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Erythrocytes

Erythrocytes are more commonly known as red blood cells, and are specialized cells that circulate in the bloodstream of animals with closed circulatory systems. These cells are unique in that they function almost exclusively as a means of transporting oxygen from the lungs (or gills) to the tissues in the rest of the body. Beyond this function and the related function of returning carbon dioxide from the tissues to the lung cells, red blood cells do very little when it comes to active biological processes, and indeed in mammals they even lack DNA and thus cannot create their own proteins once they have been generated. Despite having only one main function and little autonomy, red blood cells are essential to life and are indeed synonymous therewith, as the red color of blood is thanks to these cells, underlying their intimate association with human vitality and mortality. This article serves as a basic introduction to the structure, function, and other related areas of red blood cells, and is complete with references for those who wish to learn more about certain aspects of these fascinating and essential cells.

Basic Structure and Blood Types

Red blood cells in mammals are fairly unique in their structure, as they do not have a nucleus in their center. The nucleus is the region of the cell that contains that cell's DNA which codes for the various proteins that drive the cell's functions and determine how it responds to various circumstances. As red blood cells mature, their nuclei and the DNA contained therein are actually expelled from the cell and are degraded by other types of blood cells (discussed below), meaning that mammalian red blood cells do not have any nuclear DNA and cannot generate new proteins as a result. Other species still have nuclei and DNA in their red blood cells, and this phenomenon seems to be fairly restricted to mammals and a select subset of other species. Why this enucleation occurs is not clear and is up for debate, as are many matters of evolutionary science. One hypothesis is that the elimination of the nucleus from the red blood cell freed the rest of the genome to grow in size and complexity. The reason for this hypothesis is that red blood cells need to be compact and efficient in order to deliver oxygen to the rest of the body at sufficient levels to support survival. If the nucleus is present in these cells, then it takes up a good bit of space and reduces their efficiency, meaning that the nucleus cannot grow much larger without compromising the circulatory system. The organism's DNA is thus kept in check, until the species mutates to eliminate red blood cell nuclei, thus freeing it to mutate more readily with the potential to accumulate far more DNA.

upload.wikimedia.org_wikipedia_commons_2_24_red_white_blood_cells.jpg

Aside from their lack of nuclei, red blood cells are also noteworthy for being composed almost entirely of a single type of protein. Proteins are the functional components of most biological systems, and are constructed from a simple set of building blocks known as amino acids which endow them with certain properties and which allow them to perform a huge range of functions. As such, most cells express a wide variety of different proteins that are able to participate in a large array of processes such as immune responses or breakdown of sugars into cellular energy. In contrast, red blood cells are composed of 96% hemoglobin and 4% other proteins, demonstrating just how specialized they are to their function of oxygen delivery, as hemoglobin is the protein which is involved in oxygen binding in the lungs and transport to the external tissues for use. The cells contain enough other proteins to allow them to function and remain alive and metabolically active for their life span, but beyond their specialized oxygen delivery functions these cells are able to do little else owing to their lack of most proteins and their inability to make more due to a lack of a nucleus.

Anyone that has ever had blood drawn or has donated blood does have some additional familiarity with proteins that compose the remaining 4% of proteins found on red blood cells. Specifically, certain surface proteins on these cells are used to classify them into broad groups. The most common and well known of these groups is the A B O system of blood typing, in which people are classified based on whether their blood cells express one of two specific proteins on the surface of their cells. This protein comes in two forms (A or B), and some patients express neither A nor B (O patients). Each person has two copies of the gene encoding this blood group protein, meaning that a given person might have a blood type that is O (two copies of the O gene), A (one or two copies of the A gene), B (one or two copies of the B gene), or AB (one copy each of the A and B gene). In addition, there are other groups of proteins that can be used to classify blood cells based on whether or not they are present on the surface of cells. Another commonly referenced blood type group is the Rh blood type system, for which one is said to be wither positive (has the Rh protein on their red blood cell surfaces) or negative ( does not have the Rh protein on their red blood cell surfaces). Thus, a person might be of the blood type O-, or AB+, or any other possible combination thereof.

