IX. GENETICS AND HUMAN HEMOGLOBIN CliEMLSTRY 469 



tained by the daughter red cell. Red cells produced after few cell 

 divisions from stem cells may possibly contain more Hb-F than red 

 cells produced after several divisions of the erythroblasts. In this view 

 the information directed to the hemoglobin chain synthesis changes with 

 the aging and/or the replication of the erythroid precursors (Fig. 15). 



Sublethal irradiation of monkeys (Tuttle et al., 1961) or of humans 

 for therapeutic purposes (R. Ceppellini, personal communication), which 

 causes rapid differentiation of stem cells (Lajtha and Oliver, 1960), has 

 been reported to be followed by the appearance of Hb-F in the blood 

 of the irradiated subjects. 



The present hypothesis regarding the relationship between red cell 

 differentiation and the switch from Hb-F to Hb-A production accounts 

 formally for most of the observations made in recent years: the lack of 

 effect of birth on the switch from Hb-F to Hb-A production (Cook et al., 

 1957) and the appearance of Hb-F in conditions of abnormal eiythro- 

 poiesis. It fails, however, to provide an explanation of the mechanisms 

 involved in the control of the hemoglobin genes. This seems to be a point 

 of more general interest since it deals with the control of differentiation, 

 the challenging problem of today's biology. 



The Hb-F/Hb-A system may be useful in the study of mechanisms 

 of differentiation, because of the well-defined chemical nature of the 

 proteins involved. In the switch from Hb-F to Hb-A production, only 

 the synthesis of one type of peptide chain, the y chain, seems to be 

 discontinued, while the synthesis of a new type of peptide chain, the p 

 chain, is initiated. Only two genes, the p and the y genes, are apparently 

 involved in switching their activity; this fact may provide a unique 

 opportunity for the study of the differentiation of a simplified genetic 

 and biochemical system. 



Acknowledgments 



The author wishes to thank Dr. Vernon M. Ingram for reading this manuscript, 

 for suggesting several improvements and corrections, and for discussion and advice. 

 Thanks are due to all who have made available unpublished data and who have 

 contributed to this chapter with personal communications. The author is grateful to 

 the Medical Foundation, Inc., Boston, and to the National Science Foundation, 

 Washington, who have supported his work with grants. 



References 



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Aksoy, M, and Lehmann, H. (1957). Nature 179, 1248. 



Allen, D. W., and Jandl, J. H. (1960). J. Clin. Invest. 39, 1107. 



Allen, D. W., Schroeder, W. A., and Balog, J. (1958). J. Am. Chem. Soc. 80, 1628. 



Allison, A. C. (1955). Science 122, 640. 



Allison, A. C. (1957). Biochem. J. 65, 212. 



