Ethical and Social Issues Raised by Xenotransplantation
[Source : Health Canada, Therapeutic Products Programme, December 2000. Reprinted with permission.]
(A Glossary is provided at the end of the document entitled Scientific Issues Raised by Xenotransplantation. It explains many of the terms used in this text, such as xenotransplantation, pre-clinical trials, clinical trials, risk to third parties, etc.)
The purpose of this document is to identify ethical and social issues raised by xenotransplantation and to prompt public discussion and debate on those issues. It is acknowledged that there are a number of competing ethical theories (the rules or arguments used to evaluate whether an act is morally right or wrong) that can be used to arrive at an acceptable solution. The goal of this document is not to resolve these debates, nor to take position in favor or against any particular theory.
When discussing these issues, people bring different value systems to the debate. In doing so, they view the issues through the lens of their personal experience, culture, spiritual or religious background. Here are some examples of the kinds of arguments that often surface (they are examples only, and not intended to reflect all the arguments that might be voiced):
- Xenotransplantation should be pursued because many people stand to benefit from this new technology.
- Xenotransplantation should not be pursued because it goes against strong moral values.
- In deciding whether xenotransplantation is acceptable, we must weight both the positive and negative consequences it may have.
- It may be possible to develop conditions or set limits on xenotransplantation in order to make the risks associated with it acceptable.
- Even if it may benefit particular individuals, xenotransplantation should not be pursued because it may put others at risk of infectious diseases.
This document frames the ethical questions under the following 4 headings:
- Is it acceptable to use animals as sources of live organs and tissue for transplantation into human beings?
- Is it acceptable to create transgenic animals as a source for xenotransplants?
- Is it acceptable to use xenotransplants in human beings?
- Is it acceptable to conduct clinical trials involving xenotransplants?
1. Is it acceptable to use animals as sources of live organs and tissue for transplantation into human beings?
Xenotransplantation will lead to the breeding and killing of animals1 to provide organs for humans. Is it acceptable to use animals in this way?
People tend to respond in the following ways to the issues raised by this question:
- Some people believe it is acceptable to use animals for any purpose.
- Others have strong moral convictions against using animals for any purpose, no matter how humans might benefit.
- Finally, many people believe it would be okay to use animals if the benefits to humans are important and if the animals are properly cared for.
Many societies currently use animals for:
- biomedical research
- medical purposes (for example, as a source of heart valves or insulin)
- food, and
But people increasingly object to using animals for such purposes as the testing of cosmetics or for entertainment.
The way people feel about using animals for xenotransplantation reflects how we, as humans, feel about the moral status of animals. What are the rights of animals? When we’re talking about xenotransplantation, one way to clearly state the question is to ask ourselves:
If animals are to be used for medical purposes in ways that would not be ethically acceptable if applied to human beings, on what basis do we draw a distinction between animals and human beings?
If there are no convincing reasons to give animals a moral status lower than that of human beings then using animals for medical purposes will be hard to justify.
What are the concerns about using non-human primates for xenotransplantation?
Initially, non-human primates (such as chimpanzees, baboons and monkeys) were considered as potential sources of organs because their similarity to humans decreased the risk of immune rejection (see Glossary).
In Canada and in other countries, non-human primates are no longer being considered as source animals for xenotransplants. The reasons for this include:
- Non-human primates are thought to have a greater capacity for suffering than other animals because of their level of self-awareness, their need for social interaction and their greater sensitivity to pain and distress.
- The cost of raising them could be very high.
- They breed slowly.
- Infections might be easily transferred from them to humans.
- People might feel uneasy about having non-human primates’ organs in their bodies.
At the present time, pig organs are being transplanted into non-human primates as part of pre-clinical trials (research studies that involve testing with animals, not humans; see the Glossary).
Is this ethically acceptable? Those in favor say:
- All of society will benefit from this research.
- The living conditions of the primates being used in these studies are not as controlled as they would be if they were being bred as source animals for xenotransplantation.
- This use of non-human primates will end once scientists have obtained enough data from the pre-clinical trials.
What are the concerns about using pigs for xenotransplantation?
Recent research points to pigs as the main source animals for xenotransplants. The reasons for this include:
- Their organs are about the right size for humans.
- The risk of infection being transferred to humans may be lower than with non-human primates.
- They are already being used to treat humans: for example, as a source of heart valves for people with damaged hearts. (Currently, transplanted pig heart valves are treated with special chemicals to kill the cells and destroy any potential infectious agents; they do not pose the same safety risk as living pig cells or organs would.)
