Scientists Add Human Gene to 3 Cloned Lambs
Scottish researchers announced Thursday that they have combined genetic engineering and cloning to create three identical lambs that each contain the same human gene.
By creating the trans-genic triplets, the researchers have demonstrated a new technique that could accelerate the production of cloned livestock, customized to produce pharmaceutical products. Biomedical experts say the feat also brings the world one step closer to the genetic engineering of human beings.
The lambs, which each have a potentially profitable human gene for blood-clotting factor in their cells, were produced by a team at the Roslin Institute near Edinburgh. The team, led by Ian Wilmut, galvanized world attention earlier this year with the creation of Dolly from a normal adult ewe cell--a sheep universally considered the first true cloned mammal.
The new lambs, unlike Dolly, were cultivated from genetically engineered cells. As such, Wilmut said Thursday, they represent “the foundation for being able to make targeted change to any genes inside not only farm animals but also laboratory animals.”
The institute’s corporate partner, PPL Therapeutics, is banking on the idea that a herd of such identical trans-genic sheep can produce the clotting factor and other lucrative medical proteins on a commercial scale.
The research, published today in the journal Science, however, immediately stirred unease among legal scholars and biomedical experts in the United States.
This newest twist in genetic engineering, experts said, shows that cloning not only can serve as a kind of biological Xerox machine to efficiently churn out duplicates of customized animal stock, but also could easily become a production technique for changing the heredity of human beings.
“It could be 10 years before it is realistic” to conduct human experiments, Wilmut said. “At the present time, we are so ignorant of what genes do and what effects they would have on people that it would be appalling to think of doing an experiment with a human being.”
But “it is beginning to get to the stage where people are thinking about that, no question,” Wilmut said.
Harry Griffin, Roslin’s science director, and Wilmut both said the institute has no interest in applying its patented techniques to humans. But U.S. experts said it might be only a matter of time before someone tries to customize a human embryo by using cloning to enhance its genes or eliminate a hereditary defect.
“The most important thing about this development is what it means for the genetic engineering of humans,” said Margaret Mellon, a biotechnology expert at the Union of Concerned Scientists.
“These are technologies easily transferred to humans,” Mellon said. “However much money there is to be made from drugs, there probably is more to be made in fertility clinics where folks could be offered trans-genic humans.”
Researchers emphasized that any number of technical obstacles stand between the ability today to manipulate the genetic makeup of livestock and the possibility that the human genome could be selectively enhanced safely in the creation of a child.
But several experts in biomedical ethics said the newest development was another indication that science continues to move faster than the evolution of human values. What were only hypothetical concerns a few years ago very rapidly are becoming medical realities and thorny societal problems.
“It is bringing us to the stage that we were fearful of--the ability to engineer, select and enhance human genes,” said John Robertson, a biomedical ethics expert at the University of Texas who is co-chairman of the ethics committee of the American Society for Reproductive Medicine.
“The brave new world is upon us,” Robertson said.
Whatever its long-range impact on human affairs, the new research offers the more immediate potential for faster and more effective production of genetically engineered animals in a market that one day could be worth billions of dollars, biotechnology analysts and scientists said.
While genetically engineered plants are becoming common cash crops across the United States and Europe, the effort to alter the genetic makeup of any animal larger than a mouse so far has produced a series of unprofitable and sometimes unsettling disappointments.
Wilmut and his colleagues believe that the cloning technology embodied by the trans-genic lambs is a turning point.
“We wanted to be able to modify genes in animals either for research purposes or for commercial purposes,” he said. “This is letting us do that.”
To create a lamb, nature requires only an ewe and a ram.
But to clone trans-genic sheep that might give a useful pharmaceutical product in their milk, Wilmut needed the talents of a team of researchers that included colleagues Angelika E. Schnieke, Alexander J. Kind, William A. Ritchie, Karen Mycock, Angela Scott, Marjorie Ritchie, Alan Colman and Keith H.S. Campbell.
The new technique differs from the way that Dolly was cloned in several important ways, the scientists reported.
To clone Dolly, Roslin researchers removed the nucleus from an unfertilized egg and replaced it with the nucleus of an udder cell from a 6-year-old ewe. That egg was then placed into the uterus of a surrogate mother that eventually gave birth to the animal that has appeared on as many newsmagazine covers this year as a supermodel.
As a simple clone, Dolly was almost completely the product of the natural genes from the original adult cell.
Unlike Dolly, the new lambs were made from sheep fetal cells that first underwent a series of major changes to the genes that shape their growth and development.
Before attempting to clone the cells, the researchers inserted two new genes. One was a human gene for a blood-clotting agent called factor IX, linked to a sheep gene that increases milk production. The second was a genetic marker that confers resistance to an antibiotic, giving scientists a way to quickly sort the cells that take up a new gene from those that do not.
To determine which cells had successfully incorporated the new genes, the altered cells were grown in culture dishes and periodically dosed with antibiotics, so that only the cells that had the protection of the new genes could survive.
Those cells then were isolated and used as the donor cells in a cloning process that yielded 62 genetically engineered embryos, which were implanted in surrogate mother sheep.
In July, six trans-genic lambs were born, but only three contained both new genes, the researchers said. One of them has since died--of causes apparently unrelated to cloning or its unusual genetic status--and the surviving pair are being raised to see if they will actually produce the clotting protein in their milk.
The technique is an advance over more conventional genetic engineering because it offers animal breeders a way to ensure that a new gene has been incorporated into a cell well before any embryo is created, researchers said. Normally, breeders can’t tell if an animal has taken up a new gene in its cells until it is born.
It also appears to be twice as efficient as current attempts to create trans-genic animals, the researchers reported, and it also appears far more efficient than Wilmut’s original cloning experiment, which required 277 cloned embryos to produce one living lamb.
Some biomedical experts believe that the new technique may quickly be adopted for human research because it offers the ability to carry out genetic experiments with simple cells before the creation of a viable embryo.
That would allow scientists to sidestep moral qualms and federal restrictions about the use of human embryos for research, while speeding the pace of genetic innovation. The pressure from parents and medical researchers to adopt the technique--either to eliminate genetic disease or enhance an embryo’s genetic inheritance-- probably would be intense, they said.
“We know that parents will do just about anything to give their kids a head start,” said George Annas, an expert on health law at Boston University School of Public Health. “If they thought they could do this, they probably would.
“It is time now to decide whether we want to do genetic enhancement for humans,” he said, “now that it appears possible and no longer in the realm of science fiction.”
(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)
The Next Step
The same Scottish scientists who produced the first cloned sheep earlier this year have now successfully added genetic engineering to the process.
1) Researchers isolated a specific human gene, a potentially profitable human blood clotting factor, and then introduced that gene into the cell to be cloned.
2) The cloning process resulted in three identical lambs, each containing the gene.
Sources: AP, Los Angeles Times
