27904 
mids* . These, in turn, can be used as vec- 
tors to introduce the foreign genes into 
bacteria or into cells of plants or animals 
in test tubes. Thus transplanted, the 
genes may impart their hereditary prop- 
erties to new hosts. These cells can be 
isolated and cloned — that is, bred into 
a genetically homogeneous culture. In 
general, there are two potential uses for 
the clones so produced: as a tool for 
studying the transferred genes, and as 
a new useful agent, say for tfye produc- 
tion of a scarce hormone. 
Recombinant DNA research offers 
great promise, particularly for improv- 
ing the understanding and possibly the 
treatment of various diseases. There is 
also a potential risk — that microorga- 
nisms with transplanted genes may prove 
hazardous to man or other forms of life. 
Thus special provisions are necessary for 
their containment. 
All commentators acknowledged the 
exemplary responsibility of the scientific 
community in dealing publicly with the 
potential risks in DNA recombinant 
research and in calling for a self-imposed 
moratorium on certain experiments in 
order to assess potential hazards and 
devise appropriate guidelines. Most com- 
mentators agreed that the process lead- 
ing to the formulation of the proposed 
guidelines was a most responsible and 
responsive one. Suggestions by the com- 
mentators on broad policy considerations 
are presented below. They relate to the 
science policy aspects of the guidelines, 
the implementation of the guidelines for 
NIH grantees and contractors, and the 
scope and impact of the guidelines na- 
tionally and internationally. 
A. Science policy considerations 
Commentators were divided on how 
best to steer a course between stifling 
research through excessive regulation 
and allowing it to continue with suffi- 
cient controls. Several emphasized that 
the public must have assurance that the 
controls afford adequate protection 
against potential hazards. In the views 
of these commentators, the burden is on 
the scientific community to show that 
the danger is minimal and that the 
benefits are substantial and far out- 
weigh the risks. 
Opinion differed on whether the pro- 
posed guidelines were an appropriate 
response to the potential benefits and 
hazards. Several found the guidelines to 
so exaggerate safety procedures that in- 
quiry would be unnecessarily retarded, 
while others found the guidelines 
weighted toward promoting research. 
The issue was how to strike a reason- 
able balance — in fact, a proper policy 
“bias” — between concerns to “go slow” 
and those to progress rapidly. 
There was strong disagreement about 
the nature and level of the possible 
hazards of recombinant DNA research. 
Several commentators believed that the 
hazards posed were unique. In their 
view, the occurrence of an accident or 
the escape of a vector could initiate an 
irreversible process, with a potential for 
creating problems many times greater 
than those arising from the multitude of 
NOTICES 
genetic recombinations that occur spon- 
taneously in nature. These commenta- 
tors stress the moral obligation on the 
part of the scientific community to do 
no harm. 
Other commentators, however, found 
the guidelines to be adequate to the 
hazards posed. In their view, the guide- 
lines struck an appropriate balance so 
that research could proceed cautiously. 
Still other commentators found the 
guidelines too onerous and restrictive in 
light of the potential benefits of this re- 
search for medicine, agriculture, and in- 
dustry. Some felt that the guidelines are 
perhaps more stringent than necessary 
given the available evidence on the like- 
lihood of hazards, but supported them as 
a compromise that would best serve the 
scientific community and the public at 
large. Many commentators urged that 
the guidelines be adopted as soon as pos- 
sible to afford more specific direction to 
this research area. 
I understand and appreciate the con- 
cerns of those who urge that this re- 
search proceed because of the benefits 
and of those who urge caution because 
of potential hazards. The guidelines is- 
sued today allow the research to go for- 
ward in a manner responsive and ap- 
propriate to hazards that may be real- 
ized in the -future. 
The object of- these guidelines is to 
ensure that experimental DNA recom- 
bination will have no ill effects on those 
engaged in the work, on the general pub- 
lic, or on the environment. The essence 
of their construction is subdivision of 
potential experiments by class, decision 
as to which experiments should be per- 
mitted at present, and assignment to 
these of certain procedures for contain- 
ment of recombinant organisims. 
