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.
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.
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. Other
early experiments by Hahn and Gillespie and Scriver and Waugh demonstrated
the pH dependence and
oxygenation-induced reversibility of
the red blood cell (RBC) sickling process, respectively.
Ham and Castle proposed that a “vicious
cycle of erythrostasis” (vaso-occlusion)
explained the pathophysiology of SCD patients. 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.
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. Then, in 1948, the
insight of hematologist Janet Watson implicated hemoglobin (Hb) as the key
element in red cell sickling. 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.
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);
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
watershed event occurred in 1960 when Max Perutz determined the structure of Hb
by X-ray diffraction studies. 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; 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. Subsequently, in 1980, the Maniatis lab (Lauer et al.) also cloned and sequenced the human a-globin gene. These advances ushered in an era of investigation of SCD (i.e., Hb S; a 2bS2) at the molecular level through recombinant DNA techniques.