33044 
NOTICES 
cult to do .(70) Moreover, factual bases 
for the greater stringency of the U.S. 
(NIH) Guidelines cannot be shown. 
Five years have passed since con- 
cerns were first raised about the hypo- 
thetical hazards of laboratory experi- 
ments with recombinant DNA. The 
thousands of individual applications of 
such techniques have produced much 
useful Itnowledge. but no evidence has 
come to light of a product created by 
these techniques that has been harm- 
ful to man or the environment. For- 
eign genes Inserted into prokaryotic 
host-vector systems have been faith- 
fully replicated and produced in quan- 
tities valuable to science. On the other 
hand, prokaryotes generally have not 
been able to translate eukaryotic 
genes Into biologically active proteins. 
No new facts or unconsidered older 
ones have emerged to support the 
fears of harmful effects, and one 
prominent early proponent of guide- 
lines has repudiated his support for 
them.(ff) At the least, there is grow- 
ing sentiment that the burden of 
proof is shifting toward those who 
would restrict recombinant DNA re- 
search.f J2) 
Although clearly the time has come 
to revise the original NIH Guidelines 
for Recombinant DNA Research, it is 
not the time to conclude that they are 
being altered in preparation for their 
early abandonment. Understanding of 
gene regulation and expression is In- 
creasing inexorably and at an awe- 
some pace. We may predict that ways 
will be found to achieve and control 
the translation of foreign genes by a 
variety of hosts.dJ) As the barriers to 
translation are dropped, some of the 
larger promise of recombinant tech- 
nology will be realized. In some pro- 
portion to the harvest of positive re- 
sults. a capability must be maintained 
for observing any capacity of these ex- 
periments to yield harmful products, 
and for communicating this to all who 
have an Interest in similar experi- 
ments. 
In preparation for this next phase of 
recombinant DNA research, several 
shifts in NIH guidance are necessary. 
Experiments posing no threat to 
safety must be exempted from the 
Guidelines: and provisions must be 
made to remove others as soon as their 
harmlessness becomes evident. Any 
universal rules Imposed on this kind of 
activity derive validity from continual 
modification dictated by results of the 
experimentation they govern. 
Primary responsibility for comliance 
with the rules must be located where 
the work is done. There it must be 
shared fully by principal investigators, 
those who work In their laboratories, 
institutional biosafety committees, 
and the institutional leaders. The NIH 
Office of Recombinant DNA Activities 
(ORDA) should be relieved of its 
burden of obligatory prior approval of 
certain experiments, so that it can 
better carry out. along with the RAC. 
two central functions. These are the 
continuing synthesis and Interpreta- 
tion of the Guidelines, and the main- 
tenance of full communication among 
all who must use them. 
To recapitulate, these new proposed 
Guidelines arose from a proposal 
made to me by the RAC in September 
1977. Numerous amendments have 
been made on the basis of public com- 
ments received at the December 1977 
hearing, in extensive correspondence 
before and after that, and recommen- 
dations of special expert workshops 
whose reports were then assessed by 
the RAC in April 1978. The proposal 
and the amendments have been the 
products of long and Intense participa- 
tion by numerous persons represent- 
ing many points of view. I now summa- 
rize the more Important proposed 
changes. The basis for decision on 
each element of revision is provided In 
detail in subsequent sections of this 
document. 
SCOPE AND APPLICABILITY OP THE 
GUIDELINES 
Recombinant DNA containing syn- 
thetic sequences is now explicitly part 
of the definition of what is included 
under the Guidelines. The standards 
of the Guidelines now apply to all re- 
combinant DNA experiments conduct- 
ed in an institution that receives any 
support from NIH for recombinant 
DNA research. This includes a regis- 
tration requirement. 
The original Guidelines contain a 
number of prohibited experiments. 
There was little sentiment for the re- 
moval of all the original prohibitions— 
although it has been noted that the 
U.S. (NIH) Guidelines are the only na- 
tional guidelines to stipulate “prohib- 
ited ' activities. The original prohibi- 
tions. with one modification and a nec- 
essary “flexibility" clause.fil) are 
therefore retained In the proposed re- 
vision. They Immedip.tely precede a 
new section called “Exemptions"— a 
juxtaposition chosen to emphasize 
that the prohibitions still override. 
The first exemption from the guide- 
lines covers the handling of DNA out- 
side a host organism or virus. Such 
“naked DNA" has been handled In lab- 
oratories for years and is rapidly Inac- 
tivated In nature. 
The exempted experiments of the 
second class consist essentially in rear- 
ranging. or deleting from, molecules of 
nonchromosomal or viral DNA. No for- 
eign DNA is involved. An example 
would be the Introduction of a DNA 
molecule formed from pieces of SV40 
virus into eukaryotic cells in tissue cul- 
ture. Since there is little if any basis 
for presuming such “rearrangement" 
or “deletion” experiments to be haz- 
ardous. they are now' excluded. 
A third class of exemptions are ex- 
periments called "self-cloning,” in 
which DNA found naturally in a host 
may be reinserted into that host. 
These are reproductions in the labora- 
tory of events that occur in nature. 
Similarly, provision is made in the 
proposed guidelines for exemption of a 
fourth class of experiments that in- 
volve donor-host pairs that normally 
exchange DNA. Such genetic ex- 
change is known to occur widely be- 
tween various species of bacteria and 
is generally mediated by certain plas- 
mids or vinises. Experimental recom- 
binations of this type are only an imi- 
tation of what nature is able to accom- 
plish handily In the absence of Feder- 
al regulation. A list of donor-host pairs 
to be exempted is begun in this revi- 
sion and will be expanded periodically 
as knowledge grows. The initial choice 
from several possible lists submitted to 
me by the RAC is a conservative one. 
restricted to pairs of organisms for 
w hich there is documented evidence of 
natural exchange. 
Finally, a fifth exemption is pro- 
vided for removal of other recombina- 
tions when they are shown to be safe. 
The last two exemptions create some 
of the discretionary power for modify- 
ing the guidelines that was so lacking 
in the original. Provision will be made 
for public input to such decisions, 
either by announcement of proposed 
exemptions prior to consideration by 
the RAC or before a decision by the 
Director becomes effective. 
CONTAINMENT 
I have made one decision that will 
not be regarded with equal pleasure by 
all engaged in recombinant DNA re- 
search. PI containment previously per- 
mitted mouth pipetting. In accord 
with a previous recommendation by 
the European Molecular Biology Orga- 
nization (EMBO), its virus Working 
Group strongly recommended prohib- 
iting this practice; and so did NIH 
safety advisors. The RAC at its meet- 
ing on April 27-28, 1978. recommended 
that mouth pipetting be prohibited 
only for those PI recombinant DNA 
experiments involving viral DNA. 
Rather than create two separate 
classes of PI. and in recognition of the 
present availability of excellent me- 
chanical devices for pipetting. I am 
proposing that mouth pipetting no 
longer be permitted in PI contain- 
ment. Since it is already prohibited in 
P2-P4 containment, this bans the use 
of mouth pipetting for any experiment 
covered by the Guidelines. 
CONTAINMENT GUIDELINES FOR COVERED 
EXPERIMENTS 
The recommendations of the RAC, 
arising from the Ascot-Bethesda work- 
FEDERAL REGISTER. VOL 43, NO. 146— FRIDAY, JULY 28, 1978 
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