Topics
A New Kind of Farming
Genetic Engineering
Animal Pharming
Commercialization Issues
Regulatory and Ethical Issues
Information Sources
[Topics]
A New Kind of Farming
A new brand of farming is emerging from the research and development labs
of several universities and small biotechnology companies-so new they're
even changing the spelling to "pharming."
Pharming is the production of human pharmaceuticals in farm animals that
is presently in the development stage with possible commercialization by
the year 2000. It has been gaining application among biotechnologists since
the development of transgenic "super mice" in 1982 and the development
of the first mice to produce a human drug, tPA (tissue plasminogen activator
to treat blood clots), in 1987. Transgenic organisms have been modified
by genetic engineering to contain DNA from an external source. The first
drugs produced by this approach are about to enter clinical trials as part
of the FDA review process. These transgenic animals will likely be raised
by the pharmaceutical companies and will certainly be kept separate from
the food supply.
[Topics]
Genetic Engineering
During the 1970s, advances in DNA manipulation techniques provided a significant,
economical alternative source for many drugs made of protein. Previously,
these protein drugs were available in extremely limited supplies; for example,
human cadavers were the source for human growth hormone, and insulin to
treat diabetes was collected from slaughtered pigs.
By genetic engineering, the DNA gene for a protein drug of interest can
be transferred into another organism that will produce large amounts of
the drug. This technique (illustrated in Figure
1), can be used to impart new production characteristics to an organism,
as well as to trigger the production of a protein drug:
1) The gene of interest is isolated on a strand of DNA.
2) DNA is cut at specific points by restriction enzymes. The enzymes
recognize certain sequences of bases on the DNA strand and cut where those
sequences appear.
3) The cut DNA joins with a vector, which may be a virus or part
of a bacterial cell called a plasmid. The vector carries the gene of interest
into the organism that will produce the protein.
4) Transformation occurs when the gene carried by the vector is incorporated
into the DNA of another organism where it initiates the action desired (production
of a drug, etc.).
The first successful products of the genetic engineering process were protein
drugs like insulin and growth hormone. These drugs do not have to be produced
by mammals to be active in mammals. An inexpensive, easy-to-grow culture
of genetically engineered bacteria like the common E. coli can manufacture
these protein drugs.
Other human drugs, such as tPA for blood clots, erythropoietin for anemia,
and blood clotting factors VIII and IX for hemophilia, require modifications
that only cells of higher organisms like mammals can provide. The higher
costs of maintaining mammalian cell cultures that produce only small amounts
of the drugs have been an enormous barrier to the commercial development
of this type of cell culture production method.
[Topics]
Animal Pharming
By genetic engineering, the DNA gene for a protein drug of interest can
be transferred into another organism for production. Which organism to
use for production is a technical and economic decision.
For certain protein drugs that require complex modifications or are needed
in large supply, production in transgenic animals seems most efficient.
The farm animal becomes a production facility with many advantages-it is
reproducible, has a flexible production capacity through the number of animals
bred, and maintains its own fuel supply. Best of all, in most animal drug
production, the drug is delivered from the animal in a very convenient form-in
the milk!
Procedure
A transgenic animal for pharmaceutical production should (1) produce the
desired drug at high levels without endangering its own health and (2) pass
its ability to produce the drug at high levels to its offspring.
The current strategy to achieve these objectives is to couple the DNA gene
for the protein drug with a DNA signal directing production in the mammary
gland. The new gene, while present in every cell of the animal, functions
only in the mammary gland so the protein drug is made only in the milk.
Since the mammary gland and milk are essentially "outside" the
main life support systems of the animal, there is virtually no danger of
disease or harm to the animal in making the "foreign" protein
drug.
After the DNA gene for the protein drug has been coupled with the mammary
directing signal, this DNA is injected into fertilized cow, sheep, goat,
or mouse embryos with the aid of a very fine needle, a tool called a micromanipulator,
and a microscope (Figure 2). The injected embryos
are then implanted into recipient surrogate mothers where, hopefully, they
survive and are born normally.
[Topics]
Commercialization Issues
Success in creating a transgenic animal that can produce the drug is far
from guaranteed. About 10 to 30 percent of mouse embryos produce transgenics,
but less than 5 percent of goats, sheep, or cows do. Production of the
drug is measured during lactation after the animal is raised to maturity
and bred. Because of the long time periods involved and low success rates,
developing transgenic animals is currently very expensive, as the dollar
amounts in Table 1 indicate.
Although most protein drugs are made in milk, a notable exception is
human hemoglobin that is being made in swine blood to provide a blood substitute
for human transfusions. Because hemoglobin is naturally a blood protein,
it is likely to be one of few exceptions to the usual method of production
in milk. Furthermore, the economics of blood production are less favorable,
because to recover human hemoglobin, the animal producing it must be slaughtered.
Drugs currently made by or being developed in transgenic animals are listed
in Table 1. Notice that pharming is expected
to increase the value of animals dramatically. In general, animal pharming
is considered to be 5 to 10 times more economical on a continuing basis
and 2 to 3 times cheaper in startup costs than cell culture production methods.
[Topics]
Regulatory and Ethical Issues
Production of human pharmaceuticals in farm animals has many technical barriers
to overcome, although most technologists agree that these technical difficulties
will be easily resolved in the 1990s. As a production method, animal pharming
is entirely unprecedented and is likely to undergo significant evaluation
by the Food and Drug Administration (FDA). Human drugs purified from animal
milk or blood are likely to require exceptional levels of safety testing
before animal and human health concerns are addressed to the satisfaction
of consumers.
At a more fundamental level, many people are genuinely concerned about animal
welfare and biotechnology's redefinition of the relationship between humans
and animals. Genetic engineering and transgenic animal research are essentially
human endeavors to improve the availability, quality, and safety of drugs;
to enhance human health; and to improve animal health. Animal breeding
has gone on for centuries, but the ability to change the DNA of the animal
brings breeding to a revolutionary new level.
[Topics]
Information Sources
Frank Gwazdauskas, professor, dairy science department, Virginia Polytechnic
Institute and State University, Blacksburg, Virginia 24061-0315.
"See How They (Don't) Grow." Successful Farming. March 1991, p.
33.
"Transgenic Animals in the Production of Therapeutic Proteins."
Biotechnology International. Century Press, 1992, p. 317.
"Transgenic Pharming Advances." Bio/Technology. May 1992, p. 498.
"Whole Animals for Wholesale Protein Production." Bio/Technology.
August 1992, p. 863. Table 1
Written by David F. Betsch, Ph.D., Biotechnology Training Programs, Inc.
Edited by Glenda D. Webber, Iowa State University Office of Biotechnology.
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