Cells function as independent units, carrying out their own metabolism and activities, while at the same time receiving signals from countless neighboring cells, interpreting those signals, and actively responding to them. A cell can function on its own as an autonomous unit, yet it also constantly communicates and cooperates with other cells. That is why cells can come together to form higher-level structures such as tissues and organs, allowing the entire organism to carry out its life processes in an orderly way. After all, doesn't even a single-celled organism function as a complete living organism on its own? This alone shows that a cell is not simply a component of a larger structure, a kind of biological “part,” but the basic unit of life itself.
Multicellular organisms, including us humans, can therefore be thought of as highly sophisticated cooperative systems made up of countless independent units. That is why comparing the human body to a machine assembled from countless parts according to a predetermined blueprint seems, in a word, like an absurdly inadequate metaphor that underestimates the true nature of cells. Machine parts do not make their own decisions or actively respond to their environment. The cells that make up our bodies, however, can sense their surroundings, interpret signals, and regulate their own activities. They are independent living units in their own right.
Cell Identity and DNA
So how does a cell know what kind of cell it is, and how does it carry out the functions appropriate to its identity? The identity and function of a cell are closely connected to its genetic material, namely DNA. As we saw in the previous articles on proteins, cells can have essentially the same DNA information and yet have completely different appearances and functions. Why? Because not every cell uses the information stored in its DNA in exactly the same way. Depending on its role and its surrounding environment, a cell selectively uses the genes it needs and, as a result, produces different proteins. For example, neurons and liver cells basically contain the same genetic information, but they use different genetic information and produce different proteins. That is why one becomes a neuron specialized in transmitting signals, while the other becomes a liver cell that carries out various tasks related to metabolism. Ultimately, which information a cell uses and which proteins it produces form an important foundation for determining the cell's characteristics and functions.
And cells divide in order to maintain their own identity and pass that identity on to new cells. In other words, cell division is not simply a process for increasing the number of cells. It is a fundamental process of life in which a cell accurately copies its genetic information and passes it on to new cells, allowing its identity to be maintained and the organism as a whole to grow and survive.
So let's take a closer look at cell division. Not all cells divide in the same way. Cells can broadly be thought of as somatic cells and germ cells, and the purpose and method of division are different for each.
Classifying Somatic Cells by When They Divide
Let's take a moment to look at when somatic cells actually divide. Somatic cells can broadly be divided into three groups depending on whether they divide continuously, divide only under certain conditions, or no longer divide at all.
First, there are continuously dividing cells (proliferative cells). Think of the cells in our body that constantly need to be replaced. Cells lining the intestinal tract, which are shed every day as part of our feces, blood-forming cells, and skin cells are constantly being lost or damaged. Stem cells and progenitor cells therefore have to keep dividing to produce new cells and replace them.
Second are cells that divide only when the conditions call for it. Under normal conditions, these cells stop dividing and remain in a quiescent state, essentially resting until there is a physiological need or tissue damage that requires them to resume division for repair. Typical examples include hepatocytes and fibroblasts. Vascular endothelial cells also divide very slowly under normal conditions, but they can divide actively when blood vessels are damaged and new vessels need to be formed.
Finally, there are cells that no longer divide once they have completed their differentiation. These are called post-mitotic cells. Most neurons and cardiac muscle cells fall into this category. Once these cells have fully differentiated, their ability to re-enter the cell cycle is very limited, so they have little capacity for regeneration when damaged. Sometimes I wonder whether we should actually be grateful that neurons are not constantly being replaced. If they were, perhaps our memories would not last very long.
Reproductive Cells Differ Between the Sexes
So do reproductive cells also divide continuously or only under certain conditions? The answer is that the process of producing reproductive cells is quite different in males and females. In males, spermatogonia continue to divide and produce new sperm, so sperm production continues throughout adulthood.
In females, however, the process is somewhat different. Eggs are not produced continuously after adulthood in the same way that sperm are. Oocytes begin to form during fetal development, and most are formed by around the time of birth. They then remain stored in ovarian follicles. After puberty, some of these oocytes go through maturation and are ovulated. In other words, females generally work with a supply of oocytes that were formed earlier, with individual oocytes maturing and being ovulated over time.
