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In 1984, the critically ill infant Baby Fae sparked debate with the news that a baboon heart had been implanted in her tiny body. Sadly, Baby Fae died 22 days later from complications of her illness.
Since then, the controversy over xenotransplantation has not diminished. The flurry of debate and soul searching surrounding the transplantation of animal organs and tissue into humans shows no signs of disappearing anytime soon.
How does this debate affect people with diabetes? The successful transplantation of animal islets could free people with diabetes from the burden of having to take insulin. If a ban were put on xenotransplantation, as some doctors have proposed, then valuable research could falter.
Why ban xenotransplan-tation when it has the potential to save millions of lives? Primarily because some fear that animal viruses could transfer into humans causing an epidemic like ebola or AIDS. Doctors admit this possibility, yet many believe it may well be worth the risk in order to save countless lives.
A Human Islet Shortage
Ideally, human islets would be the preferred candidate for transplantation. Since 1974, over 300 islet cell transplants have been given to humans using adult tissue from cadaver donors. However, the 5,000 human cadaveric donors available each year could scarcely provide for millions of diabetics if islet transplantation were to become commonplace.
Growing human islets in a laboratory is yet another solution, but many researchers admit this option is still a long way off. This leaves animal islets as the best short-term solution for a cure.
Pigs vs. Primates
Chimpanzee DNA is only one percent different from human DNA. Because of this similarity, monkey islets were initially favored as the most likely donors for transplantation. It's this same similarity, however, that researchers fear could easily allow viruses in monkeys to cross over into humans.
Virologist Jonathan Allan, MD, and transplantation specialist Jay Fishman, MD, have both voiced their doubts about using non-human primates to the medical community.
Allan, who specializes in the study of monkey viruses and AIDS at the Southwest Foundation for Biomedical Research in San Antonio worries that the use of monkeys could cause an epidemic like AIDS.
"As we've seen with AIDS and ebola, a virus jumping species can be devastating," says Allan. "The concern is that it's a time bomb with a long fuse. It could be 20 or 30 years before you see its effects."
Fishman, director of the transplant and infectious disease division at Massachusetts General Hospital also acknowledges the theoretical dangers of using primates.
"AIDS research has shown that there are a large number of viruses and retroviruses in most primates that are infectious to humans," he says. "I would favor FDA guidelines that excluded primates as donors for humans."
Pigs Save Lives?
Because of these fears, many researchers have turned to pigs as a safer option. Many in the diabetes community, like Canadian Alastair Gordon, are committed to giving pig islets their day in the sun. Gordon, who was diagnosed with type 1 at the unusually late age of 40, has spent the last ten years of his life learning about biomedicine and islet cell transplantation.
"I know as much about biomedicine now as Bill Gates knows about Microsoft," says Gordon.
Two years ago he started the Islet Foundation, a fund raising and information service on islet cell transplantation. He believes pig islets are the closest thing to unlocking a cure for diabetes.
Gordon points out that pigs have approximately the same blood glucose range as humans - 70 to 105 mg/dl - and people with diabetes have used pig insulin for several decades. Pigs have also had close contact with humans for several hundred years, plenty of time for viruses to cross over into humans.
Fishman, agrees that pigs are the preferred option. "Primates must be socialized and need large living spaces. They can be quite costly to raise," he says. "Pigs, on the other hand, can be raised in herds and more easily screened for infection. The cost is significantly less."
The Moratorium Debate
While fears remained, researchers were becoming more and more optimistic about avoiding cross species infection by breeding pigs in a sterile, pathogen-free environment.
Hopes were deflated in 1997, however, when virologists Robin Weiss, at the Institute of Cancer Research in London, and David Onions at the University of Glasgow discovered pig endogenous retroviruses (PERV) had infected human cells in vitro.
Their findings caused many countries, including Italy, the United Kingdom and New Zealand, to halt xenotransplant experimentation. In the United States, researchers were sharply divided as to how Weiss and Onions' findings should affect the future of xenotransplantation.
Some prominent xenotransplantation researchers, such as Fritz Bach, MD, from Harvard Medical School, have advocated for a moratorium.
"Xenotransplantation promises significant benefits in the long-term yet also creates the risk that infectious agents from the donor animal can jump the species barrier to man, not just infecting transplant recipients but also spreading to the general population," Bach wrote in an article in Nature 4, 142-5; 1998.
Because of this risk, Bach argues that xenotransplantation experiments should not continue until the general public is properly informed as to whether and how it might affect the population.
On the other side, researchers like Jeffrey Platt, MD, at Duke University, believe that the notion of a public health concern has been greatly exaggerated.
"The FDA guidelines are the best we can do short of shutting the field down," says Platt. "The public health concern is purely theoretical. Stopping now would be a great disservice, not only to people with diabetes but also to the thousands of patients with organ failure (who might also benefit from xenotransplantation)."
The FDA has formed an advisory subcommittee and set about drafting a new set of more stringent guidelines for xenotransplantation. FDA spokesperson Lenore Gelb says it is difficult to give a timeline as to when the official guidelines will be published. "We hope to see them in 1998," says Gelb. "But that depends on a number of variables."
