coronary heart disease. Progress and prospects in this field have recently been
reviewed by Laible ( 2009 ).
Infection of the mammary gland (mastitis) is the most important disease in dairy
cows with a huge annual cost in lost milk production. As mastitis resistance has not
been substantially improved by selective breeding there have been a number of
attempts to generate transgenic cows with increased resistance. Transgenic cows
expressing lysostaphin have been shown to be resistant toStaphylococcus aureus
infection (Wall et al. 2005 ) but cows producing lactoferrin were not resistant to
Escherichia colimastitis (Hyvo ̈nen et al. 2006 ).
Finally there has been considerable interest in developing genetically modified
pigs for xenografting into humans to overcome the acute shortage of human heart,
liver, kidney and pancreatic transplants. If a standard pig heart is transferred to a
man there is a hyperacute immune rejection as soon as blood flow is established.
The reason for this is that all mammals, apart for humans, primates and old-world
monkeys, and some bacteria have a galactose alpha 1,3 galactose epitope on the
surface of most cells. Humans carry pre-existing antibodies to this epitope, proba-
bly as the result of exposure to bacteria, and these antibodies cause rapid comple-
ment activation that destroys the foreign organ. In order to address this problem a
number of different approaches have been taken including addition of human decay
accelerating factor (hDAF, CD55) to block the complement activation and removal
of the alpha 1,3 galactosyltransferase gene (Gal-KO) in pigs to reduce this hyper-
acute reaction. Such modifications aid survival of the graft in the short term but
there is still medium term rejection that cannot be controlled by immunosuppres-
sive drugs, suggesting that further genes need to be added for a protective function
and/or other endogenous genes need to be inactivated. Progress in this field has
been recently reviewed by Petersen et al. ( 2009 ).
5 Farm Animal Pharming
Therapeutic proteins have a wide number of uses but have historically proved
difficult to produce in sufficient quantities. Production of many mammalian pro-
teins in bacterial culture is ineffective as the biological activity of the protein can be
dependent on post-translational modifications which are not performed in bacteria.
An exception is human insulin which has been produced in bacteria by Eli-Lilly and
marketed under the trade name Humulin N. To circumvent the post-translational
problem, proteins can be produced in mammalian cell cultures but 20 years ago
there were substantial technical problems in producing and purifying such proteins.
Thus in the early 1990s there was considerable interest in collecting high value
therapeutic proteins from the milk of transgenic animals, essentially using the
animals as bioreactors, and this led to the phrase “pharming”.
The first demonstration that it was possible to express a transgene in the
mammary gland of a farm animal was reported for transgenic pigs by Wall and
colleagues in 1991. Subsequently transgenic rabbits, goats, sheep and cows
Genetically Modified Animals and Pharmacological Research 219