HAEMOGLOBIN SYNTHESIS DURING HUMAN FETAL DEVELOPMENT
W. G. Wood
FIG. I. Changes in erythroid cell type, site of erythropoiesis and globin-chain synthesis during human development (After Huehni & Shooter, 1945, and Klelhmuer, 1970)
HAEMOGLOBIN SYNTHESIS DURING HUMAN FETAL DEVELOPMENT W. G. WOOD Ph.D. Nuffield Department of Clinical Medicine The Radcliffe Infirmary, Oxford 1 Erythropoiesis during development 2 Haemoglobin synthesis during development 3 The relation of haemoglobin synthesis to the site of erythropoiesis 4 Abnormal haemoglobin synthesis during development 5 The switch from fetal to adult haemoglobin 6 Control of the switch References
«
JJ J t Birth
Poit-natal age (weeks)
20%) of both Hb F and Hb A comprise nearly 50 % of the cells shortly after birth (Betke & Kleihauer, 1958; Fraser & Raper, 1962; Shepard et al. 1962). Cells from which the haemoglobin has been almost fully eluted, and hence presumably contained mostly Hb A, first appear at about 34 weeks and comprise about 2-5 % of the cells at term. They increase in number as the proportion of Hb-F-containing cells ("F cells") decreases, making up over 95 % of the cells by six months of age. The slow decline in Hb-F levels in early childhood is matched by a similar decline in F cells and the small amount of Hb F present in adult life is restricted to a small clone of cells comprising up
6. Control of the Switch Whilst the timing and rate of change-over from Hb F to Hb A is fairly well described, knowledge of the mechanisms controlling the switch is still negligible. This basically stems from the lack of human experimental material during the switching period (a factor which is unlikely to change) and the absence of a suitable animal model system. In none of the common laboratory mammals is there good evidence for an easily detected Hb F (Kleihauer, 1970; Kitchen & Brett, 1974). In the mouse, embryonic haemoglobins produced in the yolk sac are replaced by Hb A as soon as hepatic erythropoiesis begins in the fetus (Craig & Russell, 1964; Fantoni et al. 1967; 285
Vol. 32 No. 3
W. G. Wood
HAEMOGLOBIN SYNTHESIS DURING HUMAN FETAL DEVELOPMENT Kovach et al. 1967); and this appears to be the case in rats, rabbits, guinea-pigs and Syrian hamsters (Kitchen & Brett, 1974). Cows, sheep, goats, deer and elephants are the only non-primate mnmmnta known to have an Hb F akin to that in man. The problem of the control of the switch needs to be understood at both the molecular and cellular levels. At the molecular level we know very little about the regulation of the °Y-AY-S-P gene complex. Several hypotheses have been proposed to explain what occurs during the switch and in those genetic disorders associated with the production of Hb F in adult life. These hypotheses include the presence of a single promoter locus at the beginning of the(c ?)-°y-A7-S-§ complex, with a progression in the actual gene transcribed being controlled by a process of intrachromosomal crossing-over (Kabat, 1972). Alternative ideas invoke a series of controller genes between the globin structural genes, with a series of overlapping deletions to explain the observed phenotypes (Huisman et al. 1974; Nigon & Godet, 1976). The rapidly developing techniques of nucleic acid hybridization, gene amplification and nucleic acid sequencing, coupled with the development of an in-vitro transcriptional system, may soon lead to new insights into the molecular aspects of the switch. At the cellular level there are several important questions requiring answers. We need to know at which level of haemopoietic stem-cell differentiation the type of haemoglobin to be synthesized is determined and whether this can be altered during the further maturation of the cell. Secondly, we need
W. G. Wood
to know what factors are responsible for initiating the switcli— humoral factors, localized tissue agents (cell-cell interaction) or possibly some form of an internal clock? Evidence that can be interpreted in favour of a humoral factor, and against localized cell effects, comes from the increase in maternal Hb-F synthesis during thefirsttrimester of pregnancy (Pembrey et al. 1973) and the apparent synchrony in the switch from Hb F to Hb A in different erythropoietic sites (Wood & Weatherall, 1973). The question of whether it is possible to reverse the switch in an individual stem cell, or whether the programming of a cell for fi- and S-chain production is a permanent commitment, is extremely important in considering the exciting therapeutic potential of manipulating the switch to increase the production of Hb F in those severe haemoglobinopathies with defective (3-chain production. If the switch is reversible in an individual stem cell, then the problem of increasing Hb-F production lies at the molecular level, in increasing the transcription of the y-chain genes relative to the f}-chain gene. If, as seems more likely, the switch is irreversible, augmenting Hb-F production in adults would involve increasing the contribution of those clones of cells in the adult which retain the capacity to produce Hb F (Weatherall & Clegg, 1972). Clearly, these are two quite different propositions. The difficulties which would appear to surround augmenting the contribution of F-cell clones in adults make it likely that the best approach to this problem would be to attempt to arrest the switch from Hb-F to Hb-A production in the newborn, while the proportion of Hb F produced is still high.
