Should xenotransplants from pigs raised at so-called organ farms be prohibited because such organs could transmit pig viruses to patients—and perhaps into the general population?

Viewpoint: Yes, xenotransplants from pigs should be prohibited because the risks of transmitting pig viruses to patients and the general population are too great.

Viewpoint: No, xenotransplants from pigs raised at so-called organ farms should not be prohibited because the risks of disease transmission are relatively small and are vastly outweighed by the need for donor organs.

The ancient idea of using the parts or products of exotic animals as tonics and medicines has been replaced by modern attempts to transplant living cells, tissues, and organs from animals to humans. A transplantation of cells or organs from one species to another is known as a xenotransplant. Scientists have been experimenting with xenotransplantation as a means of coping with the chronic shortage of donor organs. Every year tens of thousands of Americans suffer from conditions that could be alleviated by organ transplants, but the supply of human organs cannot meet the demand. Xenotransplants are also seen as a way to improve the lives of people with spinal cord injuries, Alzheimer's disease, Parkinson's disease, and diabetes. Although the field of xenotransplantation has been evolving very rapidly since the 1990s, researchers still face many practical, theoretical, and ethical obstacles.

The experimental physiologists who first attempted to transfuse blood into animals and humans in the 1660s could be considered the precursors of modern xenotransplant scientists. In both cases, the major obstacle was finding ways to deal with the immunological mechanisms that help the body distinguish between "self" and "nonself." Unlike twentieth-century surgeons, however, seventeenth-century scientists could not appreciate the immuno-logical barriers between species and individuals.

In the 1660s Jean-Baptiste Denis transfused blood from a dog to a dog and from a calf to a dog, before using animal blood to treat human diseases. Denis suggested that animal blood might actually be safer than human blood. Because humans could readily assimilate the flesh of animals, it was reasonable to assume that animal blood could also benefit humans. After two apparently successful experiments, a third patient died. When human heart transplantation began about 300 years later, the shortage of donor human hearts inspired attempts to use the organs of chimpanzees, baboons, pigs, and sheep.

The same problem that defeated seventeenth-century scientists, the body's rejection of foreign materials, ensured the failure of the early heart transplants. Unlike Denis, however, doctors in the 1960s were well aware of the powerful immunological barriers between individuals and species. Nevertheless, attempts have been made to transplant kidneys, hearts, livers, and other animal tissues into humans. In one famous case, a child known only as "Baby Fae," who was born with a malformed heart, survived briefly after receiving the heart of a baboon. A few patients have survived briefly after receiving baboon livers, and in 1995 bone marrow from a baboon was transplanted into a man with AIDS in an attempt to restore his immune system. Optimistic transplant surgeons pointed out that blood transfusion had once faced seemingly impossible obstacles, and they predicted that organ transplants would one day be as commonplace as blood transfusions. Advocates of xenotransplants from pigs specifically raised as organ donors have similar hopes that this procedure will eventually become safe and routine. Indeed, heart valves from pigs and blood vessels from cows were used successfully to repair damaged human heart valves and blood vessels before the introduction of synthetic materials such as Dacron and GORE-TEX.

Scientists believe that advances in biotechnology will make it possible to avoid organ rejection by transforming animal organs and suppressing the immune response. By establishing strains of transgenic animals that produce appropriate human antigens, animal organs might be sufficiently "humanized" to avoid or diminish the immune responses that lead to rejection. Although immuno-logical obstacles to xenotransplantation may be overcome, there may be other problems with xenotransplants.

Critics, especially virologists and epidemiologists, have argued that xenotransplants could pose a danger to patients and to society as a whole because animal organs might harbor viruses that would allow new diseases to cross over into the human population. The potential danger of transmitting new diseases is highly contested among scientists. Some scientists think that pig organs pose less of a threat for transmitting viruses than primate organs, but unknown retroviruses, which might be similar to HIV (the virus that causes AIDS), are a source of concern.

