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Research in the past millennium gave us formidable advances in the fields of Cu nutrition, biochemistry, animal and human health. Insights into Cu-Fe interactions highlighted much significant advancement. The recognition that Cu was an essential mineral for Fe metabolism and hemoglobin biosynthesis traces back to a paper by Hart et al. at Wisconsin appearing in the first third of the century. This observation came at a time when the only known function of Cu was that of a constituent of hemocyanin pigment in some mollusks and crustacea. The Wisconsin group's studies were preceded by McHargue's work, which introduced glass-lined cages to study trace mineral function, and in so doing, provided the first experimental evidence for Mn, Cu, and Zn essentiality. Here, we review the details of the experiments by Hart et al. that led to the discovery of copper's interconnection with Fe and important papers that have since given mechanistic clarity to the interaction. J. Trace Elem. Exp. Med. 14:207–210, 2001.

To the Editor: We have read with great interest a recent report by Gelvan et al[1][1] attempting to resurrect an old idea that immature erythroid cells obtain iron (Fe) from ferritin. We wish to comment on one single and extremely important issue in this report, viz, that Fe from internalized

We cultured human umbilical cord blood erythropoietic precursors in methyl cellulose clonal assay and analyzed the synthetic rates of Hb A and Hb F in individual erythropoietic bursts. Hemoglobin was labeled with 14C-amino acids in culture, separated by slab gel isoelectric focusing techniques, and quantitated by fluorographic methods. Almost all bursts exhibited both Hb A and Hb F in varying ratios. Frequencies of the individual bursts differing in percentage Hb F biosynthesis had normal distributions. Natal erythropoietic precursors appeared to be randomly committed to Hb F synthesis.

The influence of erythropoietin (Ep) and burst-promoting activity (BPA) on the relative rates of synthesis of fetal and adult hemoglobins (HbF and HbA) were investigated in clonal cell culture. In the case of crude Ep, a positive dose-response relationship between the concentration and the relative rate of HbF biosynthesis by circulating erythropoietic precursors was clearly observed. In contrast, increasing the concentration of purified Ep enhanced the synthesis of HbF and HbA equally. BPA from bone marrow conditioned media and T-cell conditioned media enhanced the relative rate of HbF biosynthesis and burst number at limiting serum concentrations (10%-15%). We, therefore, conclude that BPA is important in the modulation of HbF biosynthesis in culture.

Hemoglobin biosynthesis in rabbits with phenylhydrazine-induced anemia has been morphologically studied, comparing late bone marrow with peripheral blood erythroid cells of the same maturing degree. They were analysed through thin sections, as to their organelle type content and behavior regarding iron incorporation. Hemosomes are organelles taken as sites of final hemoglobin biosynthesis, and the ratio between their mean number in blood reticulocyte sections and that in late marrow erythroid cell sections reach about 10: 1. Late marrow erythroid cells contain practically twice the mean number of mitochondria in relation to this mean number in blood reticulocytes. Mitochondria are considered as potential acting entities for hemoglobin biosynthesis, since they participate in hemosome formation. Iron incorporation activity increases more than twice in peripheral blood reticulocytes, as compared to the mean in late marrow erythroid cells. These analytical results suggest that an enhancement of hemoglobin synthesis activity occurs when erythroid cells enter the peripheral blood.

The present studies have shown that 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-butyric acid (DBA), which does not bind covalently with hemoglobin, inhibits the loss of potassium ions from hemoglobin SS cells, and inhibits the binding of newly synthesized β S and α chains to membranes from these cells. This is the first report of an antisickling agent which does not modify hemoglobin covalently but may affect membrane-cytoskeletal interactions.

Our interest in the effects of cosmic radiation is directed towards understanding the behavior of cells in vitro rather than towards its possible consequences on man. The human cell line K-562 can be induced in culture to express erythroid-specific markers by addition of hemin. Growth, metabolism and differentiation of K-562 cells were measured. The most striking result was that hemoglobin biosynthesis was markedly depressed in flight. However, cell growth was not significantly altered while glucose consumption was increased in the flight samples. Although the results presented here are derived from one single experiment, it appears that there is a marked effect of cosmic radiation on K-562 cells in vitro.

Publisher Summary This chapter describes the methods for the identification of peptides during hemoglobin biosynthesis and measurement of their sequential synthesis. A model of protein synthesis by sequential growth whereby amino acids are joined one after the other down a polypeptide chain is postulated. Taking hemoglobin as an example, it is demonstrated that peptide chains grow by serial addition of amino acids, starting at the free amino terminal and going toward the free carboxyl terminal. A method of preparative analysis chromatography of amino acids is described in the chapter that allows the determination of specific radioactivity on any number of amino acids at once in protein biosynthesis studies. The general technical procedure presents an adaptation of paper chromatography and paper electrophoresis procedures for the isolation and characterization of tryptic peptides of hemoglobin. Another new technique is ion-exchange chromatography with volatile organic developers, which appears to have a considerably higher resolving power than paper electrophoresis. Electrophoresis on filter paper strips provides a method of separating peptides in an electric field.

Molecular analysis of normal and abnormal human globin genes and their gene products has recently provided information on the precise genetic events that result in hemoglobinopathies. In the case of structurally abnormal hemoglobins, the following mechanisms can be invoked: single nucleotide base substitutions leading to amino acid replacement or chain termination variants; nucleotide deletions (or additions) leading to deletion and frameshift variants; and nonhomologous crossing over leading to the production of fused globin chains. The molecular basis of the thalassemia syndromes, disorders characterized by absent or decreased synthesis of alpha- or beta-globin chains, is quite heterogeneous. In some cases globin gene deletions have been demonstrated; whereas in others there is probably either a defect in globin gene transcription or a defect in nuclear globin messenger RNA (mRNA) processing, mRNA transport or globin mRNA stability. In one form of beta(0)-thalassemia a nonsense mutation has recently been demonstrated, and other cases are also associated with some as yet undetermined functional abnormality of beta-globin mRNA.