The book “Ontogenesis. From cell to human

Published on October 20, 2016

The book “Ontogenesis. From cell to human

    Hello! Together with Dmitry Zimin's Book Projects, we published a book by Jamie Davis:

    imageHow did we become who we are? Why do we have two arms and legs, but only one head? Why is the human body symmetrical, but at the same time, its halves are not completely identical? Why are identical twin fingerprints not the same? How has our brain developed and what is consciousness? Why are we mortal and what is the biological meaning of this?

    People have asked similar questions to themselves since ancient times. Even now, with the modern development of science, those fundamental principles are not fully understood, due to which such a complex organization is formed from a single fertilized egg, consisting of many molecular structures that interact with each other, have their own life cycle, are capable of regeneration and self-development. “This is based on the principle of central adaptive self-organization,” says modern biology. But what is this principle?

    Jamie Davis has done a great job of adapting the most complex scientific material to a level that is understandable to the general reader. In a fascinating and ironic form, having supplied his story with more than 80 illustrations, the author invites the reader to travel through all aspects of human biological development - from conception to death. Recent advances in embryology, genetics, physics, neuropsychology will allow us to learn more about stem cells and protein metabolism, the differences between chromosomes and gene functions, neural connections and other important factors that affect the human internal evolution.

    Ethical statement


    This book describes the mechanisms of human development. It contains information published in scientific journals obtained in the study of human embryos, as well as in animal experiments. Since academic publishers and research foundations require that work be reviewed by the appropriate independent ethics commissions, I made the assumption that the experiments cited in this book met the standards of the time they were conducted. Ethical standards are constantly changing, and some research that was conducted many years ago is now prohibited. Mentioning the results of specific experiments in this book does not imply personal ethical endorsement of the methods used in them by either the author or the publisher of the book.

    Introduction
    Chapter 1.
    Encountering Alien Technologies


    In these words, the English philosopher and poet Samuel Coleridge expressed in poetic language the surprise of a child who first asked his parents: “How was I born?” Many adults believe that this issue relates to sexual relations, and begin to painfully think about what and when to tell . However, the child is not at all concerned about these psychosocial difficulties, his question is both simpler and deeper - how can a new person appear?

    Not a single child has yet received a complete and correct answer, because none of the adults knows for sure. At the time of Coleridge, certain facts were known about the sequence of anatomical changes that occur as a new person grows in the uterus, but how and why they occur remains a mystery. For the next two centuries, scientists have been trying to understand how a fertilized egg turns into a child. Over the past decade, science has stepped far forward, but as scientists decipher complex mechanisms and solve specific puzzles, the general sense of amazement only grows. The history of embryonic development, which has so far been discussed mainly in specialized scientific articles, is truly amazing. This story is about what happened to each of us, and therefore should be in the public domain.

    Our understanding of human embryonic development was not developed within the framework of a single scientific approach, but was the result of summarizing a huge amount of information from different fields of knowledge. Embryology and neonatology, which directly study human development, have placed at our disposal a large amount of anatomical and functional information. Genetics and toxicology, areas broader than developmental biology, are of great importance for identifying the causes of congenital anomalies. This is very important, because, knowing these reasons, it is possible to identify cascades of biochemical reactions (the so-called molecular pathways) necessary for the normal development of the corresponding parts of the body. Biochemistry and molecular biology are indispensable for identifying the details of the molecular pathways involved in development, up to the level of interaction of atoms of biological molecules. Cell biology allows us to explain how, through the interaction of different molecular pathways, the behavior of individual cells is controlled. By exploring a higher level of organization, physiology, immunology, and neurobiology reveal ways of communicating and coordinating multiple cells.

