The Molecular Biology Of Sickle Cell Anemia Biology Essay

Sickle cell anemia occurs when the erythrocytes of the individual have the capacity to undergo reversible changes in shape due to the changes in the partial pressure of oxygen. The red blood cells will change their forms from the normal biconcave disk to crescent, holly wreath and other forms when the oxygen pressured is lowed. Among those who suffer from the sickle cell trait, the term of sickle cell anemia is being applied when they also could suffer from a severe chronic anemia because of the excessive destruction of their erythrocytes. [1] The researchers have found that sickle cell disease is being categorized as one of the inherited disease. For a child to be infected with the sickle cell disease, the child must inherited two genes for the sickle hemoglobin from one’s parent. Meanwhile a child will has a condition called sickle cell trait when the child receive a gene for sickle cell disease from the parent who is infected or a carrier and a normal gene from the normal parent. [2] Autosomal recessive mode of inheritance happens when an individual or a child happens to inherit two copies of the abnormal gene, which one from each of their parents and then being passed on to the affected individual. An individual will be a heterozygote when that particular individual inherits a normal gene and a sickle gene both from their parent. Heterozygote also can be called as the carriers of the sickle cell anemia. They will not have the sickle cell disease and able to lead a normal life but instead since them being called as carries, they are able to pass down the sickle cell gene to their children. [3]

The reason for the persistence of the sickle cell anemia as to always to stay in the gene pool is because it always been inherited to the next generation and another factor is because due to the fact that it give benefits to heterozygotes against the malaria. People who lived in Africa, the Mediterranean, India, or the Middle East mostly will gain this benefits since malaria disease always occur on that particular area. The researchers have found that, an individual who is being a carrier or heterozygote from the sickle cell will be resisted to malaria. Malaria is a disease which being infected from the parasites that multiplies inside of the human red blood cells. It is being found that the risk for the non-carriers to dye from the malaria disease is about 1/10. Carriers of the sickle cell anemia living in malaria-ridden locales would had a much more survival benefit compared to the non-carriers, thus allowing them to live longer and have more children. This benefit is what the evolutionary biologist called as the "heterozygote advantage." And it also explains why the sickle cell trait has been persisted in the gene pool and not been eliminate by natural selection. [4]

Sickle cell anemia is caused by the mutation in the β-globin gene in which the 17th nucleotide is change from thymine to adenine and the sixth amino acid in the β-globin chain becomes valine instead of glutamic acid. The binding between β1 and β2 chains of the two hemoglobin molecules is the results when the mutation produces a hydrophobic motif in the deoxygenated sickle hemoglobin (HbS) tetramer. This crystallization produces a polymer nucleus, which grows and fills the erythrocyte, thus disrupting its architecture and flexibility and promoting cellular dehydration, with physical and oxidative cellular stress. [5] This means that the mutation of the hemoglobin beta (HBB) is the cause of the sickle cell disease. The hemoglobin consists of four protein subunits, which are two subunits called alpha-globin and two subunits called beta-globin. Hemoglobin S (HbS) is an example of an abnormal version of beta-globin that being produce by the HBB gene mutation. Other mutations for example hemoglobin C (HbC) and hemoglobin E (HbE) in the HBB gene will lead to the additional abnormal versions of the beta-globin. At least one of the beta-globin subunits in hemoglobin will be replaced with hemoglobin S which is for the people with sickle cell disease. The hemoglobin S replaces both beta-globin subunits in hemoglobin. For example, an individual who infected with sickle-hemoglobin C (HbSC) disease will have hemoglobin molecules which also include the hemoglobin S and hemoglobin C instead of beta-globin. The distortion of the red blood cells into a sickle shape can be happen in the abnormal versions of beta-globin. Anemia can be occurring when the sickle shape red blood cells die prematurely. Serious medical complications can be caused by the inflexibility of the sickle-shaped cells get stuck in small blood vessels. [3]

