Xenotransplantation: Benefits and Risks

Executive Summary

1. Human organ transplantation faces a significant challenge because the need for this procedure far exceeds the availability of donor organs. Each year fewer than half the people on transplant waiting lists receive organ transplants. Approximately 10 people die each day waiting for organs to become available. Even if all potential donors elect to donate, the supply of human organ donations will continue to fall short of the need.

2. One solution doctors along with pharmaceutical and biotechnology companies are investigating to end this acute shortage is "xenotransplantation," or the process of transplanting cells, tissues or organs from one species to another.

3. Rejection, in which the recipient’s body attacks the new organ like an infection, is the greatest practical obstacle to xenotransplantation. The breeding of transgenic pigs as well as new cloning techniques may be used to reduce the risk of organ rejection.

4. In August 1999, the results of a study were announced that found no evidence of infection among 160 people who had previously received medical treatment with living pig tissue. A number of patients in the study did show evidence of circulating pig cells, but no evidence of infection, potentially demonstrating that pig tissue can survive long-term in the human body with no ill effects.

5. At this time, there is no evidence that porcine viruses pose a risk to humans; however, researchers are proceeding with caution to address safety concerns. The U.S. Department of Health and Human Services is developing several important mechanisms to foster participation by the public, scientists and industry in the progress of xenotransplantation.

6. BIO supports public dialogue about xenotransplantation to further understanding and broaden knowledge that will offer innovative treatments for previously untreated conditions. BIO is committed to a responsible research program that is consistent with regulatory guidelines and the recommendations of ethics advisory boards within both industry and government.

Introduction

Human organ transplantation is a relatively new field of medicine that is now facing a significant challenge. Because of its clinical success, the need for this procedure far exceeds the availability of donor organs. More than 60,000 individuals in the United States (U.S.) were registered on transplant waiting lists by the end of 1998. Each year, however, less than half of the people listed receive solid organ transplants. Approximately 10 people die each day waiting for organs to become available. These numbers do not take into account the unknown number of people who are not eligible for transplants because of their age or health status. The demand for organ transplantation will continue to increase as improved technical skills and anti-rejection medication make transplant a realistic option for groups of people previously considered too vulnerable for example, those with diabetes. Also, many other people may benefit from transplantation of cells or tissues to treat countless other diseases such as diabetes, Parkinson’s, Huntington’s, cancer, and injuries to the spinal cord or other organs and limbs.

Despite significant educational efforts on both the national and local level to increase the awareness of the need for organ donation, the number of people who elect to donate their organs if they were to die remains stagnant. Even if all potential donors elect to donate, the supply of human organ donations will continue to fall short of the need.

One solution doctors along with pharmaceutical and biotechnology companies are investigating to end this acute shortage is "xenotransplantation," or the process of transplanting cells, tissues or organs from one species to another. While still in the experimental stages, xenotransplantation is a potentially life-saving option for people with such ailments as severe heart disease and kidney failure. Preliminary data from experiments using transplanted pig cells in patients with diabetes and Parkinson’s disease are encouraging. According to a 1997 survey by the National Kidney Foundation, nearly two-thirds of the American public accepts cross-species transplantation as a viable option to increase the number of organs and tissue transplanted and lives to be saved.

History of Xenotransplantation

Xenotransplantation, a subject of study and experimentation for almost a century, started to receive serious attention from the scientific community in the 1960s as a result of strides made in human-to-human transplantation. Between 1963 and 1993, 31 clinical procedures involving transplantation of solid organs from animal donors were performed in the United States and South Africa. These were extraordinary events. Physicians performed these operations as bridges to maintain life while awaiting a human donor organ.

The first experiments in transplanting chimpanzee kidneys into humans were conducted in 1963 and 1964. One of the patients who received chimpanzee kidneys lived for nine months.

Two of the most publicized xenotransplant operations in the last two decades involved Baby Fae, the infant who received a baboon heart in 1984, and Jeff Getty, an AIDS patient who received a bone marrow transplant from a baboon in 1995. Baby Fae lived with her xenotransplant for 20 days, while Getty rejected the transplanted marrow almost immediately. As of October 1998, Getty remained free of baboon-transmitted viruses and showed no signs of baboon bone marrow in his system.

Researchers are currently experimenting with pigs as sources of organs and tissues for xenotransplantation. Studies include the use of pancreatic islet cells and neural cells from pigs for insulin-dependent diabetes and refractory parkinsonism, as well as perfusion of a patient’s fluids through a pig liver situated outside the patient’s body as a temporary strategy to treat liver failure. Patients with Huntington’s disease, which is a neurodegenerative condition characterized by uncontrolled movement and mental deterioration, also are receiving modified tissues from pigs as an experimental treatment. These studies are still very preliminary in testing the safety and effectiveness of this promising treatment.

