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). Dr. James Herrick (1861–1954) taken in 1925. Photo courtesy of the late Dr. L. W. Diggs. Report of blood test on Walter Clement Noel dated 31 December 1904. The tombstone of Walter Clement Noel in the Catholic cemetery of Sauters in the north of Grenada. The tombstone of his father John Cornelius Noel is on the right. 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. Benjamin Earle Washburn. From the University of North Carolina 1906 Yearbook. Note that his paper was incorrectly attributed to R. E. Washburn. Photo courtesy of Dr. Todd Savitt and reproduced with the permission of the Virginia Medical Quarterly. 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 was advanced by Jelliffe (1952) and was supported by data from the then Belgian Congo (Lambotte-Legrand Lambotte-Legrand, 1951, Lambotte-Legrand, 1952, Vandepitte, 1952). Although most cases were consistent with the concept of homozygous inheritance, exceptions continued to occur. Patients with a non-sickling parent of Mediterranean ancestry were later recognized to have sickle cell-β thalassaemia (Powell et al, 1950; Silvestroni & Bianco, 1952; Sturgeon et al, 1952; Neel et al, 1953a), a condition also widespread in African and Indian subjects that presents a variable syndrome depending on the molecular basis of the β thalassaemia mutation and the amount of HbA produced. Phenotypically, there are two major groups in subjects of African origin, sickle cell-β+ thalassaemia manifesting 20–30% HbA and mutations at −29(A→G) or −88(C→T), and sickle cell-β0 thalassaemia with no HbA and mutations at IVS2–849(A→G) or IVS2–1(G→A). In Indian subjects, a more severe β thalassaemia mutation IVS1–5(G→C) results in a sickle cell-β+ thalassaemia condition with 3–5% HbA and a relatively severe clinical course. Other double heterozygote conditions causing sickle cell disease include sickle cell-haemoglobin C (SC) disease (Kaplan et al, 1951; Neel et al, 1953b), sickle cell-haemoglobin O Arab (Ramot et al, 1960), sickle cell-haemoglobin Lepore Boston (Stammatoyannopoulos & Fessas, 1963) and sickle cell-haemoglobin D Punjab (Cooke & Mack, 1934). The latter condition was first described in siblings in 1934, who were reinvestigated for confirmation of HbD (Itano, 1951), the clinical features reported (Sturgeon et al, 1955) and who were finally identified as HbD Punjab (Babin et al, 1964), representing a remarkable example of longitudinal observation and investigation in the same family over 30 years. The maintenance of high frequencies of the sickle cell trait in the presence of almost obligatory losses of homozygotes in Equatorial Africa implied that there was either a very high frequency of HbS arizing by fresh mutations or that the sickle cell trait conveyed a survival advantage in the African environment. There followed a remarkable period in the 1950s when three prominent scientists were each addressing this problem in East Africa, Dr Alan Raper and Dr Hermann Lehmann in Uganda and Dr Anthony Allison in Kenya. It was quickly calculated that mutation rates were far too low to balance the loss of HbS genes from deaths of homozygotes (Allison, 1954a). An increased fertility of heterozygotes was proposed (Foy et al, 1954; Allison, 1956a) but never convincingly demonstrated. Raper (1949) was the first to suggest that the sickle cell trait might have a survival advantage against some adverse condition in the tropics and Mackey & Vivarelli (1952) suggested that this factor might be malaria. The close geographical association between the distribution of malaria and the sickle cell gene supported this concept (Allison, 1954b) and led to an exciting period in the history of research in sickle cell disease. The first observations on malaria and the sickle cell trait were from Northern Rhodesia where Beet (1946, 1947) noted that malarial parasites were less frequent in blood films from subjects with the sickle cell trait. Allison (1954c) drew attention to this association, concluding that persons with the sickle cell trait developed malaria less frequently and less severely than those without the trait. This communication marked the beginning of a considerable controversy. Two studies failed to document differences in parasite densities between 'sicklers' and 'non-sicklers' (Moore et al, 1954; Archibald & Bruce-Chwatt, 1955) and Beutler et al (1955) were unable to reproduce the inoculation experiments of Allison (1954c). Raper (1955) speculated that some feature of Allison's observations had accentuated a difference of lesser magnitude and postulated that the sickle cell trait might inhibit the establishment of malaria in non-immune subjects. The conflicting results in these and other studies appear to have occurred because the protective effect of the sickle cell trait was overshadowed by the role of acquired immunity. Examination of young children before the development of acquired immunity confirmed both lower parasite rates and densities in children with the sickle cell trait (Colbourne & Edington, 1956; Edington & Laing, 1957; Gilles et al, 1967) and it is now generally accepted that the sickle cell trait confers some protection against falciparum malaria during a critical period of early childhood between the loss of passively acquired immunity and the development of active immunity (Allison, 1957; Rucknagel & Neel, 1961; Motulsky, 1964). The mechanism of such an effect is still debated, although possible factors include selective sickling of parasitized red cells (Miller et al, 1956; Luzzatto et al, 1970) resulting in their more effective removal by the reticulo-endothelial system, inhibition of parasite growth by the greater potassium loss and low pH of sickled red cells (Friedman et al, 1979), and greater endothelial adherence of parasitized red cells (Kaul et al, 1994). The occurrence of the sickle cell mutation and the survival advantage conferred by malaria together determine the primary distribution