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Embryology


Contents

Difference between Engineering and Bio-processing
Physics of Cell Division
Spatial Cue in Cell Specialization
Symmetry Breaking and Body Plan
Bio-tubing
Segmentation, Somitogenesis, and Hox Genes
Chemical Messages and Organogenesis
Cell Movement and Cell Migration
Vasculogenesis, Heart Tube Formation, and Angiogenesis
Development of the Organs
Determination of Sex
Development of Limbs
Formation of the Nervous System


In his 2014 book "Life Unfolding", Jamie A. Davies explains the development of life from a single cell to a fully grown human via the mechanism of "self-organization". Following is a summary of the explanation.


Difference between Engineering and Bio-processing

Engineering vs Bio-processing While engineering relies on a blueprint, architect, engineer and construction workers - all of them outside the finished product and involving human intelligence; bio-processing includes self-assembly of components (such as protein, RNA, DNA) via interaction between residual charges and adoptive self-organization in response to external circumstances. It's a continuous process that would have problem with disruption, rearrangement or piecemeal implementation. The process occurs naturally without any cue from a human elaboration. Figure 01 illustrates the different processes pictorially (see Self-assembly and Self-organization in previous sections).

Figure 01 Engineering vs Bio-processing [view large image]

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Physics of Cell Division

In multicelluar organisms, the egg is usually more than 10 times larger than normal cell. The initial stage of cell replication can therefore occur entirely within itself up to 32 cells. This phase is called cleavage. The division mechanism depends mainly on a special property of the microtubules which exist in one of two states - a fresh stage containing special "fresh molecule" at the end from which the tubule extends, and a stale state without the fresh molecules resulting in its gradual decimation. These tubules emanate from the centrosomes (composed of 2 orothgonally arranged centrioles, see Figure 02) which define the center of the normal cell or the opposite ends during cell division. Such remarkable features is caused by the imbalance of the number of long and short microtubules; the sum of the reaction forces create a net push toward the center when their far-ends hit the cell membrane (Figure 03, model a). The fundamental mechanism is just the physics of action and reaction from Newtonian mechanics in addition to the property of chemical bonds. In case of cell division, the same mechanism is involved.
Microtubule Microtubules in Action Both the centrosome and chromosome are divided into mother-daughter pair. The microtubules bind to a special site in the chromosomes and pull them apart (Figure 02). The binding of microtubules to the chromsomes and fresh molecules uses a trial and error approach in finding the right match. Therefore, it is expensive in terms of energy, but it is automatic. It seems to be very complicated, actually it is the feed back behavior of each individual component that gives rise to the complex from the simple. This process of first cell division is common to all cell replications by the name of mitosis. Meiosis involves further processing to produce gametes. See "Inner World of the Cell" for more information about "microtubule" and "molecular motors".

Figure 02 Microtubule [view large image]

Figure 03 Microtubules in Action [view large image]

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Spatial Cue in Cell Specialization

The first 32 cells in the egg requires only the processing of division, there is no need to turn on the genes for additional tasks. The situation changes as soon as the egg runs out of space and material. the system has to acquire room and nutrients to grow. The necessary information is provided in the form of geometry. The genes are activated in those cells (about 1/6 of the total) facing clear space. These layer of very first specialized cells (together called tissue) is the trophectoderm, which pumps in fluid and forms a capsule. The clump of inner cell mass (ICM)
Spatial Cue moves to another end (Figure 04). The layer of ICM facing the fluid now receives another geometric cue to specialize into hypoblast cells, which spread around to form the yolk sac (providing nourishment and also functioning as internal circulation). The remaining ICM collaspes toward the hypoblast layer to form the epiblast, which is destinated to be the base of next life (Figure 04 which also shows some of the specialized cells from the stem cell). The process also creates the amniotic cavity, where fetal development occurs (see chicken egg in which the yolk sac and amnotic cavity are ready-made, and mammalian fetus which is the main subject of interest here).