REFERENCES
Bard, H. (1973)/. Clin. Invest. 52,1789-1795 Bard, H. (1975) / . Clin. Invest. 55, 395-398 Bard, H., Makowski, E. L., Meschia, G. & Battaglia, F. C. (1970) Pediatrics, 45, 766-772 Basch, R. S. (1972) Blood, 39, 530-541 Bateman, A. E. & Cole, R. J. (1971) / . Embryol. Exp. Morphol. 26, 475-480 Betkc, K. (1962) In: Proceedings of the VHIth International Congress of Hematology, Tokyo, September 4-10, 1960, pp. 1033-1040. Pan-Pacific Press, Tokyo Betke, K. & Kleihauer, E. (1958) Blut, 4, 241-249 Boyer, S. H., Belding, T. K., Margolet, L. & Noyes, A. N. (1975) Science (New York) 188, 361-363 Bromberg, Y. M., Abrahamov, A. & Salzberger, M. (1956) / . Obstet. Gynaecol. Br. Emp. 63, 875-877 Capp, G. L., Rigas, D. A. & Jones, R. T. (1967) Science (New York) 157, 65-66 Capp, G. L., Rigas, D. A. & Jones, R. T. (1970) Nature (London) 228, 278-280 [Letter] Cole, R. J. & Paul, J. (1966) J. Embryol. Exp. Morphol. 15,245-260 Colombo, B., Kim, B., Atendo, R. P., Molina, C. &Terrenato, L. (1976) Br. J. Haematol. 32, 79-87 Craig, M. L. & Russell, E. S. (1964) Dev. Biol. 10,191-201 Fantoni, A., Bank, A. & Marks, P. A. (1967) Science (New York) 157,1327-1329 Finne, P. H. & Halvorsen, S. (1972) Arch. Dis. Child. 47,683-687 Fraser, I. D. & Raper, A. B. (1962) Arch. Dis. Child. 37, 289-296 Gairdner, D., Marks, J. & Roscoe, J. D. (1952) Arch. Dis. Child. 27, 214-221 Hecht, F., Motulsky. A. G., Lemire, R. J. & Shepard, T. E. (1966) Science (New York) 152,91-92 Hecht, F., Jones, R. T. &Koler, R. D. (1967) Ann. Hum. Genet. 31, 215-218 Hobbins, J. C. & Mahoney, M. J. (1974) New Engl. J. Med. 290, 1065-1067 Hollenberg, M. D., Kaback, M. M. & Kazazian, H. H., Jr (1971) Science (New York) 174, 698-702 Horton, B. F., Thompson, R. B., Dozy, A. M., Nechtman, C. M., Nichols, E. & Huisman, T. H. J. (1962) Blood, 20, 302-313
Huehns, E. R. & Beaven, G. H. (1971) Clin. Dev. Med. 37,175-203 Huehns, E. R. & Farooqui, A. M. (1975) Nature (London) 254, 335-337 [Letter] Huehns, E. R. & Shooter, E. M. (1965) /. Med. Genet. 2, 48-90 Huehns, E. R., Flynn, F. V., Butler, E. A. & Beaven, G. H. (1961) Nature (London) 189, 496-497 [Letter] Huehns, E. R., Dance, N., Beaven, G. H., Keil, J. V., Hecht, F. & Motubky, A. G. (1964a) Nature (London) 201,1095-1097 Huehns, E. R., Hecht, F., Keil, J. V. & Motulsky, A. G. (1964b) Proc. Natl. Acad. Sci. U.S.A. 51, 89-97 Huisman, T. H. J., Schroeder, W. A., Bannister, W. H. & Grech, J. L. (1972) Biochem. Genet. 7, 131-139 Huisman, T. H. J. et al. (1974) Ann. New York Acad. Sci. 232, 107-124 Ingram, V. M. (1972) Nature (London) 235, 338-339 [Letter] Johnson, G. R. & Jones, R. O. (1973) /. Embryol. Exp. Morphol. 30,83-96 Johnson, G. R. & Moore, M. A. S. (1975) Nature (London) 258, 726-728 Kabat, D. (1972) Science (New York) 175, 134-140 Kaltsoya, A., Fessas, P. & Stavropoulos, A. (1966) Science (New York) 153,1417-1418 Kamuzora, H. & Lehmann, H. (1975) Nature (London) 256, 511-513 [Letter] Kan, Y. W., Dozy, A. M., Alter, B. P., Frigoletto, F. D. & Nathan, D. G. (1972a) New Engl. J. Med. 287,1-5 Kan, Y. W., Forget, B. G. & Nathan, D. G. (1972b) New Engl. /. Med. 286, 129-134 Kan, Y. W., Dozy, A. M., Varmus, H. E., Taylor, J. M., Holland, J. P., Lie-Injo, L. E., Ganesan, J. & Todd, D. (1975a) Nature (London) 255,255-256 [Utter] Kan, Y. W., Golbus, M. S., Klein, P. &Dozy, A. M. (1975b) New Engl. J. Med. 292, 1096-1099 Karalclis, A. & Fessas, P. (1963) Ada Haematol. 29, 267-281 Kazazian, H. H., Jr (1974) Semin. Haematol. 11, 525-548 Kazazian, H. H , Jr & Woodhead, A. P. (1973) New Engl. J. Med. 289,58-62 Kitchen, H. & Brett, I. (1974) Ann. New York Acad. Sci. 241, 653-671