- Although considered to be intelligent animals, they do not share as many features with humans as non-human primates do.
- They have been used for a long time as farm animals and human food.
- They reproduce quickly.
Two other issues that relate to the use of pigs as source animals are:
- In order to ensure that source pigs are as free of disease as possible, the environment where they are raised may need to be highly controlled. If the most extreme conditions were adopted this could mean that: piglets would be delivered by caesarean section directly into an incubator, the sow would be killed after the piglets were born and the piglets would be raised in isolation from other piglets. While such measures may be critical to the success of xenotransplantation, people will need to balance the need for effective disease control against adverse effects on the pigs.
- Because the pigs would have great value in economic terms, and as a source of organs, they would likely receive a high level of care. Some people believe that one benefit to source pigs would be the continuous medical care they would receive.
Are there any limits or conditions that make the use of animals for xenotransplantation acceptable?
Both the current use of pigs as source animals and the use of non-human primates in pre-clinical trials constitute biomedical research on animals.
In Canada, no federal or provincial legislation covers all aspects of this subject. The use of animals in biomedical research is overseen by the Canadian Council on Animal Care (CCAC), through its Animal Care Committees (ACC) found in institutions. More generally, CCAC has developed guidelines on the use of animals in research and on the creation of transgenic animals.2 The CCAC guidelines are based on the premise that certain benefits to humans will justify the use of animals as long as animals are properly cared for.
The 1997 National Forum on Xenotransplantation3 stated the need to consider animal interests in the xenotransplantation debate. Its report also stated that:
- the use of animals for this purpose is not automatically justified, just because they are currently used for food, research or other purposes; and
- animals should be used only if other options do not exist.
The Proposed Canadian Standard for Xenotransplantation bases its recommendations for the ethical use of animals during clinical research on the CCAC guidelines:
“The CCAC guidelines on: animal use protocol review provides the basis for ethical review according to the following principles:
- expert opinion must attest to the potential value of studies with animals,
- animal use should be minimized,
- if animals must be used, they must be maintained in a manner that provides for their physical comfort and socio-behavioural well-being,
- animals must not be subjected to unnecessary pain or distress,
- if pain and distress is a necessary component of the study, steps must be taken to minimize its intensity and duration,
- if an animal is observed to be experiencing severe unrelievable pain or discomfort, it should be humanely killed immediately according to an approved SOP (Standard Operating Procedures),
- all proposals for the creation or use of transgenic animals must follow the CCAC guidelines on: transgenic animals, and be approved by the proposed national review board or its committees for care and use of animals in xenotransplantation, and
- animals must only be operated on once for the removal of organs.
“Investigators, animal care committees, grant review committees and referees must be especially cautious in evaluating the proposed use of animals involving severe pain, distress, or both.”4
2. Is it acceptable to create transgenic animals as a source for xenotransplants?
The most recent scientific developments in xenotransplantation point to transgenic pigs as the most promising source of organs and tissues. Transgenic pigs are pigs that have been bred with human genes (currently one or two) in order to lower the risk that their organs or tissues will be rejected by the human patient who receives them.
The genetic manipulation of pigs may, in fact, be the key to xenotransplantation’s success. The case in favour of xenotransplantation will be harder to make if people consider it morally unacceptable to transfer human genes into pigs.
The creation of transgenic pigs is linked to many broader issues around genetic modification of living organisms.
Arguments against the genetic modification of living organisms are that it:
- Interferes with the natural order of the world,
- Attempts to change the nature of animals,
- Violates species boundaries,
- Lets people “play God” and is not natural,
- May alter our views about living beings, and
- May have an impact on the environment and other animals, if inter-breeding occurs.
Arguments in favour of genetic modification are that:
- Boundaries between species are not rigid and change with evolution.
- The proposed genetic modifications only extend long-standing animal breeding practices.
- The essence of any human or animal is not contained in any one gene.
- Genetic modification would occur on a small scale and in a specific way.
Transgenic pigs would probably only receive one or two human genes. Those in favour of genetic modification argue that:
- pigs retain their physical appearance as pigs, and
- pigs do not become more human OR a hybrid human/pig as a result of having one or two human genes.
What are the other concerns raised by the production of transgenic of pigs?
Even though there has been no reported adverse effect on the pigs, currently bred with the few human genes, this possibility cannot be ruled out. We do not know however, how far the genetic manipulations could go in the future. For this reason, some people believe that pigs need to be closely monitored.
