Sickle Cell Anemia: Treatment and Effects

Sickle Cell Anemia: Treatment and Effects Sickle cell anemia is an inherited genetic blood disorder characterized by bouts of intense pain, organ damage, infection, depleted oxygen levels and at times premature death. Although it has come to be known as a disease that affects mainly people of African decent; affliction with sickle cell anemia has also been observed in those individuals with ancestry stemming from parts of the Middle East, India, Latin America, the Mediterranean and the Caribbean. The genetic aspect of the disease is as such; one gene for the illness must be inherited from both parents for that person to be determined to have sickle cell disease. Therefore, a person with sickle cell disease has inherited one mutated copy for the trait from both of its parents. The mutated trait that leads to sickle cell disease impacts the creation of hemoglobin by the body. In a normal individual without the sickle cell trait or disease, they create hemoglobin A (HbA). However, in persons with sickle cell disease, their bone marrow creates a form of hemoglobin called hemoglobin S (HbS). It is the creation of Hb(S) that causes the formation of abnormal red blood cells. In a healthy individual, the red blood cells are usually disc-shaped but with Hb(S), the red blood cells have a stretched out sickle shaped appearance (Figure 1). Although it has been around for hundreds of years, sickle cell anemia was only scientifically observed in the early 1900s when in 1910 Dr. James B. Herrick noted the presence of sickle cells in the blood of Walter C. Noel. Further scientific study showed that the sickling of the red blood cells was related to low blood oxygen. Major advancements into the study of sickle cell anemia were first achieved in 1949 by Dr. Linus Pauling who postulated that the hemoglobin produced by those with sickle cell disease was abnormal and secondly by Vernon Ingram who in 1959 discovered that the difference between Hb(S) and Hb(A) was a single amino-acid substitution in the ÃŽÂ ²-polypeptide chain (ÃŽÂ ²6Glu à ¢Ã¢â‚¬  Ã¢â‚¬â„¢ Val)(Wikipedia). Other scientists followed this line of thinking (Figure 2) and found that this switch in the ÃŽÂ ²-polypeptide chain was due to a substitution of thymine for adenine in the DNA codon for Glu (GAG à ¢Ã¢â‚¬  Ã¢â‚¬â„¢ GTG). This was the first example in any species of the effects of a mutation on a protein (ibid). Genetics of Sickle Cell Sickle cell anemia, like other traits such as height, hair and eye color is an inherited attribute. Both parents must be carriers of these particular traits in order to pass on copies of these genes to their offspring. In the case of sickle cell which is an inherited autosomal recessive point mutation (see Figure 3), the hemoglobin beta gene (HBB) that is located on chromosome 11p.15.5 is affected. The mutation that affects this gene is the direct result of a glutamate being substituted for a valine. This exchange of the ÃŽÂ ²-globin gene occurs in the sixth codon of the HBB gene and signifies that the disorder is caused by a single mutation in the nucleotide, an A to T changeover resulting in a GAG to a GTG sequence (see Figure 4). The substitution of the glutamate for valine causes a Figure 4change to the structure and the function of the HBB gene and causes it to produce structurally abnormal hemoglobin (Hb), called hemoglobin S; HbS (National Center for Biotechnology).The importance of Hb is that it serves as an oxygen carrying protein that gives red blood cells their characteristic color (ibid). As previously stated, the allele responsible for causing sickle cell anemia is autosomal recessive and can be found on the short arm of chromosome 11 (Wikipedia). This means that an individual that has been diagnosed with sickle cell disease has received both copies of the mutated gene from their parents who each carry one copy of the mutated gene. Sickle Cell Anemia and the Malaria Influence In understanding the genetics of sickle cell anemia, it is important to recognize the role in which the mosquito born disease malaria played in the high incidences of sickle cell trait. With the introduction of malaria into areas of sub-Saharan Africa over 4000 years ago, naturally occurring genetic defense mechanisms have evolved for resisting infection by malaria (Tishkoff, 2001). One such defense has been the sickle cell trait. How is this possible? The initial answer comes from the relationship between the two. As illustrated in figure 5, areas hit hardest by malaria, where the disease is endemic, also show a high frequency of individuals that carry the Hb(S) gene. The data also indicates that in areas where malaria occurs at a much lower rate, such as in cooler drier climates, the gene expression of the sickle hemoglobin is greatly reduced or nonexistant. In West Africa, where malaria is so common that most children are infected with the disease, the incidences of sickle cell trait are as high as 40%. Though many suffer symptoms that are severe enough to warrant trips to the hospital, for most, the