## 1 Introduction
Hemichrome is rarely found in erythrocytes _in situ_, so little attention has been paid to hemichrome and formation of Heinz bodies in the context of normal Hb or normal erythrocytes. Nevertheless, we carried out a series of experiments concerning normal Hb and normal erythrocytes based on the hypothesis that formation of Heinz bodies is not only a peculiarity of labile Hb in patients, but is also an innate characteristic of physiologically normal Hb molecules [23, 24]. As a consequence, it was shown that the inherent tilting capability of the distal (E7) His residue is closely related to the molecular instability (degradation) of Hb, and that this instability can trigger degradation of the molecule to hemichrome, and subsequent clustering of Heinz bodies within the erythrocyte. In the studies mentioned above [23, 24], Heinz bodies were visualized by exposing blood smears to acetylcholinesterasehydrazine and staining with crystal violet. Changes within the erythrocytes were observed using light microscopy under oil immersion. Prior to the Heinz-body formation (acetylphenylhydrazine) test, blood samples were subjected to mild heating _in vitro_ at close to physiological temperatures. The findings indicated that the number of Heinz bodies formed in red cells increased with increasing temperature of the blood sample [23, 24]. _In vitro_ evaluation of blood fluidity was also conducted under identical conditions using a micro-channel array flow analyzer to give an index of erythrocyte deformability [24]. The equipment included a characteristic V-shaped groove array with micro flow paths (width, 7 \(\upmu\)m; length, 30 \(\upmu\)m; depth, 4.5 \(\upmu\)m) engraved on a single-crystal silicon substrate in an integral circuit. This equipment made it possible to not only observe red cells passing through individual micro-channel arrays by use of an inverted metallographic microscope, but also enabled evaluation of blood fluidity through the groove array in terms of the transit time of the blood sample for a given transit sample volume. The findings indicated that erythrocyte deformability decreased with increasing temperature of the blood sample at \(>\)37 \({}^{\circ}\)C [24]. In the spleen, Heinz body-containing red cells become trapped while traversing small apertures in the basement membranes separating the cords from the sinusoids (where the spaces are sufficiently small to require extreme deformation of red cells) [25]. Thus, it was suggested that the Hb molecule controls removal of erythrocytes from the blood circulation via triggering degradation of the Hb molecule to hemichrome, and subsequent clustering of Heinz bodies within the erythrocytes depending on the internal and extraneous conditions of the erythrocyte. Cellular life is relying on rapid and efficient responses to internal and external conditions. The basic molecular events associated with these processes are the structural transitions of the proteins (structural protein allostery) involved [26]. Therefore, the tetrmeric human Hb (\(\alpha_{2}\beta_{2}\); alternatively, a dimer of \(\alpha\beta\)protomers) deserves a special position in this field. Hb has two types of \(\alpha\beta\) interface. One is the \(\alpha_{1}\)-\(\beta_{1}\) (and \(\alpha_{2}\)-\(\beta_{2}\)) and the other is the \(\alpha_{1}\)-\(\beta_{2}\) (and \(\alpha_{2}\)-\(\beta_{1}\)). The latter \"sliding\" contact is known to be associated with cooperative O\({}_{2}\) binding, and in fact has important roles if the Hb molecule goes from the deoxygenated to oxygenated quaternary structure. However, the role of the former was unclear for a long time. In this regard, important and intriguing observations have been accumulating. Thus, new roles could be attributed for \(\alpha_{1}\beta_{1}\) (and \(\alpha_{2}\beta_{2}\)). It seems that the \(\alpha_{1}\)-\(\beta_{1}\) (and \(\alpha_{2}\)-\(\beta_{2}\)) interface has dual roles.