production of vaccines (Stowers et al., 2001). Such “biopharming” applications have the potential to use well-established agricultural methods to produce large amounts of valuable products at relatively low expense as compared to fermentation. Although the end products of these applications will be novel, by and large, the process of production and the potential concerns are not likely to differ greatly from those seen in current practice, such as the use of animals or animal cell cultures to prepare live vaccines (Brown et al., 2001), hormones, or traditional products such as meat, milk, or leather. These standard products are subject to specific regulatory procedures, and essentially the same regulatory framework is expected to apply for products of both biopharming and standard technology as regards common issues such as purity of the final product, microbial contamination, levels of adventitious DNA, and the like. Nevertheless, a few more specialized concerns arise.

Contamination or Spread of Novel Pathogens

As discussed in Chapter 2, there is a theoretical potential for microorganisms to acquire—by recombination or transduction—genes from the vector constructs used to insert the transgene. Although there is no example yet of acquisition of any gene, including drug resistance markers, by bacterial flora living in a transgenic animal, the spread of introduced genes remains a possibility, albeit remote.

Of greater concern is the possibility for generation of potentially pathogenic viruses by recombination between sequences of the vector used to introduce a transgene and related, but nonpathogenic, viruses that might be present in the same animal. These concerns are particularly acute for retroviral vectors. Retroviruses appear to be efficient vehicles for inserting transgenes into many species, including chickens (Crittenden and Salter, 1990; Briskin et al., 1991), mice (Jahner et al., 1985), cattle (Chan et al., 1998), fish, and shellfish (Sarmasik et al., 2001), and might prove more successful than pronuclear injection of DNA in the generation of transgenic offspring. In many species, including chickens and pigs, there are endogenous proviruses (including the porcine endogenous viruses, PERVs, discussed below) that are competent for low-level replication in the host animal, but have no apparent pathogenic consequences (Boeke and Stoye, 1997). Endogenous proviruses are DNA sequences that were derived from infection of germline cells with a retrovirus and that are transmitted from parent to progeny like any normal gene. Their attenuation relative to their exogenous, pathogenic counterparts often is due to differences in transcriptional regulatory sequences in long terminal repeats (LTR’s; Rosenberg and Jolicoeur, 1997). Since many vectors, such as the widely-used ones derived from murine leukemia virus (MLV), have LTR sequences derived from pathogenic viruses, the presence of both vector and

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