Recombinant DNA Advisory Committee - 09/14-15/92 
Regarding germ line gene therapy, Dr. Neel added that despite the overwhelming 
scientific advances towards genome research in the last 30 years, understanding the 
anatomy and interactions of the genome is still in its infancy. He stated that in his 
opinion, it would represent intellectual arrogance for scientists to seriously consider 
embarking on human germ line gene therapy. The implications and lessons of somatic 
cell gene therapy will not be completely known for at least 30 years. Recent data 
suggests that "shotgun" injection of DNA into transgenic mice results in serious genetic 
defects for 10% of the population; this frequency may actually be higher. For this 
reason, germ line therapy carries an unacceptable level of risk at this time. 
Dr. H. Miller inquired about the following. If data demonstrates that only 10% of the 
animals acquired developmental abnormalities and since the patients who would be 
eligible for such therapy have profound life threatening diseases, is this level not 
acceptable for risk to the patient? Dr. Neel cautioned Dr. H. Miller that modifications 
incorporated through germ line gene therapy remain in the gene pool, therefore, 
affecting future generations. Although there may be an immediate gain, the inserted 
gene may be a "genetic time bomb." 
Dr. Parkman acknowledged that the RAC is not in a position to consider germ line gene 
therapy as a primary form of treatment for life threatening diseases at this time. 
However, the RAC must consider the possibility that the genetic material administered 
for somatic cell therapy could inadvertently become incorporated into the germ line of 
that patient. 
Dr. Walters asked Dr. Neel to comment on the prospects for technical breakthroughs in 
homologous recombination and site specific integration of new genes. Dr. Neel 
explained that he could not visualize any introduction of a gene so precise that there 
would be no residual change in the nucleotide composition of that particular segment of 
DNA. 
Dr. Krogstad inquired about the frequency of crossing over and reduction division that 
occurs in a single generation. Dr. Neel noted that when crossing over is not precise, 
there is potential for a mutation to occur. Experiments to address this issue are just 
beginning and are very complex to perform in higher eukaryotes. It is known that 
crossing over is sometimes imprecise, e.g., hybrids between the beta and delta locus. 
However, the extent to which there is imprecise crossing over within one locus is unclear. 
Dr. Haselkom asked about the basis for different mutation rates among different genes 
and the "real life" equivalent of five severs. Dr. Neel responded that a large gene, e.g., 
neurofibromatosis, has a higher mutation rate than a smaller gene. In addition, there 
are certain nucleotide sequences that are susceptible to mutation by methylation. Dr. 
Neel explained that during the reproductive cycle, an individual is exposed to 
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