Abstract: Sickle cell anemia is a genetic disease that slightly alters the structure of hemoglobin, the oxygen carrying protein in red blood cells. This modified hemoglobin, when not carrying oxygen, tends to clump with other deoxygenated hemoglobin, deforming red blood cells and causing blood to clot throughout the body. The disease is prevalent in Africa where incidence of malaria is high because sickle cell anemia imparts some resistance to malaria. Because the United States does not have a problem with malaria, the incidence of sickle cell anemia has decreased in the African-American population.
The direct cause of sickle cell anemia is genetic. Those with sickle cell anemia have genes that produce a modified form of hemoglobin, the protein in red blood cells that carries oxygen to tissue. When this modified hemoglobin is deoxygenated in tissue, it tends to clump with other deoxygenated hemoglobin, forming long chains. These chains deform the red blood cells that contain them, causing the red blood cells to assume a sickled shape, rather than their normal smooth disk shape. The sickled red blood cells clog capillaries, causing heart problems, skin and retinal lesions, and often death. Despite these effects, the disease does have one benefit. Those with sickle cell anemia are resistant to the parasite that causes malaria.1
[This introduction is weighted too strongly to sickle cell aspects and does not introduce the topic strings appropriate to malaria aspect of paper. Below is possible revised introducton, in which main topic strings are in bold face.
A small genetic change in hemoglobin both causes sickle cell anemia and protects against malaria. Hemoglobin is the protein in red blood cells that carries oxygen to the tissues. Deoxygenated sickle hemoglobin distorts the blood cells into a "sickle" shape that obstructs circulation and in turn damages tissues; the resulting anemia shortens life expectancy to about 45. Conversely the weakened sickle blood cell is a poor host for the malaria parasite as the cell leaks needed nutrients and is selectively eliminated by the liver (?). This selective advantage of sickle cell concentrates its occurrence to regions of high malaria incidence.
Normal hemoglobin (N hemoglobin) and sickle cell hemoglobin (S hemoglobin) differ by only two amino acids, the basic building block of proteins. Hemoglobin, both N and S types, have 574 amino acids. These amino acids are grouped in four subunits. Two of these subunits are called alpha subunits, have 141 amino acids each, and are identical to each other. The other two are called beta subunits, have 146 amino acids, and are also identical with each other. The two amino acids that differ between N and S hemoglobin are in the beta subunits of the proteins. In each of the two beta subunits of S hemoglobin, a negatively charged amino acid is replaced with an uncharged amino acid, which we call a "mutant" amino acid. Because uncharged amino acids tend to group together, these uncharged mutant amino acids are important in causing the clumping action of deoxygenated S hemoglobin.
|Fig. 1. Schematic representation of N and S hemoglobin in both oxygenated and deoxygenated form. The deoxygenated N hemoglobin has two uncharged amino acids exposed to its surface, but deoxygenated S hemoglobin has four uncharged regions exposed.|
When in deoxygenated form, N hemoglobin has two patches of uncharged amino acids exposed to its surface, but S hemoglobin has four such patches. When oxygenated, most of the amino acids on the outer surface of N hemoglobin are charged. However, as illustrated in figure 1, when N hemoglobin is deoxygenated, it changes shape, and two regions of uncharged amino acids are exposed to its surface. Likewise, when S hemoglobin is deoxygenated, these same two uncharged regions are also exposed. These two uncharged regions, when taken in combination with the two mutant amino acids in S hemoglobin, give deoxygenated S hemoglobin a total of four regions of uncharged amino acids.
Because deoxygenated S hemoglobin has four uncharged regions exposed, instead of two as in the N form, it clumps into long chains. The uncharged amino acids exposed on deoxygenated S hemoglobin are more stable when surrounded by the uncharged amino acids on other deoxygenated S hemoglobin molecules, so the S hemoglobin molecules aggregate, forming chains. This process occurs in deoxygenated sickle cell hemoglobin as in figure 2. These chains become large enough to deform the red blood cells containing them, causing the red blood cell to sickle, and therefore, the excruciating and debilitating effects of full blown sickle cell anemia.
|Fig.2 Representation of the aggregation of deoxygenated S hemoglobin to form chains. A mutant amino acid on one S hemoglobin molecule interacts with one uncharged amino acids on another S hemoglobin molecule.|
While in the red blood cell, the malarial parasite induces N and S hemoglobin to go to the deoxygenated form through a mechanism known as the Bohr effect.2,3 According to this effect, when either N or S hemoglobin is put in an acidic environment, or one high in CO2, they tend to release oxygen, and convert to the deoxygenated form. The malarial parasite metabolizes food and produces carbon dioxide as a waste product. This carbon dioxide, when in an aqueous environment like that inside a red blood cell, forms carbonic acid. Because of these high levels of C02 and acid, the hemoglobin in a parasitized red blood cell tends to be in the deoxygenated form. If a red blood cell contains S hemoglobin and a malarial parasite, the S hemoglobin will be deoxygenated, aggregate, and sickle the red blood cell.
