Original Repository: Alan Mason Chesney Medical Archives. Daniel Nathans Collection
Reproduced with permission of David A. Jackson.
Medical Subject Headings (MeSH):
Restriction Enzymes and the "New Genetics," 1970-1980
January 13, 1975
In responding to your letter of December 4, 1974, I would like to restrict my comments to the question of whether the moratorium
should be continued for Type II experiments, as defined in the initial Berg committee letter in Science.
Let me start by making what I believe is an important distinction, a distinction which was a bit fuzzy in the Berg letter
and which has continued that way in much of the subsequent discussion. I would like to differentiate clearly between viral
or plasmid-viral chimeric nucleic acid molecules which have been made and are being studied in vitro and those same molecules
once they have been introduced into a bacterium and have established themselves as replicons in a viable organism. The former
are obviously of much less potential hazard than the latter. The efficiency with which DNA or RNA molecules in vitro can establish
themselves in cells is very low. Their chemical half-life, to say nothing of their biological half-life, is generally quite
short unless they are maintained in sterile solutions of appropriate composition. There should thus be no prohibition against
making, by biochemical means, virtually any chimeric DNA or RNA molecules. Standard precautions for working with low risk
agents, as defined by the NCI, will suffice for safe handling of these molecules in vitro.
The more difficult question, of course, is what to do about chimeric molecules in which viral genes have been incorporated
into plasmid or phage DNA's, and the chimeric DNA's have been established in E. coli. Here again it is useful to make
distinctions. I see little risk in establishing, for instance, fragments of SV40 DNA containing one or several of the late
genes in E. coli. In fact, as we discussed at our meeting, considerable useful information might be derived from such experiments.
As the genomes of more and more viruses become better understood, I believe it will be possible to put the majority of the
genes in any oncogenic virus (those genes dealing with functions other than transformation) into E. coli with virtually no
risk. So it is with respect to whole viral genomes or the transforming genes from them that there is real controversy.
To answer directly the question you posed in your letter: I believe the existing moratorium should be modified to allow experimentation
with bacteria containing chimeric molecules in which transforming genes from oncogenic viruses have been incorporated. I believe
that it will be possible to handle such organisms in ways that present acceptably low risks, and I further believe that the
potential benefits to be derived from working with such organisms are great. As I indicated in our meeting in November, I
think a sensible first step would be to construct a sort of universal recipient strain of E. coli, which would be uvs, ts
lethal, and streptomycin dependent. Whatever risk is associated with putting a chimeric DNA molecules into wild type E. coli
will be very substantially decreased by using this strain instead. If, in addition, cells containing potentially hazardous
chimeric DNA's are handled in the same way that pathogens are handled in standard bacteriological practice, a further
substantial reduction in risk would occur. These handling procedures will require significant changes in the way people are
used to handling E. coli, but will certainly allow work to continue at an acceptable level in most laboratories. These two
measures should reduce what I think is an already small risk by many orders of magnitude. The classification of viruses into
low, moderate, and high risk categories proposed by the NCI should be continued for bacteria containing transforming genes
from these viruses, and precautions of increasing stringency should be applied to the handling of the presumably increasingly
hazardous bacterial strains.