    All the mentioned disciplines belong to the fields of medicine or biology, in which research on human embryology has traditionally been carried out. However, recently, fields of science that at first glance have nothing to do with this topic: mathematics, computer science, and even philosophy, have also contributed to understanding human development. They did not clarify specific details (what and when this or that cell does), but touched upon fundamental questions related to development, for example: how can the simple become complex? how development mechanisms that are unstable with respect to random errors can provide high accuracy in reproducing the final result? and isn't human development too difficult for even intellectually developed people to fully understand? The last of these questions remains open, and the subject of the dispute is the word “fully”. However, significant progress was made in resolving the first two issues. The answer lies in two related concepts: “emergence” and “adaptive self-organization”. These are actually two sides of the same phenomenon. “Emergence” is the emergence of complex structures and behaviors from simple components and rules; this term is usually used by those who look at the system “down” from the position of “high-level behavior”. “Adaptive self-organization” is a “look up”; this term allows us to describe how the application of these simple rules to the components of the system leads to their collective behavior - the implementation of complex and subtle tasks of large spatial scale. The answer lies in two related concepts: “emergence” and “adaptive self-organization”. These are actually two sides of the same phenomenon. “Emergence” is the emergence of complex structures and behaviors from simple components and rules; this term is usually used by those who look at the system “down” from the position of “high-level behavior”. “Adaptive self-organization” is a “look up”; this term allows us to describe how the application of these simple rules to the components of the system leads to their collective behavior - the implementation of complex and subtle tasks of large spatial scale. The answer lies in two related concepts: “emergence” and “adaptive self-organization”. These are actually two sides of the same phenomenon. “Emergence” is the emergence of complex structures and behaviors from simple components and rules; this term is usually used by those who look at the system “down” from the position of “high-level behavior”. “Adaptive self-organization” is a “look up”; this term allows us to describe how the application of these simple rules to the components of the system leads to their collective behavior - the implementation of complex and subtle tasks of large spatial scale. this term is usually used by those who look at the system “down” from the position of “high-level behavior”. “Adaptive self-organization” is a “look up”; this term allows us to describe how the application of these simple rules to the components of the system leads to their collective behavior - the implementation of complex and subtle tasks of large spatial scale. this term is usually used by those who look at the system “down” from the position of “high-level behavior”. “Adaptive self-organization” is a “look up”; this term allows us to describe how the application of these simple rules to the components of the system leads to their collective behavior - the implementation of complex and subtle tasks of large spatial scale.

    It is thanks to adaptive self-organization that non-living molecules can create a living cell, and cells with limited individual capabilities can form a multicellular organism capable of much. Adaptive self-organization is the leitmotif of my book, as it underlies the biology of development. The concepts of “adaptive self-organization” and “emergence” go beyond biology, and in the section “Further Reading” I have provided several links to fascinating books on this topic.

    New evidence from developmental biology clearly suggests that the body does not appear at all in the way buildings or machines are built. It’s ridiculous, but true: the methods of formation of our own body are completely alien to our ideas about how this could be. Therefore, trying to understand how the embryo builds itself, it is very useful to compare - and contrast - the development of this biological system with the usual methods of building objects.

    All engineering projects, whether assembling a locomotive or building a building, have common features. First of all, any project has a certain plan - it can be a drawing or some other scheme - clearly showing what we want to get as a result. The plan shows the expected result, but it will not be part of this result. Each project has a leader - a chief engineer or architect - who gives instructions to subordinates, and those, in turn, to workers who perform brick laying, cutting, welding and painting. Details of the future design cannot connect together on their own. This is done by workers - masons, assemblers, welders - who themselves are not part of this design. In this case, the workers and the chief engineer own a huge amount of "external" information - on welding technology or stone work, - which is not present in the objects that they create. And finally, most man-made structures are put into operation only after the completion of work.

    In biological engineering, we will not find these familiar stages. This once again emphasizes the difference between living things and engineering structures. Unlike technical projects, biological engineering does not imply any drawings and sketches of the final result. Of course, a fertilized egg contains information (in genes, in molecular structures, in the spatial distribution of chemical concentrations), but the relationship between this information and how the finished organism will eventually look is far from simple. It is known that this information controls the subsequent sequence of events (and we know this because a change in this information, for example, when a gene mutates or changes in the concentration of a certain substance in a certain place, changes the sequence of events,

    In technology, and especially in mathematics, the end result can be reached using step-by-step instructions. Consider an example: in the middle of a wheat field, stick a stake in the ground and tie a rope to it. Take the other end of it and walk a few meters to pull the rope. Then go right, keeping tension. Thus, you can draw a simple circle. Some structures are much easier to create according to the instructions than according to the drawings. If you have pencil and paper on hand, try following the instructions below to draw a geometric shape called "Sierpinski's napkin."

