THE UPJOHN COMPANY 
KALAMAZOO. MICHIGAN 49001. U S A 
TELEPHONE (616) 323-4000 
May 4, 1988 
Dr. William J. Gartland, Jr. 
Director 
Office of Recombinant DNA Activities 
12441 Parklawn Drive 
Room 58 
Rockville, MD 20852 
Dear Dr. Gartland: 
I wish to offer comment on the proposal by Eli Lilly and Company to conduct 
large-scale experiments and production fermentations with the recombinant 
Cephalosnorium acremonium strain LU4-79-6 under less than Biosafety Level 
1 - Large Scale (BL1-LS) conditions. After reviewing the information you 
provided on the details of the construction and safety of strain LU4-79- 
6, I state unequivocal support of the Eli Lilly proposal. 
Central to the discussion of safety and applicability of less than BL1-LS 
containment is the question of whether or not the non-C. acremonium DNA 
in strain LU4-79-6 changes the pathogenic character of the host and thereby 
causes strain LU4-79-6 to have a significantly greater risk to safety than 
a non -recomb inant C. acremonium strain or a recombinant C. acremonium strain 
constructed by self -cloning. Eli Lilly has done the key experiments to 
demonstrate safety of LU4-79-6 by showing the lack of transfer of hygromycin 
resistance between strain LU4-79-6 and the ancestral C. acremonium strain 
ATCC 11550, the lack of expression of the Escherichia coli chloramphenicol 
acetyl- transferase in C. acremonium . and the lack of transfer of the E. 
coli chloramphenicol acetyl- transferase from C. acremonium to E. coli. 
This taken together with the fact that the E. coli genes are well characterized 
and constitute a very minor segment of the strain LU4-79-6 genome leads 
to the conclusion that LU4-79-6 is as safe as any C. acremonium strain 
derived from ATCC 11550. The long history of safety with non- recomb inant 
C. acremonium strains and the safety record of recombinant strains at laboratory 
and pilot scales further support the position that recombinant strains 
such as LU4-79-6 are of no inherent biosafety concern. 
The Eli Lilly proposal brings a second very important issue into focus. 
That is a clear demonstration of the application of recombinant DNA technology 
to a valuable product of a traditional fermentation process. The demonstration 
of significant (-20%) productivity improvements in such a mature product 
and process are important economic benefits that should be weighed against 
any risk or safety issue. It is apparent that the risk to benefits ratio 
is extremely small if not zero. 
[356] 
Recombinant DNA Research, Volume 13 