286 Br. Med. Bull. 1976
HAEMOGLOBIN SYNTHESIS DURING HUMAN FETAL DEVELOPMENT Kleihauer, E. (1970) In: Stave, U., cd. Physiology of the perinatal period: functional and biochemical development in mammals, vol. 1, pp. 255-297. Appleton-Century-Crofts, New York Kleihauer, E. & Stoffler, G. (1968) Mol. Gen. Genet. 101, 5969 Kleihauer, E., Braun, H. & Betke, K. (1957) Klin. Wochenschr. 35, 637-638 Kovach, J. S., Marks, P. A., Russell, E. S. & Epler, H. (1967) / . Mol. Biol. 25,131-142 Lorkin, P. A. (1973) / . Med. Genet. 10, 50-64 Maximow, A. (1927) In: Mollendorff, W., ed. Handbuch der Mikroskopischen Anatomic des Menschen. Band 2: Die Gewebe, Teil 1, p. 232. Springer, Munich Moore, M. A. S. & Metcalf, D. (1970) Br. J. Haematol. 18, 279-296 Nathan, D. G. & Alter, B. P. (1975) Br. / . Haematol. suppl. to vol. 31, pp. 143-154 Nigon, V. & Godet, J. (1976) Int. Rev. Cytol. 46, 79-175 Nute, P. E., Pataryas, H. A. & Stamatoyannopoulos, G. (1973) Am. / . Hum. Genet. 25, 271-276 Old, J., Clegg, J. B., Weatherall, D. J., Ottolenghi, S., Corai, P., Giglioni, B., Mitchell, J., Tolstoshev, P. & Williamson, R. (1976) Cell, 8,13-18 Oski, F. A. & Naiman, J. L. (1972) Hematologic problems in the newborn, 2nd ed. (Major Problems in Clinical Pediatrics, voL IV). Saunders, Philadelphia, Pa, & London Ottolenghi, S., Lanyon, W. G., PauL J., Williamson, R., Weatherall, D. J., Clegg, J. B., Pritchard, J., Pootrakul, S. & Wong, H. B. (1974) Nature {London) 251, 389-392 Pataryas, H. A. & Stamatoyannopoulos, G. (1972) Blood, 39, 688-696 Pembrey, M. E., WeatheraU, D. J. & Clegg, J. B. (1973) Lancet, 1, 1350-1355 Petrakis, N. L., Pons, S. & Lee, R. E. (1969) In Vitro, 4,
Schroeder, W. A., Shelton, J. R., Shelton, J. B., ApeH, G., Huisman, T. H. J. & Bouver, N. G. (1972) Nat. New Biol. 240, 273-274 [Letter] Schroeder, W. A., Bannister, W. H., Grech, J. L., Brown, A. K., Wrightstone, R. N. & Huisman, T. H. J. (1973) Nat. New Biol. 244, 89-90 [Letter] Shepard, M. K., Weatherall, D. J. & Conley, C. L. (1962) Bull. Johns Hopkins Hosp. 110, 293-310 Stamatoyannopoulos, G. (1971) Lancet, 2,192-193 Stockman, J. A., m (1975) Semin. Haematol. 12,163-173 Szelenyi, J. G. & Hollan, S. R. (1969) Ada Biochem. Biophys. Acad. Sci. Hung. 4,47-55 Taylor, J. M., Dozy, A. [M.], Kan, Y. W., Varmus, H. E., Lie-Injo, L. E., Ganesan, J. & Todd, D. (1974) Nature {London) 251, 392-393 Thomas, D. B. & Yoffey, J. M. (1964) Br. J. Haematol. 10, 193-197 Thomas, E. D., Lochte, H. L., Jr, Greenough, W. B., m & Wales, M. (1960) Nature {London) 185, 396-397 [Letter] Van der Stricht, O. (1892) Arch. Biol. 12,199-344 Wasi, P., Na-Nakorn, S. & Pootrakul, S. (1974) Clin. Haematol. 3, 383-410 Weatherall, D. J. & Clegg, J. B. (1972) The thalassaemia syndromes, 2nd ed. Blackwell Scientific Publications, Oxford Weatherall, D. J., Clegg, J. B. & Wong, H. B. (1970) Br. J. Haematol. 