Containment is defined as physical 
and biological. Physical containment in- 
volves the isolation of the research by 
procedures which have evolved over 
many years of experience in laboratories 
studying infectious microorganisms. PI 
containment — the first physical contain- 
ment level — is that used in most routine 
bacteriology laboratories. P2 and P3 af- 
ford increasing isolation of the re- 
search from the environment P4 rep- 
resents .the most extreme measures used 
for containing virulent pathogens, and 
permits no escape of contaminated air, 
wastes, or untreated materials. Biologi- 
cal containment is the use of vectors or 
hosts that are crippled by mutation so 
that the recombinant DNA is incapable 
of surviving under natural conditions. 
The experiments now permitted under 
the guidelines involve no known addi- 
tional hazard to the workers or the en- 
vironment beyond the relatively low risk 
known to be associated with the source 
materials. The additional hazards are 
speculative and therefore not quantifi- 
able. In a real sense they are considerably 
less certain than are the benefits now 
clearly derivable from the projected re- 
search. 
For example, the ability to produce, 
through “molecular cloning,” relatively 
large amounts of pure DNA from the 
chromosomes of any living organism will 
have a profound effect in many areas 
of biology. No other procedure, not even 
chemical synthesis, can provide pure 
material corresponding to particular 
genes. DNA “probes,” prepared from the 
clones will yield precise evidence on the 
presence or absence, the organization, 
and the expression of genes in health 
and disease. 
Potential medical advances were out- 
lined by scientists active in this research 
area who were present at the meeting of 
the Director’s Advisory Committee. Of 
enormous importance, for example, is 
the opportunity to explore the malfunc- 
tioning of cells in complicated diseases. 
Our ability to understand a variety of 
hereditary defects may be significantly 
enhanced, with amelioration of their ex- 
pression a real possibility. There is the 
potential to elucidate mechanisms in cer- 
tain cancers, particularly those that 
might be caused by viruses. 
Instead of mere propagation of foreign 
DNA, the expression of the genes of one 
organism by the cell machinery of an- 
other may alter the new host and open 
opportunities for manipulating the bio- 
logical properties of cells. In certain 
prokaryotes (organisms with a poorly de- 
veloped nucleus, like bacteria), this ex- 
change of genetic information occurs in 
nature. Such exchange explains, for in- 
stance, an important mechanism for the 
changing and spreading of resistance to 
antibiotics in bacteria. Beneficial effects 
of this mechanism might be the produc- 
tion of medically important compounds 
for the treatment and control of disease. 
Examples frequently cited are the pro- 
duction of insulin, growth hormone, 
specific antibodies, and clotting factors 
absent in victims of hemophilia. 
Aside from the potential medical bene- 
fits, a whole host of other applications in 
science and technology have been en- 
visioned. Examples are the large-scale 
production of enzymes for industrial use 
and the development of bacteria that 
could ingest and destroy oil spills in the 
sea. Potential benefits in agriculture in- 
clude the enhancement of nitrogen fixa- 
tion in certain plants, permitting in- 
creased food production. 
While the projected research offers the 
possibility of many benefits, it must pro- 
ceed only with assurance that potential 
hazards can be controlled or prevented. 
Some commentators are concerned that 
nature may maintain a barrier to the ex- 
change of DNA between prokaryotes and 
eukaryotes (higher organisms, with a 
well-formed nucleus) — a barrier that can 
now be crossed by experimentalists. They 
further argue that expression of the for- 
eign DNA may alter the host in unpre- 
dictable and undesirable ways. Conceiv- 
able harm could result if the altered host 
has a competitive advantage that would 
foster its survival in some niclje within^ 
the ecosystem. Other commentators be- 
lieve that the endless experiments in re- 
combination of DNA which nature has 
conducted since the beginning of life on 
the earth, and which have accounted in 
part for the evolution of species, have 
most likely involved exchange of DNA 
between widely disparate species. They 
FEDERAL REGISTER, VOL. 41, NO. 13) — WEDNESDAY, JULY 7, 1976 
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