A Brief History of Sickle Cell Disease

William P. Winter, Ph.D.

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.