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the Guidelines. Some mentioned that 
the Guidelines were too narrow in 
their preocuppation with recombinant 
DNA. as there are other forms of ge- 
netic research capable of producing 
cells and organisms of unknown poten- 
tial hazard. It was further suggested 
that the title of the Guidelines be 
modified to reflect their concern with 
experiments involving prokaryotes and 
cells In culture and that a companion 
document be released dealing with 
higher eukaryotes. On the other hand, 
it was also argued that genetic re- 
search has not received attention far 
beyond its due and that other matters 
of experimentation await their turn. 
It Is true that other techniques in 
genetic research, such as cell fusion 
and chromosome transfer, may result 
In formation of recombinant mole- 
cules. However, there are inherent in 
these techniques a range of natural 
barriers to the formation of hazardous 
organisms which apparently afford 
adequate containment, making unnec- 
essary the issuance of Federal stand- 
ards. Such techniques have been used 
in the laboratory for decades with no 
known harmful effects on either the 
public health or the environmnent. 
The entire area of laboratory safety is 
of primary concern to NIH and is the 
subject of constant review and atten- 
tion. 
There were several suggestions that 
the purpose of the Guidelines be more 
clearly stated and that terms be more 
precisely identified. Therefore, the 
sections "Purpose.’' "General Applica- 
bility." and "General Definitions" 
have been added to part I of the guide- 
lines now being proposed by NIH— 
hereafter called "PRG-NIH." 
Purpose of the guidelines 
The Introduction to the 1978 Guide- 
lines states that "the purpose of these 
Guidelines Is to recommend safe- 
guards for research on recombinant 
DU A molecules. ” As noted above, to 
eliminate the handling of naked DNA 
from the Guidelines, the PRG-RAC 
proposed this passage to read that the 
purpose is to "establish procedures for 
handling organisms and viruses con- 
taining recombinant DNA molecules." 
This proposed revision would have 
had the effect of removing from cover- 
age by the guidelines certain experi- 
ments that are now prohibited by the 
1978 Guidelines— for example, deliber- 
ate formation of "naked" recombinant 
DNA-containlng genes for the biosyn- 
thesis of potent toxins. The Director, 
NTH. proposes to resolve this issue 
conservatively. The language in the 
PRG-NIH. therefore, clearly states 
that the Guidelines are intended to 
pertain to the construction and han- 
dling of naked recombinant DNA mol- 
ecules as well as organisms and viruses 
containing such molecules. 
General applicability 
Many commentators urged that a 
statement of general applicability of 
the Guidelines be included in an early 
part. The issues relate to (1) the appli- 
cability of the Guidelines to non-NIH- 
funded research with recombinant 
DNA at institutions receiving NIH 
funds for this purpose. (2) the applica- 
bility of the Guidelines to NIH-sup- 
ported recombinant DNA research 
conducted in foreign countries, and (3) 
the location of responsibility for en- 
suring compliance with the Guide- 
lines. Therefore, a section entitled 
"General Applicability" now appears 
after the "Purpose” section in Part I 
of the PRO-NIH. 
The existence of guidelines for re- 
combinant DNA research assumes 
their general application. Partial ad- 
herence within an Institution would 
defeat the purpose of extending mam- 
mal protection to the community. 
Thus. It would be Inconsistent for NIH 
to provide funds for biomedical re- 
search activities to an Institution that 
did not meet the standards of the 
Guidelines in all of Its recombinant 
DNA research, regardless of the 
source of funding. This principle is 
now stated explicitly in the Guide- 
lines. and we intend to consider with- 
holding NIH funds as a sanction 
against violation. 
Rules must be established for the 
conduct of recombinant DNA activities 
funded by NIH in other countries. 
Generally, the requirements in force 
in those countries shall apply. A 
Memorandum of Understanding and 
Agreement (MUA) must still be filed 
with NIH. indicating specifically 
which guidelines will govern the activi- 
ties: and NIH reserves the right to 
withhold funding If the safety prac- 
tices to be employed are not reason- 
ably consistent with the NIH Guide- 
lines. An explicit statement about this 
has been Inserted in the PRG-NIH. 
Part IV of the PRO-NIH defines the 
responsibilities of all Individuals and 
organizational entities Involved in the 
conduct and review of a recombinant 
DNA activity. Two years of experience 
with administering the NIH Guide- 
lines have demonstrated that the ulti- 
mate responsibility for ensuring com- 
pliance must be borne by the Institu- 
tion where the research is being done. 
This implies some discretion under 
well-defined limits for interpretation 
of common standards, and Imposes a 
requirement for local expertise other 
than the investigator's. Accordingly, 
part I of the PRG-NIH now requires 
that an individual receiving NIH sup- 
port for recombinant DNA research be 
associated with an institution that is 
willing and able to accept the responsi- 
bilities and conditions of local gover- 
nance. described more explicitly in 
Part IV of the PRG-NIH. 
Definition of recombinant DNA mole- 
cules 
It became apparent from the com- 
ments received that the PRG-RAC 
definition was inadequate in not ad- 
dressing the handling of recombinant 
DNA molecules containing segments 
of chemically synthesized DNA. It was 
decided that the most effective way to 
achieve this objective is simply to in- 
clude "natural or synthetic DNA” in 
the definition of a recombinant DNA 
molecule, and this has been inserted in 
the PRG-NIH definition. A new sec- 
tion. therefore, has also been aded to 
part III of the PRG-NIH giving con- 
tainment levels for work with recom- 
binant DNA molecules containing syn- 
thetic DNA. 
A perceived ambiguity in the PRG- 
RAC definition has been corrected by 
the Inclusion of language within the 
PRG-NIH definition which explicitly 
states that DNA molecules resulting 
from the replication of recombinant 
DNA molecules are subject to the 
safety provisions of the Guidelines. 
Finally, no other provisions of the 
PRG-RAC definition evoked as much 
comment as did the wording to ex- 
clude "non-novel" recombinant DNA 
from the standards. The ambiguity of 
such phrases as "known to exchange 
chromosomal DNA” and "by natural 
physiological processes" was strongly 
noted. A greater degree of clarity and 
objectivity is needed. Thus, it has been 
decided to eliminate in the PRG-NIH 
the two conditions cited above as crite- 
ria for exemption from the Guidelines. 
Staff discussions of the public com- 
ments made it clear that inclusion of 
exemption provisions within the defi- 
nition Itself was not desirable: several 
attempts at appropriate language did 
not bear careful scrutiny. 
Given this situation, and also the re- 
alization that certain categories of re- 
combinant DNA experiments are 
indeed so apparently free of causing 
harm that they should not come 
under the Guidelines, the criterion of 
"novelty" was removed from the defi- 
nition and used as a basis for the de- 
velopment of a new section entitled 
"Exemptions." 
Exemptions 
The nature of the public comments 
on the PRG-RAC exclusion of non- 
novel exchangers can be divided into 
two categories— those that pertain to 
the proposed standards and those to 
the proposed process. 
The standards proposed by the 
PRG-RAC were that novel recombin- 
ant DNA's consist of "segments of any 
DNA from different species not known 
to exchange chromosomal DNA by 
natural physiological processes * * *. 
In general, recombinant DNA mole- 
cules • • • will not be considered novel 
when all the components are derived 
FEDERAL REGISTER, VOL. 43, NO. 144— FRIDAY, JULY 28, 1978 
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