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From one cell to many

The scientific approach 13.10.2016 at 04:14

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Zygote - fertilized egg, a single-celled stage of embryo development

the Greatest irony of biology that the human body is one of the most complex entity in the Universe has a very simple beginning. An adult made up of millions of millions of cells. There are ten times more than the stars in our galaxy, or, to give a more earthly comparison, ten times more than grains of sand on a small beach. All this huge number of cells piled haphazardly, but are organized in a complex structure, and despite the long history of anatomical studies, we still don't know all the details of their structure. There are hundreds of types of cells, and each has its own function and their way of life, while the cells of each specific type appear and are updated in the right quantity and in the right place. The complex structure develops from a single fertilized egg. And modest cells, apparently devoid of any special features. And from the very beginning a gradual complication of the human body occurs in the mode of self-organization: he must act independently without any assistance.

the First step to a complication – the transition from one cell to many. This is due to simultaneous occurrence of a large number of different processes. For example, right now you breathe, digest food and create the body of harmful substances; your hair grows, the skin is refreshed, blood is filtered, the immune system fights disease causing bacteria, the body temperature is regulated; you listen, read and think, and now that you have read this offer until the end of may also listen to your body. These processes, like many others, operate with specific proteins and biochemical mechanisms. Many of these processes can not occur in the same place. For example, imagine that in one and the same place of the mother's body produces milk for the child and then to digest the milk, which she drank with tea. There are other examples of processes that are incompatible for more complex reasons: because of the specific structure of proteins or the functioning of genes.

Complex organisms cope with this problem due to the compartmentalization principle of the separation processes in space. The body is made of organs having a specific function, organs, specialized tissues and tissues from different types of cells. However, inside the cell a large part of the molecules is constantly in motion, which is difficult to achieve simultaneous execution of many operations. Compartmentalization exists on the cell level. However, "multitasking" cell has its limits. Therefore, we will assume the cell is the basic unit that performs only one or two cases. That is why the diversity of cell types is a necessary step to the creation of a complex organism.

the Mechanisms by which one cell turns into two and then into many cells, not only fundamentally important for embryonic development, but clearly demonstrate the possibility of self-organization. Small simple molecules can organize themselves into highly complex structures that have much larger spatial scale than the molecules themselves, and without any preliminary plan. This is the cornerstone underlying the understanding of embryo development. Therefore, we elaborate on the mechanisms of cell division, and will continue to take them for granted.

the Fertilized egg, which begins the development of man, unusually large. It reaches a tenth of a millimeter in diameter and visible to the naked eye. Most of the body cells is much smaller: approximately hundredth of a millimeter in diameter and a thousandth of the volume of the egg. This means that the fertilized egg can turn into a multi-celled embryo simply divided into two, then four, eight and so on, without interruption in the growth. This type of cell division – fragmentation – very convenient for the embryo, as it allows to postpone the problem of the food providing the energy for growth, - for then, namely, the stage when the embryo has become multicellular and are able to allocate to processing food specialized parts of the body.

If you do not need to grow the division process is reduced to the distribution of molecules (e.g., proteins) equally between the daughter cells. The essence of the division at constant scope is to maintain the concentration of proteins and nutrients. A bright exception to this rule is the DNA molecule: the source cell of forty-six chromosomes (twenty-three from the mother and twenty three from dad), and each new cell must contain the same number. Therefore, chromosomes must be copied (replicated) before every cell division. Moreover, there should be a special system that guarantees a "fair" distribution of replicated chromosomes in daughter cells – each of them should not get any forty-six chromosomes, and one copy of each chromosome from father and one from mother. System which provides this difficult task is one of the main systems of the cells of animals and plants and has existed for about 2.5 billion years. A couple million years ago there were creatures that are in principle able to understand how it works.

the Copying of DNA – the simplest and the most ancient part of the process, it has at least 3.5 billion years. It is based on the fact that DNA molecules exist in the form of a pair of nucleotide chains (sometimes referred to as "threads"). The adenine on one chain always corresponds to thymine on the other chain, and cytosine – guanine. This is a strict rule that is associated with the chemical structure of nucleotides, means that each chain contains all the necessary information about the sequence of neighboring chains. DNA replication begins with the enzyme complex separates two parent chain from each other. He then collects a new chain for each of them, linking the nucleotides in the order of the original circuit. Each new circuit connected to the old, which were for her the matrix. The result is two DNA molecules instead of one. That is replicating DNA. Proteins are wrapped in DNA, are added immediately after copying.

