NOTICES 
33107 
T* 
Spacers Interrupt the Ovalbumin Gene. 
Proc. Nat. Acad. Sci. USA 75.1299-1303. 
34. Efstratiadls, A., P. C. Kafatos, and T. 
Maniatis (1977). The Primary Structure of 
Rabbit p Globin mRNA as Determined From 
Cloned DNA. Cell 70/571-586. 
35. Ratzkin, B., and J. Carbon (1977). 
Functional Expression of Cloned Yeast DNA 
in Escherlcia coli. Proc. Nat. Acad. Scl. USA 
74/487-491. 
36. Cannon, F. C., G. E. Riedel, and P. Au- 
subel (1977). Recombinant Plasmid That 
Carries Part of the Nitrogen Fixation Gene 
Cluster Klebsiella pneumoniae. Proc. Nat. 
Acad. Sci. USA 74: 2963-2967. 
37. Ullrich, A., J. Shine, J. Chirgwin, R. 
Pictet, E. Tischer, W. J. Rutter, and H. M. 
Goodman (1977). Rat Insulin Genes: Con- 
struction of Plasmids Containing the 
Coding Sequences. Science 796/1313-1319. 
38. Seeburg, P. H„ J. Shine, J. A. Martial, 
J. D. Baxter, and H. M. Goodman (1977). 
Nucleotide Sequence and Amplification in 
Bacteria of the Structural Gene for Rat 
Growth Hormone. Nature 270/486-494. 
39. Shine, J., P. H. Seeburg, J. A. Martial, 
J. D. Baxter, and H. M. Goodman (1977). 
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DNA for Human Chorionic Soma- tomam- 
motropin. Nature 270/494-499. 
I. Scope of the Guidelines 
Analysis of Current Guidelines 1 
For the purposes of the current 
Guidelines, recombinant DNA experi- 
ments are defined as those involving 
molecules that consist of segments of 
DNA from different sources which 
have been joined together in cell-free 
systems, and which have the capacity 
to replicate in some host cell, either 
autonomously or as an integrated part 
of the host’s genome. The host cells in 
these experiments are generally single 
living cells. They may be microorgan- 
isms such as bacteria, or animal or 
plant cells grown in tissue culture. 
General principles 
The Guidelines start with a state- 
ment of general principles, which are 
consistent with the conclusions in the 
report of the International Conference 
on Recombinant DNA Molecules held 
at Asilomar, Calif, in February 1975. 
The first principle is that certain ex- 
periments may be judged, in the light 
of currently available information, to 
present such serious potential hazards 
that they should not be attempted at 
this time. Second, a large group of fea- 
sible experiments appear to pose less 
or no potential hazard, and can there- 
fore be performed under appropriate 
safeguards if the information or bene- 
fits sought cannot be obtained by con- 
ventional methods. Third, the more se- 
rious the nature of any presumed con- 
sequence, the more stringent should 
be the safeguards against escape of 
the potentially hazardous agents. 
Experiments to be deferred 
The first class of experiments de- 
scribed in the Guidelines are those 
’As published in the Federal Register, 
July 7. 1976 (41 PR 27902). 
that are not to be carried out at the 
present time. While it may be argued 
that a combination of maximal physi- 
cal and biological safeguards could es- 
sentially contain these recombinants, 
the magnitude of the possible dangers 
if containment were to fail dictates 
that these experiments be deferred. 
This class of experiments includes the 
following: 
• Those in which any of the recom- 
binant DNA derives from pathogenic 
.organisms listed under classes 3, 4, and 
5 of the document Classification of 
Etiologic Agents on the Basis of 
Hazard, published by the Center for 
Disease Control (CDC) of the U.S. 
Public Health Service, or from onco- 
genic (cancer-causing) viruses classi- 
fied by the National Cancer Institute 
as “moderate risk.” The CDC docu- 
ment categorizes naturally occurring 
organisms and viruses known to be 
pathogenic to man and agriculturally 
important species, on a scale of in- 
creasing hazard from 1 to 5. 