disease is not fatal. The key to their resistance is in their genes. Genes are all paired with each parent supplying one half of each pair. If either hemoglobin gene undergoes a mutation, the hemoglobin it makes will be changed. This particular mutation called the sickle cell gene is tiny but it is enough to change the shape of the hemoglobin molecules it makes. In areas where malaria is endemic, carriers of the Hb (S) gene have gained some resistance to malaria. This resistance results from the red blood cells that the Hb (S) carriers have. When the malaria parasite attempts to infect the red blood cells of an Hb (S) carrier, the abnormal hemoglobin present tends to sickle and this causes it to rupture. The rupturing prohibits the malaria parasite from reproducing. Due to their sickle shape, the infected cells die, are processed in the spleen and are then eliminated out of the body. The frequency of sickle-cell genes is around 10%. The existence of four haplotypes of sickle-type hemoglobin suggests that this mutation has emerged independently at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions(The Medical News). Thus, people that had one copy of the gene were able to survive the malaria infection. They were able to grow up, get married and have children and pass the genes on to the next generation. This is selective pressure; that gene had an advantage in that particular environment for those carriers. We all have lots of small gene mutations; they mostly go unnoticed but if the environment changes, one may suddenly show unforeseen effects both good and bad. In this case, one copy of the gene is beneficial but two can be disastrous. In the USA, where there is no endemic malaria, the prevalence of sickle-cell anemia among blacks is lower (about 0.25%) than in West Africa (about 4.0%) and is falling (National Center for Biotechnology). As such, the sickle cell trait is gradually being selected out of that population. Inheritance of Sickle Cell Trait/Disease Figure 6In order to inherit the sickle cell trait one parent must be a carrier of the HBB, ÃŽÂ ²-globin S mutation and the other a carrier of an HBB mutation such as ÃŽÂ ²-thalassemia (M.A. Bender). A person develops the disease when they receive a copy of the defective gene from both parents. An individual that is heterozygous for the trait; in which they have one mutated and one healthy allele will remain healthy, but will be able to pass on the disease to their offspring. As such, this person is referred to as a carrier. Take for example two parents who are carriers (Rr) for sickle cell trait. Were they to have a child, there is a 25 percent chance that their child will develop the disease and a 50 percent chance of that child being a carrier. These examples as well as the other statistical possibilities are depicted in Figure 6. Individuals that are heterozygous for the sickle cell trait have a higher fitness than either of the homozygotes. This is known as heterozygote adv antage (Brigham and Womens Hospital). As this has remained a favorable adaptive advantage, the high prevalence of carriers in areas where malaria is still widespread brings to the forefront the reality that sickle cell disease is still pervasive in those regions. Hemoglobin: the story of Sickle Cell I had the idea in 1945 that sickle cell anemia might be a disease of the hemoglobin molecule. No one had ever suggested the idea of a molecular disease before. As soon I had this idea, I thought it must be right. From what I know of the properties of these patients I believed that this is a disease of the molecule; that if we looked at the blood of these patients we shall find that the hemoglobin molecules are different from other people. Linus Pauling Figure 7. Linus Pauling. BioRichUSALinus Pauling began his research into sickle cell disease by paying particularly close attention to the role that hemoglobin played in its manifestation. Hemoglobin is an oxygen carrying protein found inside red blood cells. Pauling theorized that the hemoglobin that characterizes sickle cell disease is abnormal. His studies showed that sickle cell Hb (S) does differ from Hb (A) in that it has a lower negative charge and pH. In sickle cell anemia, which is a common form of sickle cell disease, hemoglobin S replaces both beta-globin subunits in hemoglobin (Genetics Home Reference). Further inspection into the nature of hemoglobin shows that the hemoglobin protein produced in adults is divided into four sub-units that are joined together. These grouped sub-units are known as protein chains. Two types of these protein chains exist: 1) the alpha (ÃŽÂ ±) globin chain and 2) the beta (ÃŽÂ ²) globin chain. Hemoglobin protein is made up of two alpha globin chains and two beta globin chains. It is important to note that the genetic information used by the body to make the two hemoglobin chains can be found in two different hemoglobin genes located on two different chromosomes (Barlow-Stewart, 2001). The two identical ÃŽÂ ±-globin genes that code for ÃŽÂ ± globin chains is located on chromosome 16. Figure 8The