18,357-367 Weatherall, D. J., Pembrey, M. E. & Pritchard, J. (1974) Clin. Haematol. 3, 467-508 Welter, S. D. V., Apley, J. & Raper, A. B. (1966) Lancet, 1,777-779 Wilson, M. G., Schroeder, W. A., Graves, D. A. & Kacb, V. D. (1967) New Engl. /. Med. m, 953-958 Wilt, F. H. (1965) Science {New York) 147, 1588-1590 Wood, W. G. & WeatheraU, D. J. (1973) Nature {London) 244, 162-165 [Letter] Wood, W. G., Stamatoyannopoulos, G., Lim, G. & Nute, P. E. (1975) Blood, 46, 671-682 Yoffey, J. M. (1971) Isr. / . Med. Sci. 7, 825-833 Zamboni, L. (1965)/. Ultrastruct. Res. 12, 525-541 Zanjani, E. D., Peterson, E. N., Gordon, A. S. & Wasserman, L. R. (1974)/. Lab. Clin. Med. 83, 281-287
Rifkind, R. A., Chui, D. & Epler, H. (1969) / . Cell Biol. 40,343365 Schroeder, W. A., Huisman, T. H. J., Shelton, J. R., Shelton, J. B., Kleihauer, E. F., Dozy, A. M. & Robberson, B. (1968) Proc. Natl. Acad. Sci. U.S.A. 60, 537-544
287 Vol. 32 No. 3
W. G. Wood
W. G. Wood
FIG. I. Changes in erythroid cell type, site of erythropoiesis and globin-chain synthesis during human development (After Huehni & Shooter, 1945, and Klelhmuer, 1970)
HAEMOGLOBIN SYNTHESIS DURING HUMAN FETAL DEVELOPMENT W. G. WOOD Ph.D. Nuffield Department of Clinical Medicine The Radcliffe Infirmary, Oxford 1 Erythropoiesis during development 2 Haemoglobin synthesis during development 3 The relation of haemoglobin synthesis to the site of erythropoiesis 4 Abnormal haemoglobin synthesis during development 5 The switch from fetal to adult haemoglobin 6 Control of the switch References
«
JJ J t Birth
Poit-natal age (weeks)
20%) of both Hb F and Hb A comprise nearly 50 % of the cells shortly after birth (Betke & Kleihauer, 1958; Fraser & Raper, 1962; Shepard et al. 1962). Cells from which the haemoglobin has been almost fully eluted, and hence presumably contained mostly Hb A, first appear at about 34 weeks and comprise about 2-5 % of the cells at term. They increase in number as the proportion of Hb-F-containing cells ("F cells") decreases, making up over 95 % of the cells by six months of age. The slow decline in Hb-F levels in early childhood is matched by a similar decline in F cells and the small amount of Hb F present in adult life is restricted to a small clone of cells comprising up
6. Control of the Switch Whilst the timing and rate of change-over from Hb F to Hb A is fairly well described, knowledge of the mechanisms controlling the switch is still negligible. This basically stems from the lack of human experimental material during the switching period (a factor which is unlikely to change) and the absence of a suitable animal model system. In none of the common laboratory mammals is there good evidence for an easily detected Hb F (Kleihauer, 1970; Kitchen & Brett, 1974). In the mouse, embryonic haemoglobins produced in the yolk sac are replaced by Hb A as soon as hepatic erythropoiesis begins in the fetus (Craig & Russell, 1964; Fantoni et al. 1967; 285
Vol. 32 No. 3
W. G. Wood