Critics in the animal rights movement object that it is unethical to use animals as a source of organs for humans. Members of People for the Ethical Treatment of Animals (PETA) are opposed to the use of animals for "food, clothing, entertainment, or experimentation." In 1999 PETA petitioned the U.S. Food and Drug Administration (FDA) to ban all xenotransplantation experiments. Most Americans, however, believe that animal research is essential to scientific progress against disease. Indeed, the Humane Society of the United States acknowledges that "biomedical research has advanced the health of both people and animals." Scientists and ethicists, however, generally agree that nonhuman primates should not be used as xenotransplant donors because of their endangered status, their closeness to humans, and their tendency to harbor potentially dangerous pathogens. Pigs that have been specially bred and raised at carefully maintained organ farms could provide a good source of donor organs. Pig cells contain the so-called porcine endogenous retrovirus (PERV) incorporated into their DNA. Researchers have not yet determined whether these viruses could spread to transplant patients or to people who come in contact with such patients.

Some critics suggest that recruiting more human organ donors would be a better approach to the organ shortage than pursuing the uncertain prospect of xenotransplants. Another important ethical concern raised during the debate about xenotransplants is the broader issue of social justice. The United States remains the only industrialized country in the world that does not have some form of national health care. Some people consider it unethical to spend huge amounts of money for xeno-transplants to help a few patients when millions cannot afford basic medical care.

—LOIS N. MAGNER

Viewpoint: Yes, xenotransplants from pigs should be prohibited because the risks of transmitting pig viruses to patients and the general population are too great.

In medicine today, transplants of organs such as hearts and kidneys are taken for granted. Following such transplants, many people who would otherwise be dead without these procedures are leading full and productive lives. However, there is a chronic shortage of donor organs. Most deaths do not occur in appropriate circumstances for organ harvesting; of those that do, the individual may not have volunteered to donate his or her organs, or the next of kin may not be willing to give consent. Given this shortage, the need for new organ sources is extreme.

Many people—both scientists and members of the public—see xenotransplantation as the solution to the problem of donor organ shortage. Since early experiments on primates proved problematical for both ethical and practical reasons, pigs have become the animal of choice in xenotransplantation. This is mainly because pig organs are an appropriate size for the human body, and pigs are easily available. Unlimited supplies of suitable organs are expected to save the many thousands of people across the world that await life-saving transplant surgery. However, there are considerable obstacles to the fulfillment of this vision. Not the least of these is the risk of infection arising from the foreign transplant, not only to the recipient, but also to the population at large.

Risks of Xenotransplantation

All transplantation poses risks, for several reasons. First, the transplanted tissue is equivalent to a direct injection of donor cells, overriding all the body's gross defenses, such as the skin and digestive juices. Second, cells from the graft (transplanted living tissue) may migrate from their original site to other areas of the body, which may be more susceptible to infection. Third, transplant patients require drugs to suppress their immune system, to prevent rejection of the grafted tissue. This drastically reduces the hosts' ability to fight any infection that might be inadvertently introduced with the transplant.

Xenotransplantation carries other risks, in addition to those mentioned above. Like all other mammals, pigs carry a wide range of bacteria and viruses. Many of these are harmless to the pigs themselves, who have developed defenses against them over millions of years; however, they can cause disease in other species, who lack this protection. Such diseases are known as zoonoses. For example, the virus responsible for the outbreak of "Spanish flu," which killed over 20 million people worldwide in 1918-19, originated in pigs, where it did not cause any harmful symptoms. While pigs used for xenotransplantation would be born and raised in sterile conditions to avoid such outside infections, there are more difficult problems, such as retroviruses, to be resolved.

Retroviruses

Retroviruses are a group of viruses that spread via RNA (ribonucleic acid). The best-known example of a retrovirus is HIV, or human immunodeficiency virus, which causes AIDS (acquired immunodeficiency syndrome). Retroviruses enter the host cell through receptors on the cell surface and use an enzyme called reverse transcriptase to make a DNA (deoxyribonucleic acid) copy of their RNA. This viral DNA is then integrated into the host cell genome and is copied into new RNA by the cellular machinery of the host. These new viral transcripts are packaged into pockets of the host cell membrane and enter the system to infect additional cells. The results of retrovirus infection are variable. Some retroviruses, such as HIV, are fatal. Others may be completely harmless. Still more can cause mild symptoms at first and then become dormant. Symptoms may be triggered long after infection, at times of stress, or may arise only if the virus infects a certain cell type or infects individuals who have a genetic susceptibility.

