One of the milestones in the history of molecular biology and genetic diseases occurred in 1949, when Lines Pauling ( 1901-1994; 1953 Nobel Prize in Chemistry) discovered that sickle cell anemia, an inherited blood disorder, was caused by a single change in the structure of a single protein in hemoglobin, the complex molecule which carries oxygen in everyone’s red blood cells. For the first time, a hereditary disease was shown to be the result of a miniscule change in DNA that leads cells to make slightly different proteins. In sickle cell anemia, the tiny substitution in the hemoglobin protein changes the way the molecule shapes itself three-dimensionally and this change causes all of the misery and illness associated with sickle cell anemia (also known as sickle cell disease).
Hemoglobin fails to stack and fold itself normally
Hemoglobin molecules carry oxygen from the lungs to the rest of the body, and pick up carbon dioxide to be expelled on the next pass through the lungs. Hemoglobin molecules are stacked neatly inside red blood cells which, under a microscope, look like plump, oval discs, flattened in their mid-sections. To hold and release oxygen and carbon dioxide, the hemoglobin molecules change their shapes, folding and unfolding in response to changes in the acidity of the blood. In sickle cell disease, hemoglobin does not stack neatly or fold correctly, and it distorts the shape of the red blood cells, damaging their membranes. Instead of flattened ovals, red blood cells containing sickle cell hemoglobin assume odd and spiky shapes which are reminiscent of sickles.
Abnormally shaped red blood cells cause trouble
Distorted, sickled red blood cells are shorter-lived than normal red blood cells, causing anemia , or low red blood cell counts, with symptoms of fatigue, weakness and shortness of breath. The abnormally shaped cells also get stuck in small blood vessels of many organs, causing pain and organ damage, and symptoms like strokes, abdominal pain, joint pain and swelling. Episodes of pain and other symptoms are called sickle cell crises, last for about a week, and often require hospitalization and narcotics. The spleen can become severely damaged and non-functional in patients with sickle cell disease. The spleen is an important part of the immune system and, without it, sickle cell patients can be subject to life threatening infections. They require prophylactic antibiotics and careful attention to immunizations. Sickle cell crises are triggered by stress, dehydration, infections and illness and the damage they cause can shorten life. Modern diagnosis and treatment have raised life expectancy of sickle cell patients to over age fifty, an improvement of almost a decade compared to the past. Some babies with sickle cell disease have been successfully treated with bone marrow transplants.
A common genetic trait
In certain parts of the world, 10-40% of the population carry one copy of the mutated gene that codes for the abnormal hemoglobin of sickle cell anemia. Those carriers are said to have sickle cell trait, and they do not suffer from sickle cell disease, which appears only if two copies of the gene are present. But since children get half their genes from each parent, if two carriers of the sickle cell trait get together and have children, the odds are that 25% of their children will be born with two copies of the gene and have sickle cell disease, 25% will have normal hemoglobin, and fifty percent will carry a single copy of the gene, without symptoms. These are the same odds that are associated with other recessive traits, such as blue eyes or red hair, that require two copies of a given gene for expression of the trait carried by the gene.
The trait has an upside – in malaria infections
Why would a genetic trait be so common when it can lead to a disease that causes illness and premature death? The geography associated with sickle cell trait provides one answer. Sickle cell trait is common in groups of people who come from the belt of the earth around the equator where malaria is or was at one time endemic: sub-Saharan Africa, India, the Mediterranean and Arabian Gulf countries, and Central and South America. What is the relationship between malaria and sickle cell trait? The malaria parasite lives in red blood cells, which are full of hemoglobin. The parasite feeds on hemoglobin as a necessary part of its lifecycle. But something about the hemoglobin produced by the abnormal gene makes carriers of the sickle cell trait less likely to succumb to malaria in infancy and less subject to severe malarial symptoms at older ages. The sickle cell trait thus confers a survival advantage on people from malarial regions of the earth, and it has persisted in the population despite the disadvantage it produces when a child inherits two copies of the sickle cell gene. Paradoxically, two copies of the gene do not protect against malarial symptoms because the infection triggers sickle cell crises.
Sickle cell disease affects as many as one in 400-500 of African Americans in the United States, and about 1 in 36,000 Hispanic Americans. About 90,000-100,000 people in the US have the disease. The sickle cell trait is present in one out of every 12 African Americans and one of every 100 Hispanic Americans. In France sickle cell disease is now the leading genetic disease because of emigration from Africa and the Caribbean. Over a long period of time, as these populations live and reproduce in regions where malaria is not a significant threat, the trait may disappear since it will no longer be conferring a survival advantage. In the meantime, researchers hope to better understand how sickle cell hemoglobin tames the malaria parasite and to use the knowledge in the battle against this ancient disease.