• Those characterized by deliberate 
formation of recombinants containing 
the genes for potent toxins. Examples 
are botulinus or diphtheria toxins, and 
venoms from insects and snakes. 
• Those involving deliberate cre- 
ation from plant pathogens of recom- 
binant DNA’s that are likely to in- 
crease the virulence of the pathogenic 
material or the range of susceptible 
species. 
• Those involving transfer of a 
drug-resistance trait to microorgan- 
isms that are not known to acquire it 
naturally if this could compromise the 
use of a drug to control disease in 
humans, animals, or plants. 
Other restrictions concern the 
volume of recombinant DNA to be pro- 
duced and the deliberate release of or- 
ganisms into the environment: 
• Experiments with recombinant 
DNA’s known to make harmful prod- 
ucts must be limited in scale to quanti- 
ties of fluid less than 10 liters. The 
RAC may make exceptions for particu- 
lar experiments deemed to be of direct 
societal benefit, if appropriate equip- 
ment is used. 
• The creation of organisms with 
ability to carry out useful environmen- 
tal functions has been contemplated. 
Release of such organisms into the en- 
vironment may be required to test 
their efficacy, and certainly to make 
use of them. The Guidelines, however, 
prohibit at present the release of any 
organism containing a recombinant 
DNA molecule. 
Alternatives: RAC-Proposed Revisions 
It was the determination of the Re- 
combinant Advisory Committee that 
advances in knowledge pertaining to 
recombinant activities in past years 
warranted significant revisions in the 
purpose, definition, and prohibition 
sections of the NIH Guidelines. A com- 
parison of the “purpose” language of 
the current Guidelines with that of 
the proposed revised guidelines of the 
RAC (hereafter called "PRG-RAC”) 
reveals that the standards in the latter 
set are meant to pertain to recombin- 
ant DNA molecules in organisms. The 
analogous language in the current 
Guidelines addresses recombinant 
DNA molecules whether or not they 
are contained within a cell or virus. 
The rationale for this change is that 
DNA by itself (commonly referred to 
as “naked” DNA) is extremely unlike- 
ly to be hazardous under experimental 
conditions, as it is rapidly inactivated 
in nature. 
The definition in the PRG-RAC 
consists of two parts: (1) an operation- 
al definition of recombinant DNA and 
(2) a qualification that the Guidelines 
would pertain only to “novel” recom- 
binant DNA’s. The operational defini- 
tion does not differ significantly from 
that in the original Guidelines. 
The second part, however, calls for 
the creation of a list of organisms that 
exchange genetic information in 
nature, commonly referred to as "non- 
novel exchangers.” Recombinant DNA 
formed with DNA from such organ- 
isms would be exempted from the pro- 
visions of the Guidelines, with the ra- 
tionale that there is no justification 
for requiring stringent containment 
procedures for the handling of recom- 
binations that occur regularly in 
nature and are not known to be associ- 
ated with any special hazards. 
The provision of an open-ended list- 
ing was recommended rather than is- 
suance of a blanket exemption, be- 
cause this would allow the RAC and 
NIH to consider evidence that (1) the 
putative gene transfers do take place 
naturally and (2) that their exemption 
from the Guidelines is justifiable. 
Although the PRG-RAC deal with 
prohibited experiments under part III, 
this assessment, for purposes that 
become apparent below, will consider 
the definition, exemptions, and prohi- 
bitions together under part I. 
A major proposed revision would 
give the Director, NIH, authority to 
grant exceptions to any of the six pro- 
hibitions. Such a determination must 
be based upon the recommendation of 
the RAC, and weight must be given in 
the decision-making “both to scientific 
and societal benefits and to potential 
risks.” The rationale for this proposed 
change was the desire of the RAC not 
to bar automatically the conduct of 
experiments desirable for some com- 
pelling social or scientific reasons— for 
example, risk assessment. 
Alternatives: Public Commentators 
There was considerable discussion at 
the public hearings over the scope of 
FEDERAL REGISTER, VOL. 43, NO. 146— FRIDAY, JULY 28, 1978 
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