Figure 04 Spatial Cue
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Symmetry Breaking and Body Plan

The initial embryonic cells has 3-D spherical symmetry until it reaches the 32 cells limit. The subsequent specialization reduces it to 2-D circular symmetry up to about 13 days (after fertilization). It is reduced further to 1-D axial symmetry when the body plan lays down the head and tail (posterior in human). Symmetry finally disappears altogether with the development of organs inside the body. In the parlance of "information", the sequence of development amounts to the acquisition of more and more information with the progression of time. It also means that the
Body Plan Body PLan 2 Germ Layers system is evolved further and further away from equilibrium in a state which requires energy infusion to sustain. It is not clear what triggers the expression of the genes that leads to all these changes. But the processes are well documented. Figures 05a and 05b depict the steps toward the laying down of the notochord from the two layers of epiblast and hypoblast (blast = form, epi = over, hypo = under). Figure 06 shows the body plan based on the three germ layers.

Figure 05a Schematic Body Plan Development [view large image]

Figure 05b Body Plan

Figure 06 Germ Layers

Followings are some elaborations on the 7 steps.

  1. The first change takes place in the hypoblast. The cells in its middle start to express a DNA-binding protein called Hex. Thes cells then move over to a point at the rim. It is not clear why they choose this particular point to congregate.

  2. The entire layer of the epiblast in the meantime receives signal to make structures characteristic of the posterior end of the body. While the Hex-expressing cells secrete proteins to suppress the formation of the posterior features.

  3. As a result, only those cells at the other end of the epiblast can escape the inhibition (because they are further away), and start making the tail end of the primitive streak.

  4. The center of the streak dips down to form a flat depression, to which other cells converge. This node grows clockwise rotating cilia to break the mirror symmetry inside the body.

  5. The converging cells have the cell-cell adhesion weaken and dive down one by one to the hypoblast. They push away the old residence of hypoblast to form the endoderm (inner skin).

  6. The cells that drop through later remain only loosely associated with one another to form the mesoderm (middle skin). Cells that never manage to drop throught and remain in the top layer (the epiblast) become the ectoderm (outer skin).

  7. Middle of the endoderm layer rises up, invaginates and then detaches to form the notochord, which is used to stiffen the body in lower vertebrates. It is replaced by the bony skeleton in more advanced species. However, it is important in secreting proteins to organize the embryo. Eventually, it breaks up and is used to make inter-vertebral discs.

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Bio-tubing

Neural Tube Gut Tube The vertebrates have two important tubing inside the body. The neural tube that contains the nerves running from the brain to the tail end, and the gut tube that retrieves nutrient from food and repels the waste at the end. Their formation is achieved either from the local change of individual cell that propagates via a continuous mechanical network or just by the growth of the body. It is the microfilaments that helps to buckle the central axis of the ectoderm to form the neural tube. While the gut tube is formed by the overgrown of the endoderm. These processes are shown in Figures 07 and 08. A brief description is provided in the followings.

Figure 07 Neural Tube
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Figure 08 Gut Tube
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    Neural Tube Formation (Figure 07) :

  1. At about 17 days after fertilization, signals from the notochord induce a form of curvature on the line of ectoderm cells immediately above as shown in Figure 07(1). The folding is caused by changing the cells (in the middle) into wedge-shaped pointing up. Since the cells are linked rigidly together by microfilaments (see Figure 07 insert at the lower left) the "chain reaction" makes the cells further away to become wedge-shaped in the opposite direction.

  2. The crests in the folding are pushed toward each others due to cell proliferation.

  3. The two sides of the folding fused to make a neural tube in the middle. At this stage there is nothing inside the tube - it is empty.

  4. The neural tube separates completely from the ectoderm layer that flanks it. The space in between is occupied by the neural crest cells. These cells are transient, multipotent, migratory cell population unique to vertebrates and gives rise to a diverse cell lineage that produces cartilage, bone, smooth muscle, and various types of nervous cells.
    Gut Tube Formation (Figure 08) :

  1. At about day 16 after fertilization, the endoderm is a flat plate at the bottom layer of the embryo, facing the open space of the yolk sac. See top view in Figure 07(1) and sagittal view in Figure 08(1).

