E T H I C S I N R E S E A R C H
huge benefits, hard choices
Organ transplants save lives, but the supply is short. Transplants of animal organs might be an answer.
What ethical questions arise as surgeons contemplate crossing the frontiers of species?By JANICE HOPKINS TANNE
SOMETIME SOONprobably this fall, if he gets approval from the Institutional Review Board at Columbia-
Presbyterian Medical Centercardiac surgeon Robert Michler will try to save the life of a desperately ill patient by temporarily implanting a baboon heart until a human heart can be found.
What Michler wants to do raises issues that he himself calls "mystical." Animal tissues have been used to benefit humans for years, but implanting an entire organ seems different.
Michler's ideal candidate will be within days of death and of an appropriate size, too small for a bulky left-ventricular assist device ("mechanical heart"). Both patient and family will be capable of making decisions. The patient will have exhausted the medical and surgical options, but his or her other organs will be sound. "Probably someone on the waiting list for a heart transplant," Dr. Michler says. "I see this first transplant as a bridge, buying time of weeks to months until a human heart is found."
Next step in surgical history?
Transspecies transplants (xenografts) are being considered today because of the dramatic success of human-to-human transplants, or allografts (see illustration). "More than 100,000 people are alive today with successfully transplanted human organs," says transplant pioneer Thomas Starzl of the University of Pittsburgh. More than 40,000 Americans are on waiting lists for human organs; one-third to one-half will die before an organ can be found.
"Use of animal cells or tissue could be beneficial in AIDS, Parkinson's disease, diabetes, spinal cord injury, acute liver failure, psoriasis, muscular dystrophy, myocardial infarction, and other conditions," says Norman G. Levinsky, chairman of Boston University's department of medicine, speaking at a June conference on xenografting sponsored by the Institute of Medicine and the National Academy of Sciences (IOM/NAS).
Michler adds: "As a cardiac surgeon, I'm faced with people who die all the time. It's abhorrent. My interest in xenografts is a direct response to a tremendous problem, the management of heart failurethe No. 1 cause of death in this country today. At least 45,000 of those people could be saved by a heart transplant, but we can transplant only about 2,000 because of the shortage of donor organs."
It may not be possible to increase the number of human organs available. "Presumed consent" laws in Belgium and Austria mean that potential donors are assumed to have authorized transplantation unless they have opted out. But in his country, many argue, such a law might be perceived as exploitation of minorities and the poor. "People may feel the physician is not doing everything to save the person's life because he wants to use the person as a donor," Michler says. In expanding the number of available organs, asserts Penn sociologist Renee Fox, transplanters are "beginning to slide down a slippery slope."
There's another slippery slope here, besides the dehumanizing of the dying process. Unless we use animal grafts there will be abuses: organs are already being sold
"There's another slippery slope here, besides the dehumanizing of the dying process," counters David Rothman, professor of social medicine and director of the Center for Study of Society and Medicine at P&S. "Animal grafts may prevent other abuses. For example, China and Taiwan use organs from executed prisoners; in India, it's commonplace to let people sell their organs."
Starzl has called for a moratorium on xenotransplants as permanent replacements; his team performed two, and both patients died from immunologic problems. But xenografting can extend a candidate's life while a human donor is sought.
CPMC has been a leading transplantation center for years. Its heart-transplant service, first under the direction of Keith Reemtsma, professor and former chairman of surgery, and later under Michler and Eric Rose, chairman of surgery, is the largest in the nation. Thirty years ago, at Tulane University, Reemtsma transplanted several chimpanzee kidneys to humans. The longest survivor, a woman of 23, lived for nine months.
Columbia faculty helped launch the recent IOM/NAS meeting on xenografting and raised the crucial issue of possible transmission of infectious diseases. Ralph Dell, professor of pediatrics and head of the medical center's Institutional Animal Care and Use Committee, called researchers at the Centers for Disease Control and Prevention, the NIH, and the FDA. A national meeting to consider social, ethical, and legal issues of xenotransplantation was being discussed, but infectious diseases"the most critical issue," Dell sayswere not on the agenda until he persuaded the IOM and NAS to add these issues to the program.
The IOM/NAS meeting in June was followed by a meeting of the FDA. After public comment, final guidelines will be issued. Says Dell: "The proposed guidelines say that animal sources should be screened for various viral diseases and not used if certain ones are found. Early research in xenotransplantation should be done at medical centers with expertise in transplantation and experience in virology and immunology. That means large academic medical centers such as Columbia-Presbyterian, Stanford, and Pittsburgh."