Appropriate Animals for Use in Xenotransplantation

Scientists and the U.S. Public Health Service advise that domesticated animals such as pigs and cows be considered as potential tissue and organ sources before nonhuman primates, such as monkeys, for a number of health, safety and logistical reasons. Pigs are preferred because they mature very quickly, produce large litters and have organs of comparable size and function to human organs in both infancy and adulthood. They also can be bred to high health standards in microbiologically controlled environments.

Monkeys, on the other hand, are undomesticated animals that do not fare well in controlled environments and, therefore, it is difficult to raise them to the same high health standards as pigs. Furthermore, their organs are much too small and, like humans, monkeys mature slowly and tend to give birth to one offspring at a time. Although humans might reject nonhuman primate organs less frequently and vigorously than those of other species because of their genetic similarities, these similarities could facilitate disease spread between the donor and recipient. This threat of disease, and ethical issues associated with the use of nonhuman primates as organ sources, have led some government agencies to consider banning the use of nonhuman primates for xenotransplantation. For example, the United Kingdom (UK) has banned the use of great apes and strongly protests the use of other primates for this purpose.

Addressing Organ Rejection

Rejection, in which the recipient’s body attacks the new organ like an infection, is the greatest practical obstacle to xenotransplantation. Traditionally in transplants of organs from one human to another, drug therapies, such as cyclosporine, are used to suppress recipients’ immune systems in order to allow transplanted organs to function without being attacked and rejected as foreign. In xenotransplantation, a more aggressive defense mechanism called "hyperacute rejection" occurs when tissue not recognized as human is introduced to the body. In a matter of minutes, an individual’s immune system sets out to destroy the transplanted organ.

One technology being developed to overcome such organ rejection is the breeding of transgenic pigs. These genetically-altered pigs express specific human proteins that make it more difficult for the human immune system to identify the porcine organ as belonging to a different species. A transgenic pig is bred by injecting a small amount of DNA (or genetic material) mimicking a human gene sequence into a fertilized pig egg and then implanting that egg into a sow leading to the pig’s birth. As demonstrated in recent studies, this technique has addressed hyperacute rejection in nonhuman primates that received organs from transgenic pigs.

New cloning techniques may further enhance the immunocompatibility of pig organs by eliminating the pig gene-products that cause hyperacute rejection. In theory these developments should mean that once transplanted, animal organs could be treated in the same way as human organs, with the use of standard immunosuppressive regimens.

Addressing Potential Risk of Infection

The transfer of infectious diseases between animals and humans, or cross-species infection, remains an important area of study even though risks have been reduced. In 1997, it was reported that two of four variants of the porcine endogenous retrovirus (PoERV) could infect cultured human cells in test tubes. An endogenous retrovirus is a type of virus that exists as part of the DNA of all mammals and is passed down to offspring over successive generations without causing harm. This earlier report does not indicate if viral transfer would occur as a result of a transplant or whether, if it did happen, it would cause any disease.

Xenotransplantation opponents voice concerns regarding the unpredictable nature of microorganisms. They point to existing human viruses suspected to have originated in animals -- human immunodeficiency virus, simian immunodeficiency virus and bovine spongiform encephalopathy (BSE), in which people developed Creutzfeldt-Jakob Disease, the human equivalent to BSE. They express concern that xenotransplantation puts society as well as the individual recipient at risk for disease.

In August 1999, the results of a study were announced which found no evidence of PoERV infection among 160 people who had previously received medical treatment with living pig tissue. A number of patients in the study did show evidence of circulating pig cells, but no evidence of PoERV infection, potentially demonstrating that pig tissue can survive long-term in the human body with no ill effects. Among the patients included in the study were a few individuals who had been pharmacologically immunosuppressed and therefore presumed to be at greater risk of infection. Another study, conducted by the Mayo Clinic, will test pork slaughtering and processing workers to determine whether PoERV is transferred to people who have a history of extensive exposure to swine tissues and fluids. At this time, there is no evidence that PoERV has been transmitted in vivo or that it poses a risk to humans; however, researchers are proceeding with caution to address these outstanding safety concerns. If PoERV’s are found to pose a risk, strategies are being developed that may provide a solution to the problem.

U.S. and International Regulation of Xenotransplantation

While governments of the United States, the United Kingdom, Spain and elsewhere share similar hopes and concerns regarding xenotransplantation, each is working independently to establish or revise guidelines regarding the regulation of xenotransplantation research. In the U.S., the Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research published its guidelines in 1999. The guidelines, shaped in part by public dialogue, include long-term monitoring of recipients and the establishment of a registry to archive patient records and donor samples. The various agencies of the U.S. Department of Health and Human Services, including the FDA, the Centers for Disease Control and Prevention and the National Institutes of Health, have encouraged open communication about xenotransplantation at public workshops for several years.

