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Milking engineered 'pharm animals.' (genetically engineered goats and sheep can secrete drugs in their milk)

In the first steps toward populating a biotechnical barnyard, research teams in the United States and Scotland report that genetically engineered goats and sheep can secrete medically useful quantities of drugs in their milk. And according to scientists in the Netherlands, cows may become the next four-legged drug factories down on the pharm.

All three groups, who describe their work in the September BIO/TECHNOLOGY, say the new findings illustrate the potential of harnessing transgenic livestock to produce drugs more rapidly, more cheaply and in greater quantities than the standard "bioreactor" approach, in which vats of gene-altered bacteria or culture dishes of animal cells churn out genetically engineered drugs.

"Commercialization of this technology will permit further development of complicated proteins that are currently difficult and expensive to produce with bacteria or mammalian cells," says Henri A. Termeer, chairman of Genzyme Corp. in Cambridge, Mass.

"Our success with transgenic goats demonstrates the feasibility of producing commercially viable pharmaceuticals from livestock," adds Karl M. Ebert of Tufts University School of Veterinary Medicine, in North Grafton, Mass., who coordinated the goat experiments in collaboration with Genzyme.

The Tufts-Genzyme study yielded two goats -- one male, one female -- carrying human genes for an enzyme called tissue plasminogen activator (TPA). Many countries, including the United States, have approved TPA for dissolving blood clots in cases of myocardial infarction, the primary cause of heart attacks.

Ebert and his collaborators produced the the transgenic goats by surgically removing fertilized eggs from normal female goats and injecting the eggs with hybrid genes, which consisted of human TPA genes embedded in genes from goat mammary glands. They surgically implanted more than 200 such eggs into 36 "foster mothers" to yield 29 offspring, only two of which actually carried the hybrid gene. When the female transgenic goat matured and bore her own offspring, she produced a daily supply of 3 to 4 liters of milk containing an average TPA concentration of 3 micrograms per milliliter. One of her five kids inherited the hybrid gene.

Analysts have predicted that milk from transgenic animals must contain more than 1 microgram of drug per milliliter in order for the procedure to prove cost effective as a means of manufacturing pharmaceuticals. The Tufts and Genzyme researchers say they have since refined their gene-splicing technique, producing a female goat that churns out 3 milligrams of TPA per milliliter - 10 times the concentration secreted by the first female. A small herd of such goats could match the daily output of a 1,000-liter bioreactor, they estimate.

Researchers in Edinburgh, Scotland, report even greater production efficiency with transgenic sheep. Alan Colman of Pharmaceutical Proteins Ltd. and his colleagues engineered four ewes to carry the human gene for the enzyme alpha-1 antitrypsin. Currently extracted from human blood serum, alpha-1 antitrypsin is used to treat people who risk life-threatening emphysema because of an inherited deficiency of the enzyme. One of the transgenic ewes secreted 35 grams of the drug per liter of milk -- nearly 18 times the concentration found in human serum and more than one-fifth the yearly dose required to treat one patient. The other three ewes produced several grams of the drug.

But the Holy Grail of "molecular pharmers" is the production of a drug-lactating dairy cow. Cows can produce thousands of liters of milk per year -- far more than goats or sheep. But the expense of performing multiple surgeries on large animals to retrieve the eggs and implant the embryos has stymied efforts at bovine bioengineering. Now, Dutch researchers say they have devised a way to circumvent the surgeries.

The team, led by Herman de Boer at Gene Pharming Europe B.V. in Leiden, obtained bovine eggs from a slaughterhouse, fertilized them in test tubes and then inserted hybrid genes coding for lactoferrin, an antibacterial protein. Using vaginal injections, they implanted 103 of the resulting embryos in the wombs of normal cows, for a yield of 19 calves. One male and one female calf carried the new gene, although the female had only an inactive fragment. The researchers hope to get better results in a repeat of the experiment.
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Author:Ezzell, Carol
Publication:Science News
Date:Sep 7, 1991
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