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SCD was first described in a scientific journal at the beginning of the 20th century and  has been intensively studied since that time.  What follows is a brief overview detailing the historical course of investigation of SCD, from its cellular defect, to the mutant hemoglobin protein, to its genetic origin.

A Brief  Historical Overview

In 1904, Dr. James Herrick made the seminal observation of elongated and crescent-shaped cells in the blood film of a young black man and later reported this finding[1]. The observation of “sickle” shaped cells-- the hallmark of SCD-- lead to a number of in vivo and in vitro experiments aimed at elucidating this newly described phenomenon. In 1917, Emmel demonstrated that red cells from a SCD patient sickled after prolonged exposure to hypoxia[2].  Other early experiments by Hahn and Gillespie[3] and Scriver and Waugh[4] demonstrated the pH dependence  and oxygenation-induced reversibility of the red blood cell (RBC) sickling process, respectively. 

In 1940, Ham and Castle proposed that a vicious cycle of erythrostasis (vaso-occlusion) explained the pathophysiology of SCD patients[5]. The theory underlying this “vicious cycle” is that RBC sickling increases blood viscosity and delays capillary transit. In turn, this delay in capillary passage results in more sickling as red cells remain in the low oxygen tension (and low pH) environment of the microcirculatory system. The microvascular trapping of RBCs then leads to chronic anemia, episodic painful crises, and end-organ damage.

The cellular defect underlying the sickling phenomenon was later determined to involve the hemoglobin protein. In 1940, Irving Sherman reported on the birefringent orientation of the molecules (hemoglobin) inside deoxygenated sickled cells when examined under a polarizing microscope[6]. Then, in 1948, the insight of hematologist Janet Watson implicated hemoglobin (Hb) as the key element in red cell sickling[7]. Watson's inference came from observing the absence of sickling in blood smears of young SCD patients with fetal Hb. These patients then became symptomatic (presenting RBC sickling) when the their infant/fetal Hb was replaced by the adolescent/adult type of Hb. Soon after this, a number of breakthroughs came from experiments that would ultimately elucidate the specific molecular defect. 

The classic experiments of Pauling, Ingram, and Perutz form the grounding , as well as the jumping off point, for basic science  research into SCD. In 1949 Linus Pauling demonstrated that Hb from adult patients with SCD (Hb SS) had a different electrophoretic mobility than Hb from patients with sickle trait (HbAS) and Hb from normal adults (HbAA)[8]; thereby, SCD was distinguished as the first molecular disease. Then, in the mid 50’s, Vernon Ingram identified the molecular defect of SCD as a substitution in the sixth amino acid (Glu Val) of the b-globin chain [9,10]. Another watershed event occurred in 1960 when Max Perutz determined the structure of Hb by X-ray diffraction studies[12]. Perutz unravelled the protein structure and stereochemistry of the Hb molecule [13,14], which led the way to determining the key amino acids responsible for the important protein folding and inter-molecular interactions that underlie normal Hb functioning, and that are central to SCD pathogenesis.  

In retrospect, the experiments by Pauling and Ingram also provided experimental support for Beadle and Tatum’s one gene-one protein theory[11]; the findings pointed to the mutant Hb protein (gene product) as the defective factor in the sickling phenomenon, and implicated an altered Hb gene sequence in sickle cell patients.

In the late 70’s, investigators were able to benefit from the advent of molecular techniques. Since the SCD cellular protein defect was ultimately genetic in origin, cloning the gene responsible for the mutant sickle protein by means of gene isolation techniques was the next logical step. In 1978, the laboratory of Tom Maniatis (Lawn et al.) cloned and sequenced the human b-globin gene[15]. Subsequently, in 1980, the Maniatis lab (Lauer et al.) also cloned and sequenced the human a-globin gene[16]. These advances ushered in an era of investigation of SCD (i.e., Hb S; a 2bS2) at the molecular level through recombinant DNA techniques.