always accurately reflect the human condition and care must be taken to understand
the limitation of such models. For example a large number of mouse models of
cystic fibrosis have been independently generated by inactivation of the cystic
fibrosis transmembrane conductance regulator (CFTR) gene (reviewed in Grubb
and Boucher 1999 ). Although these mice develop digestive problems they do not
develop the marked lung pathology seen in man and this was thought to reflect the
specific pathogen free conditions in which mice, unlike man, are commonly housed
for experimental work. However, only with repeated addition of respiratory tract
pathogens do the mice develop lung damage (Davidson et al. 1995 ). Thus treatment
of CFTR mice does not accurately reflect all the issues likely to be encountered in
treating the human disease, i.e. thick mucus, chronic infection and lung damage.
Genetically manipulated mice have proved useful in trying to understand the
mechanisms of anti-depressive drugs by manipulations of specific genes such as
those for the 5-HT (serotonin) transporter and the G protein coupled receptors,
5-HT1A, 5-HT1Band 5HT 4. Downstream targets such as the TWIK-1 related K+
channel appear to offer possible targets for new anti-depressants. For such studies,
it is vitally important that the genetic background is defined, as different genetic
backgrounds in mice show very different behavioural performances (reviewed by
Gardier et al. 2009 ).
Knockout mice have also played a very important role in understanding the
regulation of appetite and obesity and have provided a number of targets for
pharmacological intervention. Many of these models have been reviewed by
Speakman et al. ( 2008 ). Another example is the knockout of the RIP140 gene, a
nuclear receptor co-repressor (Leonardsson et al. 2004 ). These mice are lean, show
resistance to high-fat diet-induced obesity and hepatic steatosis, and have increased
oxygen consumption. Thus, this gene could be a target for the development of drugs
to treat the metabolic syndrome in man.
4 The Development and Use of Transgenic Farm Animals
The first transgenic farm animals were pigs that expressed human growth hormone
(Hammer et al. 1985 ) and further pigs were produced by other groups. However the
effects on growth rate were variable although feed conversion efficiency was
increased and fat deposition was reduced compared to non-transgenic littermates.
Unfortunately the over-expression of the growth hormone was linked with the
development of lethargy, lameness, and gastric ulcers and thus this was not an
effective method to improve pork production (Pursel et al. 1990 ).
Farm animals have also been genetically modified to improve food quality. For
example transgenic cattle have been produced containing additionalb- andk-casein
genes which increased the casein content of the milk (Brophy et al. 2003 ). This was
used to make cheese with increased levels of essential amino acids. Transgenic pigs
have been generated that produce increased levels of omega-3 fatty acids in the
meat (Lai et al. 2006 ); these fatty acids have been associated with prevention of
218 D.J. Wells