Drugs at Nature's Call

The birth of Dolly, the infamous Scottish cloned sheep, got a lot of ink earlier this year as commentators fretted about the implications for cloning people. But a more immediate goal of the research is to create a herd of genetically enhanced animals that express therapeutic proteins in their milk. Now, a team has shown that mammals can be engineered to produce human growth hormone in another bodily fluid--urine. Experts say the finding, reported in the January issue of Nature Biotechnology, breaks important new ground, but the commercial benefits of urine over milk production are uncertain.

The greatest cost in using animals to produce therapeutics is not creating the transgenic animals, but purifying the milk, which is a complex brew of fats and proteins. After physiologist Bob Wall of the U.S. Department of Agriculture's (USDA's) Agricultural Research Service, in Beltsville, Maryland, looked at the problem he realized that urine is a much simpler fluid to purify than milk. "Urine is basically salt water," he says. What's more, transgenic animals--both males and females--begin producing urine immediately after birth.

To create therapeutic proteins that would drain solely into urine, Wall and his collaborators at the USDA, New York University, and the University of Vermont in Burlington, turned to a gene called UPII that is expressed only in the bladder. They took the regulatory portion of UPII, attached it to the gene for human growth hormone, and injected copies of this artificial construct--called a transgene--into fertilized mouse eggs. Those eggs incorporated some copies of the artificial gene into their genome, and the resulting mice and their offspring produced the human hormone in their bladders.

The animals' urine contained only about 0.05% as much human growth hormone as would be expected from an equivalent amount of milk from a transgenic animal. But Wall says the savings in purification and other advantages of urine might outweigh the costs of the low production. Another drawback to the method was that the transgene was also expressed at low levels in the brain and other organs of the mice--a problem that probably caused the sterility observed in all of the females, but which may be worked out, says Wall.

This first success will help "[open] the door to other possibilities" in production of therapeutics, says Henry Lubon, a biochemist and molecular biologist who directs the transgenics program of the Red Cross. But Harry Meade, of Genzyme Transgenics Corp. in Framingham, Massachusetts, argues that the system is unlikely to be cost effective, because bladders, unlike udders, are not specialized for secretion.