Virologist Jonathan Allan sat on the FDA's advisory subcommittee. "There was a spectrum of views on the PERV consensus," says Allan. "But the majority decided that we should allow a limited number of studies and not wait. Experiments have already been conducted and you can't turn back the clock."
Because of fears of a spread of a long-dormant animal virus, the FDA has proposed that xenotransplantation recipients sign a contractual agreement accepting lifetime monitoring and that immediate family members also be monitored and barred from such things as donating blood.
Despite the strict guidelines and fear of virus infection, many doctors believe that the benefits of xenotransplantation far outweigh the potential risks.
"PERV has only been proven to infect human cells in vitro," says Platt. "There's not one bit of evidence that it has spread in the humans who have had pig islets."
Currently, the hundreds of people who have had pig skin applied as grafts for serious burns and the 10 patients who have received fetal pig islets at the Karolinska Institute in Sweden are being monitored for evidence of pig viruses.
Robert Elliott, an islet cell transplantation researcher in New Zealand, has been closely monitoring two patients he injected with pig islets in 1996. So far, both patients have shown no sign of infection.
"They show no antibodies to four common pig viruses, including parvovirus, and they show no incorporation of PERV in their DNA," says Elliott.
Jonathan Allan points out that an animal virus would have to persist in a number of ways before it could manifest itself in humans. "It's difficult to say if it could replicate or not," says Allan. "There are a number of hoops the virus would have to jump through first."
Presently, several countries are struggling with safety issues over xenotransplantation. In comparison to the United States, the European medical community has been especially cautious. The United Kingdom, having recently experienced the "Mad Cow" scare, has taken the most cautious stance by placing a ban on clinical trials until further study is conducted.
Allan believes that the differences in attitude between Europe and the United States over xenotransplantation is typical. "The philosophy in Europe tends to be more cautious and conservative than in America," says Allan. "The U.S. is more brash and more lax when it comes to infectious disease risks."
Most countries are looking to the United States for ideas on how to proceed and waiting for the new FDA guidelines to be published. Fishman believes that the United States should err on the side of caution since the eyes of the world are watching and waiting.
"It's important that we have stringent regulations in the United States because we are a leader in this field and the international scientific community will take its cue from us," says Fishman.
Some researchers worry that a moratorium in the United States or elsewhere would only cause a patient to go to another country with fewer or no regulations. For instance, Fishman points out that there are xenografts currently being done in the former Yugoslavia and this worries him.
"There are no guidelines on how to deal with people who are coming back from developing countries with xenografts," says Fishman.
Xenotransplantation has awakened everything in the public consciousness from wonder at the capabilities of modern science to fears akin to something out of a Frankenstein movie.
Bartha Maria Knoppers, a professor of bioethics and law at the University of Montreal, believes that xenotransplantation and the new guidelines will unleash a whole slew of ethical concerns.
"Basically, a patient's life will be signed away in exchange for saving his life," says Knoppers. "Never mind the technical and safety issues, transplant recipients will run the risk of being seen as different by the rest of society."
Because of this, Knoppers predicts that recipients and their families will require intensive counseling to deal with the psychological stresses. She has her doubts as to whether xenotransplantation is the answer.
"Just because you have the technology to do something doesn't always mean you should do it," says Knoppers. "Maybe we should be focusing our research and money on such things as artificial pancreases rather than fooling around with xenotransplantation."
As with everything in medicine, xenotransplantation boils down to risk vs. benefit, and several in the field feel the potential benefits far outweigh these risks.
Platt, for example, would like to see islet cell transplantation become a primary treatment in the near future. "Ten to 100 people a day could be saved if these xenotransplants were available," says Platt. "Every day counts so we are working as hard as we can to make it a reality."
Big Business Hype
Some worry that xenotransplantation is being promoted too excessively by eager biotechnology companies. In a January 1997 article in Nature, The American Society of Transplant Physicians warns that the domination of research companies "may not be in the best interests of the community," arguing that, "early clinical trials are sought without adequate documentation or publication support data in order to facilitate corporate interests."
Peter Laing, an analyst at the Societe General Strausse Turnbull in London, estimates in the same article that it could be a six billion dollar industry by the year 2010.
Alastair Gordon thinks the notion is ridiculous. "Six billion is a mere drop in the bucket in comparison to the billions that goes into diabetes care," he says. "If anything they (the biotechnology industry) would hope that xenotransplantation didn't work."
Catching up with Science
One thing most researchers agree on is that xenotransplantation is an unmarked road and no one can predict what may lay ahead. Politicians and the public are still reeling from the surprise last year that a lamb had been cloned in Scotland. After the news, President Clinton and other world leaders scrambled to form ethics committees in order to determine what to do next.
Clinton and the general public's reaction to Dolly made it evident that most are behind the times when it comes to the tremendous leaps that have been made in biomedicine. Are we ready for xenotransplantation?
Whether we are ready or not, Knoppers, believes that time and education are of the utmost importance.
"Fortunately, there is still some lead time for good public discourse and a working policy," says Knoppers. "Unlike Dolly, I don't think we should wait for something to be a fact, then worry how to control it afterward."