"There are different types of xenograftsbetween close species or between distant species, and whole-organ transplants or transplants of free tissues such as pancreatic islet cells, bone marrow, or skin," says Jeffrey Platt, professor of experimental surgery at Duke. Whole-organ transplantswhether xenografts or allograftsmay have immunologic effects on the lining of blood vessels, leading to immediate or chronic rejection. Free tissues or cells cause fewer rejection problems. Introducing human genes into the animal donor to make its organs more compatible might also reduce rejection. Continued
1628: Attempts at blood transfusion,
a form of transplantation, by Giovanni Colle; deaths lead to banning of the practice
1901: Karl Landsteiner discovers ABO blood types, allowing safer transfusion 1950: First kidney allograft performed by Richard Lawler
1963: First liver allograft performed by Thomas Starzl; first lung allograft by James Hardy; mechanical cardiac assist device implanted by Michael DeBakey 1967: First human heart transplanted by Christiaan Barnard in Cape Town, South Africa. Chest film shows location of heart in recipient Louis Washkansky 1972: Cyclosporin, powerful immunosuppressant that minimizes tissue rejection, developed at Sandoz Laboratories 1992: Starzl transplants baboon liver into human patient Any day now: Baboon-to-human heart xenograft CREDITS: 1) BETTMANN ARCHIVE; 2) GUYDOSH/SYGMA; 3) AP/WIDE WORLD PHOTOS; 4) NIH/CUSTOM MEDICAL STOCK; 5) SUPERSTOCK
Choosing a species
Chimpanzees are humans' closest genetic kin, sharing more than 99 percent of our genome, minimizing the chance of rejection. But they are an endangered species. That leaves two choices: baboons and pigs. Baboons are closely related to humans, lessening rejection risks but increasing our unease at exploiting a cousin-like speciesand raising the risk of transmitting human pathogens.
Pigs are easier to raise and have organs resembling ours. More than 90 million pigs are slaughtered each year in the United States for food, and many of their heart valves are used to repair human hearts after a tanning process renders the valves immunologically inert. Because pigs are genetically further from humans, pig organs are more likely to cause rejection but less likely to transmit viruses. To lessen rejection, Michler and others are breeding transgenic pigs, which contain parts of the human immune system.
Veterinarian Jonathan Allan of the Southwest Foundation for Biomedical Research, a primate center, riveted the IOM/NAS conference when he said, "Don't do it. Using baboon tissue in humans is dangerous."
Although baboons and pigs can be raised in "specific pathogen-free" colonies, that means only that they do not have the pathogens we can test for. "How can you screen for something when you don't know it's there?" Dr. Allan asked. "HIV is the best example. How long can you quarantine patients to protect against transmission of a cancer virus that might take 10 or 20 years to show itself? Up to 50 percent of African monkeys carry an AIDS-like virus [simian immunodeficiency virus, or SIV]. It's no problem, no disease, for them"yet HIV-1 and HIV-2 are widely believed to have evolved from their close relative SIV because of monkey-human blood contact.
"Every single retrovirus has the possibility of causing cancer," Allan warns. Some cause only minor disease in the monkey but are lethal in humans. "AIDS is the best example of what we don't want to do. We need new, reliable assays for baboon viruses," Allan said. Pigs, too, harbor retroviruses.
"The idea that we're going to create a plague is defused by the hundreds of thousands of transplant patients who've returned to their pets, farms, homes, and families," Starzl said. They have not spread viruses, despite receiving immunosuppressive drugs. Furthermore, human exposure to blood does not seem to have led to major outbreaks of disease, with the possible exception of AIDS. In Africa, some monkeys are hunted. Farmers and butchers everywhere are exposed to animal blood, but no major outbreaks of disease have been identified among them.
"The concern is with viruses, like the AIDS virus or hepatitis B, that are present in blood and body fluids. If it were a respiratory virus, we'd already have it," says Dell. Universal precautions to avoid contact with body fluids will protect health care workers. Recipients of animal organs would be advised to practice safe sex, avoid donating blood, and undergo careful follow-up by physicians.
"Scientists alternate between 'what if' and 'so what,'" says Stephen Morse of Rockefeller University, an authority on emerging viruses. He points out that a new epidemic would require two steps: viral infection of a person and transmission of the virus to others. Before xenotransplantation is done, he says, monitoring systems should be set up to seek unusual events in recipients, health care workers, and family members.