HAEMOGLOBIN SYNTHESIS DURING HUMAN FETAL DEVELOPMENT Kovach et al. 1967); and this appears to be the case in rats, rabbits, guinea-pigs and Syrian hamsters (Kitchen & Brett, 1974). Cows, sheep, goats, deer and elephants are the only non-primate mnmmnta known to have an Hb F akin to that in man. The problem of the control of the switch needs to be understood at both the molecular and cellular levels. At the molecular level we know very little about the regulation of the °Y-AY-S-P gene complex. Several hypotheses have been proposed to explain what occurs during the switch and in those genetic disorders associated with the production of Hb F in adult life. These hypotheses include the presence of a single promoter locus at the beginning of the(c ?)-°y-A7-S-§ complex, with a progression in the actual gene transcribed being controlled by a process of intrachromosomal crossing-over (Kabat, 1972). Alternative ideas invoke a series of controller genes between the globin structural genes, with a series of overlapping deletions to explain the observed phenotypes (Huisman et al. 1974; Nigon & Godet, 1976). The rapidly developing techniques of nucleic acid hybridization, gene amplification and nucleic acid sequencing, coupled with the development of an in-vitro transcriptional system, may soon lead to new insights into the molecular aspects of the switch. At the cellular level there are several important questions requiring answers. We need to know at which level of haemopoietic stem-cell differentiation the type of haemoglobin to be synthesized is determined and whether this can be altered during the further maturation of the cell. Secondly, we need
W. G. Wood
to know what factors are responsible for initiating the switcli— humoral factors, localized tissue agents (cell-cell interaction) or possibly some form of an internal clock? Evidence that can be interpreted in favour of a humoral factor, and against localized cell effects, comes from the increase in maternal Hb-F synthesis during thefirsttrimester of pregnancy (Pembrey et al. 1973) and the apparent synchrony in the switch from Hb F to Hb A in different erythropoietic sites (Wood & Weatherall, 1973). The question of whether it is possible to reverse the switch in an individual stem cell, or whether the programming of a cell for fi- and S-chain production is a permanent commitment, is extremely important in considering the exciting therapeutic potential of manipulating the switch to increase the production of Hb F in those severe haemoglobinopathies with defective (3-chain production. If the switch is reversible in an individual stem cell, then the problem of increasing Hb-F production lies at the molecular level, in increasing the transcription of the y-chain genes relative to the f}-chain gene. If, as seems more likely, the switch is irreversible, augmenting Hb-F production in adults would involve increasing the contribution of those clones of cells in the adult which retain the capacity to produce Hb F (Weatherall & Clegg, 1972). Clearly, these are two quite different propositions. The difficulties which would appear to surround augmenting the contribution of F-cell clones in adults make it likely that the best approach to this problem would be to attempt to arrest the switch from Hb-F to Hb-A production in the newborn, while the proportion of Hb F produced is still high.