    1. Draw an equilateral triangle with a horizontal base. The more he gets, the better. We will consider it a “starting triangle”.
    2. Inside this triangle, draw three segments. Each of them should pass from the middle of each side to the middle of the adjacent. These segments form an inverted triangle, occupying a quarter of the original area.
    3. Shade the resulting triangle.
    4. Now you see three unshaded triangles inside the original one. Do the same operations with each of them as with the original triangles, starting from point 2.
    5. (Continue until you get tired: if you are armed with a good pencil, this activity can last forever.)

    “Sierpinski's napkin” (thanks to shaded areas, the drawing resembles openwork knitting) is an example of a fractal structure. At any magnification, we get the same image. Another example of a fractal is the Cantor set. It is most convenient to draw on a surface with which it is easy to wash. A blackboard will do. Draw a line, then erase its middle third, then erase the middle thirds of the two lines received, and so on. After a while, you will get many points located at certain intervals. The statistical properties of these intervals are identical to the properties of many natural phenomena, whether it is shedding of sand from a dune or the gaps between drops of water from a leaking tap, earthquakes, epidemics, and cases of mass extinction of animals.

    Step-by-step instructions, not sketches, are used to create objects not only in mathematics, but also in everyday life; the simplest example is a culinary recipe. Textile production works on the same principle, from hand knitting (“we knit one loop, we throw one loop”) to the “jacquard machine” (1801), the first industrial robot in the world on which you could switch difficulty levels by changing punch cards from the simplest to the most complex pattern. Music is also reproduced thanks to instructions, the role of which is played by musical notes on the stave, according to which the musician can play sounds of the necessary pitch and duration at the right time.

    The centuries-old experience of using instructions to get the intended result with minimal time and effort leads to the fact that we tend to believe that biological information determines our appearance in some similar way. This is a dangerous fallacy. There is a significant difference between living organisms and man-made objects: in the latter case, instructions are followed by an external conscious agent of action. Even such seemingly obvious exceptions as an automatic knitting machine or a mechanical piano were created according to the instructions and plans by the same external agents, which means that they are no exception. Simply put, cardigans, symphonies, cars and cathedrals did not create themselves. Following the instructions, introducing the necessary information about the process (the ability to knit, to prepare or lay a brick) and actually work with materials is carried out not from the growing structure, but from the outside. On the contrary, the information contained in the embryo is read and processed by the embryo itself; he has no one to pass on to either hard physical work or thought about optimizing the process. As we will soon see, this means that the responsibility for biological engineering lies with all of its participants, and not with the leader, as in the case of engineering projects. The process of creating a human body is controlled not by some individual parts of the embryo, but by the system as a whole. this means that the responsibility for biological engineering lies with all its participants, and not with the leader, as in the case of engineering projects. The process of creating a human body is controlled not by some individual parts of the embryo, but by the system as a whole. this means that the responsibility for biological engineering lies with all its participants, and not with the leader, as in the case of engineering projects. The process of creating a human body is controlled not by some individual parts of the embryo, but by the system as a whole.

    To understand the features of the construction process, you must also have some idea of ​​the nature of the materials used. Near my laboratory at the University of Edinburgh there are three famous bridges: the elegant Dean bridge built by Thomas Telford, the legendary rail bridge across the bay built by Benjamin Baker, and, not far from it, the Ford Road highway bridge. Telford built a bridge of stone blocks - heavy, bulky, reliable only due to compressive stress. Therefore, he used the traditional method: first, supports were built, then a wooden frame was constructed for the arched span, then stones hewn in the shape of an arch were laid out on it. After the weight of the stone stabilizes the span, the frame can be removed.

    Baker used for the construction of the railway bridge a material radically new at that time - steel. This material can hold both due to tension and due to compressive stress, therefore, construction could be started from any support by attaching sections to it with one end. To place the long and relatively light steel sections in place, cranes were used. Between themselves, these sections were connected using rivets.

    The cable-stayed bridge, the newest of the three, is supported by steel cables, cables that are mounted on pylons on different banks. In this case, pylons were first installed, then reference points for fastening the cables were outlined, and then the guys holding the bridge were gradually pulled.