The malarial parasite can not live in a sickled red blood cell for two reasons. First, the body sends sickled red blood cells to the spleen for elimination. The body senses that sickled red blood cells are improperly formed, so destroys as many sickled cells as possible. If a parasite is in the cell, it also is destroyed. Second, because the cell membrane of the sickled red blood cell is stretched by its unusual shape, it becomes porous. The sickled cell "leaks" nutrients, like potassium, that the parasite needs to survive, so the parasite dies. Because the malarial parasite can not live in sickled cells, an individual with S hemoglobin is therefore resistant to the malaria.
If people with genes for S hemoglobin are debilitated or even die, how has the disease been perpetuated? The disease is perpetuated because there are two genetic levels of severity of the disease: full blown sickle cell anemia, which causes severe blood clotting and even death, and sickle cell trait, which causes fewer complications. Every organism has two entire sets of DNA, one from the mother and the other from the father. Each set has genes for eye color, hair color, etc., as well as a gene for hemoglobin. Most of us have two genes for N hemoglobin, so our hemoglobin does not clump together when deoxygenated. Those who have two S hemoglobin genes produce only S hemoglobin, and are said to have full-blown sickle cell anemia. These people usually die at an early age from excruciating, severe blood clotting. The third group has one N gene and one S gene. In this group, half of the hemoglobin will be of N type, and the other half will be of the S type and clump when deoxygenated. They are said to have sickle cell trait, rather than sickle cell anemia. This group has enough N hemoglobin to live a relatively normal life, since blood clotting is less severe.4 More importantly, this group has enough S hemoglobin to retain malarial resistance. This third group, those with sickle cell trait, perpetuate the disease.
Since sickle cell anemia is only advantageous in regions where incidence of malaria is high, it occurs less often in populations rarely exposed to malaria. For millions of years, whenever malaria swept through an area of Africa, those with sickle cell trait had a greater chance of survival than those without the trait. Those with sickle cell trait perpetuated the disease. Even today, in some areas of Africa like Uganda, up to 46% of the population may have sickle cell trait, and 2% have full-blown sickle cell anemia. In areas without malaria, sickle cell anemia and sickle cell trait are disadvantageous because of their debilitating side effects. Those with the disease can not compete against those without the disease, so reproduce less often. Therefore, the S hemoglobin gene is passed on less frequently in these populations, and the incidence of sickle cell anemia and sickle cell trait decreases. For instance, in the United States, where malaria is not a problem, only 8% of the African-American population has sickle cell trait, and 0.25% have full blown sickle cell anemia.1Sickle cell anemia and even sickle cell trait are enough of a disadvantage in malaria-free parts of the world4that their frequency of incidence decreases.
The relationship between malaria and sickle cell anemia is undeniable: both biochemical evidence and demographic evidence support the theory that sickle-cell anemia imparts malarial resistance. Biochemically, we understand that deoxygenated S hemoglobin clumps, sickling cells. We also understand that when the malarial parasite inhabits a red blood cell, it induces the cell to sickle by the Bohr effect. This sickling of cells imparts malarial resistance to the inflicted person. Demographically, we find a decreasing incidence of sickle cell anemia in African-Americans as opposed to Africans. Since sickle cell anemia is disadvantageous without the presence of malaria, those with sickle cell anemia pass on their genes for S hemoglobin less often. This biochemical and demographic evidence demonstrates how a small parasite, rampant in Africa for millions of years, has genetically influenced humans.
1. M. I. Barnhart, Sickle Cell. (Upjohn, Kalamazoo, 1979).
2. M. D. Young and G. R. Coatney, in Human Malaria, edited by F. R. Moulton (Science Press Printing Company, Lancaster, 1941), pp. 25-29.
3. W. Jarra, in Malaria and the Red Cell, edited by David Evered and Julie Whelan (Pitman, London, 1983), pp. 137-152.
4. S. Edelstein, The Sickled Cell. (Harvard University Press, Cambridge, 1986).