REFERENCES
Bard, H. (1973)/. Clin. Invest. 52,1789-1795 Bard, H. (1975) / . Clin. Invest. 55, 395-398 Bard, H., Makowski, E. L., Meschia, G. & Battaglia, F. C. (1970) Pediatrics, 45, 766-772 Basch, R. S. (1972) Blood, 39, 530-541 Bateman, A. E. & Cole, R. J. (1971) / . Embryol. Exp. Morphol. 26, 475-480 Betkc, K. (1962) In: Proceedings of the VHIth International Congress of Hematology, Tokyo, September 4-10, 1960, pp. 1033-1040. Pan-Pacific Press, Tokyo Betke, K. & Kleihauer, E. (1958) Blut, 4, 241-249 Boyer, S. H., Belding, T. K., Margolet, L. & Noyes, A. N. (1975) Science (New York) 188, 361-363 Bromberg, Y. M., Abrahamov, A. & Salzberger, M. (1956) / . Obstet. Gynaecol. Br. Emp. 63, 875-877 Capp, G. L., Rigas, D. A. & Jones, R. T. (1967) Science (New York) 157, 65-66 Capp, G. L., Rigas, D. A. & Jones, R. T. (1970) Nature (London) 228, 278-280 [Letter] Cole, R. J. & Paul, J. (1966) J. Embryol. Exp. Morphol. 15,245-260 Colombo, B., Kim, B., Atendo, R. P., Molina, C. &Terrenato, L. (1976) Br. J. Haematol. 32, 79-87 Craig, M. L. & Russell, E. S. (1964) Dev. Biol. 10,191-201 Fantoni, A., Bank, A. & Marks, P. A. (1967) Science (New York) 157,1327-1329 Finne, P. H. & Halvorsen, S. (1972) Arch. Dis. Child. 47,683-687 Fraser, I. D. & Raper, A. B. (1962) Arch. Dis. Child. 37, 289-296 Gairdner, D., Marks, J. & Roscoe, J. D. (1952) Arch. Dis. Child. 27, 214-221 Hecht, F., Motulsky. A. G., Lemire, R. J. & Shepard, T. E. (1966) Science (New York) 152,91-92 Hecht, F., Jones, R. T. &Koler, R. D. (1967) Ann. Hum. Genet. 31, 215-218 Hobbins, J. C. & Mahoney, M. J. (1974) New Engl. J. Med. 290, 1065-1067 Hollenberg, M. D., Kaback, M. M. & Kazazian, H. H., Jr (1971) Science (New York) 174, 698-702 Horton, B. F., Thompson, R. B., Dozy, A. M., Nechtman, C. M., Nichols, E. & Huisman, T. H. J. (1962) Blood, 20, 302-313
Huehns, E. R. & Beaven, G. H. (1971) Clin. Dev. Med. 37,175-203 Huehns, E. R. & Farooqui, A. M. (1975) Nature (London) 254, 335-337 [Letter] Huehns, E. R. & Shooter, E. M. (1965) /. Med. Genet. 2, 48-90 Huehns, E. R., Flynn, F. V., Butler, E. A. & Beaven, G. H. (1961) Nature (London) 189, 496-497 [Letter] Huehns, E. R., Dance, N., Beaven, G. H., Keil, J. V., Hecht, F. & Motubky, A. G. (1964a) Nature (London) 201,1095-1097 Huehns, E. R., Hecht, F., Keil, J. V. & Motulsky, A. G. (1964b) Proc. Natl. Acad. Sci. U.S.A. 51, 89-97 Huisman, T. H. J., Schroeder, W. A., Bannister, W. H. & Grech, J. L. (1972) Biochem. Genet. 7, 131-139 Huisman, T. H. J. et al. (1974) Ann. New York Acad. Sci. 232, 107-124 Ingram, V. M. (1972) Nature (London) 235, 338-339 [Letter] Johnson, G. R. & Jones, R. O. (1973) /. Embryol. Exp. Morphol. 