7 
[Rapporteur's Note: Oicoqenes were first identified as the transforming (one) 
aenes of retroviruses. Typically, these viruses initiate and maintain cancers 
with autonomous one genes that are dominant in susceptible cells. The viral 
one genes are not essential to the multiplication of the virus. The oncogenic 
retroviruses are the products of recombinational events between retroviruses 
and normal cellular genes. The normal cellular genes related to transforming 
retroviral one genes are termed "proto-onc" genes. The relationship between 
viral one genes and proto-onc genes shows the proto-onc genes to be genes 
which normally produce products necessary to cellular growth which if subjected 
to abnormal reaulation can be involved in carcinogenesis. Same evidence indicates 
that activated proto-onc aenes are involved in carcinogenesis.] 
Dr. Gottesman asked the workina aroup to construct a "worst case" analysis and to 
consider potential effects of oncoaene products if these products are expressed 
by a bacterial host-vector system which can colonize the human gastrointestinal 
(G I) tract. Dr. Gottesman said in a "worst case" hypothetical analysis, one 
would assume that an coli host-vector system expressing high levels of the 
product had colonized a human GI tract. One would also assume that a high 
level expressing strain would produce approximately 10^ molecules of oncogene 
product per cell per generation (about 30 percent of the possible protein 
initiations) . Another assumption in a "worst case" calculation is that a 
human GI tract completely colonized by the engineered bacterial strain would 
contain 2 x 10^ engineered _E. coli duplicating about every 12 hours. Assuming 
such an event, is there any mechanism by vhich the product could affect the cells 
of the gut? Is there any basis for believing the bacteria could proliferate 
and deliver the oncogene product to target cells in the GI tract? 
Dr. Grodzicker said the normal function of the proto-oncogenes is poorly under- 
stood. On the basis of _in vitro assays one product appears to be a growth 
factor, another is a membrane protein growth factor receptor, others probably 
have different functions. TVjo of these genes resemble genes of the yeast cell 
cycle. Dr. Grodzicker said the effect of some oncoqene products (e.g., the 
ras gene, SV40T, the sre gene) has been tested in vitro in tissue culture. A 
short term effect is seen when cells are exposed to some oncoqene products, 
but this effect disappears ouickly When the oncogene products are removed. 
Dr. Joklik said he knew of no reports of irreversible effects frcm exposure of 
tissue culture cells to oncogene products. Dr. Rapp said the gene is oncogenic 
not the gene product. 
Dr. Landy said the important issue is that recombinant ENA technology can 
produce large amounts of viral products that could not be obtained with the 
virus itself. He asked if in addition to GI exposure there were other routes 
of exposure which should be considered such as systemic infection or aerosol 
exposure. He asked whether exposure to large amounts of an oncogene product 
could affect an individual. Dr. Rapp said large amounts of any natural sub- 
stance introduced into a subject will have an effect. The question is whether 
there is a route of entry for such a large amount of substance. 
[ 446 ] 