  2. Elongation of the body pulls on the ends of the endoderm, causing them to overshoot the entrance to the yolk sac and to be drawn out to make short tube-like extensions into the growing head and tail ends of the embryo.

  3. The extensions become even longer as the embryo keeps growing.

  4. The opening to the yolk sac progressively becomes insignificaent. This branch is eventually closed off, leaving the gut as a tube fully enclosed within the body. The insert at the lower left of Figure 08 shows the location of the various organs corresponding to different section of the gut tube.

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Segmentation, Somitogenesis, and Hox Genes

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Determination of Sex

Sex is necessary to refresh the genes. It is the germ cells that provide the raw material for reproduction. The germ line becomes identifiable when a group of around 50 cells is set aside in the epiblast at the posterior end of the primitive streak (Figure 08), just before gastrulation at about 13 days after fertilization. They proliferate to a population of thousands and crawl to the developing gonads (Figure 22), where they will
Sex Determination Difference of Genitals undergo the process of meiosis to become sperms (cells in haploid state with either X or Y chromosome) or eggs (cells in haploid state with only X chromosome) depending on whether further development is following the male or female path (Figure 23). In boys, meiosis does not begin until puberty but in girls all of the germ line cells begin meiosis almost as soon as the overy begins developing. Every egg that a woman can ever have is already in meiosis when she is born. The determination of sex is governed by the gonad, which begins to make a protein called WT1 at about day 42.

Figure 23 Sex Determination
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Figure 24 Genitals, Difference

See "Sex and Death" for a philosophical discourse on mortal life.

    The process for the determination of sex can be separated into three steps or levels from the expression of triggering proteins, to the formation of the internal structures, then the different external appearances between male and female :

  1. Molecular Cascade - Release of the WT1 proteins triggers two difference pathways (Figure 23). If the SRY proteins secreted by the Y chromosome are presence, it induces the secretion of SOX9 (with the corresponding gene in chromosome 17), which opens the pathway to maleness. Otherwise, WT1 produces WNT4 leading to femaleness. SOX9 also cleans up any WNT4 residuals to make sure there is no mixture of maleness and femaleness - a transsexual. Obviously, the mechanism is not foolproof as about 3.5% of adults in the United States are identified as lesbian, gay, or bisexual.

  2. Internal Re-organization - The chemical avalanche of either pathway modifies the Wolffian and Mullerian ducts (Figure 22) to become male or female reproductive apparatus. The end result of the process is summarized in Table 01 below.

  3. External Appearance - The development goes on to make male or female external genital as shown in Figure 24. The difference in appearance actually is based on the same starting tissues. All the three openings were developed from the cloaca (Figure 22) in the beginning. And then, there is the secondary sex characteristic, which is not directly related to reproduction; the traits are believed to be the product of sexual selection. Table 01 also shows some of those traits in human.
Substance (level) Male Female
Sex Chromosome Pair (1) XY XX
SRY Protein (1) Yes No
WNT4 Protein (1) No Yes
Mullerian Duct (2) Eliminated Develops to oviducts, uterus, upper vagina
Wolffian Duct (2) Becomes sperm transport duct Eliminated
Genital (3) Penis and scrotum Vagina and labia
Mammary Glands (3) Vestiged Presence
Bones and Muscles (3) Larger Smaller
Hair (3) More Less

Table 01 Differences between Maleness and Femaleness

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Development of Limbs

Development of Limbs The two pairs of limbs start out as small projections underneath the ectoderm that covers the outside of the embryo. The proliferation is driving by signals from the mesoderm of the trunk. They switch on the production of the WNT proteins, which in turn induce the FGF signalling family. The FGF is the driving force to move the limb bud called "Progress Zone" outward (Figure 25a). Further development of the limb is explained by two different models as outlined below.

