"You'll need a liver transplant," Dr. Zeno says. She scribbles quickly on her prescription pad and dates it: April 17, 2025. "Take this to the hospital pharmacy and we'll schedule the surgery for Friday morning."Rebuilding Bodies
The patient sighs--he's visibly relieved that his body will be rid of hepatitis forever.
"What kind of liver will it be?" he asks.
"Well, it's from a pig," Zeno replies. "But it will be genetically altered with your DNA. Your body won't even know the difference."
Obviously, this is science fiction. But according to some scientists, it could be a reality someday. An animal organ, probably from a pig, could be genetically altered with human genes to trick a patient's immune system into accepting it as its own flesh and blood.
Called "xenotransplants," such animal-to-human procedures would be lifesaving for the thousands of people waiting for organ donations. There have been about 30 experimental xenotransplants since the turn of the century.
Xenotransplants are on the cutting edge of medical science, and some scientists think they hold the key not only to replacing organs, but to curing other deadly diseases as well.
Last December, for example, after getting permission from the Food and Drug Administration, researchers at the University of California, San Francisco, injected an AIDS patient with baboon bone marrow. The hope was that the baboon bone marrow, which is resistant to HIV and a source of immune cells, could provide a replacement for the patient's damaged immune system.
In April 1995, also with FDA permission, doctors at Lahey Hitchcock Medical Center in Burlington, Mass., injected fetal pig brain cells into the brains of patients with advanced Parkinson's disease. The hope was that the fetal tissue would produce dopamine, which the patients' brains lack. Both experiments were primarily to test the safety of such procedures, not whether they are effective.
Other xenotransplant experiments have involved implanting animal hearts, livers and kidneys into humans.
According to Scott McCartney's book on transplantation, Defying the Gods: Inside the New Frontiers of Organ Transplants, the first organ transplant was performed in the early twentieth century by Alexis Carrel, a French physician practicing in Chicago. He had developed a technique to sew blood vessels together, and in 1906 he transplanted a new heart into a dog and a new kidney into a cat.
The first animal-to-human transplant was in the same year, when the French surgeon Mathieu Jaboulay implanted a pig's kidney into one woman and a goat's liver into another. Neither survived.
Today, human organ transplants are commonplace. For example, more than 10,000 Americans received kidney transplants last year, with a three-year life expectancy of more than 85 percent, according to the United Network for Organ Sharing (UNOS), an organization of transplant programs and laboratories in the United States. Under contract to the U.S. Department of Health and Human Services, UNOS administers a national organ network, and its members set policies for equitable organ allocation.
Surgeons have made great strides in perfecting transplant techniques, but two problems endure. First, there are never enough organs to go around (see "Transplant Organs: Too Little, Too Late"). Second, once patients receive organs, it is a constant battle to keep their immune systems from rejecting them. Both problems may be eventually solved by xenotransplants and the genetic engineering techniques developed from such experiments.
Of all animals, baboons and pigs are the favored xenotransplant donors. Baboons are genetically close to humans, so they're most often used for initial experiments. Six baboon kidneys were transplanted into humans in 1964, a baboon heart into a baby in 1984, and two baboon livers into patients in 1992.
Although all the patients died within weeks after their operations, they did not die of organ rejection. Rather, they died of infections common to patients on immunosuppressive drugs.
One drawback to using baboons is that they harbor many viruses. They also reproduce slowly, carrying only one offspring at a time. Some people have raised ethical objections, especially since baboons are so similar to humans. They have human-like faces and hands and a highly developed social structure. Although it's conceivable that baboons could donate bone marrow without being killed, recent experiments have required extensive tissue studies, and the animals have been sacrificed.
For long-term use, pigs may be a better choice. Pigs have anatomies strikingly similar to that of humans. Pigs are generally healthier than most primates and they're extremely easy to breed, producing a whole litter of piglets at a time. Moral objections to killing pigs are fewer since they're slaughtered for food. (Select the graphic at right to see an enlarged JPEG version [131k].)
Pig organs have been transplanted to humans several times in the last few years. In 1992, two women received pig liver transplants as "bridges" to hold them over until human transplants were found. In one patient, the liver was kept outside the body in a plastic bag and hooked up to her main liver arteries. She survived long enough to receive a human liver. In the other patient, the pig liver was implanted alongside the old diseased liver, to spare the patient the rigors of removing it. Although that patient died before a human transplant could be found, there was some evidence that the pig liver had functioned for her.
By genetically altering pig livers, some scientists believe they can make a pig liver bridge more successful. In July 1995, FDA permitted the Duke University Medical Center to test genetically altered pig livers in a small number of patients with end-stage liver disease. The pig livers contained three human genes that will produce human proteins to counter the rejection process.
Safe or Disastrous?
Xenotransplantation could be very good news for patients with end-stage organ diseases. There would be no more anxious months of waiting for an organ donor. Disease-free pigs would provide most of the organs. Raised in sterile environments, they would be genetically altered with human DNA so that the chance of rejection is greatly reduced.
Transplant surgery would be scheduled at the patient's convenience, as opposed to emergency surgery performed whenever a human donor is found. Patients wouldn't have to wait until their diseases were at a critical stage, so they would be stronger for recovery.
Today, however, xenotransplantation is still experimental, and there are serious risks to the procedures.
Although many researchers believe it is slight, one legitimate concern is that animal diseases will be transmitted into the human population. Baboons and swine both carry myriad transmittable agents that we know about--and perhaps many more we cannot yet detect. These bacteria, viruses and fungi may be fairly harmless in their natural host, a baboon or pig, yet extremely toxic--even deadly--in humans.
