Human Gene Therapy 
should not be harmful. In addition, in the case of all three disorders, 
the normal gene has been cloned and is available. 
Previously, clinical investigators thought that the human genetic 
diseases most likely to be the initial ones successfully treated by gene 
therapy would be the hemoglobin abnormalities (specifically, beta- 
thalassemia) because these disorders are the most obvious ones 
carried by blood cells, and bone marrow is the easiest tissue to mani- 
pulate outside the body. Regulation of globin synthesis, however, 
is unusually complicated. Not only are the embryonic, fetal, and 
adult globin chains carefully regulated during development, but also 
the subunits of the hemoglobin molecule are coded by genes on two 
different chromosomes. To understand the regulatory signals that 
control such a complicated system and to develop means for obtain- 
ing controlled expression of an exogenous (i.e., inserted by gene 
therapy) beta-globin gene will take considerably more research effort. 
Severe combined immunodeficiency due to a defect in the ADA 
gene can be corrected by infusion of normal bone marrow cells from 
a histocompatible donor. Therefore, selective replication of the nor- 
mal marrow cells appears to take place. This observation offers hope 
that defective bone marrow can be removed from a patient, the nor- 
mal ADA gene inserted into a number of cells through gene therapy, 
and the treated marrow reimplanted into the patient where it may 
have a selective growth advantage. There is also evidence that marrow 
cells containing the normal gene for HPRT may have a selective 
advantage (in both mice and humans) over cells that do not. If selec- 
tive growth occurs, elimination of the patient’s own marrow would 
not be necessary. If, however, corrected marrow cells have no growth 
advantage over endogenous (i.e., the patient’s own untreated) cells, 
then partial or complete marrow destruction (either by irradiation 
or by other means) may be required in order to allow the corrected 
marrow cells an environment favorable for expansion. The latter situa- 
tion would require much greater confidence that the gene therapy 
procedure would work before a clinical trial should be undertaken. 
Ethics 
The ethics of gene therapy in humans has been discussed for many 
years and is being widely debated at present. John Fletcher (1985) 
has reviewed this area in detail in this issue. Essentially all observers 
have stated that they believe that it would be ethical to insert 
genetic material into a human being for the sole purpose of med- 
ically correcting a severe genetic defect in that patient, in other 
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Recombinant DNa Research, Volume 12 