After replication of the forty-six chromosomes, single-celled embryo should be distributed so that each daughter cell will get one copy of each maternal chromosome and paternal chromosome of each. This process can be divided into several stages:

1) determination of the centers of the two daughter cells;

2) alignment of all chromosomes copied between these centres;

3) "Stripping" of copies – one copy of each pair moves to each daughter cell;

4) separation of daughter cells from each other. Each of these stages involves a coordinated action at a spatial scale significantly exceeding the sizes of the involved molecules.

the entire process should proceed without bias, despite the fact that the exact location of the major components (chromosomes, for example) will constantly change. So all these steps rely heavily on adaptive self-organization and can serve as a great example to illustrate this principle.

the First problem is to identify centers of new daughter cells. The easiest way to understand how to determine the centre in a typical adult cell that is not going to share, but simply is at rest. At first glance the problem seems simple. However, upon closer examination, things get complicated. Cells do not have a clear form: it depends on their environment. This eliminates any pre-prepared plan. The diameter of typical human cells – about one-hundredth of a millimeter – seems to us small, because we are composed of millions of cells. However, it is a thousand times more than the length of a regular protein molecule. However, the protein complexes somehow find the center of the cell. It would be like to run in the albert Hall deaf people with a blindfold and ask them to find the middle of it.

Cage found a very ingenious way of solving this problem. It illustrates well how important it can be trivial details of biochemical processes for the functioning of the cells. The "star" of the action tubulin is a protein whose molecules are linked together to form long structures, the microtubules. One of the features of the Assembly of tubulin molecules is that the Union of several molecules of tubulin for the formation of new microtubules is an unlikely event, but a process of joining the molecules of tubulin to existing microtubules, that is, its elongation is relatively easy. Therefore, microtubules usually are not formed spontaneously, but once they are formed they are capable of spontaneous growth.

The second feature of the biochemistry of tubulin is that each individual molecule can be in one of two States, "fresh" or "stale". "Fresh" molecules slowly become "stale". Only "fresh" molecules are able to join the ends of existing microtubules. The ends of the microtubules are stable only when they are created from fresh tubulin (if the ends remain "fresh", it doesn't matter whether the tubulin will lose the "freshness" throughout the length of the microtubule). If at the end of microtubules "stale" tubulin, the end begins to disintegrate, and the disintegration continues as long as the microtubule does not attach stable "fresh" tubulin. Given that tubulin away from the ends of the microtubule, most likely, was in its structure longer than the one that is the end of it, these "internal" molecules, most likely, has long spoiled, and "fresh" tubulin, is able to prevent the destruction of the microtubules that remained. In this case, the microtubules disintegrate. The only way to avoid the collapse, without the help of other molecules, is the rapid growth, in which "fresh" tubulin is attached to the end of the microtubule faster than destroyed "stale". Thus, microtubules are either growing rapidly or catastrophically disintegrate rapidly. There is a constant probability of failure, and this means that long tubes are always less than short. This feature is directly related to the mechanism of finding the cell centers.

the molecules of tubulin rarely spontaneously unite in the new microtubule, so in the cell there are special protein complexes that can catalyze this process. These complexes are located in key location of the cell, namely the centrosome, from which microtubules radiate out like spokes from a wheel hub. As they grow quickly enough to tubulin at their ends, they were still fresh, the microtubule will elongate toward the cell periphery. There are two theories on how they help the centrosome to the center of the cell. They are based on experimental data obtained in the study of various organisms. It is not yet clear which of them is true for human embryos, it is possible that both. One of the theories is connected with the repulsion, and the other with a pull – up.

the Mechanism of repulsion is based on the ability of a growing microtubule to push off from the inner surface of the cell membrane. If the centrosome is located close to one side of the cell, even short microtubules are able to reach the surface of the membrane and pull it through. As a result, the centrosome moves away from this side. The opposite side of the cells reach only a very long microtubules, but they are for reasons mentioned above are rare. And since such microtubules less, they will be weaker to push the centrosome from the side of the cage. This uneven distribution of forces will repel the centrosome from the nearest membrane, and it will take a stable position only when the repulsive forces will come into balance. Equilibrium also occurs when the centrosome is located at the same distance from all sides: in other words, in the center of the cell (Fig. 1, a). Scientists have placed the centrosome fabricated "cell" and proved that they were able to find the center "cell" through the mechanism of repulsion.

the lifting Mechanism based on the action of a small motor proteins distributed throughout the cell. They can contact the microtubules and move them in the direction of the centrosome. Moving to the centrosome, each of these proteins generates a force that slightly pulls the microtubule in the opposite direction, displacing it to the side of the cell membrane. So people going forward along the boat, pushing it, pushing it back. The longer the microtubule, the more motor proteins can reach her and the stronger they are for it pulled in the right direction. Thus, if the centrosome is closer to one wall of the cage than to the other motor proteins strongest pull for long microtubules directed to the far side, shifting the centrosome to the cell center (Fig. 1, b). A careful study of fertilized eggs simply organized organisms (such as sea urchin or nematode) showed that the most important role in these cells is played by the lifting mechanism. For example, if a portion of the microtubules cut with a laser, the centrosome will bounce back like she kept the strained mikrotrubocki. It is possible that in some cells both mechanisms: strong tension, long microtubules "outwards" further reduces their ability to push the centrosome and increases the imbalance of repulsive forces.