I used to think that all the countless cells in our bodies must be dividing vigorously all the time. I assumed that even after growth was complete, most cells would still have to keep dividing. But the reality is somewhat different. It was quite surprising. In an adult body that has finished growing, most of the cells in our bodies are non-dividing cells, while tissues that continuously produce new cells are relatively limited in number. Some cells can resume division when needed, but overall, cell division is actually quite limited. If cardiac muscle cells could divide as actively as skin cells, the heart might be able to quickly produce new cells after damage and completely recover. If that were the case, heart diseases such as myocardial infarction might look very different from what they do today.
But, as is so often the case, there must have been good reasons why evolution favored minimizing cell division. If new heart cells were constantly being produced, their electrical signals would have to be precisely coordinated with those of the surrounding cells every time new cells were added. If something went wrong in that process, couldn't problems such as arrhythmia potentially arise? Thinking about it this way, minimizing cell division actually seems like a very reasonable strategy.
Cell division requires a great deal of energy and material, and the DNA replication that has to take place beforehand also creates opportunities for errors or DNA damage to occur. If these errors accumulate over time, they can interfere with cell function and may even lead to diseases such as cancer. So rather than having every cell constantly produce large numbers of new cells, it seems quite reasonable that living organisms evolved a strategy of producing new cells only where and when they are needed, while keeping the rest as stable as possible. From the perspectives of energy efficiency and genomic safety, this seems like a remarkably sensible solution.
This becomes even clearer when we look at cancer cells, in which the regulation of cell division has broken down.Cancer cells escape the normal controls of the cell cycle and continue dividing and proliferating, eventually taking over surrounding tissues and potentially the entire body. Here, an interesting question comes to mind. Wouldn't large animals with enormous bodies and huge numbers of cells, such as whales and elephants, be much more likely to develop cancer than humans? As the saying goes, “The more branches a tree has, the more likely it is to be disturbed by the wind.” If there are more cells, it seems intuitive that there should be more cell divisions and therefore more opportunities for errors to occur during DNA replication. Surprisingly, however, this is not actually the case. This phenomenon is known as Peto's paradox. Large animals such as whales and elephants do not appear to have cancer rates as high as we might expect from their enormous body size and number of cells. One possible explanation is that these animals have evolved stronger systems for controlling cell division, detecting and repairing DNA damage, and eliminating cells that have become dangerous. So, what matters is not simply how many cells there are, but how safely those cells are managed. This is another fascinating example of just how important it is for living organisms to regulate and limit cell division with great precision.
Now let's take a closer look at cell division.
Mitosis and Meiosis
Cell division can broadly be divided into mitosis and meiosis. We have already divided cells into somatic cells and reproductive cells. Mitosis is mainly the type of division used to increase the number of somatic cells and maintain and grow tissues, whereas meiosis is a special type of division used to produce reproductive cells such as sperm and eggs. As its name suggests, one of its defining features is that it reduces the number of chromosomes by half.
The purposes of the two types of division may be different, but they share one important feature. Before a cell actually divides into two, it must first replicate its DNA. And this preparation process is much more important and complicated than we might imagine.
Preparation for Cell Division: Interphase
Before dividing, a cell first needs to grow to an appropriate size. Before distributing its DNA between two daughter cells, it must first replicate the DNA once. The seriousness of this process hardly needs to be emphasized. The cell carefully checks at multiple stages to make sure that the genetic information is properly replicated and that the process is proceeding without major errors. The entire preparation period is called interphase. Interphase can be further divided into three stages: G1, S, and G2.
During the G1 (first gap) phase, the cell begins actively preparing at the biochemical level. It gathers the materials needed for DNA replication and stores the energy required for the process. Its organelles are also actively functioning, and various preparations for DNA replication take place.
The S (Synthesis of DNA) phase is the stage in which DNA replication actually occurs. DNA polymerase copies the DNA, and each replicated chromosome now consists of two nearly identical sister chromatids. These sister chromatids remain attached to one another by a protein complex called cohesin, allowing them to be separated accurately later. The connection is particularly strong around the centromere. During this period, the centrosome, a cellular organelle involved in organizing microtubules, is also duplicated. The two centrosomes later move toward opposite sides of the cell and prepare to form the mitotic spindle, which will pull the chromosomes toward opposite poles.