The mutation causes the red blood cell to become stiff and sometimes, sickle shaped is formed when they release their load of oxygen. These sickled cells tend to get stuck in narrow blood vessels, blocking the flow of blood. As a result, those with the disease suffer painful at their joints and bones. There are two alleles important for the inheritance of sickle cell disease which are A and S. Individuals with two normal A alleles (AA) have normal hemoglobin. Those with two mutant S alleles (SS) will develop sickle cell disease. Heterozygous individuals (AS) are usually healthy, but they may suffer some symptoms of sickle cell disease under conditions of low blood oxygen, such as high elevation. Also the heterozygous individuals are said to be "carriers" of the sickle cell trait. This is due to both forms of hemoglobin are made in heterozygous individuals, the A and S alleles are co-dominant. [6]

There are a few ways to manage people who in this condition which one of it is to consume hydroxyurea. The function of hyroxyurea is that, it is able to reduce the frequency of the painful crises and it can also reduce the need to undergo blood transfusion when it is taken daily. However, hydroxyurea is not a given choice for the adult that have severe disease. Hydroxyurea helps to prevent the formation of sickle cell by stimulating the production of the fetal hemoglobin. Fetal hemoglobin is a type of hemoglobin that can be found in newborns. Another method is to consume antibiotics. Usually children when they are about 2 months old will consume the antibiotic penicillin until they are about 5 years old. By doing this method, a life threatening infections such as pneumonia to an infant or child with sickle cell can be prevent. This method also can help the adult who is being infected with sickle cell anemia to fight with certain infections. Blood transfusion method can also be implementing to the individual who has sickle cell anemia. The red blood cells are being removed from the supply donated blood in the process of blood transfusion. The individual who is being infected with the sickle cell anemia then will be given the donated cell intravenously. Through the method of blood transfusions, it will help relieving the anemia by increasing the number of red blood cell in circulation. Usually, children who being infected by sickle cell anemia, has a high risk to get stroke, so in order to reduce the risk, they can do the blood transfusion regularly. Meanwhile for stem cell transplant, also called as bone marrow transplant, involves replacing the bone marrow that being affected by sickle cell anemia with healthy bone marrow from a donor. Meanwhile stem cell transplant is suitable for an individual who have significant symptoms and problems from sickle cell anemia. When a donor is found to be suitable or compatible with the patient, then the patient bone marrow is being depleted first with radiation or chemotherapy. The donor’s healthy stem cell will then be filtered from the blood. New blood cells will begin generating when the healthy stem cells are being injected intravenously into the bloodstream of the patient who being infected by sickle cell anemia. [7]

Allogeneic bone marrow transplantation is also a way to cure the sickle cell disease, but this procedure is limited to a minority of patients with an available, histocompatible donor. Autologous transplantation of bone marrow stem cells that are transduced with a stably expressed, antisickling globin gene would benefit a majority of patients with sickle cell disease. A method is described in which immobilized, highly purified bone marrow stem cells are transduced with a minimum amount of self-inactivating (SIN) lentiviral vector containing a potent antisickling β-globin gene. These cells, which were transduced in the absence of cytokine stimulation, fully reconstitute irradiated recipients and correct the hemolytic anemia and organ pathology that characterize the disease in humans. Recently, several groups have used lentiviral vectors for globin gene transfer to bone marrow mononuclear cells and this work has resulted in the correction of sickle cell anemia and β-thalassemia in relevant mouse models of these human diseases. The equivalent treatment in humans is mobilization of hematopoietic stem cells (HSCs) with granulocyte colony-stimulating factor (G-CSF) or stem cell factor (SCF) or both. This treatment is effective for mobilizing bone marrow HSCs into peripheral blood and these HSCs successfully engraft in recipients. In recent gene therapy, the transduction protocol is used in the studies for hemoglobinopathies is the ex vivo stimulation of HSCs with cytokinesis. This treatment is included in the protocols to increase the number of stem cells that are actively progressing through the cell cycle, therefore to increase the efficiency of retroviral or lentiviral transduction.[8]

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