Sickle Cell Disease

Sickle cell disease is an inherited blood disorder in which red blood cells become rigid and crescent-shaped. It is caused by a single-letter mutation in the gene for the beta chain of hemoglobin, and it was the first disease to be explained at the molecular level.

A change of one nucleotide in the HBB gene swaps the amino acid glutamic acid for valine at position 6 of the beta chain. Under low oxygen, the altered hemoglobin, called HbS, sticks together into long fibers that deform the cell. Linus Pauling showed in 1949 that the protein was different, and Vernon Ingram located the exact amino acid change in 1956. The disease is inherited as an autosomal recessive trait, so a person needs two copies of the allele.

Sickled cells block small blood vessels, causing sudden episodes of severe pain, organ damage and stroke, and they break apart early, leading to anemia. Children with the disease are also more susceptible to infections. Treatments include hydroxyurea, blood transfusions and, in a few patients, bone marrow transplant. In late 2023 the first CRISPR-based gene therapy, Casgevy, was approved in the United Kingdom and the United States.

People who carry one copy of the allele, the sickle cell trait, are largely protected from severe malaria caused by Plasmodium falciparum, a case of balancing natural selection called heterozygote advantage. This explains why the allele is frequent in regions of Africa, the Mediterranean and India where malaria has been common. The case is a standard example in population genetics of how a harmful genetic mutation can persist.

• Genetic Mutation — the kind of change behind it
• Malaria — the disease the trait protects against
• Natural Selection — why the allele stays common