of the sickle cell gene. Equatorial Africa is highly malarial and the sickle cell mutation appears to have arisen independently on at least three and probably four separate occasions in the African continent, and the mutations were subsequently named after the areas where they were first described and designated the Senegal, Benin, Bantu and Cameroon haplotypes of the disease (Kulozik et al, 1986; Chebloune et al, 1988; Lapoumeroulie et al, 1992). The disease seen in North and South America, the Caribbean and the UK is predominantly of African origin and mostly of the Benin haplotype, although the Bantu is proportionately more frequent in Brazil (Zago et al, 1992). It is therefore easy to understand the common misconception held in these areas that the disease is of African origin. However, the sickle cell gene is widespread around the Mediterranean, occurring in Sicily, southern Italy, northern Greece and the south coast of Turkey, although these are all of the Benin haplotype and so, ultimately, of African origin. In the Eastern province of Saudi Arabia and in central India, there is a separate independent occurrence of the HbS gene, the Asian haplotype. The Shiite population of the Eastern Province traditionally marry first cousins, tending to increase the prevalence of SS disease above that expected from the gene frequency (Al-Awamy et al, 1984). Furthermore, extensive surveys performed by the Anthropological Survey of India estimate an average sickle cell trait frequency of 15% across the states of Orissa, Madhya Pradesh and Masharastra which, with the estimated population of 300 million people, implies that there may be more cases of sickle cell disease born in India than in Africa. The Asian haplotype of sickle cell disease is generally associated with very high frequencies of alpha thalassaemia and high levels of fetal haemoglobin, both factors believed to ameliorate the severity of the disease. The promotion of sickling by low oxygen tension and acid conditions was first recognized by Hahn & Gillespie (1927) and further investigated by others (Lange et al, 1951; Allison, 1956b; Harris et al, 1956). The morphological and some functional characteristics of irreversibly sickled cells were described (Diggs & Bibb, 1939; Shen et al, 1949), but the essential features of the polymerization of reduced HbS molecules had to await the developments of electron microscopy (Murayama, 1966; Dobler & Bertles, 1968; Bertles & Dobler, 1969; White & Heagan, 1970) and Xray diffraction (Perutz & Mitchison, 1950; Perutz et al, 1951). The early observations on the inducement of sickling by hypoxia led to the first diagnostic tests utilizing sealed chambers in which oxygen was removed by white cells (Emmel, 1917), reducing agents such as sodium metabisulphite (Daland & Castle, 1948) or bacteria such as Escherichia coli (Raper, 1969). These slide sickling tests are very reliable with careful sealing and the use of positive controls, but require a microscope and some expertise in its use. An alternative method of detecting HbS utilizes its relative insolubility in hypermolar phosphate buffers (Huntsman et al, 1970), known as the solubility test. Both the slide sickle test and the solubility test detect the presence of HbS, but fail to make the vital distinction between the sickle cell trait and forms of sickle cell disease. This requires the process of haemoglobin electrophoresis, which detects the abnormal mobility of HbS, HbC and many other abnormal haemoglobins within an electric field. The contributions of several workers on the determinants of sickling (Daland & Castle, 1948), birefringence of deoxygenated sickled cells (Sherman, 1940) and the lesser degree of sickling in very young children which implied that it was a feature of adult haemoglobin (Watson, 1948) led Pauling to perform Tiselius moving boundary electrophoresis on haemoglobin solutions from subjects with sickle cell anaemia and the sickle cell trait. The demonstration of electrophoretic and, hence, implied chemical differences between normal, sickle cell trait and sickle cell disease led to the proposal that it was a molecular disease (Pauling et al, 1949). The chance encounter between Castle and Pauling who shared a train compartment returning from a meeting in Denver in 1945, its background and implications, has passed into the folklore of medical research (Conley, 1980; Feldman & Tauber, 1997). The nature of this difference was soon elucidated. The haem groups appeared identical, suggesting that the difference resided in the globin, but early chemical analyses revealed no distinctive differences (Schroeder et al, 1950; Huisman et al, 1955). Analyses of terminal amino acids also failed to reveal differences, although an excess of valine in HbS was noted but considered an experimental error (Havinga, 1953). The development of more sensitive methods of fingerprinting combining high voltage electrophoresis and chromatography allowed the identification of the essential difference between HbA and HbS. This method enabled the separation of constituent peptides and demonstrated that a peptide in HbS was more positively charged than in HbA (Ingram, 1956). This peptide was found to contain less glutamic acid and more valine, suggesting that valine had replaced glutamic acid (Ingram, 1957). The sequence of this peptide was shown to be Val-His-Leu-Thr-Pro-Val-Glu-Lys in HbS instead of the Val-His-Leu-Thr-Pro-Glu-Glu-Lys in HbA (Hunt & Ingram, 1958), a sequence which was subsequently identified as the amino-terminus of the β chain (Hunt & Ingram, 1959). This amino acid substitution was consistent with the genetic code and was subsequently found to be attributable to the nucleotide change from GAG to GTG (Marotta et al, 1977). Haemolysis and anaemia The presence of anaemia and jaundice in the first four cases suggested accelerated haemolysis, which was supported by elevated reticulocyte counts (Sydenstricker et al, 1923) and expansion of the bone marrow (Sydenstricker et al, 1923; Graham, 1924). The bone changes of medullary expansion and cortical thinning were noted in early radiological reports (Vogt & Diamond, 1930; LeWald, 1932; Grinnan, 1935). Drawing on a comparison of sickle cell disease and hereditary spherocytosis, Sydenstricker (1924) introduced the term 'haemolytic crisis' that has persisted in the literature to this day, despite the lack of evidence for such an entity in sickle cell disease. The increased requirements of folic acid and the consequence of a deficiency leading to megaloblastic change was not noted until much later (Zuelzer & Rutzky, 1953; Jonsson et al, 1959; MacIver & Went, 1960). The haemoglobin level in SS disease of African origin is typically between 6 and 9 g/dl and is well tolerated, partly because of a marked shift in the oxygen dissociation curve (Scriver & Waugh, 1930; Seakins et al, 1973) that HbS within the red cell with a low oxygen This patients at their haemoglobin levels of anaemia and fail to from blood to oxygen of bone marrow by of from the blood and a haemoglobin termed the was first recognized by et al case report contained many features characteristic of this a a became and the haemoglobin from to g/dl within 3 and were examination revealed an of red cell which was replaced 9 later by with an of and into the was admitted to with similar on the same The for to predominantly to occur in and to siblings was consistent with an but it was not until a chance observation in et al, that the of the was shown to be et al, marrow after and, oxygen is by the is has never been The and in several early reports (Washburn, Graham, et al, The lack of data on the history of led to from and a to However, data from the report a prevalence of by the age of 25 years, and no differences between patients with and without or within patients with before and after their development et al, of asymptomatic and has been by in only of SS patients with known The of was recognized more areas of were described by (1924) and & and noted that and contained fresh and blood and a consequence of fresh and of the and was recognized & and Diggs noted the of to of the of polymerization and sickling led & Castle to an early of the of as a in which increased blood further reducing oxygen leading to more sickling and further These have much more with the extensive on endothelial adherence of cells by the groups of & and et al these studies on the abnormal red blood cells be the data on the possible of high white cell counts et al, et al, and increased to the of The in early observations of sickle cell disease. A occurred in the first (Sydenstricker et al, leading to the that might account for the of and the proposal that the disease was a and hereditary of the as a of the of blood into the but this concept was by who considered the to be the of sickled There was on was characteristic of early reports 1930; & & but was common in young patients in others and, in the appeared to during & marked to the & and were removed in children under 3 years of age et al, & from this confusion with the that the was frequently in young children and became with age & The concept of was by Hahn & Gillespie (1927) when they that the by its continued and its history as an of a and the sequence of this process was by Diggs The role of followed removal of some large & & but were less in others et al, and the removal of an The concept of with of red cells much later et al, 1956) and is still and in sickle cell disease. acute was first recognized by features by & and the role of in and of in early diagnosis at was by et al In to the of acute and the early loss of et al, patients to with the was first described by & but the and of this relationship was much later & 1966; & may be by in early childhood et al, et al, and by at later and effective to survival et al, These may in the with the of and the development of a that may be effective when at and 6 A occurred in a reported by Sydenstricker et al (1923) and the first major review et al, 1940) described patients and 25 cases from the This review the early age of and the high frequency of features in subsequent & et al, A mechanism was proposed and confirmed by et al and or of major occurred in of seven children et al, clinical features of in SS disease the young age of age 6 the of in children and of in and a to within 3 years of the et al, et al, 1992). of of the primary not and is confined to of by early of of by and of has reduced et al, but the many with changes The first review of bone changes (Diggs et al, was followed by reports of the bone changes associated with et al, cortical & & 1948) and of the & & 1947). of active bone marrow for and of the of the and in children under years syndrome or and a similar the areas of and in children and young the The features of were first by et al and the of in the by & bone marrow is to by despite several reports & Diggs et al, the association was not until & The is the most frequent of in SS disease and for of sickle in the UK and the its high it is remarkable that studies have only and factors et al, et al, clinical features et al, mechanism & associated et al, and et al, Although to be in origin the term the frequency of as a factor et al, greater prevalence in with less sickling disease and homozygous thalassaemia and sickle cell-β0 and and distribution are to on this basis, leading to the hypothesis that this may a syndrome & may be by and of which is the most frequent in The of a high haemoglobin as a factor et al, et al, for but only data are and Although most attention has been to the of it is clear that a to with is determined by many of which and around the occurred in all of the first four case reports despite a of cases presented at the of & and the it was not until that became recognized as a of the disease & occur in other hereditary suggesting common although they are almost with contributions from and

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