What the biological significance of these blood group proteins are is uncertain and why the different alleles exist is not clear, however they are very important for people receiving blood transfusions. If the body receives blood of a type with which it is not familiar, then it will interpret these cells as being foreign and potentially pathogenic or cancerous. As such, the body will target them for destruction, leading to hemolysis of these cells. Because the molecules contained in hemoglobin can be highly toxic to other tissues, and because the death of red blood cells means that they will not be able to transport oxygen to tissues, hemolysis is very problematic when it occurs in large amounts. For this reason, it is essential that blood transfusion recipients receive blood types with which they are compatible. As a general rule of thumb, patients are compatible with any blood type that they themselves express, as well as any blood type that involves the absence of a surface protein (as the immune system does not recognize the lack of these proteins as being a problem). For example, if someone has type A- blood, then they can receive blood from a type A- or O- donor as they are compatible with these donors, but they cannot receive blood from someone with type B blood, or from anyone that is Rh positive. This means that someone with type AB+ blood can receive blood from anyone (“universal recipient”) and someone with type O- blood can only receive blood from other O- donors even though anyone else can use their blood in a transfusion (“universal donor”).

While blood type is very important in the context of transfusions and blood donations, in most other contexts it has little relevance even within the field of biology. Ones blood type does not determine the function of one's own organs in other contexts, and indeed does not even affect the function of other cells that are also present alongside the red blood cells in the bloodstream. Even so, blood type is a trait that most people are very familiar with, and because it is used to classify people into groups, some people try to use it to predict things about these groups of people. For example, in Japan and Korea there are popular tests that predict ones personality based on their blood type, and these tests are widely used (although not necessarily widely respected). Furthermore, there are certain so called “blood type diets” which claim that the blood type a person has determines how their body processes food, and thus if people want to lose weight then they need to eat a diet that is tailored to their blood group. While these blood based classifications may have come into vogue in a time when what constituted a blood type was still being understood, it is now clear that none of these factors are predicted by blood type and as such it is ludicrous to use blood type for planning anything other than blood transfusions. Nonetheless these diets and tests persist, preying on the ignorant and the gullible alike.

Hemoglobin and Oxygen Transport

As mentioned above, red blood cells function primarily to transport oxygen to the tissues of the body from the lungs, and to transport carbon dioxide from the tissues back to the lungs to complete the gas exchange cycle. Hemoglobin is the protein that is involved in oxygen transport, and as it composes 96% of the protein in the red blood cell it is no surprise that this protein determines the majority of the characteristics of the red blood cell and its physical and chemical properties. Each hemoglobin protein is actually composed of four identical subunits that associate in a round, rough globular shape (hence “globin” in the protein name). Each of these subunits is in turn composed of protein structures that contain a central chemical compound known as heme, which is the portion of hemoglobin that is responsible for storing and transporting oxygen. Heme is fairly unique among biological molecules in that it contains an iron molecule in its center. This iron molecule is essential for the protein to bind oxygen, and is what gives the red blood cells their characteristic coloration (the color is bright red when oxygen is bound, and darker red when oxygen is not bound; blood cells are never blue, this is just a trick of light). Heme is also the reason why people need to eat iron in their diet, why blood has a metallic taste to it, and why people with anemia are told to eat more iron.

Red blood cells constantly circulate throughout the body at all times, and it is this circulation that enables them to take oxygen from the lungs where it is inhaled and disperse it to all of the cells of the body, which require oxygen in order to generate energy. In smaller organisms, sufficient oxygen can be obtained directly from the environment and there is no need for red blood cells or for lungs, however in larger organisms a circulatory system and specialized cells and lungs is the only known way to efficiently provide all tissues with the oxygen they need to function. This issue is one that commonly comes up in biology and is partially related to the fact that there is not a linear relationship between surface area and volume, and as a result the larger an organism grows, the more its volume outpaces its surface area, creating increased energy demands that in this case cannot be met through passive absorption of oxygen through the skin.

Heme is able to bind oxygen fairly well without binding it irreversibly thanks t the chemical properties of the iron molecule located in its core region. When red blood cells pass along the capillaries of the lung and come into close contact with the alveoli, there is a very high local concentration of oxygen particles and low pressure, which favors the binding of oxygen to heme, causing the blood cells to become oxygenated. As the blood cells leave the lung, they begin to encounter conditions that favor the release of oxygen from hemoglobin. These conditions include increased stress, lower (more acidic) pH, certain chemicals in the local blood, and a lower amount of oxygen. As red blood cells encounter these conditions and begin to shed all of their oxygen, this oxygen enters into nearby cells where it is used to make new energy in a process that involves the breakdown and processing of sugars into a substance known as ATP. Carbon dioxide is the end product of this energy production in cells , and they release it as they take up new oxygen. This carbon dioxide is able to bind to red blood cells that no longer have oxygen bound to their hemoglobin, although it does so weakly. Because this binding is weak, when the blood cells make it back to the lungs the carbon dioxide is displaced by oxygen and is released into the lungs where it is dispersed by exhalation, completing the cycle of gas exchange. Note that not all carbon dioxide is bound to hemoglobin, and that much of it is in fact removed from the body after being dissolved in the blood as the chemical compound sodium bicarbonate.