In the United States, several scientists who attended the public conference in January 1998, "Developing U.S. Public Health Policy on Xenotransplantation," urged the FDA to ban cross-species transplantation research until ethical issues and health risks are resolved. They specifically discussed the potential risk to public health from a viral transfer across species that could result in a new disease epidemic. In April 1999, the FDA released a guidance document stating that any clinical protocols proposing the use of nonhuman primates should include sufficient clinical evidence addressing the risks of such use. At the time of the guidance document, the FDA felt that this evidence did not exist. The FDA decided it was appropriate to allow well-defined and highly controlled clinical trials, which are proceeding at a cautious pace.

The U.S. Department of Health and Human Services is developing several important mechanisms to facilitate participation by the public, scientists and industry in the progress of xenotransplantation. The DHHS is establishing the Secretary’s Advisory Committee on Xenotransplantation (SACX) to review clinical protocols, conduct discussions and make recommendations about the appropriate conditions for use of nonhuman primate organs. In October 1999, the DHHS announced the creation of the SACX and requested nominations for the committee membership. The U.S. Public Health Service is also planning to develop a national patient registry and a biological specimen repository for tissues. The biotechnology industry continues to work closely with the government in the responsible development of regulations and guidelines on the appropriate safeguards for xenotransplantation.

Spain and the UK announced their guidelines in June and July 1998, respectively. Prior to the start of human clinical studies, according to Spain’s regulations, preclinical studies must demonstrate a minimum six-month survival and function period of cells, tissues and organs to be transplanted and the absence of infectious pathogen transmission. People who receive organs, as well as their families and friends, will have to sign informed consent documents indicating that they understand and accept the medical risks and inconveniences involved in these early transplant procedures, such as potential for infections, life-long medical surveillance and potential media attention associated with xenotransplantation. In January 1999, the parliamentary assembly of the Council of Europe called for a worldwide moratorium on xenotransplantation, until technology is evaluated and guidelines are established. A month later, members established a Working Group for the purpose of drafting xenotransplantation guidelines.

The UK’s guidance documents were developed by the UK Xenotransplantation Interim Regulatory Authority (UKXIRA), which is charged to regulate cross-species transplantation on a non-regulatory basis. The guidelines include the following safeguards: the UK Secretaries of State for Health will review each application for a human trial for an organ transplant and make a decision based on advice from UKXIRA; the welfare of animals bred for human transplants will be protected; and the existing Advisory Committee on Dangerous Pathogens will advise on the risks of infection from different types of xenotransplantation therapies proposed.

Ethical Issues Surrounding Xenotransplantation

In addition to the critically important potential public health issues in xenotransplantation, there are a number of ethical issues that should be addressed. These include: deciding upon the fairest way to allocate donor animal organs in a society where thousands of people die while waiting for a transplant; deciding whether or not persons who receive xenografts may be compelled to participate in long term follow-up programs because of the theoretical public health risk from endogenous viruses; developing a carefully constructed ethics concerning the creation and care of those animals that will be created to serve as donors; determining when and under what circumstances children and infants may be considered as recipients of xenografts; and studying the potential emotional impact on people of having had their lives prolonged with donor animal organs.

It would be naive to think that all these and other ethical issues will be resolved in advance of the technological readiness to attempt animal to human xenografts. However, it is crucial that those in the biotechnology industry who are working in this area help to initiate and sustain an ongoing public dialogue on these and related issues. BIO is committed to assisting in this process.

Conclusion

BIO supports a full and open debate about xenotransplantation to further understanding and broaden knowledge which will hopefully , offer innovative treatments for previously untreated conditions. Understandably, this subject raises concerns among many people. BIO encourages a full and open discussion of this issue and welcomes the opportunity to address any concerns people have.

BIO is committed to a responsible research program that is consistent with regulatory guidelines as well as with the recommendations of ethics advisory boards within both industry and government. Our colleagues at EuropaBIO have made the same pledge helping to ensure international consistency. BIO’s bioethics committee is engaged in the dialogue on the appropriate safeguards on this technology and educating the public on the importance of these techniques in treating disease. BIO also is working with the FDA to ensure that appropriate safeguards exist for the proper use of this promising new medical treatment.

A number of independent bodies across the world have considered the ethics of xenotransplantation and found it to be ethically acceptable. While we believe that xenotransplantation could be the answer for thousands of patients who will require transplants of tissues or solid organs, the industry and the scientific community must proceed with caution to ensure the safe development of this potentially life-saving technology.