Biomedical Engineering Reference
In-Depth Information
Paddington train crash, in which one carriage was
completely incinerated.
Just as the mitochondrion is transmitted maternally,
the Y chromosome is transmitted only through male
descendants. Because there is only a single copy of
the Y chromosome in normal diploid cells, recom-
bination between different Y chromosomes does not
occur. Any changes that do occur in the Y chromo-
some from generation to generation must arise
from DNA rearrangements or by accumulation of
random mutations. That is, the Y chromosome
should be highly conserved. Sykes and Irven (2000)
obtained proof of this. They probed a randomly
ascertained sample of males with the surname 'Sykes'
with four Y-chromosome microsatellites and found
that half of them had the same Y haplotype. This
suggests that all those with the same haplotype have
a common ancestor, even though conventional
genealogical analysis suggests otherwise.
The first generation of protein drugs were exact
copies of the human molecules but protein engineer-
ing is now being used to develop second-generation
molecules with improved properties (see theme 4,
p. 299). More recently, macromodifications have
been made to proteins, as exemplified by the recently
approved drug (Table 14.3) for rheumatoid arth-
ritis, which consists of the tumour necrosis factor
receptor fused to the Fc portion of human IgG1.
Transgenic animals and plants as
bioreactors: 'pharming'
'Pharming' is the play on words that refers to the use
of transgenic animals and plants to produce recom-
binant therapeutic proteins. As discussed in earlier
chapters, recombinant-protein synthesis in animal
cells has a number of advantages over microbial
expression systems, the most important of which
is the authentic post-translational modifications
that are performed in animal cells. However, large-
scale culture of animal cells is expensive, due to
the amount of medium and serum required and
the necessity for precise and constant growth condi-
tions. The production of growth hormone in the
serum of transgenic mice (Palmiter
et al.
1982a) (see
p. 209) provided the first evidence that recombinant
proteins could be produced, continuously, in the
body fluids of animals. Five years later, several groups
reported the secretion of recombinant proteins in
mouse milk. In each case, this was achieved by join-
ing the transgene to a mammary-specific promoter,
such as that from the casein gene. The first proteins
produced in this way were sheep
Theme 2: New drugs and new therapies
for genetic diseases
Introduction to theme 2:
proteins as drugs
One of the earliest commercial applications of
gene-manipulation techniques was the production
in bacteria of human proteins with therapeutic
applications. Not surprisingly, the first such prod-
ucts were recombinant versions of proteins already
used as therapeutics: human growth hormone and
insulin. Prior to the advent of genetic engineering,
human growth hormone was produced from pitu-
itary glands removed from cadavers. Not only did
this limit the supply of the hormone but, in some
cases, it resulted in recipients contracting Creutzfeld-
Jakob syndrome. The recombinant approach resulted
in unlimited supplies of safe material. This safety
aspect has been extended to various clotting factors
that were originally isolated from blood but now
carry the risk of HIV infection. As the methods for
cloning genes became more and more sophisticated,
an increasing number of lymphokines and cytokines
were identified and significant amounts of them
produced for the first time. A number of these were
shown to have therapeutic potential and found their
way into clinical practice (Table 14.3).
-lactoglobulin
(Simons
et al.
1987) and human tissue-plasminogen
activator (tPA) (Gordon
et al.
1987, Pittius
et al.
1988). There have been over 100 such reports since
these early experiments, and a selection is listed in
Table 14.4.
Although proteins can be produced at high con-
centrations in mouse milk (e.g. 50 ng/ml for tPA),
the system is not ideal, due to the small volume of
milk produced. Therefore, other animals, such as
sheep and goats, have been investigated as pos-
sible bioreactors. Such animals not only produce
large volumes of milk, but the regulatory practices
regarding the use of their milk are more accept-
able. An early success was Tracy, a transgenic ewe
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