STANFORD UNIVERSITY MEDICAL CENTER 
STANFORD, CALIFORNIA 94305 
Stanford University School of Medicine 
Department of Medicine 
December 20, 1977 
Donald S. Fredrickson, M.D. 
Director 
DHEW, PHS 
N.I.H., Bldg. 1, Rm. 124 
Bethesda, MD 20014 
Dear Don: 
Paul Berg has sent me a copy of his recent letter to you containing 
his modified definition of recombinant DNA which includes synthetic genes. 
While I agree with his definition, I do not agree with the proposal in his 
letter to handle synthetic genes at the same level of containment as purified 
DNA from the natural source. 
The original rationale for requiring higher containment levels for work 
with recombinant molecules that carry natural DNA from higher mammals was 
that genetic material from humans and other primates might be more likely to 
contain viruses capable of producing human disease. So far as synthetic genes 
are concerned, there is no reason whatsoever for requiring higher containment 
levels for work with an entirely synthetic human insulin gene, for example, 
than for work with a synthetic gene for pig or fish insulin. Yet, this is 
precisely the effect of Paul’s proposal. 
I urge that the revised Guidelines deal with this problem by stating 
that synthetic -genes (which represent the highest degree of purity imaginable), 
can be handled at the same level of containment used for purified DNA from 
lower eukaryotes, such as Drosophila, sea urchins, etc., provided that the 
synthetic genes do not code for known toxins. Any possible biohazard related 
to work with such genes would result from the "novelty" of their introduction 
into an organism such as IS. coli , and the "novelty" factor should be no 
different so far as IS. coli is concerned whether the sequence is that of fish 
insulin, porcine insulin, bovine insulin, or human insulin. 
I have discussed this point with Paul Berg and he agrees with the 
arguments I've put forth. 
I hope that you will deal with this matter in your revision of the Guide- 
lines. 
With best wishes, 
Professor of Medicine and 
Professor of Genetics 
SNC:seh 
cc Paul Berg 
Maxine Singer 
[Appendix A — 136 J 