Figure 25 Development of Limbs [view large image]


Both models predict that only the upper arm will form if the progress zone or limb tip is removed (Figure 25d). Observations reveal that the process is more complicated than these simple minded models. There could be more signalling proteins involved. Abnormal growth of limbs is not limited to the temptation of the progress zone. Disruption of the capillaries to supply oxygen and nutrient to the growing cells could also arrest the formation of a proper limb. The adverse effect was demonstrated between 1958 and 1961 by babies with deformed limbs when their mothers took the tranquillizer thalidomide which inhibits outgrowth of new and immature blood vessels.

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Formation of the Nervous System

The next phase after the formation of the neural tube at day 23 is dominated by cell proliferation. The cells navigate using the types of mechanism mentioned earlier in "Cell Movement and Cell Migration". As we have learned recently in the 2010's in the concept of "Connectome", the most important aspect of our mental capacity comes from the inter-connection of the neural cells. The task is achieved by sending out fine appendages from the cell body to seek out each other. The shorter ones are the dendrites for receiving bio-electrical signals while the very long axon is for transmitting sensory messages or relaying central commands. The axon can extend to nearly a meter long by
Growth Cone Meningeal Layers crawling with the growth cone (Figure 26). The direction of growth is specified by the adhesion of the substratum. The branching tends to follow a stickier path. Other guidance cues work by signalling to the molecular machinery that assembles the growth cone's leading edge. Since the movement of these migrating cells excesses the growth of the embryo, they all piled up at the wall to become the meningeal layers of the CNS (Figure 27).

Figure 26 Growth Cone
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Figure 27 Meninges [view large image]


The brain grows at the head end of the neural tube with the development of three bulges - the prosencephalon (future forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain) as shown in Figure 28 at 4 weeks. Further development at 6 weeks shows more features (identified by numerals : 1. olfactory 2. optic 3. oculomotor 4. trochlear 5. trigeminal sensory 6. trigeminal motor 7. abducens 8. facial 9. vestibulocochlear 10. glossopharyngeal 11. vagus 12. cranial accessory 13. spinal accessory 14. hypoglossal 15. cervical I, II, III and IV); diencephalon refers to the posterior forebrain, and telencephalon the cerebrum at maturation. In simple vertebrate, such as fish, the brain remains as a straight tube with swellings. In mamals, and especially in humans, the process of formation involves bending and folding, and then go on to become furrowed
Embryo Brain Brain Development to cram even more surface area into the available space (Figure 29). The process follows the basic principle of chemical signalling over and over, getting more and more complicated. This is the physical base of mentality provided by nature, the owner of such system has much to learn to become a viable being after birth (see "Nervous System" for the mature version of CNS, PNS, ANS, ENS, etc.).

Figure 28 Embryo Brain at 4 and 6 Weeks
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Figure 29 Development, Brain [view large image]


Similar to the wiring of the neurons, the immune system is developed after birth. The womb is sterile, the baby encounters the bacteria the very
Asthma first time at the birth canal. Delivery by caesarean section delays the contact until it is handled by the mother (see "Immune System" for the different forms of immunity). Since the adaptive immune system is acquired, the practice of good hygiene in developed countries has been accompanied by an increase in the incidence of diseases such as asthma, which reflect an immune system out of balance and inclined to be excited by harmless substances such as dust, animal hair, and pollen (Figure 30).

Figure 30 Asthma
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BTW, It is found that infants delivered by cesarean section exhibit a distinct microbiome (the micro-ecosystems on and in our body) more colosely resembles the composition of the mother's skin.

It is not possible to describe the detail mechanism of growth as the embryo organizes itself into a very complicated system few weeks after fertilization. The two videos from YouTube below serve as supplements to the text in this topic. More details of the early embryonic development in the first 50 days can be found in the "Time Line".

Early Embryo Development General Embryo Development

Video 01 Early Development,
Embryonic [view video]

Video 02 General Development,
Embryonic [view video]