18 
IX. PROPOSAL TO CLONE DIPHTHERIA TOXIN AND CONSTRUCT A HYBRID GENE 
A. Review of the Proposal to Clone the Diphtheria Toxin Gene 
Dr. Berns asked Dr. Gottesman to review (tabs 1087, 1090) the history 
of the proposal by It. John Murphy of Harvard Medical School to clone 
the diphtheria toxin gene. Dr. Gottesman said tabs 1087 and 1090 pro- 
vide background information on the proposal to clone the diphtheria 
toxin gene, and the minutes of the meetings of the ad hoc Working Group 
on lb x ins which generated Appendix F of the Guidelines” Dr. Gottesman 
said Dr. Murphy's proposal to clone the diphtheria toxin gene generated 
a fair amount of publicity, and several letters were received by the 
NIH suggesting that NIH and IBC approval was ill advised. 
Dr. Gottesman said when the proposal was first introduced, the RAC con- 
cerned itself only with setting appropriate containment. It did not 
discuss questions of risk vs. benefit; in the P4 facility, risk 
was perceived to be reduced to such minimal levels that little discus- 
sion of benefit occurred. In the past, the committee has not evaluated 
risk vs. benefit questions as part of its safety review procedure. 
In contrast, the IBCs which reviewed Dr. Murphy's proposal discussed 
issues of benefit vs. risk. The questions raised in the letters to the 
NIH also dealt with this issue; the correspondents did not feel the 
benefits were sufficient to justify any risk. Dr. Gottesman said no 
new containment issues, beyond those considered by RAC, have been 
raised by the IBCs or the correspondents. 
Dr. Kaper asked if RAC and the NIH had already approved Dr. Murphy's 
experiments, and, if so, at what containment. Dr. Gartland said the 
proposal came before the RAC on two separate occasions. In March 
1981, RAC recommended P4 containment for the experiments. In September 
1981, RAC recommended that within the P4 facility laboratory practices 
and containment equipment to be used were to be specified by the IBC. 
The NIH IBC set containment for most of the work at P3 in the P4 facility. 
Since then, the Frederick Cancer Research Facility IBC has set contain- 
ment at P4 in the P4 facility. 
Dr. Kaper said no data exist on the effect of EL_ coli producing diph- 
theria toxin. Cn the other hand, the effect of EL_ coli producing Shiga 
toxin has, in human volunteers, been extensively studied. Dr. Kaper 
said that to be consistent containment for experiments involving 
diphtheria toxin should be set as high as for experiments involving 
Shiga toxin. 
Dr. Gill commented on the risk assessment aspects of Dr. Murphy's proposal. 
He said when the ad hoc Working Group on Tbxins was considering potential 
dangers associated with cloning toxin genes, it became apparent that 
data were severely lacking. Some experiments were proposed by the ad 
hoc working group, e.g., that purified toxins be placed in the bowels 
of test animals. Diphtheria toxin, which is cytotoxic for all cells and, 
[24] 