Red blood cells are able to deliver oxygen to all the cells of the body thanks to the complex network of veins and capillaries which permeate the space between all cells of the body and ensure that they all have access to oxygen. Without this access, these cells enter a state known as hypoxia which is normally toxic and prevents cell survival. Unfortunately, some tumors are able to survive in hypoxic conditions, allowing these cancers to survive even if they have a reduced blood flow, although they still need some oxygen to be able to grow and survive. Most cells are not good at storing oxygen and must use it immediately upon receiving it from red blood cells. Muscle cells, however, are only in need of oxygen for quick bursts of activity and as a result are specialized to temporarily store oxygen. They do so by binding it to a protein called myoglobin which is structurally and functionally similar to hemoglobin, and which holds onto the oxygen until the muscle cell is active at which point it is released, thereby allowing the muscle cell to generate the energy that it needs to carry out its contraction.

Storage and Degradation

Red blood cells are made throughout your life and are replenished as needed. New red blood cells are created from the hematapoetic stem cells present in your bone marrow and are frequently replaced. In a healthy individual, the average red blood cell can live anywhere from 80 to 120 days, during which time it will primarily recirculate through the body and continuously distribute oxygen to the tissues. Because new blood cells are constantly being generated, it is necessary for the extant cells to eventually be degraded in order to prevent an excess of blood from developing. Because new cells are constantly being produced, someone that gets a transfusion of bood due to an injurt or illness will be able to replace the transfused red blood cells from the blood donor as those donated cells begin to degrade over time, thereby restoring their blood back to normal and allowing them to eliminate the need for blood from external donors. Additionally, because people can regenerate blood over time, it is possible for people to donate their blood banks in the first place. We have more blood in our bodies than we absolutely require to live, so it is possible for us to donate a pint of blood every few months without causing any negative effects on our own health. This blood is simply replaced over time, with the only real risk being that you will feel lightheaded due to decreased blood flow temporarily after donating.

New red blood cells are generated in the bone marrow, and once they have developed and expelled their nuclei they can enter into the circulation in the bloodstream. Alternatively, these red blood cells may move to an organ known as the spleen which his located on the left side of the human body near the stomach. The spleen is composed of two major sections - the red pulp and the white pulp. The white pulp is a region primarily composed of various types of white blood cells discussed below, and is most important for immune responses to infections. The red pulp, on the other hand, is primarily composed of red blood cells as well as regulatory macrophages, resulting in the red color of this portion of the spleen. The red pulp makes up the majority of the spleen in terms of total volume, and is a site of red blood cell storage when these cells are not actively circulating through the body. By allowing the body to store red blood cells that are not currently needed rather than discard them, the spleen ensures that you will have a resevoir of blood available to replenish and sudden loss in blood due to injury or blood donation that may occur during life. Individuals who do not have spleens as the result of infection or damage to the organ are able to live a fairly normal life, however they lack this buffering pool of red blood cells and are thus not as able to quickly replenish their blood supplies.

Over time, red blood cells accumulate damage and die, just as any cell in the body or any body for that matter does. The constant binding and release of oxygen and the constant circulation through the veins of the body where cells are subject to intense sheer forces and changes in pressure, temperature, and chemical conditions causes a good bit of wear and tear on these cells, which eventually compromises their integrity or causes them to stop transporting oxygen efficiently. Much of this age related damage in these cells is also likely the result of oxidative stress within the cells, as these cells will produce reactive oxygen species (ROS) over time, which can cause damage to cellular structures (and DNA, however red blood cells in mammals do not have DNA as discussed above making this not relevant for a discussion of red blood cells). Once red blood cells have lived out their natural life span, they are again transported to the red pulp region of the spleen. In this case red pulp serves as a site of red blood cell degradation where macrophages “eat” the dying red blood cells. This regulated consumption and destruction of red blood cells in the red pulp ensures that these cells are disposed of in an orderly fashion, rather than simply dropping dead in the blood stream all of a sudden. Such widespread red blood cell death would be very toxic to the host and would also prevent the normal flow of oxygen, making regulation of this process very important.

