Animals become living factories in Md. research


BELTSVILLE -- Among all the world's female pigs, a few in Beltsville must rank among the oddest: They're making mouse's milk.

The pigs are being used to test scientists' ideas that ordinary farm animals can be genetically engineered and converted into living pharmaceutical factories. If they are successful, blood-clotting factors, anti-viral agents and other rare and expensive human proteins may someday be harvested from the milk of farm animals.

The pigs at the U.S. Department of Agriculture's reproduction laboratory were given an extra gene that makes a major mouse milk protein, called WAP for whey acidic protein. Normally WAP is found in rodents such as mice, rats and rabbits, but also in camels. Now, pigs are making milk rich in WAP, and nursing piglets don't seem to notice any difference.

"Our primary goal is to find a gene that will produce more of the product we want" in an animal's milk, said Dr. Robert J. Wall, a physiologist. "We're not necessarily hoping to use the pig to produce chocolate milk."

Dr. Wall and colleagues at Beltsville, including Dr. Lothar Hennighausen, a molecular biologist with the National Institutes of Health, speak of such pigs as an early step among many. They see animals as potential "bio-reactors," living systems that make high-value medical products that are expensive or unavailable otherwise.

If their ideas work, Dr. Wall explained, just a few engineered animals could have tremendous impact. One engineered pig, for instance, could yield enough of a blood-clotting substance -- Factor IX -- to control the bleeding of every patient in the world with a form of hemophilia called Von Willebrand's disease. Commercial milking animals -- cows, goats and sheep -- will be the prime targets for such research, he said. In addition to making medical products, they may be redesigned to improve nutritional qualities of their milk, for higher production of dairy products such as cheese or even for different kinds of milk.

According to animal reproduction physiologist George Seidel at Colorado State University, re-engineering the animal's mammary glands to produce new proteins "is an eminently solvable problem," since the mammary gland naturally secretes protein substances. "A lot of us have been talking for a long time about [producing] pharmaceuticals in milk. You can have the animal secrete many proteins such as TPA [tissue plasminogen activator], interferons or whatever."

TPA is used widely by doctors trying to dissolve blood clots in heart attack victims. Interferons are anti-viral agents made by living cells. The genes for making such proteins already have been isolated.

In their recent tests, Dr. Wall and his colleagues isolated the WAP gene from mice and then inserted the gene into pig embryos. Once the pig matured and began making milk, out came WAP.

The pigs at Beltsville are not the first animals engineered to produce unusual proteins in their milk. Several years ago -- at an international genetics meeting in Toronto, Canada -- Dr. John Clarke, another physiologist, announced that sheep were induced to yield an important human protein, alpha-one-antitrypsin, in their milk. Dr. Clarke works for the Agricultural and Food Research Council in Edinburgh, Scotland.

The amount of the protein produced by Dr. Clarke's sheep, however, was disappointingly small, so efforts have been focused on improving production. Now, with their genetically engineered pigs, Dr. Wall and his colleagues seem to be overcoming the same type of problem by using the mouse WAP gene to stimulate production of a different protein.

"It actually works better in the pigs than in mice," even though the gene originally came from a mouse, he said in a telephone interview. "We don't know why, but we speculate that maybe the pig is missing some controlling elements that would tone it down."

So the WAP gene seems to work harder than usual when placed in a different host such as a pig, where it may lack the controls normally found in rodents.

Use of the WAP gene is important because it is active solely in mammary gland tissue and only during lactation. As a result, it is inactive in the rest of the body's tissues and has no effect elsewhere.

Once the production barrier has been surmounted, Dr. Wall said, "there are several things we're thinking about in terms of milk. One is to increase the [amount of] casein, the primary protein for cheese production, in cow's milk. It turns out that if you can boost casein content by 20 percent, that's worth $200 million to the [U.S.] cheese industry annually."

Another possibility, Dr. Wall said, would be to "try to make cow's milk emulate human breast milk more closely. The two [kinds of milk] have about the same components, but the ratios of these are different. In cow's milk lactoferrin is very low, but it's high in human breast milk."

Lactoferrin is special, he said, because "it has several very interesting properties. It binds iron for a living. And that characteristic makes lactoferrin a bacteriostat. The bugs [bacteria] need iron to grow, so it binds up the iron and inhibits bacterial growth."

"Another change we're anticipating is to reduce the content of lactose," the milk sugar in cow's milk, he said. "If you're an ice cream eater, that's important because the lactose in milk causes it to freeze with crystals in it. Premium ice cream makers add enzymes to break down the lactose before freezing."

More important, however, he said, is the fact that "lactose is the molecule in milk that about 80 percent" of the world's adults "are intolerant to. So by reducing or eliminating lactose we may open the market for more adults to drink milk."

If the milk-based system works as hoped, Dr. Wall and his colleagues wrote in the Proceedings of the National Academy of Sciences, just "one sow could satisfy current world demand for clotting Factor IX."

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