous contact with the immune system of the mother; therefore, reasonable compromises must be found.

Although a child of its mother the fetus is not molecularly identical because half of the maternal genes have been singled out in the meiosis of the oocyte, and were replaced by paternal genes in fertilization. This applies also to the genes of the MHC (Major Histocompatibility Complex I, (in humans also known as human leukocyte antigen HLA). The complex codes for multimeric proteins that are exposed on the surface of somatic cells as an individual identity card. The barcode characterizing each individual encompasses a set of 14 different MHC proteins. Checking this card the immune system identifies foreign cells and tissues, for instance transplants, as being foreign. Foreign tissue is destroyed by cytotoxic T cells at the boundaries of transplants taken from a genetically different donor (heterologous transplants). The residual transplant is rejected. Why not the embryo?

One reason is that the cells of the trophoblast do not express the set of classical MHC molecules. On the other hand, cells lacking the classic MHC, as those of parasites, would evoke aggressive behaviour of the natural killer cells. To dampen the aggressive behaviour of the maternal natural killer cells the embryo expresses a set of peculiar embryonic HLA-G molecules. The mechanism by which these molecules locally shut down the immune system of the mother is currently under investigation.

But even when protection of the ‘transplant child’ against rejection by the maternal immune system is successful, the immunological coexistence of mother and child remains endangered; because a reliable barrier against antibodies, which are much smaller than immune cells, does not exist.

We refer to the Rhesus factor (Fig. 6.13). In the case of incompatibility it can lead to haemolytic disease of the fetus and newborn. This occurs when foetal Rh-positive erythrocytes find their way into the blood system of a Rh-negative mother; their immune system produces anti-Rh antibodies and these enter the foetal blood, passing the placental barrier. The antibodies release an immune response, the attacked red blood cells release haemoglobin and this causes a yellow colour of the skin (jaundice). Problems raised with chromosomal disorders in the child, such as trisomy 21 (Fig. 6.16) are discussed in Box 6.3.

Teaching experience, gained in elementary and high schools as well, tells us that most children (and adults) are not aware that before birth they lived completely under water without any access to air, for 9 months. (As far as children in the womb hear voices or music, the voices and sounds are acoustically heavily distorted; therefore, some popular allegations by psychologists and the media about prenatal communication should be heard with due reservation).

The fluid in which we lived was the water of the amniotic cavity. Life under water and without atmospheric oxygen was possible because we got oxygen and disposed of carbon dioxide through the umbilical cord. With the increasing size of the fetus also the placenta grows so that efficient exchange is always possible.

The child is connected with the placenta by three main vessels. Two umbilical arteries leave the child at the site of the future navel, cross the amniotic cavity within the umbilical cord, and ramify in the placental villi into capillaries to facilitate exchange of substances. Enriched with oxygen the foetal blood returns to the embryo through the umbilical vein.

Thus, oxygen-loaded blood does not arrive from the lungs. Blood enriched with oxygen flows through the venous system into the undivided heart, is distributed in the body, collected and pumped back through the umbilical arteries to the villi of the placenta. The fetus has a circulatory system in the form of a single circle, like a fish, with the placental villi serving as gills. Because the lungs of the fetus do not yet function, but have to take over their vital task immediately after birth, the circulatory system must be prepared for a rapid conversion into a double-circle (body and lung) system. The solution to this serious technical problem is described in Chap. 17.

In humans, the human blastocyst leaves the oviduct and settles itself into the uterine wall about one week after fertilization. The time point of nidation defines the start of pregnancy (gestation). The embryo is usually called fetus with beginning of the 10th week of pregnancy, that is 56 days after fertilization (about 10 days after Fig. 6.25d). At this age the heart beats already since a month. The embryo has attained a size of about 45 mm, is recognizable with ultrasound and begins to move its arms. However, prior to this stage 40–50 % of the implanted embryos perish as consequence of faulty development. Most disappear undetected with some blood during menses. Presumably a considerable part of mal-development is caused by the immune system of the mother.

The child is ready to be born after 38 weeks (266 days) of pregnancy. Birth represents another serious risk.

It is a risk to the mother: when the placental villi are pulled out from the uterus, blood flows out from the lacunae and is lost. The mother might be in danger of bleeding to death. Will the uterus succeed in sealing the large openings in time?

It is also a risk to the baby: in an instant, the lungs must be blown up and blood pumped through the lungs. At this time point a short circuit in the circulation (ductus botalli, see Fig. 17.​10) must be closed, so that the pulmonary circulation is completely separated from the great body circulation. If it fails to close a congenital heart condition results, called patent ductus arteriosus. In spite of all these risks, the benefits of being harboured within a protecting and nourishing mother is worth these risks. The evolutionary success of the placental mammals, and of man in particular, is a testament to the value of this developmental innovation.