PERVs

The retroviruses that are of most concern in xenotransplantation are called endogenous retroviruses, or ERVs (in the case of the pig, porcine endogenous retroviruses, or PERVs). These viruses have succeeded in integrating themselves permanently into the host genome, so that they are passed onto the off-spring in each succeeding generation as an inherited genetic trait. Examples of such viruses have been identified in all mammals that have been tested, including humans. These viruses may be a legacy of virulent plagues that decimated populations in the distant past until the virus became integrated into certain species' egg and sperm cells, or germline. Once an ERV has become integrated, it is in its evolutionary interests that the host species survives. This leads to an evolutionary armed truce, so to speak, where the host transmits the virus without causing any detrimental effects. However, if the ERV suddenly finds itself in a new host with no evolved defenses, the truce may be called off.

Most ERVs have become inactive over many generations, losing the ability to be passed on and cause infection, but some remain potentially infective. One ERV, for example, does not affect chickens but can cause disease in turkeys and quail.

ERVs might be responsible for autoimmune diseases (a collapse of the body's immune system causing the immune system to attack the body's own organisms). Like all genes, the ERVs can move around the genome during recombination. Depending on the new site, the retroviral proteins may be activated and expressed in certain cells, causing the immune system to attack them. They could also be inserted into functional genes, making them inactive, or they could activate proto-oncogenes (genes that produce tumors), leading to cancers. Introducing PERVs into the genome via xenotransplantation could activate human ERVs, causing similar symptoms. Recombination with human ERVs could create previously unknown infectious viruses, for which we have no diagnostic tests.

Virologist Robin Weiss and his colleagues have discovered up to 50 PERVs in the pig genome, and their experiments have shown that three of these have the ability to infect human cells in culture. The likelihood of infection varies depending on the human cell type involved and the length of time of exposure. This obviously has implications for xenotrans-plantation. The risk of infection depends on the type of transplant, and migration of cells from the original transplant site to other areas may increase the risk. In a whole-organ transplant, the organ would be expected to function for months or years, so long-term exposure to PERVs could occur.

Another researcher, Daniel Saloman, has shown that pig pancreas cells transplanted into mice with lowered immunity can cause active infection in the mouse cells in vivo. Virus production in the pig cells actually increased—probably as a result of the stress of the transplant procedure—and virus production continued for the full duration of the three-month experiment. The infection produced no symptoms in the mice and appears to have become dormant after a few cycles of replication. Researchers in France have identified 11 types of PERVs in major organs of the pig, including the heart, liver, pancreas, and kidneys: all prime candidates for transplantation.

Viruses closely related to PERVs, found in dogs, cats, and mice, can cause lymphoma and other diseases, so it is likely that similar illnesses could result from activation of the viruses in humans.

Engineering Disaster?

In xenotransplantation, the risk of viral infection is higher than in other transplantations. This is because not only are the T cells (the cells that congregate at the site of infection and mount a direct attack on the foreign matter) artificially suppressed, as in human transplants, but the antibody-producing B cells must also be suppressed, to avoid hyper-acute rejection.

Hyperacute rejection involves a specific sugar molecule that is expressed on the membrane of pig cells and is recognized by the human immune system as foreign, invoking a massive and rapid immune attack. PPL Therapeutics (the company that created Dolly the sheep) has engineered a "knockout" pig that lacks the enzymes to make this sugar, so the human immune system will not see the cells as foreign. The problem lies in the fact that if the PERVs become active and bud from the cell, they will be surrounded by this "disguised" membrane, which will further hamper the body's attempts to attack the virus. In effect, the new virus particles will have a "free ride" to infect the host's system. The next planned step in this technology is to add three other human genes to the pig cells that will help to combat a longer-term immune response. This will even further protect the virus from immune attack.

Unknown Enemies

While the problems of PERVs may possibly be overcome, given time and research, the problem of the unforeseen will persist. We have sophisticated tests for known viruses but no way to detect anything new and unexpected. We cannot predict what mutations and recombinations might occur in these viruses once they are established in the human body. ERV-type viruses can be very elusive. The HTLV virus, for instance, is infectious in humans but has an incubation period of decades. It causes lymphomas and other diseases but only in about 4% of infected people, and the symptoms do not show for 20 to 40 years after initial infection. It is possible that a new virus arising from xenotransplantation could have similar characteristics. We would have no tests to detect it, and by the time the symptoms became apparent it could be widespread in the population.