Fig. 1. Two theories explaining how the centrosome finds the center of the cell via microtubules. In the model of repulsion (a) microtubules are repelled from the cell membrane. Short tubes are always more than long. Hence, the centrosome starts stronger from the nearest cell membrane. In the model pull-UPS (b) motor proteins, distributed throughout the cell, are attached to the long microtubules. Short microtubules lot from all sides of the centrosome, and long can be formed with a remote from the membrane side. Therefore, the centrosome is pulled to the far side of the cell and is removed from the closest membrane

However, any of these mechanisms might be used by the cells of the human embryo, the result is the same: the centrosome'll centre itself automatically, although none of the involved components of the cell does not "know" its shape and is not guided to find center of any coordinate system. The system organizes itself. For such a self-organizing system, able to adapt to almost any conditions, you have to pay the energy required for Assembly of microtubules and motor proteins work; the high energy consumption is characteristic of adaptive self-organization.

During cell division it is necessary to determine not just the center of one of the cells, and the points that are the centers of the two daughter cells to chromosomes moved in the right direction. Fortunately, the cell can use the same mechanism to determine and two centers; all you need is two centrosome.

the Centrosome is composed of a "cloud" of proteins around a pair of connected together tubular structures containing tubulin. This pair is an organizational center for the material of the centrosome. In preparation for cell division the tubes are disconnected from each other, and each of them is a matrix for the Assembly of the missing partner. Thus, after some time in the neighborhood will be located two pairs of tubular structures. Each of them organizes itself around centrosomal material and initiate the formation of new microtubules radiating from the centrosome. In a cage with two centrosome radial microtubule system one "encounter" with another microtubule. In the model of repulsion of microtubules one system will start from the microtubules another system, exactly the same as from the cell membrane. The presence of the second and the second centrosome microtubule system creates a "false impression" about how close each centrosome is the cell membrane. Therefore, each centrosome is not the centre of the cell, and at a maximum distance from the other centrosome (Fig. 2). Similarly, in the model pull-UPS with each system, consisting of the centrosome and microtubules, serves as a shield for the other and does not drag the centrosome to the far side of the cell. Both mechanisms, which in human cells can work at the same time, will have the same effect: none of the centrosome is not located in the center of the cell. Instead they occupy a position about midway between the true center and the periphery of the cell (Fig. 2). Thus, the two centrosome identify future centers of the two new cells formed during division of the parent cell. Again, this happens "automatically" – the participants of the process do not "know" about the shape of the cell.

Fig. 2. When the two cell centrosome, the interaction of microtubules leads to their divergence

Radial microtubules extending from the centrosome, serve not only to determine the future of cell centers. They also contribute to the discrepancy of the double set of chromosomes to each new cell has got the full set. To make this happen, you first need to microtubules connect to the chromosomes. Again, none of the components do not require "knowledge" on the situation of other stakeholders. The system again uses the instability of microtubules, which are the periods of Assembly and catastrophic collapse. Unprotected ends of microtubules are especially vulnerable to the takedown, but if they are surrounded by special proteins are able to bind to microtubules, the situation is slightly stabiliziruemost.

In each chromosome there is one special site containing such proteins, therefore, any growing microtubule can randomly "stumble" on this site and obtain protection. Thus, a system in which microtubules diverge at random and do not die only in the case if faced with a chromosome leads to the fact that all chromosomes are "anchored" with the help of microtubules.