Finally, during the G2 (second gap) phase, the cell makes its final preparations for division. Additional cellular components and organelles may be prepared, and the cell makes a final check to ensure that the DNA has been replicated correctly. The cytoskeleton is also reorganized into a form suitable for cell division. At this point, the cell is fully prepared to enter M phase, the stage in which the chromosomes are actually separated.
When we think of cell division, we often imagine the dramatic moment when chromosomes are pulled apart toward opposite sides of the cell. But if we look at the cell cycle as a whole, the actual division is remarkably short compared with the preparation that comes before it. In human somatic cells, the M phase (Mitotic Phase), typically takes only several tens of minutes to about an hour, while interphase can last for several hours to several tens of hours and accounts for most of the cell cycle. In other words, the moment we think of as “the cell dividing” is actually the final grand finale of a much longer preparation process.
Now let's see what happens once a cell has completed all of that preparation. First, let's look at mitosis in somatic cells
Mitosis
Once all the preparations have been completed during interphase, the M phase, or Mitotic Phase, begins. This is when the chromosomes are actually separated and the cell is divided into two. [1] Mitosis itself can also be divided into several stages.
First, during prophase, the chromosomes that have already been replicated begin to condense into clearly recognizable chromosome structures as they become more tightly coiled with the help of condensin proteins. Membrane-bound organelles such as the Golgi apparatus and endoplasmic reticulum also become reorganized for the division process, with their membranes becoming fragmented into smaller structures. Meanwhile, the centrosomes begin moving toward opposite poles of the cell.
During prometaphase, the nuclear envelope breaks down, and spindle fibers extending from the two poles attach to the chromosome around its centromere.
During metaphase, the chromosomes line up neatly along the middle of the cell. At this point, the cell checks once again whether the chromosomes are properly attached and ready to be divided accurately.
Anaphase is the critical moment. The sister chromatids that had been held together finally separate and are pulled toward opposite poles of the cell by the action of the spindle. In this way, the replicated genetic information is accurately divided and delivered to both sides.
During telophase, new nuclear envelopes form around the chromosomes that have arrived at the two poles. The condensed chromosomes also begin to loosen and return to their more relaxed chromatin state. At the same time, cytokinesis takes place. The cytoplasm and cellular components are physically divided into two parts, and finally one cell becomes two separate daughter cells. The cell division cycle is now complete.
Mitosis basically occurs to increase the number of somatic cells and maintain tissues. Cells that retain the ability to divide repeat this cell cycle and continue producing new cells. But not every cell keeps dividing. Some cells can leave the cell cycle under normal conditions and remain in a long-term G0 state, which is often referred to as a quiescent state. The cell itself continues to function normally, but because there is no immediate need for division, it simply stops dividing. Some cells can return to the cell cycle and divide again when needed. Others, such as neurons and cardiac muscle cells, can remain in a long-term non-dividing state and are described as post-mitotic cells.
Meiosis, on the other hand, has a completely different purpose. Meiosis is a special type of cell division used to produce sperm and eggs. If mitosis essentially copies genetic information and distributes the copies to two cells, meiosis reduces the number of chromosomes by half and mixes genetic information inherited from both parents to create new combinations.
Meiosis
Now let's take a closer look at meiosis. Like mitosis, meiosis begins with a preparation stage that includes DNA replication. The difference is that the cell then undergoes two successive divisions, ultimately reducing the chromosome number by half. During the first division, the homologous chromosomes inherited from the parents are separated. During the second division, the sister chromatids that were replicated and held together are separated.
And during this process, a very important event occurs that helps create genetic diversity: crossing over. Once DNA has been replicated, as we saw earlier, each chromosome consists of two identical or nearly identical sister chromatids, which remain attached to one another by cohesin. In mitosis, these sister chromatids are simply separated from one another and distributed to the daughter cells. In meiosis, however, the homologous chromosomes first pair up and exchange portions of their genetic information before the chromosomes are separated. This may well be one of the most important moments in meiosis. To understand it better, let's first go over a few key concepts.