ÃŽÂ ²-globin gene codes for the beta (ÃŽÂ ²) globin chain is located on  chromosome 11 (see Figure 8). Two copies of each of these chromosomes can be found in body cells. Everyone therefore has four copies of the alpha globin gene and two copies of the beta globin gene in their body cells (ibid). According to statics posted by the World Health Organization, it is estimated that five percent of adults are carriers for a hemoglobin condition with approximately 2.3% of that number accounting for those adults diagnosed with sickle cell disease. Interestingly enough, there is a correlation between a persons ancestry and the influence it has on the likelihood of that person being a genetic carrier for a hemoglobin condition such as sickle cell anemia. Detection and Treatment Detection of sickle cell disease can take place in one of two ways amniocentesis and blood testing. Blood testing on newborns is now conducted in more than 40 states. The use of pre-implantation genetic diagnosis (PGD) is also being utilized to help those parents that are undergoing in vitro fertilization and are also carriers of the sickle cell trait identify those embryos that have the defective sickle cell hemoglobin. In so doing, this allows the parents to choose only to implant those embryos that are free of the defect. The treatment of sickle cell disease has taken on the form of prescribing hydroxyurea, an antitumor drug that aids in the creation of fetal hemoglobin. Increased production of fetal hemoglobin helps to prevent the hemoglobin from sickling. New therapies have begun to be developed to treat sickle cell disease at the genetic level. Since December 2001, scientists have conducted research into looking at curing sickle cell disease by correcting the defective hemoglo bin; further testing needs to occur to determine the effectiveness of these genetic treatments. Conclusion Sickle cell is a uniquely fascinating disease in that it is one of a few genetic abnormalities that actually have a positive effect: it can be immensely beneficial protecting its carriers from facing the full brunt of the malicious malaria virus, as it renders the cells the virus invades as inhospitable. On the other end of the spectrum, however, it can also be a devastating affliction that leaves its victims with lives marked by constant pain crises and frequent stays in hospitals. Unfortunately, for those suffering from particularly severe sickle cell disease, there is no guaranteed cure for it, but there are potential treatments that scientists are researching to determine their plausibility. How Celtic was Iron Age Britain? How Celtic was Iron Age Britain? The concept of classifying a period of prehistory as the Iron Age was first introduced in the 19th century, and later validated by the massively significant discoveries at Hallstatt and La Tà ¨ne. Subsequently, the era was broken down into chronological periods, against which the British Iron Age is now defined. For ease of definition, The British Iron Age tends to be broken into three periods, Early, Middle and Late, spanning roughly 1000 years, from 800 BC to the 2nd century AD, and is so named owing to the discovery and development of iron taking prevalence over the use of bronze. The term Celtic, having passed into the vernacular, is now nothing more than a vague generic term. The traditional view was that Iron Age Britons were part of a vast Celtic Commonwealth which then stretched across Europe, a world of peoples who spoke related languages, and who shared a distinctive set of values, social institutions, spirituality, art and other aspects of life and culture. (James 1997, 2). This is now acknowledged to be a massive oversimplification, a romanticised notion born of theories put forward by 18th century scholars, based on classical Latin and Greek sources. Edward Lhuyd proposed that Welsh, Scottish and Irish languages all stem from the ancient Gaulish. The label Celtic was then transposed from the languages to the people themselves, landscapes, and their perceived culture and art. Historically and archaeologically speaking, this word is unhelpful and uninformative. Indeed, Simon James has suggested that calling the Iron Age Celtic is so misleading that it is best abandoned. (James S. 01.06.98) As the term Celtic is virtually meaningless, for the purpose of this piece we shall investigate to what extent the indigenous population of Britain were influenced by their continental counterparts. It was thought that the Iron Age Britons (comprising of diverse and often warring tribes and were in no way unified) were subject to a number of Belgic invasions during the Iron Age. Some of the evidence for this model comes from Caesar, who states that prior to his own expeditions of 55 and 54 B.C., the population of the coastal regions of south-eastern Britain had themselves migrated from Belgic Gaul, first in search of plunder, and subsequently in order to settle permanently. He also reported that in his own lifetime, Diviciacus had been not only the most powerful ruler in all Gaul, but had also exercised sovereignty