    In each of these cases, the bridge construction strategy was determined by the nature of the materials. None of them could be built using a strategy designed for a different type of bridge. The same is true in biology: the design strategy depends on the nature of the components involved. Thus, it is time to introduce you to three key biological components that will be mentioned many times in this book - these are proteins, messenger RNA (mRNA) and DNA.

    Proteins are the main building materials in biology. Most of the physical structures that shape cells are created from them; they form channels and pumps that regulate the circulation of substances in cells. In addition, proteins are catalysts. They trigger and control biochemical reactions and metabolic pathways, the products of which are other components of the body, such as DNA, fats and carbohydrates. The relative importance of proteins can be illustrated, for example, by the following fact: red blood cells (red blood cells) lose their nuclei in the process of maturation, which contain all their genes, but after that they live about a hundred and twenty days. A cell in which genes are preserved, but the function of proteins is disturbed, will die within a few seconds.

    A protein consists of a long chain of individual blocks - amino acids. About twenty types of amino acids are known that differ in structure and chemical properties. They interact with each other, and this means that the chains of amino acids can twist into intricate forms - spontaneously or under the influence of other proteins. This twisting process is so complicated that it is impossible, knowing only a sequence of amino acids, to predict which protein will result. (Computer programs for predicting the shape of the protein exist, but they use a combination of calculations and probabilistic reasoning based on the already known structure of proteins and amino acid sequences identified experimentally by x-ray crystallography. Thus, these programs are similar to computer programs, which use weather forecasters; however, it should be noted that the prediction of protein structure is still more accurate than the weather forecast.)

    Different proteins are made up of different amino acid sequences. One by one they attach to the growing protein chain in the order that is established by a molecule called messenger RNA (abbreviated mRNA) (Fig. 1). The mRNA molecule also represents a single chain of individual blocks - nitrogenous bases: adenine (A), cytosine ©, guanine (G) and uracil (U). In their structure, they are similar and not so interesting in comparison with amino acids in terms of chemical properties: mRNA molecules do not play a large role in the cell, in addition to regulating the amino acid sequence in the forming protein. This sequence is determined by the sequence of bases in mRNA. Each amino acid has its own code of three nitrogen bases.
    image

    The sequence of bases in mRNA molecules is determined by the sequence of bases in DNA. DNA is a very long molecule, consisting of combinations of four nitrogenous bases: adenine, cytosine, guanine and thymine (T), which can be arranged in different sequences. The individual DNA molecules that make up the majority of the forty-six chromosomes in each cell of our body contain millions of nitrogenous bases. Individual sections of this chain are genes. When genetic information is read, the RNA molecule encodes the sequence of DNA bases (A, C, G, T) in the language of its bases (A, C, G, U). Thus, RNA is essentially a copy (transcript) of a gene in another medium. Actual gene reading is done by whole protein complexes. They first bind to various short base sequences at the start of the gene, ATAAT or TCACGCTGA. Different genes have different combinations of such short sequences marking their beginning, and each sequence binds to a specific protein. Thus, different combinations of proteins are involved in the activation of the reading process of various genes.

    The fact that different genes are activated by different DNA-binding proteins is very important because different cells of the body must synthesize different types of proteins. For example, intestinal cells produce proteins that allow you to digest food, ovarian cells synthesize proteins for sex hormones, and white blood cells produce proteins to fight microbes. All these cells contain all genes of the genome, even those that they will never need. However, only the genes necessary for specific cells are read, and this is due to the presence of "exclusive" DNA-binding proteins.

    Now, we will, perforce, have to abandon the idea that any of these components may be responsible for the development of the cell - or embryo - as a whole. I repeat: proteins are formed only because their genes are dictated (via mRNA) by active genes. In turn, these genes are active only because they were activated by existing proteins. Thus, a vicious circle is obtained: control is not concentrated at any particular point, because it is carried out everywhere (Fig. 2).
    image

    The cycle diagram of which is shown in Fig. 2, leads to one interesting thought. In order for the cell to maintain stability, among the active genes there should be genes that determine which proteins will bind to sequences marking these same genes. In this case, however, the set of active genes should not include any proteins that activate the currently inactive genes. If these conditions are not met, the proteins created by the set of active genes will not be able to maintain the activity of the same set of genes - some of them will turn off, others will turn on, and as a result a completely different set of proteins will be made, and so on. These changes will continue until a stable state is reached. It is this pattern that underlies how the cells of our body are transformed in the process of development into cells of new types. Such a change, as a rule, occurs under the influence of external signals that change the ability of specific proteins to activate genes: they violate stability and cause a transition to a new state. We will constantly encounter examples of such signals in subsequent chapters of the book.