Homologous Chromosomes
Most plants and animals, including humans, are diploid organisms, meaning that they inherit one set of chromosomes (n) from each parent, giving them two sets of chromosomes in total (2n). Therefore, human somatic cells contain 23 pairs, or 46 chromosomes. The chromosomes inherited from the father and mother that make up each pair are similar in size and shape, and the same kinds of genes are arranged in the same order on them. Although they are not 100% identical, they are similar enough to be considered corresponding copies, so they are called homologous chromosomes. For example, chromosome 1 inherited from the father and chromosome 1 inherited from the mother form a homologous pair. They contain the same genes, but the DNA sequences of those genes can differ slightly. These differences allow different versions of the same gene to exist. In humans, the 22 pairs of autosomes are all homologous pairs. In females, the sex chromosomes (XX) can also be regarded as a homologous pair. In males, however, the X and Y chromosomes are visibly different and differ considerably in their gene content, so they are not homologous chromosomes in the usual sense.
Alleles: Dominant and Recessive Are Relative Concepts
Different versions of the same gene that occupy the same locus on a pair of homologous chromosomes are called alleles. For example, suppose a particular gene has two versions, A and a. Since an individual normally inherits one copy from each parent, that individual usually has two alleles for that gene.
These alleles are related to the concepts of dominance and recessiveness. Dominant and recessive do not mean that one allele is a “good gene” and the other is a “bad gene.” They are relative concepts used to describe which phenotype appears when the two alleles are present together. In other words, if an allele's effect is expressed in the phenotype when it is present, that allele is described as dominant, whereas an allele whose phenotype is generally masked when paired with a different allele is described as recessive. So dominance and recessiveness describe a relative relationship between alleles in a particular genetic context.
Let's digress just a little and talk about this a bit more. One allele does not always hide the other. Sometimes the characteristics of both alleles appear together. This is called codominance. A classic example is the ABO blood group system. The ABO blood group gene has three major alleles: A, B, and O. The A allele produces an enzyme that creates the A antigen, while the B allele produces an enzyme that creates the B antigen. The O allele has lost the functional activity needed to produce these antigens. Looking at their relationships, A and B do not mask each other's effects. When both alleles are present, both A and B antigens are expressed, making the AB blood type possible. O, on the other hand, is a nonfunctional allele. When it is paired with A or B, its effect is not expressed, so it behaves as a recessive allele. Thus, AO produces type A, BO produces type B, and only OO produces type O. As a result, the ABO system produces four major phenotypes: A, B, AB, and O. The important point here is that A and B do not hide each other; both are expressed together.
Codominance and MHC Molecules
This concept of codominance is actually very important in the immune system. Our immune system is constantly checking a fundamental question: “Is this cell one of my body's normal cells?” Being able to distinguish self from non-self is extremely important to the immune system. To help with this, cells display molecules called the Major Histocompatibility Complex (MHC) on their surface, essentially identifying themselves to the immune system.
MHC molecules are broadly divided into class I and class II. Most nucleated cells display MHC class I molecules on their surface, much like an identification card. Along with these molecules, cells present small fragments of proteins that were made inside the cell and later broken down. A passing T cell can examine the peptide displayed on MHC class I and monitor whether the cell appears to be in a normal state or whether it may be undergoing something abnormal, such as a viral infection or cancerous transformation. It is somewhat like a cell constantly posting an internal report about what is happening inside itself, while immune cells pass by and inspect those reports. If the cell is recognized as abnormal, cytotoxic T cells can attack and eliminate it. Viruses and cancer cells can sometimes try to evade this system by reducing or interfering with MHC class I presentation. When cells fail to display the expected MHC class I signals, NK (natural killer) cells can recognize this “missing self” pattern and attack them as well.
MHC class II is a little different. MHC class II molecules are mainly used by specialized antigen-presenting cells, such as dendritic cells, macrophages, and B cells. After these cells take up pathogens from outside the cell, they process them and display fragments of those pathogens on MHC class II molecules at the cell surface. Other immune cells, particularly helper T cells, can then recognize these presented peptides and initiate a broader and more coordinated immune response. In this way, MHC molecules play an important role in helping the immune system distinguish self from non-self and monitor the state of cells.
