IX. GENETICS AND HUMAN HEMOGLOBIN CHEMISTRY 467 



normal animals, only 10% are found to be labeled in bled animals (Alpen 

 and Cranmore, 1959) ; the average generation time of the erythroblast 

 does not appear to be different in bled or control animals. The erythro- 

 blasts seem to be a partially self-maintaining cell population, supple- 

 mented by the differentiation of the stem cells. This implies that the 

 eiythroblasts are able to make a choice between dividing only or dividing 

 and differentiating. 



A definite correlation exists between higher erythropoietic activity 

 in pathological conditions and the appearance of Hb-F in adults. Al- 

 though w^e are far from a full understanding of the process of red cell 

 differentiation, some of the above-mentioned facts suggest a possible 

 explanation for the switch from Hb-F to Hb-A production at the end 

 of fetal life and for the synthesis of Hb-F in anemic individuals. 



It may be assumed that the hemoglobin type synthesized by a red 

 cell precursor is determined by the genetic infonnation possessed by that 

 cell at the moment of initiating hemoglobin synthesis and during the 

 course of hemoglobin synthesis. By analogy with protein synthesis in 

 bacteria, we can speculate that the hemoglobin genes are repressed in 

 stem cells and that when these cells differentiate into erythroblasts, 

 specific hemoglobin genes become derepressed or activated by genetically 

 determined mechanisms. The factors determining derepression or activa- 

 tion of (3 rather than y genes are unknowTi. It has been suggested that the 

 change in oxygen tension from the uterine environment to the extra- 

 uterine environment after birth may be the activating mechanism for the 

 synthesis of ft chains (Allen and Jandl, 1960; Thomas et al., 1960) or 

 that gonadotropic hormones may play a similar role (Rucknagel and 

 Chernoff, 1955). None of these proposed mechanisms accounts satisfac- 

 torily, in the author's opinion, for the synthesis of Hb-F in pathological 

 conditions of severe anemia during adult life. 



By analogy with the observations in bled animals, we can speculate 

 that in anemic subjects the stem cells differentiate into red cells after a 

 limited number of cell divisions, while in normal erythropoiesis a con- 

 siderable number of cell divisions occur at the eiythroblast stage 

 before maturation of the red cells. It has been reported that stem cells 

 may sometimes differentiate into red cells without intervening division 

 (Suit, 1957). Similarly, in the fetus the red cells are released in circula- 

 tion after a number of divisions of the erythroid precursors, limited by 

 the age of the fetus itself and possibly by the accelerated fetal ejythro- 

 poietic activity. A correlation may thus exist either between the number 

 of divisions that the progenitors of a red cell have undergone in the 

 absence of morphological differentiation or the time spent in the bone 

 marrow by these cells as erythroblasts and the hemoglobin type con- 