the Simplest connection of microtubules with the chromosomes enough to each chromosome moved to the centers of the daughter cells, but cell division requires something more. One copy of a chromosome, say the 9-th chromosome of the father, should join the microtubules of one centrosome, and the second copy should join the other microtubules of the centrosome. Thus, each of them will go in her cage. This is achieved another effect on the stability of microtubules. Two copies of each chromosome, formed during DNA replication, coupled with a special protein complexes. These complexes are in a state of mechanical tension, when the two sets of microtubules and their associated motor proteins play in the "tug of war" and trying to pull apart two copies of the chromosomes to the opposite centrosome. In this situation signal is generated, which leads to more reliable stabilization of microtubules than in the absence of mechanical stress. If both copies of a chromosome are attached to microtubules from a single system, voltage will not occur, and the microtubules will not last long. If they are attached to different microtubules centrosome, trying to pull them apart, the signal stabilization is strong enough, and the microtubules are much more likely to survive. Therefore, the system is constantly changing, continues to be at the "search behavior" until he finds the same condition in which copies of the chromosomes will be continuously pulled down in opposite directions. This method requires a lot of energy, but operates automatically and allows you to cope even with the extra chromosome appeared in the cage in the process of evolutionary change, or in experiments.

When all chromosomes are lined up, the cage can move to the next stage on the space where proteins connecting sister copies of the chromosome, release them, allowing you to shift to opposite sides of the cell. The process will not start until then, until all the chromosomes are lined up properly, otherwise the daughter cells receive the incorrect number of chromosomes and will lose important genes. Therefore, there should be a system to prevent premature divergence. Once again, use the ability of proteins connecting the copies of chromosomes, to "sense" voltage that occurs when copies of a chromosome are attached to microtubules from two different systems. When the voltage is missing, the protein complexes continue to generate the signal, a small molecule that can spread throughout the cell and block the transition to the next stage of cell division. It's like she screams "Not now!" in the language of biochemistry. Until all pairs of chromosomes are not attached to the right microtubules and will not be Stripping, the signals will continue and the cell will have to wait. Only when the tension of all protein complexes will be adjusted, the signals will cease and you can begin the next stage of division. Again, this system can adapt to any number of chromosomes.

When all chromosomes are lined up in the middle of the spindle, and the signals "Not now!" subsided, the cell is ready for the next stage. Protein complexes that connect pairs of copies of chromosomes, let them go, allowing motor proteins to freely pull the chromosomes along the microtubules to the corresponding centrosome. After all chromosomes are distributed, one automatic system places the ring of contractile proteins in the "equator" of the cell between the poles, the position of which is determined by the centrosome. These proteins can slide relative to each other, forming the drawstring "belt" of cells. The "belt" will be delayed until until the source cell is not divided completely into two new ones.

the above-described system may seem very complex and confusing. However, if their device can figure out sequentially, component by component, they are very simple. Each protein has its own simple task. The system's ability to perform complex tasks such as the detection and separation of the sister chromosomes, regardless of their original position in the cell is provided by interaction of the simple components of the system, not their complexity. In particular, it stems from the fact that there is an inverse relationship between the behavior of system components and of the information they receive about the state of the system as a whole, at what stage of a process it is at the moment (for example, whether all chromosomes to the desired position). The use of simple components linked into a single whole through the close system of feedback is typical for living matter, I delved into the details is to show how the system "stupid" biological molecules can organize themselves to solve serious problems, in other words, to show how simple complicated.

Systems, which launched the first cell division, continue to work in the cells of the embryo, and now we won't discuss them in such detail. It is typical for biology: if the mechanism works, it can be reused, sometimes with minor amendments, during the entire embryonic development. Almost immediately after the first cell division is completed, each of the two resulting cells begins to replicate chromosomes and divide. It turns out the embryo of four cells. Synchronous cell division continues for some time, but sooner or later synchrony of division in different cells is lost, and from the stage about sixteen cells, the number of cells of the embryo starts to deviate from the value of "two to the power n". As a rule, the cells of the early embryo, resulting in the course of crushing are fairly freely relative to each other. Sometimes, about once in twelve hundred cases, cells break up into two separate lump. From each clump will separate the embryo, which will have its own placenta and membranes. This is one of the three options of birth of identical twins, and accounts for about one third of all cases. The fact that the embryo may divide and give rise to two babies, tells us about the very important features of the development: all the cells must be able to create any part of the body, and there is one special cell which corresponds, for example, for the creation of the head or deterministic as the cell head. If the cells from the beginning were different, if one or more of the cells were determined by making specific parts of the body or if one cell was responsible for the whole process, the separation of the embryo would lead to the fact that at least one of the halves would not have been of vital cells and its development would be doomed to failure. However, thousands of living in each country, identical twins are eloquent testimony to the equal opportunities cell at early stages of crushing.

so, the embryo reaches a stage of approximately sixteen cells. This means that he has enough cells to change the shape of the body and to begin cell differentiation, i.e. to make cells different. The prelude is over, and starts substantive work on the embryonic development.

the Passage from the book Jamie Davis "the Ontogeny. From cell to man"

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