Page two 
Dr. Donald Fredrickson 
August 31, 1978 
I am in sympathy with their action, but surely it was not the intention of the 
Guidelines to put these elegant and simple tools of molecular biology within 
reach of only the well-endowed or well-connected. I share with many of our 
colleagues a sense of urgency that these revisions be adopted as quickly as 
possible and that the NTH give top priority to establishment of mechanisms 
which will allow the Guidelines to be more responsive to changes in the state 
of our knowledge. 
Finally, I would like again to draw your attention to a detail in the 
containment guidelines for permissible experiments, which I first discussed in 
comments regarding the PRG-RAC (copy attached), namely, the lack of flexibility 
provided for'shotgun" experiments with DNA of higher eukaryotes. The present 
"Decision" section (p33059) quotes the 1976 Guidelines in providing two 
rationales for establishing containment levels for such shotgun experiments. 
One, the "more concrete reason" for scaling containment upward with evolution 
was the concern for contamination with viral DNA sequences. This, of course, 
is no longer applicable since in most cases the new proposals provide more 
flexibility for work with pure viral DNAs than with the DNAs of higher 
eukaryotes. What remains then are the second, less concrete "assumptions" 
based on the probability that a prokaryote might translate eukaryotic DNA to 
produce a harmful product, with the resulting concern that a "rogue" bacterium 
containing this gene would escape and spread in the environment. These, of 
course, were the very questions addressed at the Falmouth Conference. As you 
are aware, the participants at Falmouth concluded that the chance of an E^. coli 
K12 host being converted into an epidemic pathogen by insertion of random bits 
of foreign DNA was negligible. If the "rogue" bacterium cannot be spread 
by virtue of pathogenicity then the relevance of this concern must surely be 
brought into question. Furthermore, more recent findings which show extensive 
modification of mRNA in eukaryotes (cites on p33047) indicate that faithful 
expression of eukaryotic genes in prokaryote will probably be much less frequent 
than first imagined. Indeed, as of this date, the only eukaryotic genes which 
have been found to function in prokaryotes are those of the lowest forms, i.e. 
yeast and Neuospora . 
I note in the discussion of these shotgun experiments (p33060) that the 
reason given for a lack of flexibility in the case of higher eukaryotes was 
an "...increased confidence in the biological containment offered by the EK2 
system..." While, as a member of an "EK-2-vector" RAC working group, I share 
this confidence, this line of reasoning hardly seems applicable. What would 
be applicable is a technical appraisal of the possible risks that might be 
associated with these experiments, using criteria similar to that applied in 
the establishment of other levels. As discussed above, in light of the Falmouth 
report and other recent findings, it is hard to imagine how any realistic 
assessment could conclude that the probability of inclusion of an expressed 
"harmful" gene in an EK-1 host would be significant enough to place these 
experiments at a level of containment higher than that now utilized routinely 
to handle concentrated cultures of true pathogens (i.e. P3) . Furthermore, 
continued . 
[A-69] 