Blood Cells and Disease

As with any cells of the body, red blood cells can be affected by disease and by infectious pathogens, resulting negative consequences for the infected individual. Because red blood cells are so important to the most basic processes of the body, it is essential that the body retains sufficient numbers of them at all times to meet oxygen requirements of the tissues, so any disease that negatively impacts the red blood cell pool can result in debilitating conditions, unconsciousness, and even death as a consequence of this lack of oxygen. Fortunately, as has been mentioned throughout this article, the body has many systems in place that make both the red blood cells themselves resistant to disease, and fairly easy to replace. For one, red blood cells are recycled every ~100 days throughout the life span, ensuring that there is a constantly fresh pool of cells and therefore allowing damaged or defective cells to be naturally destroyed over time. Additionally, because each red blood cell is identical in terms of function, they are very redundant and thus easily replaceable - no one red blood cell is essential for the body, and if one cell dies another will come along to take its place. The constant storage of red blood cells in the spleen also makes this replacement even easier. As an added benefit, red blood cells do not have nuclei as discussed above, which makes them poor targets for infection by viruses, as viruses require nucleic acids to reproduce.

Even with all their benefits and guards against infection, certain diseases and infections still affect these cells. One of the most well known such diseases is the parasitic infection known as malaria. Malaria is common in tropical regions of the world, and is a small worm like parasite that is spread through blood transferred from infected to uninfected individuals by certain species of mosquitos. The disease takes many forms and goes through a life cycle that infects multiple cell types, but one important cell type that infects are the red blood cells. The worm enters into red blood cells, which because they lack nuclei also lack any inducible defenses, and inside this cell it is able to acquire the proteins and energy that it needs to grow and multiply. As the worms multiply to a high enough count, they overwhelm the red blood cell and it lyses, spilling its content and the new worms. The worms then go off to infect the hepatocytes of the liver, while the contents of the red blood cells are free to float through the bloodstream. While part of the damage done by malaria infection involves damage to the liver by the pathogen itself, the release of red blood cell contents into the blood results in high levels of free heme. This heme causes oxidative damage to the rest of the cells of the body, and is a serious consequence of malarial parasitic infection which, if the body can not induce sufficient defenses to control, can be fatal or at least very detrimental.

Another commonly cited disease of red blood cells is so called “sickle cell disease”, and while the connection may not be immediately apparent this disease is actually closely linked to malaria. Normal red blood cells are circular and are able to deform to squeeze through the increasingly small capillaries of the blood stream, enabling them to take blood everywhere that it needs to go in the body. In certain individuals with a specific genetic mutation, however, their blood cells are an unusual shape that looks like a crescent moon or a sickle. In addition, these cells are very rigid and do not deform as well as normal healthy red blood cells. As a result, these sickle cells will tend to get stuck as they travel through the blood stream, which can result in them forming impromptu clots or preventing the blood from getting to the tissues that it needs to in order to properly oxygenate them. The genetic mutation that underlies this disease stems from a mutation in the structure of hemoglobin, which causes it to form in an abnormal shape that is still able to bind oxygen, but that also causes it to force the cells into awkward and rigid sickle shapes. Patients with sickle cell disease may be either homozygous or heterozygous for the disease - that is, they have two mutant hemoglobin genes or one, respectively. Heterozygous patients have roughly half of their blood cells that function normally, meaning that they tend to suffer fewer complications than do homozygous sickle cell patients.

Heterozygous sickle cell patients also attain a benefit from their mutation, which explains why it has not been removed from the gene pool by natural selection - they are somewhat resistant to malaria infection. As discussed above, one of the primary problems caused by malaria is infection of the red blood cells and their subsequent destruction resulting in the release of their toxic intracellular components. These toxic components can be managed by the body, but in order to manage them quickly the body needs to upregulate the expression of certain proteins that oxidize the heme protein into a non harmful form. In most people, the body does not normal see free heme in the blood stream, so these defenses are not rapidly induced. In heterozygous sickle cell patients, however, there is a low level of heme in the blood at all times, which causes these defenses to be induced at all times. This means that when these sickle cell patients are infected by malaria, their body is better able to manage the toxicity that is associated with the lysis of red blood cells during infection. This does not help the person to clear the infection faster necessarily, but it does allow them to better tolerate the damage caused by infection, thus increasing their survival. Malaria is a major selective pressure in tropical regions where it is endemic, which explains why this otherwise harmful genetic mutation is fairly common in tropical reasons, particularly among native inhabitants of India and sub Saharan Africa.

