In 1904, James Herrick, a Chicago physician, examined a 20-year-old black dental student who had been admitted to the hospital because of a cough and fever. The patient felt weak and dizzy and had a headache. For about a year, he had been having palpitations and shortness of breath. On physical examination, the patient appeared normal except that his heart was distinctly enlarged and he was markedly anemic.

The patient’s blood smear contained unusual red cells, which Herrick described as sickle shaped (Figure 9.18). Other cases of this disease, called sickle-cell anemia, were found soon after the publication of Herrick’s description. Indeed, sickle-cell anemia is not a rare disease, with an incidence among blacks of about 4 per 1000. In the past, it has usually been a fatal disease, often before age 30, as a result of infection, renal failure, cardiac failure, or thrombosis.

Sickle-cell anemia is genetically transmitted. Patients with sickle-cell anemia have two copies of the abnormal gene (are homozygous). Offspring who receive an abnormal gene from one parent and a normal gene from the other have sickle-cell trait. Such heterozygous people are usually not symptomatic. Only 1% of the red cells in a heterozygote’s venous circulation are sickled, in contrast with about 50% in a homozygote.

Examination of the contents of sickled red blood cells reveals that hemoglobin molecules have bound together to form large fibrous aggregates that extend across the cell, deforming the red cells and giving them their sickle shape (Figure 9.19). Sickle-cell hemoglobin, referred to as hemoglobin S (HbS) to distinguish it from normal adult hemoglobin A (HbA), differs from HbA in a single amino acid substitution of valine for glutamate at position 6 of the β chains. This mutation places the nonpolar valine on the outside of hemoglobin S. This alteration markedly reduces the solubility of the deoxygenated but not the oxygenated form of hemoglobin. The exposed valine side chain of hemoglobin S interacts with a complementary hydrophobic patch on another hemoglobin molecule (Figure 9.20). The complementary site, formed by phenylalanine β85 and leucine β88, is exposed in deoxygenated but not in oxygenated hemoglobin. Thus, sickling results when there is a high concentration of the deoxygenated form of hemoglobin S (Figure 9.21). The oxygen affinity and allosteric properties of hemoglobin are virtually unaffected by the mutation, but large hemoglobin aggregates form that ultimately deform the cell.

A vicious cycle is set up when sickling takes place in a small blood vessel. The blockage of the vessel creates a local region of low oxygen concentration. Hence, more hemoglobin changes into the deoxy form and so more sickling takes place. Sickled red cells become trapped in the small blood vessels, which impairs circulation and leads to the damage of multiple organs. Sickled cells, which are more fragile than normal red blood cells, rupture (hemolyze) readily to produce severe anemia. Unfortunately, effective treatment of sickle-cell anemia has remained elusive. Note that sickle-cell anemia is another example of a pathological condition caused by inappropriate protein aggregation.

Approximately 1 in 100 West Africans suffer from sickle-cell anemia. Given the often devastating consequences of the disease, why is the HbS mutation so prevalent in Africa and in some other regions? Recall that both copies of the HbA gene are mutated in people with sickle-cell anemia. However, if only one allele is mutated, the result is sickle-cell trait. People with sickle-cell trait are resistant to malaria, a disease carried by a parasite, Plasmodium falciparum, that lives within red blood cells at one stage in its life cycle. Because malaria is such a debilitating disease, people with the sickle-cell trait survive longer and have more children, increasing the prevalence of the HbS allele in regions where malaria is endemic.

Sickle-cell anemia is caused by the substitution of a single specific amino acid in one hemoglobin chain. Thalassemia, another prevalent inherited disorder of hemoglobin, is caused by the loss or substantial reduction of a single hemoglobin chain. The result is low levels of functional hemoglobin and a decreased production of red blood cells, which may lead to anemia, fatigue, pale skin, and spleen and liver malfunction. Thalassemia is a set of related diseases. In α-thalassemia, the α chain of hemoglobin is not produced in sufficient quantity. Consequently, hemoglobin tetramers form that contain only the β chain. These tetramers, referred to as hemoglobin H (HbH), bind oxygen with high affinity and no cooperativity. Thus, oxygen release in the tissues is poor. The most severe forms of α-thalassemia, in which the the α chain of hemoglobin is essentially absent, are usually fatal shortly before or just after birth. However, these forms are relatively rare.

In β-thalassemia, the β chain of hemoglobin is not produced in sufficient quantity. In the absence of β chains, the α chains form insoluble aggregates that precipitate inside immature red blood cells. The loss of red blood cells results in anemia. The severity of thalassemia depends on how much the gene is disrupted. The most severe form of β-thalassemia, called thalassemia major or Cooley anemia, results when genes from both parents are defective. Blood transfusions are the most common treatment for thalassemias.