So what does all of this have to do with codominant alleles? In humans, MHC genes are commonly referred to by the special name Human Leukocyte Antigen (HLA). Representative MHC class I genes in humans include HLA-A, HLA-B, and HLA-C, while class II genes include HLA-DP, HLA-DQ, and HLA-DR. This is where HLA becomes a particularly difficult issue in organ transplantation. The immune system of the transplant recipient can recognize the HLA molecules on the surface of cells in the transplanted organ as foreign. That is why doctors try to find donors whose HLA types match the recipient's as closely as possible. But the problem does not end there. HLA genes are codominantly expressed. In other words, cells can simultaneously display multiple HLA molecules inherited from both parents. This means that the immune system has many different molecular features by which it can recognize a transplanted organ as foreign. As a result, finding a close match becomes much more difficult. It is like trying to find a key that fits a door. That would already be difficult enough, but imagine that the door has several locks, all of which have to match before the door can be opened.
The codominant expression of HLA genes is extremely useful under normal circumstances because it broadens the range of molecular information available to the immune system for surveillance. But in organ transplantation, the same feature can become a major obstacle because it makes it much less likely that two unrelated people will have sufficiently similar HLA types, making it harder to minimize immune rejection and achieve a successful transplant.
Crossing Over
Now that we have looked at homologous chromosomes and another important concept related to them, HLA genes, let's turn to what may be one of the most important events in meiosis: crossing over. The chromosomes replicated during the preparation stage of interphase remain closely connected. The homologous chromosomes inherited from the father and mother each now consist of two sister chromatids. Unlike mitosis, where sister chromatids line up vertically at the center of the cell and are divided equally to opposite sides, during prophase I of meiosis, the two sets of homologous chromosomes line up side by side. In other words, if one chromosome inherited from the father pairs with the corresponding chromosome inherited from the mother, we can imagine all four chromatids—two from the paternal chromosome and two from the maternal chromosome—lined up alongside one another. In this arrangement, portions of DNA are exchanged between non-sister chromatids, meaning chromatids originating from the paternal and maternal homologous chromosomes.
If we observe under a microscope the point where the chromatids appear to cross in an X-shaped pattern, that visible structure is called a chiasma. These structures can appear at multiple locations, and their number varies depending on the species and chromosome length. As chromosomes inherited from the parents are mixed in this way, new combinations of genes are created. This is one reason why even siblings born to the same parents can have somewhat different genetic characteristics. Crossing over is one of the major reasons meiosis generates genetic diversity.
After genetic recombination has occurred through crossing over, the homologous chromosomes line up at the center of the cell. This is metaphase I. They then move toward opposite poles and separate during anaphase I. Because each pair of homologous chromosomes is divided between different cells, the chromosome number is reduced by half. This is meiosis I. The important point here is that it is the homologous chromosomes, not the sister chromatids, that separate first. Each chromosome therefore still consists of two sister chromatids. The stage in which these sister chromatids finally separate and become independent chromosomes is meiosis II.
Meiosis II is very similar to mitosis. The chromosome sets line up at the center of the cell and are then pulled toward opposite poles and separated. Because the homologous chromosomes have already been separated into different cells during meiosis I, the chromosome number is already reduced by half. After crossing over and the separation of homologous chromosomes, the cells enter the second division while the sister chromatids remain attached. During meiosis II, the sister chromatids are finally separated. After prophase II and metaphase II, the cell reaches anaphase II. The cohesin holding the sister chromatids together around the centromere is broken down, and the sister chromatids finally separate.
In the typical male pathway, one diploid precursor cell ultimately gives rise to four haploid cells. In other words, the process can be thought of as: DNA replication → crossing over and separation of homologous chromosomes → separation of sister chromatids. Through these steps, one cell ultimately gives rise to genetically different haploid cells. Meiosis does more than simply reduce the chromosome number by half. It also mixes genetic information and creates new combinations.
As we have taken a closer look at cell division, we can now see that cell division is not simply a process for increasing the number of cells. Whether a cell is passing its identity on to a new cell or passing genetic information on to the next generation, the DNA it contains must first be accurately copied and then properly distributed. In mitosis, genetic information is passed on to two daughter cells as faithfully as possible. In meiosis, genetic information is mixed through crossing over to create new combinations.
At the center of all these processes is DNA, the molecule that carries the information of life. Now it is time to take a closer look at what DNA actually is.
[References]
[1] Cell Proliferation
https://www.ncbi.nlm.nih.gov/books/NBK12640/
