Redesigning Animal Agriculture

104 D.N. Wells and G. Laible
organs, the potential for cross-species viral
infection, not so much for the individual
but for the community at large, is a risk
that needs to be managed (Fishman and
Patience, 2004).
Disease models
In some cases it may be ethically acceptable
to genetically modify farm animals to serve
as models for various inherited human
genetic diseases to aid research and preliminary
evaluation of novel therapies (Petters,
1994). An ovine model of cystic fibrosis, for
example, is considered superior to available
mouse models because of the greater similarity
in lung anatomy and physiology with
humans (Harris, 1997); however, gene targeting
at this non-expressed locus in fibroblasts
has proved difficult (Williams et al.,
2003). Transgenic pigs have been de veloped
as useful models for the rare human eye
disease retinitis pigmentosa (Mahmoud et
al., 2003). Conventional livestock are not
appropriate in all instances because of their
long generation intervals, physical size and
costs involved. Hence, more suitable laboratory
models have been the motivation for
developing NT from cultured somatic cells
in species such as the rat (Zhou et al., 2003),
rabbit (Chesne et al., 2002), and ferret (Li
et al., 2006) and now the opportunity exists
to couple this with cell-mediated genetic
modification.
Livestock transgenics for agriculture
As understanding of the genes that influence
livestock production traits improves from the
sequencing and comparison of the genomes
of livestock species with mouse and human
(Fadiel et al., 2005; Womack, 2005), so does
the knowledge to accurately modify the
appropriate genes and regulatory sequences
to generate new and desired animal products
in the future. However, as most of the relevant
livestock traits are complex and controlled
by multiple genes, useful transgenic
intervention is considerably more difficult
than mere over-expression for a biopharming
application. Agricultural applications of
livestock transgenesis are primarily aimed
at increasing: (i) animal productivity; (ii)
the quality of valuable meat, milk and fibre
components; (iii) disease resistance; and
(iv) improving environmental sustainability.
Genuine improvement in these attributes
will have economic benefits for farmers and
processors, and additional health benefits for
consumers or the livestock themselves.
Meat
Many initial livestock transgenic experiments
focused on modifying body composition
by introducing growth hormone or
insulin-like growth factor I (IGF-I). However,
this pioneering work only resulted in slightly
increased growth rates and was severely
hampered by poor transcriptional regulation
of the transgenes, resulting in high
levels of these hormones in systemic circulation,
with animals consequently suffering
a number of deleterious side-effects including
lameness, susceptibility to stress and
reduced fertility (Pursel et al., 1989; Pursel
and Rexroad, 1993). More desirable effects
on growth rate and body composition have
been achieved without apparent abnormalities
by restricted expression of the human
IGF-I transgene to skeletal muscle (Pursel
et al., 1999). This manipulation resulted in
female transgenic pigs having ~10% more
carcass lean tissue and ~20% less total
carcass fat, but there was no change in the
body composition of transgenic males compared
to conventional boars (Pursel et al.,
1999). An even tighter control of transgene
expression can be achieved with inducible
control elements which essentially function
as on/off switches, such as the metallothionein
promoter which can be regulated by
manipulating the level of zinc in the diet
(Nottle et al., 1999). Using a similar promoter
regulating ovine growth hormone,
transgenic sheep grew significantly faster
and were leaner but were burdened with
a greater parasite fecal egg count, possibly
indicative of a compromised immune system,
and also displayed some foot problems
similar to those observed in animals treated
with exogenous growth hormone (Adams
et al., 2002).