Depending on the technique or process used to create transgenic pigs (i.e. cloning or inserting a gene into a sow), the number of piglets born with the human gene may be quite low. This will result in surplus piglets that are not useful as source animals for xenotransplants. These animals will be euthanized and cannot be released into the environment nor introduced into the food chain.
Are there currently any limits or conditions on the creation of transgenic pigs?
The CCAC guidelines on: transgenic animals (see Footnote #2) states that the creation of a genetically-modified animal falls into the category of experiments which cause moderate to severe distress or discomfort. The guidelines also state that researchers must report on the animals’ phenotype (or physical appearance) and on any evidence of pain or distress. If the animals do not show signs of pain and/or distress the category may be revised.
3. Is it acceptable to use xenotransplants in human beings?
What effect might xenotransplantation have on our sense of what it means to be human?
Some people may think the procedure tends to reduce the human body to bits and pieces that can be tinkered with or replaced.
What effect might xenotransplantation have on how a person feels about his/her body? If people identify themselves with all the organs inside their body, if they feel that being human means having a body, and if various organs have emotional importance, then any transplant, human or animal, may be difficult to accept. (Please note that in the following quote, a graft is the term used to describe a transplant.)
“An animal organ will be thought of as even more destructive of identity. In fact, a graft of any kind breaks through the usually intact frontier between self and non-self, and the psychological repercussions of the “violation” has been studied with attention in the case of allografts (human-to-human organ transplants). With xenografts, there is further violation, that of the frontier between humans and animals, and this is of particular significance.”5
Another concern is how the type of xenotransplant (such as heart or stem cells) and the location of the transplant (such as having fetal pig tissue injected into a human brain) could affect a person’s identity, behavior or personality.
Some people believe that the essence of what it means to be human does not lie in the body, but elsewhere—in our minds or spirits. Their willingness to transcend the purely physical level of being means that such people might not argue against either human OR animal organ transplants.
Other people oppose the use of animals for medical purposes based on religious or spiritual beliefs. While it will be crucial that the personal views of a patient be considered when treatments are being discussed, it is difficult to translate religious views into public policy.
The arguments over natural and unnatural practices also have a place in this debate. Artificial medical devices and non-living animal materials (such as pigs’ heart valves and pigs’ insulin) are commonly used to treat patients. There do not seem to be moral objections to these practices, which some people would describe as unnatural.
Reaching general agreement on these issues is highly unlikely. The delicate question is: how much public support is needed in order to justify the development of this technology, even though its use in individual patients will be a personal decision?
What are the risks and benefits for patients who might receive xenotransplants?
To the best of our knowledge, the possible benefits are:
- Xenotransplantation could provide an alternative source of organs and tissues for use in patients.
- Xenotransplantation could provide cells and tissue for new treatments of diseases where human organ transplants are not an option.
- Xenotransplantation could alleviate the shortage of human organs and tissue.
- Xenotransplantation could provide temporary treatment options while patients wait for a human organ to become available.
- Xenotransplantation could provide more equal access to organs by increasing supply and by allowing transplants to be more effectively planned and coordinated.
- Patients, who do not meet the criteria for human organ transplantation because there is a short supply, could be offered xenotransplants as an option.
As discussed more fully in Scientific Issues Raised by Xenotransplantation6, the medical and safety risks for the patient who receives a xenotransplant include:
- The risk of immune rejection.
- The need for high doses of immunosuppressive drugs to fight rejection, which puts a patient at risk for other kinds of potentially fatal infections.
- Risk of infection by microorganisms transferred from pigs that could cause a range of more or less serious diseases, some of which may still be unknown to us.
- Risk that the animal organ will not be able to perform well inside the human body.
The psychological and social issues that might affect patients include:
- How will a person accept and feel about having pig organs or tissue inside their body?
- How easy will it be to accept some of the precautions that may need to be taken to limit the transmission of infectious agents? Such precautions might include restricted physical contact between patients and their loved ones.
What are the risks and benefits for society?
One of the most serious concerns about xenotransplantation involves the possibility and risk of infectious agents (such as a virus) from the donor pigs being transferred through the xenotransplant patient to:
- persons in close contact, such as family members or health care professionals
- the general public.
This risk to the public’s health is often called the risk to third parties. Scientific Issues Raised by Xenotransplantation provides an overview of the medical aspects of these risks.
This potential for disease transmission from a xenotransplant patient to the general public makes the risks posed by xenotransplantation a societal issue.