Worst-Case Scenario

The present state of knowledge suggests that changes in infectious agents such as PERVs will not be particularly infectious or virulent, but they evolve very quickly, given their short life cycles. Experiments with successive generations of PERVs exposed to human cells have shown that the PERVs do become more prolific over time. Virologist Robin Weiss has speculated that, given the nature of ERVs, they may well become more active in a new host that has had no time to develop specific defenses.

If these viruses were to become infectious and virulent, transmission would probably be via body fluids and sexual contact. Based on our knowledge of related viruses, the incubation period might be very long, and the symptoms could include lymphoma, neurodegenerative disease, or autoimmune disease. The result could be a plague to equal AIDS. This may not happen, but the risk is not calculable, and thus it is not meaningful to talk of making informed decisions at this time.

Informed Consent

A patient who will die within weeks without a transplant may, for example, find an undefined risk of developing lymphoma in 20 or 30 years worth taking. However, if there is a risk of passing the infection on to family members and close contacts, and further into the general population, then the issue becomes much more complex.

Very close monitoring of such patients would be required. They would have to undergo regular tests of blood, saliva, and, possibly, semen to test for viral infection. The conditions under which they would need to live would be similar to those for HIV-positive individuals, who need to practice safe sex and record their sexual partners and who cannot give blood donations. Decisions about having children would be affected for the patients. This monitoring would continue for many years, possibly for life. In the event of an infectious, virulent virus occurring, quarantine measures would need to be considered. The problem lies in enforcing such stringent conditions. At present there is no legal structure to oblige a patient to continue with a program, and he or she could drop out at any time.

Alternatives

Although there is a great need for transplants at the current time, there are alternatives to xenotransplantation, with all its risks and ethical dilemmas. Improved health education and preventative care could dramatically reduce the incidence of a great deal of heart disease and other disorders, and so decrease the need for transplantation. At present, only a very small percentage of people carry donor cards, and their wishes can be overridden at the time of death by their next of kin. There is great scope for increasing awareness of the need for donor organs and improving this situation.

In the long term, where there is no alternative to transplantation, stem cell technology holds out hope for the creation of human cells and/or organs especially for transplants. Cloned cells from the patient could be used to create the required organ, without risk of rejection or infection. This technology lies far in the future at present, and many workers in the field believe that xenotransplantation will be necessary in the meantime. However, a great deal of research into the nature and behavior of PERVs, to allow more informed debate regarding the risks, is required. Medical progress is not, and can never be, entirely risk-free, but public understanding and involvement in decision-making is essential. Only then should tightly controlled clinical trials even be considered.

—ANNE K. JAMIESON

Viewpoint: No, xenotransplants from pigs raised at so-called organ farms should not be prohibited because the risks of disease transmission are relatively small and are vastly outweighed by the need for donor organs.

Every day in the United States, at least 10 people die while waiting for an organ transplant that could save their life. Countless more battle diabetes or Alzheimer's disease, or lose their mobility to spinal cord injuries. All these people can benefit from the various forms of xenotrans-plants. The procedures are not risk-free. Like most advances in medicine (and many other areas of science), we must weigh the potential risks of xenotransplants against the benefits the procedures offer.

An Abundance of Transplant Candidates

Obviously, any person on a transplant waiting list would benefit from an unlimited supply of organs. But many other people might benefit from xenotransplants as well. There are people with failing organs who never make it to the

transplant list. The current organ shortage necessitates strict rationing of available organs to the patients who can benefit the most from them. Some patients have conditions that make them unsuitable candidates for a transplant procedure. In their book Xeno: The Promise of Transplanting Animal Organs into Humans (2000), Drs. David K. C. Cooper and Robert P. Lanza list several examples of what they call "borderline candidates." One such example is the patient with mild heart disease who requires a liver transplant. Such a patient is at risk of suffering a heart attack during the transplant surgery. In the worst-case scenario, the patient will die as a result of a heart attack, and the liver will have been wasted. If the patient survives, he will not get the full benefit of his healthy liver as a result of his heart condition. The transplant surgeon, faced with a limited supply of livers, will likely pass this patient over in favor of a recipient whose only problem is a failing liver. An unlimited organ supply from pigs will allow even the borderline patients a chance at life.

