It's a Gene Pool Party

In 1667, French physician Jean-Baptiste Denys treated one of his patients with a transfusion of lamb's blood. Denys reported that the patient, a young man made lethargic and feverish by the excessive application of leeches, "awakened wonderfully composed and in his right mind." Despite complications, including urine so black "you would have said it had been mixed with soot," the patient survived. Unfortunately, another of Denys's lamb-transfusion subjects was not so lucky, and the doctor was eventually tried for murder. He was acquitted--turned out the dead man's wife had poisoned him--but in the wake of the trial, animal-to-human transfusions were banned.

More than three centuries later, biomedical explorers are still trying to cross the barriers that nature has erected between different species. Using recombinant-DNA technology, scientists are mingling genetic material--humans and animals, plants and viruses--in combinations intended to produce therapeutic products like edible vaccines and pig organs that resist rejection when transplanted into people. The modern pioneers of transgenic medicine, as the field is known, want to reduce suffering, save lives and, in some cases, make a profit as well. And progress is being made. But daunting technical challenges remain, along with public concerns about the safety and legitimacy of the daring research.

"Nobody here is trying to make a humanized goat," says Tom Newberry, vice president of corporate communications for GTC Biotherapeutics. "These are goats with a little bit of genetic programming." More specifically, the goats Newberry is talking about contain a human gene that enables them to produce a human blood protein, antithrombin, in their milk. Anti-thrombin, an anticoagulant, is the first of a series of human blood proteins GTC plans to develop using transgenic-animal technology. The market for such products has been created in part by ongoing questions about the safety of the worldwide blood supply. Using transgenic goats to make antithrombin and other blood proteins is also cheaper and more efficient than traditional lab techniques. "We're basically harnessing nature's own organ for making proteins," says Newberry, "and simply giving it an additional set of instructions to make a protein that we're interested in therapeutically."

Using established recombinant-DNA techniques, GTC scientists transfer the designated human gene (called a transgene) into fertilized goat eggs, then transfer the embryos into surrogate mothers. The baby goats are tested for the presence of the transgene and for their milk productivity. Typically, traditional breeding methods are then used to create a "production herd." GTC's antithrombin product, brand name Atryn, is currently under review by the European Medicines Agency, and the company is in the process of enrolling patients (with a hereditary deficiency of antithrombin) for a clinical trial in the United States that builds on an earlier clinical trial in Europe.

Researchers are also engineering the genes of plants in pursuit of new types of medicine. At Arizona State University's Biodesign Institute, Charles Arntzen and his colleagues are using recombinant technology to develop "plant-based vaccines" they say will have several major advantages over existing drugs. Their chief focus right now is improving on a hepatitis-B vaccine that was first engineered from the virus in 1986. "It's marvelous," says Arntzen. "It's safe, it's effective, it's everything you want, except 60 percent of the world's population doesn't get it." Besides being comparatively expensive by Third World standards, the current vaccine requires three shots--"so you have to have a health-care network that keeps records," says Arntzen--and it has to be refrigerated, which can be a real problem in places like Bangladesh.

Arntzen's solution is to insert the gene for the hepatitis-B vaccine into the DNA of a wild-tobacco plant, grow the plants, then freeze-dry and process the plant material. The result: a new form of oral, edible vaccine that is cheap to produce and doesn't require refrigeration. Arntzen initially worked with potatoes and bananas, but public concerns about contamination of the food supply prompted a switch to wild tobacco and a virtually inedible tomato. "There's a perception problem with genetically modified foods that could derail this whole technology," he says. "So we're going to make male, sterile, funny-looking, tasteless tomatoes that function very well as our production system. And hopefully, since they don't have pollen and they'll end up with no seeds, rational people will accept that." Phase-one clinical trials, completed on the potato-based vaccine, will be redone using freeze-dried material.

Xenotransplantation is probably the most provocative type of transgenic medicine. "When you start putting living animal parts in human beings, then you are going to have some people upset because the barriers instilled in nature by God are being broken," says medical ethicist Harold Vanderpool, chair of the Department of Health and Human Services advisory committee on xenotransplantation. To overcome such fears, Vanderpool says, the benefits of the work need to be clear.

Solving the drastic shortage of human organs (people are dying on waiting lists, which now have nearly 90,000 patients on them) is the benefit cited by Dr. David Cooper, editor of the medical journal Xenotransplantation. So scientists are adding human genes to pigs (and knocking out specific pig genes) to increase their resistance to the human immune response and prevent post-transplant organ rejection. (Hearts, kidneys and insulin-creating cells called islets are the tissues targeted for transplant.) In an effort to avoid the spread of infectious diseases from pigs to humans, researchers are also developing "virus-free" pigs. Clinical trials are still years away, but Cooper is optimistic. "Initially," he says, "there will be people who say, 'Oh, it's immoral and we wouldn't have it.' But in 50 years' time, nobody will think twice about it."