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Red blood cells (RBCs), in human beings, carry oxygen, and are in the shape of turgid biconcave discs. However, in some individuals who possess a mutated form of the hemoglobin gene (HBB), the cells may appear to be sickle shaped, and the mutated gene (Hb S, S stands for sickle) gives rise to severe anemia, strokes, and lung problems. Physiologically, the HBB gene contributes to the formation of a protein called beta hemoglobin that is responsible for transporting the oxygen throughout the body via the blood. The mutated gene, Hb S (S stands for sickle), results in the formation of dysfunctional form of hemoglobin, such that its structure is modified, and this causes the change in shape of the red blood cells. This change in shape also alters the oxygen carrying capacity of the RBCs, and results in the drastic reduction of the amount of oxygen molecules that can be transported by it at any given time.

Sickle cell anemia (SCA) is an autosomal recessive disorder. This implies that an individual will exhibit this condition only if both the alleles (homozygous) of the HBB gene, possessed by him/her, are mutated. These individuals usually perish at an early age. However, this does not mean that people with only one mutated allele (heterozygote) are not affected at all. In such a case, the individual does not develop a full-blown case of SCA, but still shows the presence of a few sickle-shaped RBC in his/her blood. Such a condition is referred to as sickle cell trait, and the person is said to be a "carrier".

Relation Between Sickle Cell and Malaria
An interesting pattern of incidence of sickle cell has been observed in Africa, where malaria is a widely prevalent disease. The relation between sickle cell and anemia gains further ground on the fact, that there is a greater incidence of sickle cell in the African lowland populations, where malaria is severe and widespread than among their highland counterparts. It is believed that sickle cell provides resistance against the malarial parasite. The various explanations for this relationship are as follows:
  • Malaria is caused by Plasmodium falciparum, a parasite that completes a part of its life cycle in the red blood cells of human beings. It enters the human bloodstream when a female Anopheles mosquito, carrying the parasite, bites a healthy individual. It has been observed that the red blood cells of individuals with sickle cell trait, break down when infected with the malarial parasite. Since the parasite needs to complete a part of its life cycle inside the red blood cells, destruction of the cells does not allow the disease to get established in the individual.
  • The parasite thrives on hemoglobin in order to grow. The mutated Hb S leads to the formation of a polymerized form of hemoglobin that cannot be ingested by the parasite. Hence, the malarial parasite is not able to complete its life cycle, and cause disease in the individual.
  • The red blood cells of people with sickle cell trait, tend to sickle under very low oxygen tension. The parasite reduces the oxygen tension in the blood cells that they infect, because they use up the oxygen carried by the hemoglobin for their own metabolism. This sickles the red blood cells that is destroyed by the phagocytes.
  • In case of low oxygen concentration, the potassium in the red blood cells leak out of the cells that contain the abnormal hemoglobin. The parasite needs high levels of potassium to develop and due to its leakage the parasite fails to grow in a blood cell, that have the abnormal hemoglobin.
More research is required to get a conclusive explanation for the association of sickle cell in areas with high incidence of malaria. However, this association is a remarkable example of heterozygous advantage, in which the carriers of a recessive allele have higher chances of survival than those homozygous for the mutated gene.