in Britain. (D.W. Harding 1974, 201) There is archaeological evidence which has been used to support this model. The discovery of the Battersea shield in 1857, an intricately decorated piece, is similar to a bronze shield found in the river Witham in Lincolnshire. Both are similar in design to artefacts found at La Tà ¨ne. These finds, combined with cemetery sites in Aylesford, Welwyn and East Yorkshire, which bore close relation to Gaulish burial rites, were taken as verifying the theory of invasion as the principal, even sole, cause of change in prehistoric Britain. (James 1997, 12) With the coming of iron came a number of fortified defences or hillforts. There are approximately 3,300 such defences on mainland Britain. It was originally thought that these were a response to an invasion in the 3rd century B.C. letting loose bands of Celtic warriors over large parts of the south country. (Harding 1974, 54) However, subsequent investigation has found that techniques such as timber lacing, which was prevalent on the Continent, was also adopted in Britain. This presents us with the fact that there were indeed links with the Continent, which were not necessarily hostile, as their technology is shared and assimilated. Some tribes depended entirely on agriculture where the land and soil permitted; others in coastal regions where the land was not so hospitable, subsisted entirely from the sea. Settlement types varied accordingly, from the commonly used roundhouse, to the Lake Village near Glastonbury in the Somerset levels, to the stone built brochs of Northern Scotland. Such diversity does not seem to have been echoed on the Continent, although there were similarities in some areas. Referring to a settlement in Kent, Caesar wrote that the buildings were situated in close proximity to each other, and very similar to the settlements of the Gauls. However, there remains little evidence to date to suggest a strong relationship between the dwellings on the continent, and those in Britain. The economy mainly relied on agriculture and the manufacture of certain goods. Barry Cunliffe describes it thus: a broadly parallel development between Britain and the Continent, the two areas retaining a close contact, which encouraged a free flow of ideas and an exchange of goods, while indigenous traditions remain dominant. (Cunliffe 1991, 442) The use of coinage came into practice around 100 B.C. and directly emulated the Gallic system. There were comparisons with the economy of the Continent, but the British remained insular to some extent until the later Roman invasion. We have some archaeological evidence of the funerary practices of ancient Britain, but only classical references inform us as to the gods, druids and priesthoods intrinsic to these beliefs. According to Caesar, the Gauls and the British shared several practices, including the training of Druids. In the early Iron Age, the disposal of bodies left no archaeological trace. The middle iron age sees cemeteries and inhumations with goods, whilst the late Iron Age sees the introduction of cremations form Gaul. In addition, many bodies from this era have been retrieved from peat bogs throughout northern Europe, often with signs of multiple causes of death, perhaps indicating ritual sacrifice. Evidence suggests that similar beliefs are held throughout Europe at this time, and would seem to denote a belief in some form of afterlife. Much is made of the Celtic head cult, but this largely depends on interpretation of the evidence. ‘There is no doubt that the head was considered the most im portant part of the human body the emphasis on head-hunting demonstrates this and the stress on the head in Celtic art is incontestable. Yet I believe it is a mistake to think in terms of a specific head-cult’ (Green 1986, 216). In conclusion, how Belgae Gallic was Iron Age Britain? Certainly, many aspects of Iron Age life were influenced by the Belgic Gauls, to varying degrees throughout the period. But to call the British Iron Age Celtic is a simplified generalisation; some areas were touched by Continental practices, others, more geographically remote from the south coast will have felt their influences far less. However, it seems far less likely that Britain was invaded per se. Simon James states that Britain in the Iron Age grew with vital, if not erratic, contributions and influences from continental Europe in the form of trade, kinship links, and pretty certainly some localised immigration, especially in the late Iron Age South. (James 1997, 84)The revisionist theory seems at this moment far more plausible than the concept of wholesale invasion. BIBLIOGRAPHY Cunliffe, Barry, Iron Age Communities in Britain, Routledge 1991 Green, Miranda, The Gods of the Celts, Gloucester 1986. Harding, D.W., The Iron Age in Lowland Britain, Routledge and Kegan Paul, 1974 James, S. Rigby, V., Britain and the Celtic Iron Age, British Museum Press 1997 James, S., 1998 Peoples of Britain (online) UK; Available: http://www.bbc.co.uk/history/ancient/prehistory/peoples_03.shtml Accessed 29th April 2005