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Federal Register / Vol. 44, No. 232 / Friday, November 30, 1979 / Notices 
Government Printing Office) as part of 
Volume 5 of ‘‘Recombinant DNA 
Research,” a series constituting a public 
record of activities in regard to the NIH 
Guidelines. 
I have carefully examined this 
extensive record in detail. A summary of 
the record is as follows: 
1. A proposed exemption was 
published for public comment in the 
Federal Register on April 13, 1979, as 
follows: 
Those recombinant DNA molecules that 
are propagated in E. coli K-12 hosts not 
containing conjugation-proficient plasmids or 
generalized transducing phages, when 
lambda or lambdoid bacteriophages or non- 
conjugative plasmids are used as vectors, are 
exempt from the Guidelines. 
2. Dr. Wallace Rowe, a member of the 
RAC and one of the two proposers of the 
exemption, sent to the RAC members on 
May 4 a document supporting the 
exemption, including copies of a number 
of published scientific papers and letters 
from immunologists concerning their 
assessment of the possibility of 
autoimmune disease being caused in 
man as a result of recombinant DNA 
experimentation. 
3. Also sent to the RAC members prior 
to their May 21-23 meeting were other 
docuemnts commenting on risk- 
assessment in general and the Rowe- 
Klartin polyoma experiments in 
particular, as well as four letters 
commenting directly on the proposed 
exemption: two supporting the proposal 
and two considering it premature. 
4. At the May 21-23 meeting, the RAC 
discussed the proposed exemption for 
several hours. A motion was passed by 
a vote of 17 to 0, with 3 abstentions: 
That the chair appoint a working group to: 
(a) conduct a rigorous scientific analysis of 
the E. coli K-12 host-vector systems with 
specific regard to the state of evidence of 
attendant biohazards of such studies/ 
systems; (b) explore existing nonRAC 
(medical microbiology) mechanisms for 
regulating these specific host-vector systems; 
(c) develop proposals for “new" devices for 
ensuring laboratory safety standards with 
such systems; and (d) report the results of 
this working group to the full RAC for its 
consideration. 
Later in the meeting, Dr. David 
Baltimore recommended that 
recombinant DNA experiments 
involving E. Coli K-12 host-vector 
systems be permitted under Pi 
conditions, rather than be totally exempt 
from the Guidelines. He said that his 
proposal would involve registration with 
the local IBC with the forwarding of a 
registration document to ORDA. The 
RAC voted 18 to 3, with 1 abstention, in 
favor of recommending Dr. Baltimore's 
proposal for consideration by the 
Working Group. 
Later in the meeting, Dr. Jane Setlow, 
the RAC chairman, appointed Drs. 
Luther Williams (chairman), Susan 
Gottesman, Richard Novick, and Samuel 
Proctor to this “Pl/EKl" Working 
Group. 
5. The Pl/EKl Working Group 
deliberated and submitted the following 
proposal which was published for 
comment in the Federal Register on July 
31, 1979: 
Those recombinant DNA molecules that 
are propagated in E. coli K-12 hosts not 
containing conjugation-proficient plasmids or 
generalized transducing phages, when 
lambda or lambdoid bacterio-phages or non- 
conjugative plasmids are used as vectors, can 
be handled at Pi and are exempted from the 
Guidelines. 
6. Between the May and September 
RAC meetings, 14 letters commenting on 
the proposal were received and 
transmitted to the RAC members. All 
the commentators expressed strong 
support for the proposed exemption. 
Most of them supported the original 
proposal for complete exemption as 
published in the Federal Register on 
April 13, 1979. One of these letters was 
signed by 183 scientists who attended 
the 1979 Gordon Research Conferences 
on Nucleic Acids and on Biological 
Regulatory Mechanisms. 
7. In addition to letters commenting 
directly on the Federal Register 
proposal, other relevant documents sent 
to the RAC prior to the September 6-7 
meeting included an additional letter on 
the Rowe-Martin polyoma experiment, a 
background document from the Pl/EKl 
Working Group, and a manuscript on a 
framework for assessing the potential 
risks of recombinant DNA experiments 
prepared by Dr. Sidney Brenner for the 
United Kingdom Genetic Manipulation 
Advisory Group. 
8. Distributed at the September 6-7 
meeting were a summary of the major 
recommendations of an ad hoc National 
Institute of Allergy and Infectious 
Diseases working group on risk- 
assessment and a more detailed 
background document on E. coli K-12, 
prepared by the Pl/EKl Working Group. 
9. At the September 6-7 meeting, 
several hours were spent discussing this 
proposal (I have reviewed a transcript of 
this portion of the meeting). Among the 
items covered during the discussion 
were: the interpretation of the Rowe- 
Martin polyoma experiments; the 
interpretation of two papers which 
appeared in the July 1979 edition of thf 
recombinant DNA Technical Bulletin, 
“Testing of Host-Vector Systems in 
Mice” by Rolf Freter et al„ and 
“Survival of E. coli Host-Vector systems 
in the Human Intestinal Tract" by Stuart 
Levy and Bonnie Marshall; and the 
status of the NIH Risk Assessment 
Program. Questions discussed included: 
How likely is the escape' of E. coli K-12 
from the laboratory? What is the 
likelihood of its persistence? (survival 
without selective advantage?) What is 
the possibility of a reversion of its 
disabling properties? — or transfer of its 
DNA to a wild type strain? How likely 
and how dangerous would the 
colonization of humans by E. coli 
bacteria making a "foreign” protein 
be? — considering the danger either due 
directly to action of the “foreign" protein 
or due to induced autoimmunity? How 
much should the RAC consider 
imaginary hypothetical hazards and 
how much should it concentrate on 
perceived real hazards? How should one 
extrapolate from current data to set 
reasonable containment levels for 
experiments? 
Concluding this discussion, the RAC 
voted 10 to 4, with 1 abstention, for the 
“E. coli K-12-P1 Recommendation.” 
Section III— B of this document 
analyzes in detail the issues discussed 
by the RAC prior to their voting on the 
"E. coli K-12/P1 Recommendation.” 
Ill— B. Analysis: 
This section begins with a framework 
for analyzing how a hazardous situation 
might result from the recommended 
changes in the Guidelines, and then 
shows the low probability of each of a 
series of steps required for a harmful 
effect. 
Framework for Analysis 
As a framework for analyzing how 
recombinant DNA experimentation 
might lead to a hazardous situation, the 
following appeared in the NIH 
Environmental Impact Statement on the 
1976 Guidelines, and remains valid 
today: 
The hypothetical mechanisms by which 
insertion of foreign genes into cells or viruses 
might result in the formation of hazardous 
agents are ... in principle, applicable to 
persons, animals, and plants. There is. as 
stated before, no know instance in which a 
hazardous agent has been created by 
recombinant DNA technology. Current 
Knowledge permits no more than speculation 
that such agents may be produced and an 
equally speculative assessment of the nature 
and extent of hazards associated with a 
particular recombinant DNA 
experiment. . . . 
In order that any potential hazard be 
realized, it is necessary that each of a number 
of sequential events occur. Each event in the 
sequence is possible only if the earlier events 
have occurred. The organism must — 
(a) Contain foreign genes, 
(b) Escape from the experimental situation, 
(c) Surviv® after escape, 
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