    The "cyclic" control distributed throughout the system is by no means the only strange feature of biological construction. There is another feature that seems simply fantastic when viewed from the perspective of traditional engineering. Its essence is that biological molecules can spontaneously combine into structures of a larger spatial scale. Bricks and bolts are definitely not capable of this! This process, which is crucial for life, is a bit like crystal growth. Ordinary crystals, as in the sets of a young chemist, are formed because their constituent molecules can bind to each other, usually due to local electric charges. Proteins also have local electric charges, often located in hard-to-reach areas inside the protein or on its convex parts. The charge distribution and the shape of the protein are dictated by the sequence of amino acids. Sometimes a protein molecule is concave in front and convex in the back, so that the convexity of one protein coincides with the concave part of another, like the details of the Lego constructor. In this case, protein molecules can line up “head to tail” into a thin structure of arbitrarily long length (Fig. 3). More often, however, a protein can recognize binding sites not only in other proteins or any other molecules, but also in its own structure. This means that it cannot create endless filaments with identical molecules, as occurs in crystals, but binds only to a certain amount of proteins, forming multicomponent complexes of a special structure. These complexes play an important role in cells because they act like tiny machines, which can carry out complex chemical reactions or even organize the assembly of structures that are too large and complex for spontaneous organization. An example is the protein complexes mentioned above for reading genes.
    image

    The level of organization of protein complexes brings us to a very important point. The organization of proteins into complexes is based on information that is only in the proteins themselves ("information" in this case is a synonym for structure). This is essentially a chemical process, and its result is always the same - it is reliable, reproducible, but unchanged. At higher levels of organization, biological structures are more variable, they adapt to certain conditions. For example, the shape of a cell depends on its place in the composition of the tissue. Its connections with neighboring cells are determined by their relative position. Such formations cannot be determined solely by the information embedded in the chemical structure of their molecular components; more information required. So, we are moving from an internally managed structure to a structure

    In biological systems, multi-level regulation is added to chemical self-assembly, and as a result, systems are obtained in which structures adapt to environmental conditions. At this stage, the concept of adaptive self-organization mentioned above is of particular importance. It turns out to be the key to understanding how just a few thousand genes and proteins, which have no idea about the structure and functions of the human body as a whole, can nonetheless build it. What a contrast with engineering projects, in which external agents of action are necessary for the correct assembly of components, whether they are workers or robots! In the following chapters, we will discuss the importance of adaptive self-organization for human development at various levels, from self-organization of molecules within a cell to the formation of complex tissues.

    Biological construction has another unusual feature, and it is associated with a restriction that lies at the very core of life: it cannot be stopped to reflect, and then start over. Man-made mechanisms, such as computers and airplanes, should only function after completion of work, and while the assembly process is in progress, nothing is required of them. The development of the embryo is accompanied by a strict condition: at all stages of development, it must remain alive. If the plumber wants to install a layering, he closes the water and installs a T-pipe on the main pipe. When the work is completed, the water can be turned on again. And if such an approach was used to create a human body, for example, when a new vessel was removed from the aorta? The fetus would die immediately. The same applies to other important body systems. The unquestioned requirement of constant viability in the conditions of the development of the organism is a very serious condition. This is another reason why the development of the human body may seem so strange and so complicated compared to the usual methods of construction.

    Trying to understand the earliest stages of our existence, we must be prepared to discard the usual ideas about the process of creating things and look at the development of the embryo in the light of its own laws. This journey to uncharted territory, it requires a new way of thinking. And no engineering metaphors! In the end, we do not create embryos, they create us.

    »More information about the book can be found on the publisher’s website
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