In countries where allotransplants (trans-plants between human donors and recipients) are taboo, the situation is even more dire and has given rise to various morally objectionable practices, including organ brokerages. Many more people die for need of an organ transplant in those countries than in places like the United States and Europe. Thus, the benefits of xenotransplants to people in need of organ transplants can be measured in many thousands of lives saved each year.

People with diseases or conditions that cannot be successfully treated today might benefit from xenotransplants. Many conditions that involve cell destruction may be improved or cured with cell implants from pigs. For example, fetal neural cells from pigs have been implanted in a small number of stroke victims, and notable improvements followed in some of these patients. Researchers are eyeing Huntington's chorea patients (persons with a hereditary disease of the brain), among others, as candidates for trials with pig neural cells. A study done on rats with severed spinal cords showed that it is possible to restore nerve fibers using nerve cells from pigs. Scientists may be on the brink of being able to repair spinal cord injuries, and xenotransplant may be one way to achieve this goal.

Extracorporeal Liver Perfusion

Robert Pennington is a living example of the benefits xenotransplantation can bring. In 1997, Pennington lay in a deep coma at Baylor University Medical Center in Texas. He was in acute liver failure. His condition is known as fulminate liver failure, an irreversible destruction of the liver. When the liver ceases to function, toxins that the body creates during normal biological processes accumulate in the blood. These toxins make their way to the brain, eventually causing coma and death in a few days. Fulminate liver failure can be the result of a disease, such as hepatitis, or an exposure to certain chemicals or toxins, such as the toxin found in Amanita mushrooms. Fulminate liver failure often requires a speedy liver transplant. It has a mortality rate as high as 95%.

Pennington's name was placed at the top of the liver transplant list, but his condition was deteriorating rapidly. His transplant surgeon, Dr. Marlon Levy, suggested a new experimental procedure. Pennington's blood was routed through a pig liver that was taken from a specially bred transgenic pig. Transgenic pigs are pigs that have human genes in them. These genes code for human cell-surface proteins that then coat the pig organ, to minimize the risk of the organ's rejection by the human immune system. The pig liver was able to provide a sufficient amount of cleaning to keep Pennington alive until a suitable human liver donor was found. Pennington is alive and healthy today. Neither he nor his family show signs of any viral infection acquired through this procedure, known as extracorporeal liver perfusion.

The FDA (Food and Drug Administration) halted the perfusion trials shortly after Pennington's successful treatment. A specific pig virus known as porcine endogenous retrovirus (PERV) was found capable of infecting human cells in laboratory conditions. The discovery of PERV's prevalence in pigs, and the fact that there were at least two different strains of the virus, alarmed many scientists and regulators. The clinical trials resumed when detection methods for PERV in humans and pigs were refined. Nevertheless, the PERV controversy focused attention on the issue of viral infections resulting from xenotransplants.

When it comes to individual patients, it is easy to see why many will grasp at the chance to live, despite the risk of an unknown, potentially deadly infection from the donor animal. These patients have nothing to lose—they are dying. Pennington's family took a chance on what was described as "uncharted territory" so that he might live. The problem with xenotransplants is that we do not know if an unfamiliar animal infection contracted by the human patient can mutate and become another acquired immunodeficiency syndrome (AIDS)-like pandemic. This possibility puts not only the patient but also society at large at risk. The risk is real and warrants further investigation and careful control measures, according to everyone involved in xenotransplants. It is also, according to many virologists, a rather small risk. When weighed against the potential benefits of xenotransplants, in these scientists' opinion, the remote likelihood of a novel infection does not warrant banning the research and eventual implementation of xenotransplant.

