Sickle al., 2000). The abnormally shaped erythrocytes cause cells

Sickle cell anemia is an
inherited autosomal recessive disease, caused by abnormalities in the ?-globin
gene (Ashley-Koch et al., 2000; Williams et al., 2005; Ferreira et al., 2011).
Individuals who possess this disorder often experience chronic anemia, strokes,
and increased susceptibility to bacterial infections, among other symptoms
(Ashley-Koch et al., 2000). The
abnormally shaped erythrocytes cause cells to be unstable, which triggers
premature cell death and causes these symptoms.

Sickle cell anemia is one
of the most prevalent inherited genetic disorders worldwide (Ashley-Koch et
al., 2000; Gluckman et al., 2017). J.B.S Haldane (1949), as cited in Lederberg
(1999), observed that red blood cell disorders were more prominent in tropical
regions, where malaria was endemic. Since then, it was hypothesized that such erythrocyte
disorders may offer some protection against the parasitic disease caused by the
Plasmodium parasite (Lederberg, 1999).
This hypothesis served as an example of genetic selection for more than half a
century, where natural selection had acted by increasing the prevalence of
these traits in a protective manner (against infectious diseases). (Lederberg, 1999; Williams et
al., 2005). Nonetheless, the mechanism by which this protection occurs was the
subject of speculation for many years (Williams et al., 2005). Recent studies
suggest possible answers to this conjecture, and remarkable advances have since
been made in the treatment of patients with sickle cell disease (Gluckman et
al., 2017). Despite these remarkable advances, sickle cell anemia is, by
definition, a common disease, where most patients suffer from considerable
disabilities and mortality rates (Ashley-Koch et al., 2000; Gluckman et al.,
2017).

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Williams et al. (2005) investigated
the immune basis for protection against malaria by the sickle cell trait. They
hypothesized that if protection against this parasite was inherent, then it
should be unrelated to malaria exposure and remain constant with age. In
contrast, if immune mechanisms were involved, then the degree of protection
should increase with age up to a certain point. They
found that protection via the sickle cell trait (HbAS) against clinical
malaria nearly tripled over the first ten years of life in their subjects (20% to 56%), returning to about 20% thereafter (Williams et al., 2005). These results
demonstrated that protection did indeed vary with age, suggesting that immune
mechanisms must be involved in the protection against malaria by HbAS.

A more recent study
conducted by Ferreira et al. (2011) tempted to explain how this protection
mechanism may occur in individuals with sickle cell disease. Using genetically
modified mice with one faulty copy of the sickle cell hemoglobin (SCH) gene,
they found that protection against malaria occurs after infection of the Plasmodium parasite, and that the SCH
gene does not protect against the parasite itself (Ferreira et al., 2011).
These findings were consistent with Williams et al. (2005) study. High levels of the prosthetic
group heme in the blood of mice, after infection with the Plasmodium parasite, seemed to increase the probability of
contracting malaria (Ferreira et al., 2011). Conversely, low levels of heme
in the blood, found only in the heterozygote mice, prompted the production of
the enzyme heme oxygenase-1, which in turn released carbon monoxide. When found
in low concentrations in the blood, carbon monoxide seemed to prevent the
accumulation of heme after infection with the parasite, demonstrating
therapeutic properties in small concentrations (Ferreira et al., 2011). Hence,
the heme oxygenase-1 system, induced by the SCH gene, has been identified as an
important component in the protection mechanism against malaria. It may be used
therapeutically to treat severe forms of malaria in the future and presents the
possibility of potential treatment against this deadly disease (Ferreira et
al., 2011).

At the molecular level, a
single point mutation on chromosome 11 in the ?-globin gene seems to be responsible
for sickle cell disease. This missense mutation causes a substitution of
glutamic acid, the sixth amino acid in the ?-globin, for valine (Ashley-Koch et
al., 2000). Because the primary sequence of amino acids determines the protein’s
tertiary structure or conformation, this substitution alters the shape of
hemoglobin. This change in the conformation of hemoglobin is what gives erythrocytes
their characteristic sickled shape and altered function in sickle cell disease. Because the
proteins encoded for on this gene are developmentally regulated, it is essential
to produce the right amount of proteins for proper development (Ashley-Koch et
al., 2000). Because
improper gene dosage occurs in individuals with sickle cell disease, high
mortality and morbidity rates were observed (Ashley-Koch et al., 2000; Gluckman et al., 2017).

Thus far, the only
curative treatment for sickle cell disease is allogeneic hematopoietic stem
cell transplant. (Gluckman et al., 2017). This treatment has some major limitations,
including economic barriers and donor availability, since the donor’s human
leukocyte antigen (HLA) must match the recipient’s (Gluckman et al., 2017). By
studying 1000 recipients of HLA-identical transplants between 1986 and 2013, Gluckman
et al. (2017) found the mortality rate in children to have improved to 0.5 per
100 000 persons. Conversely, the survival rate in adults was lower, exceeding
2.5 per 100 000 persons. This lead them to suggest that young patients with
sickle cell disease and an HLA-identical sibling should be transplanted as
early as possible in life for the best chance of survival (Gluckman et el.,
2017).

To conclude, patients
with sickle cell disease suffer from considerable disabilities and early
mortality. Treatment for this disease is dangerous and limited by a number of
factors. However, numerous studies and observations suggest a clear association
between sickle cell disease and malaria. This association was one of the first
known and studied examples of genetic selection, illustrating how evolution can
act in a protective manner by increasing or decreasing the prevalence of a
trait within a population. Understanding these interactions and associations
opens doors towards potential treatment options against infectious diseases in
the future. 962

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