These risks to third parties are difficult to manage because of the limits of today’s science. Based on our current knowledge, and as is often the case with new medical advances, it is impossible to:
- fully understand all the risks,
- eliminate all the risks, or
- predict all the risks.
At the moment, the risk to third parties is a major obstacle to clinical trials with xenotransplantation. (Clinical trials are research studies on new drugs or treatments which are carried out with human patients.)
Some of the issues that come up when discussing clinical trials and the risk to third parties include:
- Because it is potentially at risk, the general public must be involved in discussing these issues. Is some type of “third party consent” necessary or possible?
- The risk that an individual might be willing to bear when it comes to xenotransplantation must be weighed against the possible spread of infection or disease to the whole population. Does the fact that an individual consents to this kind of risk justify exposing the public to the same risk?
- The local Research Ethics Boards (REBs) which usually evaluate whether the risks associated with clinical trials are ethically acceptable are accustomed to looking at risks and benefits to patients not to the general public.
The effects of xenotransplantation on society may not be limited to medical and safety risks. Various social, moral and cultural values may be “at risk” because of its development. For example, xenotransplantation may:
- Affect our views about what it means to be human.
- Affect what it means to act in a selfless way (be altruistic).
- Affect how we see nature and the environment.
- Disrupt social relationships.
- Disrupt views of death and immortality.
- Affect our understanding of medicine by relying too heavily on a technical solution to health problems.
- Affect our trust in biotechnology and government regulation of biotechnology.
- Concentrate economic resources in one area.
- Divert social attention from other solutions.
- Enforce the technical concept of progress.
How could xenotransplantation affect the search for other ways to meet the medical needs of patients?
Research on xenotransplantation is driven by the desire to find alternative sources of organs and tissues. Aside from xenotransplantation, what alternative solutions might alleviate the shortage of human organs and tissues for transplant? Some of these alternatives might be:
- Promoting the prevention of diseases that lead to organ failure,
- Finding ways to increase the supply of human organs,
- Researching artificial organs or devices, and
- Researching tissue and organ engineering from human sources.
Some people fear that by putting a strong focus on xenotransplantation, public attention and government funding may be diverted away from health care initiatives or research into the alternatives listed above.
If alternatives to xenotransplantation existed, would the case for xenotransplantation be harder to make, given the possible risks to public health and the harm it might cause animals? Should research into xenotransplantation be funded only if there is parallel support for the alternatives listed above?
Or, are there any unique benefits from xenotransplantation that justify its use (and research into making it a success), even if a solution to the shortage of human organs and tissues were found? Some people point out that xenotransplantation may offer new treatments to patients who cannot benefit from human organ transplants.
What effect might the development of xenotransplantation have on the numbers of people willing to donate organs after they die? It is hard to know whether its development would raise or lower human organ donation rates, because:
- Some people might react to high profile media reports about xenotransplantation by deciding to donate their organs to those in need.
- Others might believe that if animal organs and tissues can be used for transplants, they do not need to donate their own organs.
How might xenotransplantation affect the ethics of human organ donation and existing health services?
The need for human organ donation, after death, could be eliminated if xenotransplantation became a standard treatment. Doctors would no longer need to consult relatives about donating the organs of their loved ones, at a time when they are coping with that person’s recent or approaching death. It could also eliminate the need for other and sometimes controversial methods for obtaining human organs or tissues.
Even if xenotransplantation looks promising for patients, the demand for human organs will continue for some time. This could result in two organ allocation lists: one for human organs and one for xenotransplants. Thoughtful policies will need to be developed in order to manage these lists and ensure fair treatment for all patients.
If there were more animal organs available, this could affect how decisions are made about who would be eligible to receive human organ transplants. Xenotransplantation could eliminate difficult choices and it could also increase the demand for organs.
For some patients it is difficult to find a suitable organ or compatible tissue from human donors. These patients might benefit from access to animal organs.
In addition, animal organs or tissues may be of higher quality than human organs, which could be infected with a disease from the donor.
The economic impact of xenotransplantation on our health care system will need to be examined, and public policy makers will need to decide at what point in the introduction of a new technology such decisions will be made. Usually, these kinds of questions are addressed when new technologies are on the brink of being introduced into the health care system. Should this still be the case, if public money is spent on the research phase and if public health is at risk because of the technology?
Are there any conditions might make the risks of xenotransplantation acceptable?
Whether any conditions might make the risks of xenotransplantation acceptable is another subject of debate. Some of the conditions that might need to be in place include:
- Xenotransplant producers might be asked to institute tighter safety measures than usual.