The Dangers of Retroviruses

Animals who routinely carry an infectious agent are called hosts for the agent (virus, bacteria, or parasite). Endogenous retroviruses are viruses whose DNA (deoxyribonucleic acid) sequence is integrated into the host's DNA in each cell of the host. We as humans carry our own endogenous viral sequences in our DNA. Because the viral sequence is integrated into the host's DNA, it is extremely difficult, and often impossible, to eliminate the virus from the host. There is concern that by transmitting PERV to humans, especially immunosuppressed individuals, the virus can become "hot" and cause infection. Or perhaps a PERV particle, or even an unknown virus that has not yet been detected in pigs, might combine with some of the human endogenous viral DNA to form a new, possibly infectious, virus. The concern is a valid one and should be investigated. This concern also makes a good case for strict follow-up of xenotrans-plant patients and their families. But the PERV situation is not unique. The current MMR (measles, mumps, rubella) vaccine, made with chicken cells, contains particles of an endogenous avian (bird) retrovirus. Because the vaccine is a live one, there is a possibility of combination between the avian virus and the MMR infectious particles. To date, no infections of any kind have been reported as a result of the MMR vaccine. The chance of a recombination event between retrovirus particles is far less likely to occur between non-homologous sequences (sequences that share little similarity to one another) such as pig and human retroviruses.

A study of 160 patients who were exposed to living pig tissues or organs for lengthy periods showed no evidence of PERV infection, or infection with any other known pig viruses. Patients in this study, many of whom were immunosup-pressed during their treatment periods, were followed for more than eight years post-treatment. The study is not a guarantee that such infections have not or will not occur, especially in individuals who receive heavy doses of immunosuppression drugs. Nonetheless, this study is an encouraging sign. Dr. Robin Weiss, a virologist specializing in retroviruses, estimated in an interview for Frontline's Organ Farm that the chances of a human PERV epidemic infection are remote. Other scientists support his view. In addition, Dr. Weiss noted that a currently available anti-HIV (human immunodeficiency virus) drug has proven very effective against PERV. In a worst-case scenario, scientists already have at least one drug that can fight PERV infection, should one occur. Drs. Walter H. Günzburg and Brian Salmons, in a 2000 paper assessing the risk of viral infection in xenotransplants, pointed out that safety techniques used in gene therapy today can be successfully adapted to control a "hot" PERV in humans.

Infectious Agents

The danger of transmitting potentially lethal infections through transplants is not unique to xenotransplants. Hepatitis, HIV, cytomegalovirus (a virus that results in dangerous cell enlargement), and Epstein-Barr virus (associated with lymphoma and some cancers) are all examples of infections that have been transmitted through allotransplants. As we know, hepatitis and HIV can spread from the patient to other people. No one today is calling for a stop to allotransplants. Instead, better detection methods and screening procedures have been implemented, to try and minimize the danger of infections transmitted from donor to recipient. There are still cases, however, when the urgency of the situation overrides safety concerns, and the donor is not screened adequately, or is known to carry an infection and the organ is still used. In that respect, xenotransplant will have an advantage over conventional allotrans-plants. As the World Health Organization pointed out in a 1997 report: "Totally infectious agent-free human donors are not available." It is, however, possible to raise pigs in a specific pathogen-free environment (an environment free of specific disease-causing organisms). In such an environment (an "organ farm"), pigs can be raised free of most known and suspected infectious agents.

The chances of an infectious agent jumping species and establishing itself in a new host are greater the closer the two species are, genetically. This is a good argument against using non-human primates as organ donors, and indeed the current policy bans their use as donor animals. After all, the AIDS epidemic started in monkeys in Africa, when the Simian Immunodeficiency Virus (SIV) jumped species and established itself in humans as HIV. An argument could be made that by creating a transgenic pig, we are increasing the risk of an infectious agent (not necessarily PERV) jumping species. The argument has two valid points. By expressing human genes in pig organs, we are making pigs more genetically similar to humans. Additionally, the human genes that are currently expressed in transgenic pigs actually code for molecules that viruses use as receptors to gain access into the human cells. This concern is not to be taken lightly. However, even if a pig virus established itself in an immunosuppressed individual, it may not necessarily be able to spread beyond the recipient. Our immune system, when not compromised by drugs, can fight off a variety of viruses. In addition, not all viruses are created equal. Even in the case of the dreaded AIDS virus, not all the HIV virus groups spread through the population. Each of the two distinct types of HIV currently known is further divided into subgroups, some of which (HIV-2 C through F) have not spread at all, and some of which (HIV-1 O and N) only spread in a limited area in Africa. Variables in the environment, the host, and the virus itself can all combine to affect the pathogenicity of a virus—its ability to infect an individual and spread throughout the population.