30,83-96 Johnson, G. R. & Moore, M. A. S. (1975) Nature (London) 258, 726-728 Kabat, D. (1972) Science (New York) 175, 134-140 Kaltsoya, A., Fessas, P. & Stavropoulos, A. (1966) Science (New York) 153,1417-1418 Kamuzora, H. & Lehmann, H. (1975) Nature (London) 256, 511-513 [Letter] Kan, Y. W., Dozy, A. M., Alter, B. P., Frigoletto, F. D. & Nathan, D. G. (1972a) New Engl. J. Med. 287,1-5 Kan, Y. W., Forget, B. G. & Nathan, D. G. (1972b) New Engl. /. Med. 286, 129-134 Kan, Y. W., Dozy, A. M., Varmus, H. E., Taylor, J. M., Holland, J. P., Lie-Injo, L. E., Ganesan, J. & Todd, D. (1975a) Nature (London) 255,255-256 [Utter] Kan, Y. W., Golbus, M. S., Klein, P. &Dozy, A. M. (1975b) New Engl. J. Med. 292, 1096-1099 Karalclis, A. & Fessas, P. (1963) Ada Haematol. 29, 267-281 Kazazian, H. H., Jr (1974) Semin. Haematol. 11, 525-548 Kazazian, H. H , Jr & Woodhead, A. P. (1973) New Engl. J. Med. 289,58-62 Kitchen, H. & Brett, I. (1974) Ann. New York Acad. Sci. 241, 653-671
286 Br. Med. Bull. 1976
HAEMOGLOBIN SYNTHESIS DURING HUMAN FETAL DEVELOPMENT Kleihauer, E. (1970) In: Stave, U., cd. Physiology of the perinatal period: functional and biochemical development in mammals, vol. 1, pp. 255-297. Appleton-Century-Crofts, New York Kleihauer, E. & Stoffler, G. (1968) Mol. Gen. Genet. 101, 5969 Kleihauer, E., Braun, H. & Betke, K. (1957) Klin. Wochenschr. 35, 637-638 Kovach, J. S., Marks, P. A., Russell, E. S. & Epler, H. (1967) / . Mol. Biol. 25,131-142 Lorkin, P. A. (1973) / . Med. Genet. 10, 50-64 Maximow, A. (1927) In: Mollendorff, W., ed. Handbuch der Mikroskopischen Anatomic des Menschen. Band 2: Die Gewebe, Teil 1, p. 232. Springer, Munich Moore, M. A. S. & Metcalf, D. (1970) Br. J. Haematol. 18, 279-296 Nathan, D. G. & Alter, B. P. (1975) Br. / . Haematol. suppl. to vol. 31, pp. 143-154 Nigon, V. & Godet, J. (1976) Int. Rev. Cytol. 46, 79-175 Nute, P. E., Pataryas, H. A. & Stamatoyannopoulos, G. (1973) Am. / . Hum. Genet. 25, 271-276 Old, J., Clegg, J. B., Weatherall, D. J., Ottolenghi, S., Corai, P., Giglioni, B., Mitchell, J., Tolstoshev, P. & Williamson, R. (1976) Cell, 8,13-18 Oski, F. A. & Naiman, J. L. (1972) Hematologic problems in the newborn, 2nd ed. (Major Problems in Clinical Pediatrics, voL IV). Saunders, Philadelphia, Pa, & London Ottolenghi, S., Lanyon, W. G., PauL J., Williamson, R., Weatherall, D. J., Clegg, J. B., Pritchard, J., Pootrakul, S. & Wong, H. B. (1974) Nature {London) 251, 389-392 Pataryas, H. A. & Stamatoyannopoulos, G. (1972) Blood, 39, 688-696 Pembrey, M. E., WeatheraU, D. J. & Clegg, J. B. (1973) Lancet, 1, 1350-1355 Petrakis, N. L., Pons, S. & Lee, R. E. (1969) In Vitro, 4,
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