Further risks and rewards
Other ethical considerations include the use of animals and of financial resources in an era of managed care and tight research funding. Animal-rights activists strongly oppose xenografting, although they are less vocal about porcine insulin, heart valves, and skin grafts. Some religious groups might object to xenotransplantation as "playing God."(1) The costs of xenotransplantation also raise questions of access: "Who pays for it? Who gets it? Somebody has hypertension and can't get the medicine because of lack of insurance, so he ends up in the hospital and gets a baboon heart," says Dr. Stuart Youngner of University Hospitals in Cleveland.
Like allografting and other costly procedures, xenografting may defy economic valuation; the cheapest choice, after all, would be death. "The cost is irrelevant," asserts Michler. "We're in the business of saving lives. I deal with a patient on a one-to-one basis."
"This is an ethical subject created by the relationship of humans to animals," Starzl says. "All of society ought to decide. Regulating something that doesn't exist yet is the best way to ensure that it won't exist."
Do the potentially life-saving benefits of xenotransplantation outweigh the risks and costs? Michler's answer is an unqualified yes. He quotes ethicist M.R. Shimkin: "To do nothing, or to prevent others from doing anything, is itself a type of experiment, for the prevention of experimentation is tantamount to the assumption of responsibility for an experiment different from the one proposed."(2)
The FDA agrees. Despite reservations about the chance of success, an advisory panel in July gave the go-ahead for one bone-marrow transplant from a baboon to a human with AIDS. By the time this article is read, the transplant may already have taken place at the University of California, San Francisco.
Will there be monkey business
LAST YEAR, researchers at Columbia-Presbyterian sparked a nationwide debate about xenotransplantation. When Dr. Robert Michler submitted his protocol to the CPMC Institutional Review Board (IRB) and Institutional Animal Care Utilization Committee in April 1994 to perform a baboon-to-human heart transplant, the committees decided three areas needed further examination: the current status of immunologic research, infectious disease issues, and ethical issues.
The discussions at a June 1994 seminar satisfied committee members that all the pertinent issues had been adequately covered except one: the potential for an epidemic of transspecies infection. The committees determined that this was outside the scope of their mandates, since one exists to ensure humane care of animals in experiments and the other looks out for individual patients' interests. According to Ralph Dell, "neither group is constituted to look after the public health."
Thus, the Institute of Medicine, the Food and Drug Administration, the Centers for Disease Control and Prevention, the National Institutes of Health, and the Department of Defense all have considered the immunologic, technical, ethical, and public policy implications of xenotransplantation.
The IOM/NAS meeting concluded that xenotransplants should proceed and institutions need to monitor themselves. On July 13 and 14, 1995, the FDA Biological Response Modifiers Advisory Committee met to decide whether to recommend that the FDA allow a baboon bone-marrow transplantation.
Even researchers who support xenotransplantation express concern about pathogen transmission. Researchers are not as concerned about highly infective viruses that manifest quickly (such as Ebola) as they are about retroviruses, which can exist in the host for a long period before becoming apparent. Non-human primates being considered as donors are known to carry herpesviruses and retroviruses. The simian agents' ability to cause disease in humans is poorly defined.
At a joint meeting of CPMC's IRB and animal-care committee on July 26, a discussion focused on a type of retrovirus called spumaviruses or foamy viruses. While foamy viruses are not endemic to newborn baboons, 80 to 100 percent acquire them from other baboons in the colony. It is unknown whether the foamy virus causes disease in humans, but it has been associated with neurodegenerative disease in mice. One solution is to exclude carrier baboons; however, its prevalence would make this difficult.
The FDA committee ultimately decided to recommend approval of the marrow graft, reasoning that proposed precautions will minimize the risk of spreading an unknown pathogen. The committee also decided not to prohibit any baboon transplants but to leave responsibility for approval up to IRBs and animal-care committees. Meanwhile, guidelines are soon to be published in the Federal Register.
Dr. Michler and his colleagues have been asked to provide a revised protocol, including viral surveillance procedures for baboon donors, exclusion criteria, and monitoring methods for patients. The CPMC committees will then decide whether to proceed. At press time, no decision had been made.
United Network for Organ Sharing
International Society for Heart and Lung Transplantation
Heart Surgery Forum
McCarthy, Charles R. "Ethical Aspects of Animal-to-human Xenografts." Institute of Laboratory Animal resources Journal.37(1):3-9.
Shimkin, M. R. "The Problem of Experimentation on Human Beings: the Research Worker's Point of View." Quoted in Edsall G. "A Positive Approach to the Problem of Human Experimentation." Daedalus 1969; 98:463-79.
JANICE HOPKINS TANNE is a contributing editor for New York and an award-winning medical journalist whose work has appeared in the British Medical Journal, American Health, GQ, Mirabella, and the New York Times Health Supplement. She recently served as president of the American Society of Journalists and Authors.