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Biotechnology and Society---Part
23
Medicines from blood and eggs
With time and patience, the mulberry leaf becomes a silk gown. - Chinese proverb
In part-I of this series we
described how a gene transfer procedure can be adopted to modify animals
genetically and produce therapeutic proteins in their milk. Apart from milk, we
can also produce transgenic therapeutics from animal blood and chicken eggs. Let
us see how it can be done.
For more than half a century,
some of the therapeutic proteins required for treatment have been isolated from
outdated human blood (the surplus from the blood transfusion programme).
Examples include serum albumin, immunoglobulin, alpha fetoprotein and
antithrombin, just to name a few. With the incidence of infectious diseases
arising out of the blood programme contaminated with HIV,
hepatitis and others,
it has become necessary to produce the needed therapeutics from other sources.
Mammalian cell culture came to the rescue and currently several therapeutic
proteins for human use are made that way.
The transgenic route is another
way to produce these therapeutics in a cost-effective manner, such as animal
milk or plant products. We mentioned that several products are being produced in
animal milk and some are in late stage clinical trials. Antibodies are widely
used in medicine, one of the best known being the gamma globulin used against
hepatitis. Other uses target tetanus and shingles.
Another
novel route to make antibodies, which are used for the treatment of various
immune deficiencies, is to produce them in animal blood and use the blood “donated”
by the animals for human treatment. The antibody that is naturally found in
animal blood will produce allergic reactions in humans since the composition is
slightly different. However, if the animal genes for the antibody are replaced
by the human genes through a cloning programme, then the animal will make the
human antibody which can be used for human treatment.
A team of US (Hematech,
Westport, CT, and Sioux Falls, SD) and Japanese (Kirin Brewery, Tokyo)
scientists has cloned calves carrying human genes for immunoglobin using a
technology called TransChromo™ technology whereby a human artificial
chromosome (HAC) is inserted with human antibody genes in a bovine cell line
knocking out the heavy and light chain cow antibody genes. The HAC vector is
introduced into bovine foetal fibroblasts (skin cells). The cells which contain
the vector were then fused with enucleated (nucleus-removed) oocytes (eggs).
Subsequent embryo transfer into surrogate mothers produced calves which carried
the human antibody genes and made human immunoglobulins in their blood.
Such transgenic cows, when
immunised against a particular pathogen, will produce polyclonal antibodies
which can then be isolated and purified from the blood drawn periodically from
such cows. The blood from the animal - up to 10 liters at a time - can be drawn
every two weeks. Cattle are attractive donors because they are large animals
that are capable of producing large quantities of immunoglobulin in their blood
(3.5 kilograms/year) at low cost. Several groups of cows can be cloned with the
HAC and each group can be immunised against a specific pathogen. The blood from
each group (producing specific antibodies) can be pooled and the antibody
purified.
The US government has given a
contract to Dynport Vaccine Company, LLC, to develop a bovine system for
producing human polyclonal antibodies against botulinum neurotoxins. Botulinum
neurotoxins are the most poisonous natural biological substances known and pose
a major bio-weapons threat. Botulinum toxin causes muscle paralysis. If
untreated, death will be the ultimate result due to respiratory failure.
Antibodies can also be developed against other bio-weapons such as anthrax,
shigella and other agents which can be targeted by terrorists.
Numerous technical hurdles,
besides a decade or so of efforts, remain before any product could be marketed.
The long-term production capacity of each cow is not assured. A potential
problem could be the cow getting sick due to the production of foreign
antibodies in its own system. Despite such uncertainties, this technology is
hailed as a great advance.
Golden egg: Although
animal milk is probably the best source for large batches of transgenic
proteins, Avigenics (Athens, GA) makes a good case for chicken eggs. Transgenic
chickens should be ideal bioreactors for making human recombinant proteins.
Avigenics expresses human proteins in chicken eggs at concentrations of about 1
milligram in an egg containing 4.5 grams of protein.
The advantages of using
chickens include their early sexual maturity, high egg output, and prolific
breeding. A typical hen starts laying eggs at five months of age and produces
between 600 and 700 eggs in her lifetime. There are other benefits as well.
Commercial egg farms are already secure enough that containment of transgenic
chickens is not an issue. Besides, several vaccines (non-transgenic) are now
produced in chicken eggs.
Using the breeding and
processing techniques from the egg and poultry industries, it is possible to
raise a flock of 100 million chickens from a single rooster in two years. The
human recombinant proteins that are produced in the egg are in a “sterile
environment”. Storage, before processing, does not require special conditions.
Processing the egg white is also a facile effort. Avigenics has expressed human
serum albumin, interferons, antibodies and several cytokines (cellular
activators) in eggs.
Other companies which are in
the chicken eggs race are: Origen Therapeutics, TranXenogen, Viragen,
BioAgri,
and GeneWorks. None of the companies has a flock of transgenic chickens ready to
produce a commercial product. There are some potential difficulties to overcome.
Eggs are easy to harvest when laid, but by that stage the zygote (egg cell) has
already grown into a 60,000-cell mass. The strategy is to harvest the zygote
from the chicken’s oviduct, where it is a single cell which is amenable to
genetic manipulation. It is a difficult and expensive process. But the stage is
set and persistent efforts can pay off.
What
is next?: Despite its attractiveness, transgenic animal
technology, be it cows, goats, or chickens has not caught on like
wildfire. The technology appears to work and the regulators are not
overly concerned either about the safety. However, as in the case of
transgenic plants, the major problem is perception. A product has to
come to market and its safety assured before the technology and the
market catch on. Some resistance from anti-GM activists has to be
expected and handled effectively. At the end, it may all boil down to
economics. The old adage that “if you build a better mousetrap the
world will beat a path to your door” still holds good.
Take it Easy Definitions
Won Ton soup = 2000 lbs of Chinese soup
Semi colon = Half a large intestine
Pound cake = 453.6 gra(ha)m crackers
Paradigm = 4 nickels (a dime = 2 nickels) (dime and nickel are US coinage)
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