STANFORD UNIVERSITY MEDICAL CENTER 
STANFORD, CALIFORNIA 94305 
Stanford L'niversitv School of Medicine 
Department of Medicine 
November 9, 1977 
Donald S. Fredrickson, M.D. , 
Director, 
National Institute of Health 
Building 1, Room 124 
BETHESDA, Md. 20014 
Dear Don: 
I believe the proposed revisions of the NIH Guidelines on recombinant 
DNA research, as recently published in the Federal Register, represents a 
substantial improvement over the earlier version of the Guidelines. 
However, I do have a few comments and suggestions about the revisions. 
(1) Definition of Recombinant DNA . There is an ambiguity in the 
proposed definition of "novel recombinant DNA." In order for a recombinant 
DNA molecule not to be considered novel, the Guidelines require that all 
of its components be derived from species that are known to exchange 
chromosomal DNA by natural physiological processes. This suggests that 
even if plasmids can be exchanged between two bacterial species by 
physiological processes, recombination of plasmid DNA segments in vitro is 
considered "novel" if exchange of chromosomal DNA has not also been 
demonstrated. However, further down in the same paragraph there is the 
statement that "all recombinant DNA molecules formed from any combination 
of DNAs will not be considered novel when all components are derived 
from genomes known to replicate within the organism used to propagate 
the recombinant DNA." This sentence implies that plasmid recombinants would 
not be considered novel if the plasmids can be exchanged, regardless of 
whether exchange of chromosomal DNA can occur. I think this apparent 
contradiction needs to be resolved. 
My suggestion would be to define "novel recombinant DNAs" as follows: 
"molecules that consist of segments of any DNA from different species that 
are not known to exchange DNA by natural physiological processes." I know 
of no scientific basis for suggesting that organisms known to exchange 
extrachromosomal genetic information cannot also transfer chromosomal genes. 
Transduction and intracellular recombination between chromosomal and extra- 
chromosomal DNA are well recognized biological processes. 
[Appendix A — 312] 
