sion, and this final version is based on 
the replies of all the participants.” . 
The report of the Virus Working 
Group, which considered the Ascot 
Report, was published as Appendix F 
to the EIA in the Federal Register 
July 28, 1978, pp. 33167-33174. 
The 36 participants at the Falmouth 
meeting are listed in the report of the 
meeting ( Journal of Infectious Dis- 
eases, Vol. 137, PP. 613-614, May 1978). 
Most of the participants were invited 
by the organizing (steering) committee 
for the meeting, and the members of 
that committee are listed on these 
pages. In addition to invited partici- 
pants, others arrived uninvited and 
participated. 
The participants and the reasons for 
holding the Ascot meeting are dis- 
cussed in my Decision document (Fed- 
eral Register, July 28, 1978, p. 33060) 
and in the EIA, p. 33159. 
The participants in the Virus Work- 
ing Group, which met on April 6-7, 
1978, to review the report of the U.S.- 
EMBO Workshop, are described in the 
EIA. (Federal Register, July 28, 1978, 
p. 33167). This meeting was announced 
in advance in the Federal Register on 
March 17, 1978; it was entirely open 
and was attended by others than the 
participants. 
The results of the Falmouth, Ascot, 
and Virus Working Group meetings 
were discussed at a number of meet- 
ings of the Recombinant DNA Adviso- 
ry Committee (RAC), where they led 
to recommendations for changes in 
the Guidelines. All meetings of the 
RAC have been announced in advance 
in the Federal Register, have been 
open to the public, and have been at- 
tended by many nonmembers. 
The NIH is sensitive to the need for 
all concerned to have access to the ad- 
visory deliberations contributing mate- 
rially to the substance and use of 
these Guidelines. Ordinarily, such 
meetings will be open' to the public 
and announced in advance in the Fed- 
eral Register. We have become aware 
that publication in the Federal Regis- 
ter is not sufficient notice for many, 
and the Recombinant DNA Technical 
Bulletin and other media will be used 
whenever possible to supplement an- 
nouncements of meetings and dissemi- 
nate reports emanating from them. 
NIH will also continue its publication 
of all commentary, transcripts of hear- 
ings, and other materials relevant to 
the “public record” of deliberations on 
the subject of the Guidelines. 
Commentators state that the ab- 
sence of untoward events in five years 
of experiments with recombinant DNA 
is not a valid ground upon which to 
Justify the lowering of containment 
levels. 
There is some merit in this objec- 
tion, but experience to date should 
contribute to the basis for revision of 
FEDERAL 
NOTICES 
the Guidelines. When organisms con- 
taining recombinant DNA began to be 
constructed in 1973, it seemed unlikely 
to most that hazardous organisms 
would be produced, yet no one knew 
for sure. No basis for certainty has yet 
arrived, but some of the fears have 
justifiably diminished. The results to 
date have revealed no major biological 
factor overlooked in the initial analy- 
sis that suggests the guidelines should 
be stricter than they are. Indeed, sev- 
eral separate lines of evidence indicate 
the probability of hazards to be even 
lower than originally thought. That 
no one has become ill is the least im- 
pressive of these. More important lines 
include the following: 
1. Numerous analyses and hewer 
data indicating the very low probabil- 
ity that E. coli K-12 will establish 
itself in the human intestinal tract, 
thus limiting escape of the organisms 
in numbers sufficient to infect other 
living things. 
2. The now widely made observation 
that organisms containing recombin- 
ant DNA compete very poorly for sur- 
vival as compared with organisms not 
containing recombinant DNA. This 
was an anticipated finding (see Octo- 
ber 1977 Environmental Impact State- 
ment) but has now been documented 
in various instances. It is true even 
under laboratory conditions designed 
to be optimal. Only when the growth 
medium for the E. coli cells containing 
recombinant DNA is specifically de- 
signed to impose selective pressure on 
the recombinant organisms do they 
outgrow “Natural” competitors. (Se- 
lective pressure could be imposed, for 
example, by the presence of an antibi- 
otic to which the recombinant organ- 
isms are resistant but the natural com- 
petitors are sensitive.) 
3. The repeated observation that 
genes of higher organisms, introduced 
into E. coli by shotgun experiments, 
are not generally expressed. Many of 
the concerns about possible hazards 
center on the ability of a host cell to 
synthesize a foreign protein that 
might be detrimental to an organism 
with which the host cell comes into 
contact. 
One correspondent said that assign- 
ing a higher degree of containment to 
organisms that are phylogenetically 
closer to man is unjustified, with the 
possible exception of clones capable of 
harboring viral sequences. The corre- 
spondent noted that “even if the 
cloned DNA were highly homologous 
to human DNA, how is it envisioned 
that when carried in a bacterial host it 
would somehow be more dangerous to 
man than a non-homologous DNA?” 
The commentator went on to state 
that the “production of pharmacologi- 
cally active agents will clearly not 
depend upon evolutionary similarity 
to man” and that in fact such prod- 
60087 
ucts will likely be specified by lower 
organisms. 
In responding, I must note that a 
primary concern in the original assign- 
ment of containment levels was the 
possibility that viruses capable of 
propagating in human tissues could 
contaminate the DNA. The concern is 
greatest when the DNA donors are pri- 
mates or other mammals, and so, for 
these, higher containment levels are 
provided. 
A secondary consideration involves 
the possibility that the recombinant 
DNA may itself transform the host. 
The likelihood of such DNA integrat- 
ing into the human genome, and con- 
sequently undergoing replication and 
expression, is directly related to the 
extent of homology between the for- 
eign and host DNAs. 
Another reason for making distinc- 
tions on the basis of phylogenetic re- 
latedness is that the more closely re- 
lated the species, the more likely that 
polypeptide hormones or related pro- 
teins would be pharmacologically 
active. 
A more extensive discussion of the 
issue of phylogenetic relatedness is 
given in the Environmental Impact As- 
sessment (Federal Register, July 28, 
1978, pp. 33102-33104). This matter 
lies in a crucial area of risk analysis 
and will undoubtedly continue to be 
subject of both further debate and im- 
proved understanding in the coming 
months. 
Commentators discuss a number of 
scientific "fears where there remains 
reason for caution,” including that the 
virulence of E. coli may be increased 
by recombinant DNA, that recombin- 
ant plasmids might be transferred to 
more virulent strains of bacteria, and 
that bacteria or viruses containing re- 
combinant DNA could cause autoim- 
mune disease. 
In reply, I note that these issues are 
discussed extensively in the proceed- 
ings of the Falmouth Conference 
( Journal of Infectious Diseases, May 
1978) and in the EIA of July 28, 1978 
(Federal Register ). 
At the Falmouth conference, evi- 
dence was presented on the attempts 
to make E. coli K-12 pathogenic. 
Even the introduction of Shigella 
genes into E. coli by nonrecombinant 
DNA techniques failed to produce a 
pathogenic organism having any phen- 
otype suggestive of Shigella. There 
was concensus of all participants at 
Falmouth that E. coli K-12, could not 
be converted into an epidemic patho- 
gen by recombinant DNA techniques. 
There are great safety differences 
between E, coli K-12, an attenuated 
laboratory strain, and wild-type E. 
coli, as discussed in the EIA. 
For an EK2 host to be certified as 
such, “no .more than 1 in 10 s host cells 
should be able to perpetuate a cloned 
REGISTER, VOL 43, NO. 247— FRIDAY, DECEMBER 22, 1978 
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