- Appropriate measures would need to be put in place to ensure that both xenotransplant patients and the public would be protected from infectious animal diseases.
- Governments would need to oversee and control the process.
Given the current scientific uncertainty and lack of information on xenotransplantation, it is difficult to decide how strict and exactly what the conditions should be. This is why some people believe that in order to properly assess the risks, researchers should be allowed to conduct carefully controlled clinical trials. Others argue that these trials could put public health at risk.
4. Is it acceptable to conduct clinical trials involving xenotransplants?
It is very difficult to decide if and when it will be acceptable to go forward with clinical trials. Clinical trials with xenotransplants must be authorized by Health Canada’s Therapeutic Products Programme (TPP). The TPP will conduct the scientific and technical evaluations that usually precede such decisions. Many factors that Health Canada will need to consider in making the decision fall outside of this scientific and technical evaluation.
First, the various sectors of society, which may be affected by xenotransplantation, should be considered in the decision-making process, including:
- The public interest
- Scientists’ freedom to pursue research
- Economic and technological development
- The interests of other countries
Second, given that no technology is risk free, decision-makers will need to identify the level of risk the public is prepared to accept, and try to balance the risks and benefits as they affect:
- Recipients, who may tolerate greater risks so they can benefit from the technology.
- Patients, who stand to lose if there are unjustified delays in developing new procedures.
- The public, which could face and bear risks, without gaining any direct benefit.
- Animals, if pre-clinical trials continue despite the fact that such trials no longer provide useful information.
Third, as with many new technologies, we are not sure how well it works or how safe it will be. It will be important for Health Canada to ask:
- What level of success can we expect from clinical trials that would justify authorizing them?
- Can we safely control clinical trials to reduce the risk of infectious disease in recipients, or should we conduct more pre-clinical research?
- What kinds of follow-up or surveillance measures will need to be in place to ensure that any transfer of animal infection is confined to the recipient and will not spread to third parties. Can we count on these surveillance measures?
- Do we need to take special precautions or increase safety because of:
- The risk of infection to both the recipient and the general public?
- The impacts on public health at an international level?
- The social acceptability of crossing species, both on an individual and societal basis?
- Should there be an extra level of review beyond what already exists for biomedical research with human subjects?
Fourth, given this complex issue, which potentially poses serious risks to public health and has many scientific uncertainties, what decision-making framework would be appropriate.
Evaluation of the ethics of clinical trial protocols
Xenotransplants are considered therapeutic products. Until they are approved for general use, xenotransplants can only be used in clinical trials authorized by Health Canada’s TPP.
Patients who participate in a xenotransplant clinical trial will be considered research subjects. At present, no federal legislation applies to research on human subjects. Some provinces have conditions in regulations. Otherwise, in order to be acceptable, clinical trials must follow ethical guidelines. In 1998, three research arms of the Federal government developed the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans.7 It is the most widely used document in research institutions today.
Clinical trials are usually reviewed in several ways:
- A local Research Ethics Board (REB), either institutional or private, reviews the ethical aspects of the trial.
- TPP reviews the researchers’ submission to conduct clinical trials to determine the safety, effectiveness and quality of the new product, as well as the acceptability of the clinical trial protocols that are being proposed.
The role of an REB is to ensure that people who take part in the trials are protected and that other ethical guidelines are followed. Is the usual REB review of clinical trials sufficient or is additional review required?
REBs usually review the following:
- The balance of risks and benefits to the subject: the potential benefits should be greater than the possible risks.
- How subjects are selected: Who will be invited to participate in the clinical trials? Will it be patients whose life hangs in the balance, or those who are healthier? Should minors or adult who cannot consent alone be included? Should patients be selected based on their perceived commitment to follow-up surveillance?
- Consent process: What measures can be put in place to ensure that the patient’s consent is truly voluntary? What information should the patient receive in order to make the decision? Will a patient be allowed to drop out of the study at any time? Is the consent of the patient’s family and friends also necessary?
- The impact on patient privacy and confidentiality: How will patient privacy be protected if the media focus intensely on the trials? What impact might the follow-up surveillance have on the patient, and how will their privacy be protected during the follow-up phase?
- The effect of clinical trials on normal patient care: Taking part in a clinical trial should not affect the care a patient receives. How will this affect patients waiting for human organs?
- Conflict of interest issues: Many companies and institutions will be investing in the development of this new technology. Should the potential for financial gain be disclosed to patients? How should the REB act in such situations? How should a company’s desire to keep information confidential be balanced against the public’s desire to be informed?