94
FRED H. WILT
Lamfrom, 1961). The quantitative importance of this phenomenon and
its mechanism are not understood. The recent experiments showing that
template RNA is probably associated with a subribosomal constituent
prior to the final assembly of a ribosome may offer an avenue for
explanation (McConkey and Hopkins, 1965; Henshaw et al., 1965). The
soluble portion may contain free messenger RNA or ribosomal subunits
associated with messenger. But for the present, we must adopt the attitude that the template is possibly not the sole source of specificity. It is
possible that ribosomes might influence the rate of biosynthesis, even if
they do not specify amino acid sequence. Also, the interaction of species
specific tRNA molecules with the ribosome-messenger complex might
play a role. In support of this possibility, it can be mentioned that
Weisblum et al. (1965) found different leucine tRNA molecules from
E. coli could discriminate between various leucine positions of a rabbit
Hb template.
Another consideration bearing on the rate and type of Hb formed is
the interaction which might occur between polypeptide subunits, and
its possible role in production of a fully formed Hb molecule. Recent
attention has been given to the biochemical lesion in the thalassemic
anemias, which bears on this important point. Ingram and Stretton
(1959) originally proposed structurally abnormal Hb's might produce
the low rate of HbA synthesis associated with the disease, but lack of
evidence for structural abnormalities has favored other hypotheses that
postulate a defect in regulation of synthesis. Thalessemia major has been
studied in detail by Marks and his co-workers (Burka and Marks, 1964;
Marks and Burka, 1964; Bank and Marks, 1966), and compared to other
anemias and fetal blood cells. The Hb's of a thalassemic cell are apparently normal, but there is a decreased ability to synthesize HbA; the
rate of HbF formation is comparable to that in hemolytic anemias. The
ribosome content per cell (1.3 mg/10
10
reticulocytes) and percentage of
ribosomes in polysomal structures is also normal. The ability of thalassemic ribosomes to respond to polyuridylic acid, in vitro, to synthesize
polyphenylalanine is comparable to ribosomes from nonthalassemic cells.
Nevertheless, the endogenous rate of incorporation of amino acids into
Hb, in whole cells, or in vitro, is reduced, and this is mainly due to a
decreased formation of HbA. Since both HbF and HbA contain «-chains,
it is postulated that the primary defect in thalassemia major is a
decreased ability to synthesize ^-chains, and Bank and Marks (1966)
propose that this is a defect, in the ribosome-messenger complex for
ß-chains. A decrease in the quality or quantity of ß-chain message might
regulate the rate of «-chain production, for «-chain tetramers are not
found in thalassemic cells, but ß-chain tetramers are found (Motulsky,
1964). Colombo and Baglioni (1966) have directly measured the ratio
FRED H. WILT
Lamfrom, 1961). The quantitative importance of this phenomenon and
its mechanism are not understood. The recent experiments showing that
template RNA is probably associated with a subribosomal constituent
prior to the final assembly of a ribosome may offer an avenue for
explanation (McConkey and Hopkins, 1965; Henshaw et al., 1965). The
soluble portion may contain free messenger RNA or ribosomal subunits
associated with messenger. But for the present, we must adopt the attitude that the template is possibly not the sole source of specificity. It is
possible that ribosomes might influence the rate of biosynthesis, even if
they do not specify amino acid sequence. Also, the interaction of species
specific tRNA molecules with the ribosome-messenger complex might
play a role. In support of this possibility, it can be mentioned that
Weisblum et al. (1965) found different leucine tRNA molecules from
E. coli could discriminate between various leucine positions of a rabbit
Hb template.
Another consideration bearing on the rate and type of Hb formed is
the interaction which might occur between polypeptide subunits, and
its possible role in production of a fully formed Hb molecule. Recent
attention has been given to the biochemical lesion in the thalassemic
anemias, which bears on this important point. Ingram and Stretton
(1959) originally proposed structurally abnormal Hb's might produce
the low rate of HbA synthesis associated with the disease, but lack of
evidence for structural abnormalities has favored other hypotheses that
postulate a defect in regulation of synthesis. Thalessemia major has been
studied in detail by Marks and his co-workers (Burka and Marks, 1964;
Marks and Burka, 1964; Bank and Marks, 1966), and compared to other
anemias and fetal blood cells. The Hb's of a thalassemic cell are apparently normal, but there is a decreased ability to synthesize HbA; the
rate of HbF formation is comparable to that in hemolytic anemias. The
ribosome content per cell (1.3 mg/10
10
reticulocytes) and percentage of
ribosomes in polysomal structures is also normal. The ability of thalassemic ribosomes to respond to polyuridylic acid, in vitro, to synthesize
polyphenylalanine is comparable to ribosomes from nonthalassemic cells.
Nevertheless, the endogenous rate of incorporation of amino acids into
Hb, in whole cells, or in vitro, is reduced, and this is mainly due to a
decreased formation of HbA. Since both HbF and HbA contain «-chains,
it is postulated that the primary defect in thalassemia major is a
decreased ability to synthesize ^-chains, and Bank and Marks (1966)
propose that this is a defect, in the ribosome-messenger complex for
ß-chains. A decrease in the quality or quantity of ß-chain message might
regulate the rate of «-chain production, for «-chain tetramers are not
found in thalassemic cells, but ß-chain tetramers are found (Motulsky,
1964). Colombo and Baglioni (1966) have directly measured the ratio