#WorldSickleCellDay A Brief History of Sickle Cell Disease, how is sickle cell anemia inherited ?
A Brief History of Sickle Cell Disease
in the annals of medical history, 1910 is regarded as the date of the discovery of sickle cell disease, making 2010 the 100th anniversary of that discovery, but just what does it mean to say the disease was “discovered”? The disorder we call “Sickle Cell Disease” often abbreviated as SCD, had been present in Africa for at least five thousand years and has been known by many names in many tribal languages. What we call its “discovery” in 1910 occurred, not in Africa, but in the United States. A young man named Walter Clement Noel from the island of Grenada, a dental student studying in Chicago, went to Dr. James B. Herrick with complaints of pain episodes, and symptoms of anemia. Herrick was a cardiologist and not too interested in Noel’s case so he assigned a resident, Dr. Ernest Irons to the case. Irons examined Noel’s blood under the microscope and saw red blood cells he described as “having the shape of a sickle”. When Herrick saw this in the chart, he became interested because he saw that this might be a new, unknown, disease. He subsequently published a paper in one of the medical journals in which he used the term “sickle shaped cells”.
As more cases began to surface, the mystery of just what this disease was only deepened. It was clear that for whatever reason, it occurred only or primarily in persons of African origin. In 1927, Hahn and Gillespie discovered that red blood cells from persons with the disease could be made to sickle by removing oxygen. This was exciting because red cells are the oxygen transporters of the body. The trouble was, that there were people –often relatives of the patient – whose red cells had this trait of sickling when deprived of oxygen but who had no disease. This condition became known as “sickle trait”.
In the late 1940’s and early 1950’s the nature of the disease began to become clearer.
In 1949, two articles appeared independently showing conclusively that SCD was inherited and that people with sickle trait were heterozygous (carriers or AS) for the gene whereas people with the disease were homozygous – i.e., had a double dose of the gene (SS). One was published by a military doctor in what was then known as Portuguese East Africa (now Mozambique) named Col. E. A. Beet. His article was in an African medical journal. The other was by Dr. James V. Neel, Chairman and founder of the Department of Human Genetics at the University of Michigan. It was in his department that I worked for seven years and was on the staff of one of the first Centers for Sickle Cell Disease in 1972. Neel published his article in the prestigious American journal Science. As a result of the much wider readership of that journal, Neel usually gets the credit for the discovery although most authors are careful to cite both and many people think that Neel and Beet worked together. As an aside, some years ago, I visited Dr. Neel (he has died since), and I remarked that I always tell my classes about his discovery and the 1949 article and the dual publication by Beet. He smiled, got up from his desk and opened a file drawer. He pulled out a reprint of a 1947 paper he had written, also from Science as I recall, and showed me where he had said, “this [referring to data in the paper] almost certainly shows that sickle cell anemia is hereditary. I prefer to cite this paper these days,” he said with a puckish grin on his face.
Two years later, in 1951, the famous Nobel Prize-winning chemist, Dr. Linus Pauling and his colleague Dr. Harvey Itano, discovered that the red, oxygen-carrying protein called “hemoglobin” had a different chemical structure in persons with SCD. This led Dr. Pauling to coin the term “molecular disease” for disorders that resulted from proteins with abnormal chemical structures. Today, thousands of such diseases are known but in 1951, SCD was the first. The details of the abnormality were worked out by Dr. Vernon Ingram in 1956. In the 1970’s, more details of how this abnormal structure affects the red blood cells were revealed and better tests for the detection of the disease were developed. In the years following, better ways of treating sickle cell patients and potential treatments appeared. The life span and the quality of life of patients were improved. Genetic counseling became an important tool for informing people about the risks of having a child with sickle cell disease. Today, 100 years later, physicians and scientists continue to move forward in new understanding of the disease and new ways to treat it. The goal of a total cure has not been reached but great progress has been made. Perhaps within the lifetime of some of us, that goal will be reached.
In summary, in 1910, Herrick described an anemia characterized by bizarre, sickle-shaped cells. The role of deoxygenation was discovered in the 1920’s by Hahn and Gillespie. The hereditary nature of the disease was suspected but not demonstrated until 1949 by Dr. James V. Neel. The association with hemoglobin was discovered by Linus Pauling and Harvey Itano in 1951 and the actual amino acid substitution by Vernon Ingram in 1956. Thus the 100th anniversary marks the discovery of this ancient disease from Africa by western medicine and naming of the disease for a simple agricultural implement to which a medical resident in 1910 likened the shape of the abnormal cells he saw under the microscope.
How is sickle cell anemia inherited?
Sickle cell anemia is inherited as an autosomal (meaning that the gene is not linked to a sex chromosome) recessive condition. This means that the gene can be passed on from a parent carrying it to male and female children. In order for sickle cell anemia to occur, a sickle cell gene must be inherited from both the mother and the father, so that the child has two sickle cell genes.
The inheritance of just one sickle gene is called sickle cell trait or the “carrier” state. Sickle cell trait does not cause sickle cell anemia. Persons with sickle cell trait usually do not have many symptoms of disease and have hospitalization rates and life expectancies identical to unaffected people. When two carriers of sickle cell trait mate, their offspring have a one in four chance of having sickle cell anemia. (In some parts of Africa, one in five persons is a carrier for sickle cell trait.)
Signs and symptoms of sickle cell anemia, which vary from person to person and change over time, include:
Anemia. Sickle cells break apart easily and die, leaving you without enough red blood cells. Red blood cells usually live for about 120 days before they need to be replaced. But sickle cells usually die in 10 to 20 days, leaving a shortage of red blood cells (anemia).
Without enough red blood cells, your body can’t get the oxygen it needs to feel energized, causing fatigue.
Episodes of pain. Periodic episodes of pain, called crises, are a major symptom of sickle cell anemia. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to your chest, abdomen and joints. Pain can also occur in your bones.
The pain varies in intensity and can last for a few hours to a few weeks. Some people have only a few pain episodes. Others have a dozen or more crises a year. If a crisis is severe enough, you might need to be hospitalized.
Some adolescents and adults with sickle cell anemia also have chronic pain, which can result from bone and joint damage, ulcers and other causes.
Painful swelling of hands and feet. The swelling is caused by sickle-shaped red blood cells blocking blood flow to the hands and feet.
Frequent infections. Sickle cells can damage an organ that fights infection (spleen), leaving you more vulnerable to infections. Doctors commonly give infants and children with sickle cell anemia vaccinations and antibiotics to prevent potentially life-threatening infections, such as pneumonia.
Delayed growth. Red blood cells provide your body with the oxygen and nutrients you need for growth. A shortage of healthy red blood cells can slow growth in infants and children and delay puberty in teenagers.
Vision problems. Tiny blood vessels that supply your eyes may become plugged with sickle cells. This can damage the retina — the portion of the eye that processes visual images, leading to vision problems.
What conditions promote the sickling (distortion) of the red blood cells in sickle cell anemia?
Sickling of the red blood cells in patients with sickle cell anemia results in cells of abnormal shape and diminished flexibility. The sickling is promoted by conditions which are associated with low oxygen levels, increased acidity, or low volume (dehydration) of the blood. These conditions can occur as a result of injury to the body’s tissues, dehydration, or anesthesia.
Certain organs are predisposed to lower oxygen levels or acidity, such as when blood moves slowly through the spleen, liver, or kidney. Also, organs with particularly high metabolism rates (such as the brain, muscles, and the placenta in a pregnant woman with sickle cell anemia) promote sickling by extracting more oxygen from the blood. These conditions make these organs susceptible to injury from sickle cell anemia.