Xenotransplant Research Must Continue

In a sense, the debate about xenotransplant is moot. The concept of xenotransplantation is not new. Xenotransplants have been done from a variety of animals since the beginning of the twentieth century. Pig-to-human xenotrans-plant has been taking place for a while, mostly on the cellular level in clinical trials. Parkinson's disease patients and stroke patients have been transplanted with pig neural cells. Diabetes patients have received pig islets cells. Pig livers have assisted several patients with liver failure. No one is arguing that there is no risk involved. As Dr. Weiss noted in a recent paper: "With biological products, as with crossing the street, there is no such thing as absolute safety." However, we must consider the potential benefits xenotransplant could bring to millions of people worldwide. The debate about the potential dangers is a valuable one. It supplies us with knowledge and helps us proceed with our eyes wide open. Strict safety regulations and patient monitoring are required because medicine offers no guarantees, and though the chances are small, we could face another AIDS. But when a vast number of people contracted AIDS as a result of tainted blood products, no one called for a stop to blood transfusions. Better screening procedures for blood and donors were developed, and a push was made to develop artificial blood, the latter already in clinical trials.

Weighed against a risk that is likely remote, and with few other options currently available, to abandon xenotransplant research and implementation would be wrong. Cloning, stem cell research, and artificial organs are other avenues that may offer us the same hope as xenotrans-plants. But until such a day that one of these options becomes a real solution, we cannot afford to turn our back on the others for fear of the unknown.

—ADI FERRARA

Further Reading

Bryan, Jenny, and John Clare. Organ Farm. Pig to Human Transplants: Medical Miracle or Genetic Time Bomb? Carlton Books, 2001.

Cooper, David K. C., and Robert P. Lanza. Xeno: The Promise of Transplanting Animal Organs into Humans. New York: Oxford University Press, 2000.

Council of Europe. State of the Art Report on Xenotransplantation (2000). <http://www.social.coe.int/en/qoflife/publi/artreport/clinact.htm>.

Fishman, Jay. British Medical Journal 321 (September 23, 2000): 717-18.

Furlow, Bryant. "The Enemy Within." New Scientist, no. 2252 (August 19, 2000): 38-41.

Günzburg, Walter H., and Brian Salmons. "Xenotransplantation: Is the Risk of Viral Infection As Great As We Thought?" Molecular Medicine Today 6 (May 2000).

Hahn, Beatrice H., George M. Shaw, Kevin M. De Cock, and Paul M. Sharp. "AIDS as a Zoonosis: Scientific and Public Health Implications." Science 287 (January 28, 2000): 607-14.

Lower, Roswitha. "The Pathogenic Potential of Endogenous Retroviruses." Trends in Microbiology 7, no. 9 (September 1999): 350-56.

Olson, Lars. "Porcine Xenotransplants—WillThey Fly?" Nature Biotechnology 18, no. 9 (September 2000): 925-27.

Organ Farm . A PBS Frontline Documentary onXenotransplantation. <www.pbs.org/wgbh/pages/frontline/shows/organfarm/>.

Paradis, K., et al. "Search for Cross-SpeciesTransmission of Porcine Endogenous Retrovirus in Patients Treated with Living Pig Tissue." Science, no. 20 (August 20, 1999): 1236-41.

Patience, C., Y. Takeuchi, and R. Weiss. "Infection of Human Cells by an Endogenous Retrovirus of Pigs." Nature Medicine, no. 3 (1997): 282-86.

"Report of the Cross-Species Infectivity andPathogenesis Meeting." July 21 and 22, 1997. <www.niaid.nih.gov/dait/cross-species/final.pdf>.

Stolberg, Sheryl Gay. "Could This Pig Save YourLife?" New York Times (October 3, 1999).

Vanderpool, Harold Y. "Commentary: A Critique of Clark's Frightening Xenotransplantation Scenario." The Journal of Law, Medicine and Ethics 27, no. 2 (Summer 1999): 153-57.

Weiss, Robin A. "Adventitious Viral Genomes inVaccines but Not in Vaccinees." Emerging Infectious Diseases 7, no. 1 (January/February 2001). <http://www.medscape.com/govmt/CDC/EID/2001/v07.n01/e0701.24.weis/e0701.24.weis.html>.