One other common problem that affects red blood cells is carbon monoxide poisoning. This poisoning arises when an environment with limited ventilation, such as a car or a house, has a build up of the toxic gas carbon monoxide, which can come from vehicle exhaust or other natural sources. The gas has no odor and cannot be detected except with specialized carbon monoxide detectors that are standards in many houses in the USA. The reason that carbon monoxide is so toxic is that it affects red blood cells and prevents them from taking blood to the body. The reason hemoglobin is able to deliver oxygen efficiently is because it can reversibly bind to oxygen so that when it reaches peripheral tissues, the oxygen is readily released to the nearby tissues. If carbon monoxide binds to hemoglobin, however, then the structure of the protein changes such that the oxygen is much harder to dissociate from the protein. This means that even though the red blood cells can take the oxygen to the tissues, the carbon monoxide prevents it from releasing most of that oxygen to the tissues. Normally the body makes only small amounts of carbon monoxide which are quickly eliminated, but when exogenous carbon monoxide is introduced it can quickly build up and can overwhelm blood cells, preventing them from delivering the much needed oxygen to the tissues resulting in symptoms that include confusion, unconciousness, and death from lack of oxygen.

Other Cells of the Blood

While blood appears uniformly red to the naked eye, it is in fact made up of many kinds of cells rather than merely of red blood cells, which do make up a substantial fraction of the blood. The other cells of the blood are all related to red blood cells in that they all come from a specific lineage of precursor cells known as hematapoetic stem cells that give rise to all manner of blood cells, including red blood cells. While red blood cells do not have nuclei, other blood cells and especially hematapoetic stem cells do have nuclei and as a result they are able to carry out many independent functions and replication cycles that are not possible for red blood cells. Broadly, the non-red cells of the blood are often called “White blood cells” as they lack a characteristic coloration since they do not contain abundant iron, and they make up the remaining cellular fraction of the blood. In addition to red and white blood cells, the blood is composed of a liquid fraction called plasma which contains many important proteins, chemicals, and other compounds that are necessary for the body to function normally. In addition to donating red blood cells at a blood bank, people are able to donate their plasma as in some cases donors are in desperate need of additional plasma without a corresponding need for red blood cells.

Many of the white blood cells of the circulatory system have functions in maintaining the normal or “homeostatic” state of the the host organism. These include cells of the immune system that serve to restore normalcy and help resolve infections when disease arises in the host, as well as cells that are more broadly involved in inflammation and wound healing in other contexts beyond simply infection. One specialized set of white blood cell fragments are the platelets, which are important for wound resolution. Platelets are fragmentary cell bodies that are derived from a precursor called a megakaryocyte. When a wound is detected in the body, platelets aggregate together as a result of special chemical clotting reactions, forming a blood clot that prevents additional blood loss and helps the body begin to resolve the wound, leading to the formation of a scab and eventually the formation of scar tissue that replaces the originally damaged tissue in form (if not in function).

White blood cells of the immune system include a subset of cells that are involved in the “eating” of dangerous molecules or organisms such as invading bacteria or viruses. These cells include cells called monocytes, macrophages, dendritic cells, and neutrophils. When these cells sense an infection, then they are able to consume the source of the infection and destroy it thanks to the caustic conditions on their interior compartments, ensuring the destruction of most invading organisms. These cells are then also able to show fragments of these destroyed organisms to the immune system, alerting it to the presence of a foreign entity, leading to immune activation. This activation leads to the activation of so called T and B cells. These cells are able to specifically recognize foreign entities with their specialized receptors, and they are able to target these entities for destruction by producing antibodies and by directly causing the lysis of infected cells or agents.

Other white blood cells include those that are involved in allergic responses and control of parasitic infections. These cells, including basophils, eosinophils, and mast cells are able to respond to signs of parasitic infection or certain stimuli that promote asthma in order to trigger a very rapid inflammatory response. This response is important for clearing parasitic infections and evading certain toxic stimuli, although it can be very deleterious in the context of asthma or allergic reactions, suggesting that these blood cells can have negative effects in the wrong contexts (as can red blood cells, or other white blood cells in the case of autoimmunity). Proper control and regulation of these kinds of white blood cells is important for regulating allergic responses, however complete elimination of them can also be deleterious indicating that it is very important to maintain a state of balance in the immune system which allows cells to activate specialized responses in certain contexts without allowing them to non specifically activate those same responses to deleterious effect.

Conclusions

In summary, red blood cells represent a small fragment of the grander picture of what composes the blood in a functioning mammal. Even so, these cells are very important and have certain unique properties that allow them the specialized ability to bind to oxygen and transport it to all of the tissues of the body. This specialized function has allowed animals to develop into large forms without suffering from a lack of oxygen, and this oxygen is used by cells in order to generate the energy that they need to survive. These cells are produced abundantly, and research into understanding these cells has led to breakthroughs in transfusion medicine which has saved millions of lives of people in need of blood due to illness or injury. Further research into the understanding of the other cells of the blood compartment is ongoing and is important for appreciating the full picture of how blood determines biological responses, providing us with a superior understanding of life and of how to save it in cases of sickness or damage.

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