Future farmers may collect urine, not milk

The grandchildren who revamp Old MacDonald's Farm years from now may end up harvesting a product their forebear ignored. If so, they can thank the first researchers to genetically engineer animals that concentrate a pharmaceutical product in urine.

 Robert J. Wall of the U.S. Department of Agriculture in Beltsville, Md., and his colleagues have developed transgenic mice that produce human growth hormone in their bladders. Although the mice produce only a tiny amount, Wall says they show that urine farming techniques work.

 The notion of turning livestock into four-footed pharmaceutical factories has intrigued researchers for at least a decade, Wall's team notes in the January Nature Biotechnology. So far, most of the effort has gone into developing cows, sheep, and goats that secrete commercially interesting proteins in their milk. No such products have yet reached the market, but Wall says several are now being tested in people. The furthest along, he estimates, is a milk-produced blood-clotting agent, antithrombin III, developed by Genzyme Transgenics Corp. in Framingham, Mass.

 Despite the unappealing image, a drug company already sells natural horse estrogen from urine as a hormone replacement. 

 Urine could offer the drug farmer significant advantages over milk, says Wall. Both male and female animals urinate, starting soon after birth. The urine of large animals carries much less protein than their milk, which could cut the processing costs. "The really expensive part is actually the cost of purifying the drug," Wall explains.

 Even though creating a transgenic animal is not cheap -- $60,000 for a sheep or goat -- standard breeding techniques can then produce an entire herd. "It's only that founder cost that is so staggering," he says.

 The possibility of urine farming arose in 1995, when Tung-Tien Sun of New York University identified genes that are active only in the bladder. The genes encode proteins called uroplakins, which form part of the bladder lining. David E. Kerr, then at the Agriculture Department, attached the genetic sequence for human growth hormone to the uroplakin gene promoter, which controls where and when the gene switches on.

 Mice engineered to carry the new gene have produced up to 500 nanograms of the hormone in each milliliter of their urine. Kerr, now at the University of Vermont in Burlington, does not recommend mice as commercial sources of drugs -- although collecting their urine was easy. All he had to do was hold the mice over a piece of plastic wrap.

 Whether urine farming turns out to be economically feasible remains to be seen, say Harry Meade and Carol Ziomek from Genzyme. In an accompanying editorial, they say the idea "deserves further investigation." However, they judge the yields to be "too low to make it a viable alternative at present (10,000 fold lower than in milk)." Pumping up yields may be tricky, since gene activity in the mice already seemed high. "This could mean that the secretory pathway of the bladder is very inefficient," they say.

 Collecting urine from farm animals may also prove challenging, Meade and Ziomek warn. Drug farmers may have to keep their herds attached to catheters.

 Wall acknowledges that the bladder does not compare to the mammary gland as a secretion powerhouse, but he suggests that bladder yields may improve and that the ease of processing urine might make up for the smaller amount of product.

 It's too early to dismiss urine farming, says Henryk Lubon, who directs transgenic research at the American Red Cross laboratory in Rockville, Md. Some proteins might not be suitable for milk farming because they damage mammary tissue, he says, and he hesitates to compare the initial urine results to the more mature transgenic milk production. "Ten years ago," he says, "who knew that milk was going to work out?"