The emerging understanding of sickle cell disease

The first indisputable case of sickle cell disease in the literature was described in a dental student studying in Chicago between 1904 and 1907 (Herrick, 1910). Coming from the north of the island of Grenada in the eastern Caribbean, he was first admitted to the Presbyterian Hospital, Chicago, in late December 1904 and a blood test showed the features characteristic of homozygous sickle cell (SS) disease. It was a happy coincidence that he was under the care of Dr James Herrick (Fig 1) and his intern Dr Ernest Irons because both had an interest in laboratory investigation and Herrick had previously presented a paper on the value of blood examination in reaching a diagnosis (Herrick, 1904±05). The resulting blood test report by Dr Irons described and contained drawings of the abnormal red cells (Fig 2) and the photomicrographs, showing irreversibly sickled cells, leave little doubt that the diagnosis was SS disease. The subsequent history of Dr Walter Clement Noel, that first patient, is described in a fascinating account by Dr Todd Savitt (Savitt & Goldberg, 1989) who found that, on Dr Noel's return to Grenada in 1907, he set-up a dental practice in the capital St. Georges, died from the acute chest syndrome aged 32 years and is buried in the Catholic cemetery at Sauteurs in the north of Grenada (Fig 3). The second case, Ellen Anthony, aged 25 years, had already been under observation in the wards of the University of Virginia Hospital from 1907 and the strange blood film sent to pathologists at Johns Hopkins University Hospital was considered an unusual case of pernicious anaemia (Savitt, 1997). The diagnosis became clear with the publication of Herrick's paper in November, 1910 (Herrick, 1910) and, within 3 months, this second case was reported in February 1911 (Washburn, 1911) (Fig 4). The third case, a woman aged 21 years, reported from Washington University Medical School in 1915 (Cook & Meyer, 1915), raised suspicions of a genetic basis, as three siblings had died from severe anaemia, and blood from both the patient and her asymptomatic father showed a sickling deformity of the red cells on incubation (Emmel, 1917). The fourth case was a 21-year-old black man in the wards of Johns Hopkins Hospital (Mason, 1922). It was Mason who noted the similar features of the first four case reports, he was the first to use the term `sickle cell anaemia' and, finding that the cases were all black, he began the popular misconception that the disease was confined to people of African origin. Genetics of sickle cell disease The discovery by Emmel (1917) of the sickle cell phenomenon in the father of the third case not only suggested a genetic basis for sickle cell disease, but led to a period of confusion in the genetics of the disease. Both Huck (1923) and Sydenstricker et al (1923) noted `latent sicklers' among relatives of patients with the disease, and further analysis of the pedigree of Huck's patients led to the conclusion that the sickle cell phenomenon was inherited as a Mendelian autosomal characteristic (Taliaferro & Huck, 1923). People with positive sickle tests were divided into asymptomatic cases, `latent sicklers', and those with features of the disease, `active sicklers', and it was Dr Lemuel Diggs of Memphis who first clearly distinguished symptomatic cases called sickle cell anaemia from the latent asymptomatic cases which were termed the sickle cell trait (Diggs et al, 1933). Several years were to elapse before the relationship of the trait and the disease was clarified. A review of 32 apparent cases of the disease with data in both parents showed sickling in both parents in 10 cases, in one parent in 15 cases and in neither parent in seven cases (Neel, 1947). Prospective data collection in 29 cases of the disease showed sickling in all 42 parents tested (Neel, 1949), providing strong support for the theory of homozygous inheritance. A Colonial Medical Officer working in Northern Rhodesia (Beet, 1949) reached similar conclusions at the same time with a study of one large family (the Kapokoso-Chuni pedigree). The implication that sickle cell anaemia should occur in all communities in which the sickle cell trait was common and that its frequency would be determined by the prevalence of the trait did not appear to fit the observations from Africa. Despite a sickle cell trait prevalence of 27% in Angola, Texeira (1944) noted the active form of the disease to be `extremely rare' and similar observations were made from East Africa (Lehmann & Milne, 1949; Mackey, 1949; Raper, 1949; Lehmann, 1951), West Africa (Edington, 1954) and Northern Rhodesia (Beet, 1947). In Uganda, Lehmann and Raper (1949, 1956) found a positive sickling test in 45% of one community, from which homozygous inheritance would have predicted that nearly 10% of children had SS disease, yet not a single case was found. The discrepancy led to a hypothesis that some factor inherited from non-black ancestors in America might be necessary for expression of the disease (Raper, 1950). The explanation for this apparent discrepancy gradually emerged. Working with the Jaluo tribe in Kenya, Foy et al (1951) found five cases of sickle cell anaemia among very young children and suggested that cases might be dying at an age before those sampled in surveys. A similar hypothesis