NOTICES 
331C5 
that regulate gene expression and the 
construction of new host/vector clon- 
ing systems. 
Many of the basic concepts of molec- 
ular biology have had to be based 
upon work on prokaryotes. These con- 
cepts have influenced the interpreta- 
tion of data on the structure and pos- 
sible mode of functioning of the eu- 
karyotic genome. Recombinant DNA 
technology, however, has allowed the 
structure of the genomes of higher or- 
ganisms to be examined in a manner 
previously restricted to studies on bac- 
teria. Some of the results have upset 
earlier assumptions. For example, the 
cloning of eukaryotic DNA sequences 
that specify the proteins /? globin ,(24, 
25, 30, 34) ovalbumin,! 26, 27, 28, 32, 33) 
and immunoglobulin! 29, 31) has dem- 
onstrated that certain basic facts of 
DNA organization in prokaryotes are 
not applicable to eukaryotes. The 
major new finding of “intervening” se- 
quences in these higher forms (dis- 
cussed in footnote 13 to the “Introduc- 
tion and Overview” of the accompany- 
ing decision document) may provide 
an explanation for the cause of the 
hereditary disorder, /3 + thalassemia. It 
also demands a reconsideration of the 
basic mechanisms of differentiation 
and evolution. 
The work on immunoglobulin! 29, 31) 
has shown that the DNA sequences 
that encode two different regions of 
an immunoglobulin polypeptide are 
widely separated in germ-line cells. 
During differentiation, these DNA se- 
quences move closer together but do 
not become contiguous. Detailed ex- 
amination of DNA fragments has re- 
solved one of the fundamental and 
longstanding puzzles of immunology. 
Very recent data indicate that the in- 
tervening sequences found in the gene 
for ovalbumin differ from individual 
to individual! 32, 33), indicating that 
genetic variability may occur within a 
species to an extent not previously 
imagined. 
Practical implications 
The possibility that recombinant 
DNA techniques could be used to alter 
the properties of recipient organisms, 
or to produce desired substances, such 
as peptide hormones, rests largely 
upon two factors: !1) the fidelity of 
the cloning procedures and !2) the 
ability to obtain expression of the 
cloned DNA sequence. It has been 
demonstrated that cloning does pro- 
vide faithful copies of the original se- 
quence.! 34) More recently, experi- 
ments in which cloned fragments of 
yeast DNA were introduced into E. 
coli have provided further evidence 
that fidelity is maintained and that 
expression of cloned sequences can be 
achieved. All the bacterial strains used 
contained genetic lesions that ren- 
dered them incapable of synthesizing 
a particular amino acid. However, the 
yeast DNA sequences were capable of 
correcting these deficiencies! 35) and 
were shown to specify the synthesis of 
a yeast protein that substituted suc- 
cessfully for its defective bacterial 
counterpart. 
There have been several accomplish- 
ments during the last year and a half 
that may be expected to yield both 
economic and medical benefits in the 
near future. Work has begun on the 
cloning of the nitrogen fixation genes 
of the bacterium Klebsiella pneumon- 
iae.(36) The introduction of these 
genes into appropriate plant or bacte- 
rial hosts may drastically reduce the 
requirement for nitrogenous fertiliz- 
ers. Such fertilizers, currently con- 
sumed at the rate of 40 million tons 
per year, are synthesized by processes 
involving large energy costs. 
An area that has proved to be ex- 
tremely productive has been the clon- 
ing of DNA sequences specifying pep- 
tide hormones. During 1977 there were 
succeses in the cloning of genes for 
the following hormones: 
Insitlin.(37) 
Somatostatin, (6) a hormone that in- 
hibits the secretion of glucagon, insu- 
lin, and growth hormone; potentially 
useful in the treatment of acromegaly, 
acute pancreatitis, and insulin-depend- 
ent diabetes. 
Growth hormone, (38) used in the 
treatment of dwarfism; in short supply 
throughout the world. 
Somatomammotropin, (39) a hor- 
mone secreted by the placenta; ap- 
pears to act on maternal metabolism 
to insure that the fetus obtains nutri- 
ents required for normal growth. 
The cloning of the somatostatin 
gene is particularly noteworthy, since 
the gene was synthesized chemically, 
thus avoiding any risk of inadvertant 
cloning of contaiminating sequences, 
and was then inserted into a specially 
constructed plasmid vector. The in- 
serted DNA sequence was expressed 
and an inactive precursor of somatos- 
tatin was synthesized and isolated. 
From this, active somatostatin was 
subsequently liberated. Because the 
polypeptide precursor synthesized 
within the E. coli K-12 host is inac- 
tive, the procedure also decreases mar- 
kedly and likelihood that the host cell 
itself could be hazardous. This same 
strategy may be used in the cloning of 
any of the small peptide hormones. 
Long-range implications 
The experimental situations treated 
in the guidelines are those that appear 
feasible either currently or in the near 
future. The experiments primarily in- 
volve insertion of recombined DNA 
into bacteria or into single cells de- 
rived from more complex organisms 
and maintained under special labora- 
tory conditions. It is only in the case 
of plants that the guidelines cover ex- 
periments involving insertion of DNA 
into cells capable of developing into 
complex, multicellular organisms. The 
guidelines and the discussions leading 
to their development have focused on 
problems of safety. 
It is possible that techniques similar 
to or derived from current recombin- 
ant DNA methodology may, in the 
future, be applicable to the deliberate 
modification of complex animals, in- 
cluding humans. Such modification 
might serve to correct an inherited 
defect in an individual, or to alter 
heritable characteristics in the offspr- 
ing of individuals or a given species. 
The latter type of alteration has been 
successfully achieved in agriculture 
for centuries by classical breeding 
techniques. It may be that recombin- 
ant DNA methods, should they devel- 
op in appropriate ways, will offer new 
opportunities for specificity and accu- 
racy in animal breeding. It should be 
noted, however, that the techniques 
covered by the NIH guidelines involve 
the recombining of DNA fragments in 
the test tube, and the guidelines pro- 
hibit the deliberate release into the 
environment of any organism contain- 
ing recombinant DNA molecules. 
Should the deliberate application of 
such methods for the correction of in- 
dividuals genetic defects or the alter- 
ation of heritable characteristics in 
man ever become possible, it will raise 
complex and difficult problems. In ad- 
dition to philosophical, moral, and 
ethical questions of concern to individ- 
uals, serious societal issues will be in- 
volved. Broad discussion of these prob- 
lems in a variety of forums will then 
be required to inform both private and 
public decisionmaking. 
Possible Deliberate Misuse 
In the event that recombinant DNA 
technology can yield hazardous 
agents, such agents might be consid- 
ered for deliberate perpetration of 
harm to animals (including humans), 
plants or the environment. The possi- 
bilities include biological warfare or 
sabotage. Because it is not known 
whether recombinant DNA technology 
can yield such agents, discussion of 
these problems, such as theft by sabo- 
teurs, is hypothetical and difficult. 
With regard to biological warfare, the 
use of recombinant DNA for such pur 
poses is prohibited by the Biological 
Weapons Convention. In a statement 
to the Conference of the Committee of 
Disarmament, on August 17, 1976, Am- 
bassador Joseph Martin, Jr., made the 
following remarks on the subject: 
When advances in science and technology 
are made, it is natural to ask about their 
possible use for hostile purposes and wheth- 
er or not such uses are prohibited or re 
stricted by existing international agree 
ments. In the case of potential use of recom 
binant DNA molecules for weapons pur 
FEDERAL REGISTER, VOL. 43, NO. 146— FRIDAY, JULY 28, 1978 
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