The two types of animal viruses that are especially troublesome are herpes viruses and retroviruses. Both types have already been proven to be rather harmless in monkeys, but fatal to humans. HIV, for example, is a retrovirus that many researchers believe was transmitted to humans from monkeys. The problem occurs in reverse as well. Measles, for example, a serious but manageable disease in humans, can destroy a whole colony of monkeys quickly.
By regulating xenotransplants, FDA will provide a framework for collecting safety data and tracking patients' health. The process should involve open and public discussion by scientists about their experiments, allowing their peers to evaluate and critique them, and their patients to understand the risks and make informed decisions.
"Will [xenotransplants] cause an outbreak of a new infectious disease? We don't know," says Phil Nogouchi, M.D., a pathologist and director of FDA's division of cellular and gene therapies. "But we want all these procedures discussed in public. We need to make people aware of the hazards."
Nogouchi emphasizes the importance of monitoring and tracking all recipients of xenotransplants so that if any new diseases do develop, they will be detected quickly and the threat to public health will be minimized.
"We cannot say that's not a possibility," says Nogouchi. "But we do feel the potential benefits are great and that efforts can be made to make everyone responsible. There are ways to deal with problems should they arise."
At press time, FDA, the national Centers for Disease Control and Prevention, and the National Institutes of Health were working on recommendations for researchers doing xenotransplant experiments.
Although the new recommendations will be for researchers, patients will likely also recognize their importance.
"Our biggest allies are the patients," says Nogouchi. "They should be asking, 'Where'd you get that pig?'" Xenotransplants cannot be "fresh off the farm." They should be bred and raised in a biomedical animal facility under strict conditions.
The other formidable obstacle to xenotransplants is that posed by the human body's own immune system. Even before a person is born, his or her immune system learns to detect and resist foreign substances in the body called antigens. These could be from anything that's not supposed to be there: viruses, bacteria, bacterial toxins, any animal organs, or even artificial parts.
Antigens trigger the body's white blood cells, called lymphocytes, to produce antibodies. Different lymphocytes recognize and produce antibodies against particular antigens. B cell lymphocytes produce antibodies in the blood that remove antigens by causing them to clump or by making them more susceptible to other immune cells. T cell lymphocytes activate other cells that cause direct destruction of antigens or assist the B cells.
Transplant physicians try to suppress the immune system with powerful drugs. While these drugs are often successful, they leave the patient vulnerable to many infections. FDA-approved immunosuppressive drugs include Sandimmune (cyclosporine), Imuran (azathioprine), Atgam (lymphocyte immune globulin), Prograf (tarolimus), and Orthoclone (muromonab-CD3). New drugs are also being researched, including some "designer" immune suppressants. These drugs may enable doctors to suppress the immune system from rejecting a particular organ, but leave the rest of the body's immune system intact.
Drugs designed to help transplant patients may end up also aiding those who are stricken with diseases such as arthritis, multiple sclerosis and diabetes, because these involve problems with the human immune system. For example, Imuran is approved to treat severe rheumatoid arthritis, and Prograf has already shown some promise to MS patients. A large study is under way to determine if it is effective.
Genetic engineering is the next step in battling organ rejection. Researchers have begun experimenting with ways to insert human genes into animal organs, so that the organs will produce proteins the body will recognize as "human." FDA is active in basic research that may lead to better gene therapies and ways of manipulating animal organs.
For example, Judy Kassis, Ph.D., an FDA biochemist, has been studying a fruit fly gene that is important to the insects' early development. Using some DNA and a harmless virus, she has developed a way to insert this gene precisely into its natural position on the fly's chromosomes. Carolyn Wilson, Ph.D., an FDA virologist, has been researching pig viruses and whether they could infect humans in a transplant setting.
FDA scientists are also studying ways that individual genes "turn on" as they develop, how viruses activate each other, and how viruses can be used safely to deliver genes for new therapies.
"Gene therapy is really in its infancy," says Kassis. "That's the thing about basic research--you can't really predict how useful this will be in the future. Hopefully, it will have direct relevance someday."
Gene therapies and their role in xenotransplantations are still in the early stages of development. For now, it's only in science fiction that doctors can order a custom-designed pig liver from the hospital pharmacy. Whether or not that ever becomes reality, FDA's goal in regulating xenotransplant experiments is to make sure these procedures are openly discussed, that data is carefully collected, that patients give their fully informed consent, and that safety precautions are taken with every effort.
Rebecca D. Williams is a writer in Oak Ridge, Tenn.
Human organs must be taken quickly from healthy people who have died through trauma such as car and motorcycle wrecks. The potential donor pool is small, and only about 20 percent of the families of trauma victims consent to have their loved ones become donors. Stricter seat belt and helmet laws have reduced motor vehicle deaths and the numbers of potential donors.
Even with increased public awareness of the need for organ donors, transplant surgeons predict the shortage will only get worse.
As of January, there were 44,000 Americans waiting for organ transplants, yet only 18,270 transplants were performed last year, according to the United Network for Organ Sharing, the organization that oversees organ donations. More than 28,000 people die of liver failure each year, yet only about 3,800 donors are available. Thousands of people die every year waiting for other organs. Many more never make the organ recipient list because they are too ill to receive one.
Organ donation is free to the donor. After organs are removed, the body is suitable for viewing and burial. Becoming a donor is simple--there are organ donor cards on the back of driver's licenses in many states. Even if you sign a card, make sure your family knows you want to be an organ donor. Hospital staffs always ask permission before arranging for donations.