World Health Organization, Emerging and other Communicable Diseases, Surveillance and Control. "Xenotransplantation: Guidance on Infectious Disease Prevention and Management." <http://www.who.int/emc-documents/zoonoses/docs/whoemczoo981.pdf>.

KEY TERMS

ALLOTRANSPLANT:

Transplant between genetically different individuals. Used to describe human-to-human transplants.

ENDOGENOUS RETROVIRUS (ERV):

A retrovirus that has permanently integrated into the host genome and is transmitted through generations as a genetic trait.

EXTRACORPOREAL PERFUSION:

Ameans of treating a person's blood outside his or her body, whether through a machine or an organ.

HYPERACUTE REJECTION:

A fast and widespread immune antibody response to "foreign" cells in the body.

RETROVIRUS:

An RNA-based virus that replicates itself as DNA and integrates into the host genome, where it highjacks the host's cellular machinery for viral proliferation.

XENOZOONOSIS/XENOSIS:

An animal disease that infects humans as a result of xenotransplant. Currently a theoretical occurrence.

ZOONOSIS:

A disease normally affecting animals (with or without symptoms) that can be passed on to humans.

A BRIEF HISTORY OF XENOTRANSPLANTS

The idea of xenotransplants is not new. In fact, quite a few of our myths involve creatures such as centaurs, which are a combination of different species' anatomy. Actual xenotransplants from animals to humans date back as far as the 1600s. At that time, a nobleman in Russia with a skull disfigurement had the defect repaired with fragments from a dog's skull. The Russian church, however, threatened to excommunicate the nobleman, and he had the fragments removed. Sheep blood was trans-fused into humans as early as 1628 and was used throughout the following centuries.

The breakthrough that allowed true organ transplants to become a reality came from a French surgeon named Alexis Carrel. In 1912 Carrel won the Nobel Prize in physiology and medicine for developing the techniques that allowed blood vessels to be joined together. Interestingly, Carrel had also predicted, in 1907, the use of transgenic pigs in xenotransplant work.

Interest in xenotransplants declined following many failures in the early twentieth century. But as medicine advanced, interest increased again. In 1963 Dr. Keith Reemtsma, then at Tulane University in Louisiana, transplanted chimpanzee kidneys into 13 patients. Remarkably, one of the patients survived for nine months. It is thought she died of an electrolyte imbalance brought on by a difference in the functioning of human and chimpanzee kidneys. An autopsy showed no signs of kidney rejection. The other 12 patients survived for periods of between 9 and 60 days. A year later, three years prior to the first cardiac allo-transplant, Dr. James Hardy, working in Mississippi, performed the first cardiac xenotransplant, using a chimpanzee heart. The heart proved too small, and the patient died two hours following surgery. In London in 1968 Dr. Donald Ross tried using a pig's heart as a "bridge" to keep a patient alive while the patient's own heart recovered. The pig's heart was immediately rejected. But the bridging idea stuck, and it was tried several times later. In 1984 Dr. Leonard Bailey and his team in Loma Linda, California, transplanted a baboon heart into a newborn baby. "Baby Fae" was born with a severe heart defect, and she lived for 20 days with the baboon's heart while doctors tried to find a suitable human donor for her. Sadly, no suitable heart was found in time. Blood group incompatibility may have contributed to the rejection of Baby Fae's baboon heart.

In 1992 and 1993 Dr. Thomas Starzl (University of Pittsburgh, Pennsylvania) used baboon livers on two patients with hepatitis B (baboon livers are resistant to hepatitis B). Both patients died of massive infections, but they survived longer than any other animal-liver recipients. Also in 1992, Astrid, the first transgenic pig, was born in Cambridgeshire, England. Astrid was created by scientists at Imutran, a British biotechnology firm. Transgenic pigs are considered the best hope to overcoming acute rejection problems in xenotransplants of solid organs.

Today, the shortage of human organs pushes research into xenotransplants forward. Researchers focus their efforts on cellular xenotransplants as potential cures for diseases such as Huntington's chorea and diabetes. Other researchers are trying to overcome the severe rejection processes that make solid organ xenotransplants currently impractical. In addition, efforts are ongoing to reduce the risk of a novel virus epidemic transmitted through xenotransplants as a result of exposure to donor animals.

—Adi Ferrara