In 1973 most sickle cell patients lived only to the age 14 (Bloom 1995). With the average life expectancy now around 40 or 50, we have clearly made significant progress in treating the symptoms of sickle cell anemia. But, of course, there is always a more beneficial treatment or one with fewer side effects to be found.
Several new therapies have shown to be effective in increasing production of hemoglobin F. Butyrate is produced in people with hyperglycemia and its presence in babies born to hyperglycemic mothers causes them to produce hemoglobin F longer than other babies (Bridges 2002). This compound, however, is short-lived, causes many side-effects, and only has variable results (Bridges 2002). Erythropoietin has been shown to increase hemoglobin F concentrations in many cases; it is a hormone naturally made in the kidneys that initiates the production of red blood cells (Bridges 2002).
Avoiding Cell Dehydration
The drug Clotrimazole helps prevent water from leaving the cell, and thus avoids increased HbS levels and sickling in the cells (Bridges 2002). Although the drug does have a number of side-effects, it is effective in inhibiting the calcium-activated potassium transport out of the cell, which helps keep water from following the potassium out of the cell (Bridges 2002).
Decreasing Polymerization of Hemoglobin
Nitric oxide is a gas that relaxes smooth muscle and helps blood flow easily. It is a new treatment possibility for sickle cell anemia patients as a result of its binding ability. Nitric oxide binds to hemoglobin S molecules very near the site of polymerization with other hemoglobin molecules (Bridges 2002). The binding of NO changes the affinity of hemoglobin S molecules for each other, reducing the instances of hemoglobin polymerization (Bridges 2002).
Avoiding Leaky Channels and Irreversibly Sickled Cells
When cell membranes are damaged by reactive oxygen species (due to heme presence in the membrane), both potassium channels and the protein beta-actin are affected (Goodman, et al. 1998). Leaking potassium through the damaged channels takes water with it, causing the cell to become reversibly sickled (meaning that when it is in the presence of higher oxygen concentrations it will un-sickle). When beta-actin is damaged through oxidation, it causes these cells to convert to irreversibly sickled cells (ISCs), cells which maintain their sickle-shape even in high oxygen concentrations (Goodman, et al. 1998). The antioxidant NAC (N-acetylcysteine) has been shown to prevent the oxidation of potassium channels (helping keep the cell hydrated) as well as the oxidation of beta-actin (preventing reversibly sickled cells from becoming irreversibly sickled) (Goodman, et al. 1998).
While not presently technologically possible, gene therapy may in the future become an effective treatment or cure for sickle cell anemia. Once the technology is perfected, mutated beta-globin genes could be replaced with non-mutated ones, preventing the formation of cells with the potential to sickle. In 1995 Takekoshi, et al. created a hybrid beta/gamma-globin gene. To the beta-globin gene they added amino acid sequences found to prevent sickling in the gamma-globin gene (HbF’s beta-globin replacement) (Takekoshi et al. 1995).
There are many factors that need to be worked out in order for gene therapy to become a real treatment option. First, the replaced beta-globin gene must be expressed as frequently as the alpha-globin gene in order to create hemoglobin molecules with two alpha and two beta-globin chains each. The large control region of the gene must also be inserted and made effective. Yet another obstacle is the fact that pluripotent cells must be the acceptors of the replaced genes for continued expression of the gene (Bridges 2002).
Sickle Cell Trait and Malaria
Although sickle cell anemia can be a severe, debilitating disease, the mutated gene responsible for the disorder has surprisingly remained in the gene pool. This seeming failure of natural selection can be explained by the heterozygote advantage. People heterozygous for the sickle cell gene have an increased resistance to malaria. While people homozygous for sickle cell suffer heath problems associated with the mutated gene and often die young and people homozygous for the normal hemoglobin gene are unable to resist malaria, heterozygotes do not suffer most of the effects of sickle cell anemia and are better able to resist malaria. In areas where malaria is a real threat, this heterozygote advantage plays a large role in keeping the mutated sickle cell gene in the gene pool.
A simplified diagram, illustrating the increased ability for sickle cell heterozygotes to survive where malaria is common. Image used with permission from Dr. Kenneth Bridges. http://sickle.bwh.harvard.edu
The heterozygote resistance to malaria cannot be fully explained. It is likely that P. falciparum, the parasite responsible for malaria, decreases oxygen in red blood cells it infects (Bridges 2002). As a result of low oxygen concentrations, hemoglobin S within cells polymerizes, forming a sickled cell. These cells are then marked for cell death since they are unhealthy, and the parasite-infected cells are destroyed before they can cause harm (Bridges 2002).
Other Hemoglobin Diseases
Sickle cell anemia is not the only blood disorder related to defective hemoglobin genes. Thalassemias are conditions in which either the alpha or the beta-globin chains do not form. Like people with a single copy of the hemoglobin S allele, people heterozygous for thalassemia are for the most part healthy, since at least half of the hemoglobin in their cells is hemoglobin A (Dulbecco 1997).
Alpha-thalassemia is the condition in which one or more of the four genes that code for the alpha-globin protein has been lost, often as a result of crossing-over during meiosis. A single lost alpha-globin gene is very hard to detect and shows no symptoms (Bridges 2002). If two genes are lost, people may have a minor case of anemia and their blood cells are smaller, but for the most part are unaffected by the missing genes (Bridges 2002). People missing three of the alpha-globin genes have severe anemia and need blood transfusions to survive (Bridges 2002). Since beta-globin chains are being produced at normal levels and alpha chains are not, hemoglobin molecules form from 4 beta chains (rather than two alpha and two beta), forming hemoglobin H, which does not carry oxygen as well (Bridges 2002). Survival with none of the four alpha-globin genes is not possible (Bridges 2002).