The Big Issues - Background
Animal-to-human transplantation: Should Canada proceed?
Introduction
Xenotransplantation is the transfer of living cells, tissues or organs from one animal species to another for medical purposes. We use the term here to refer to animal-to-human transplants. The transplanted material is called a xenotransplant.
| “Xeno” is a Greek word meaning “stranger.” The “x” is pronounced like a “z” (zeeno). |
Any disease that is treated by human-to-human transplants could potentially be treated by xenotransplantation. Organ xenotransplants could include whole hearts, lungs, livers, kidneys or pancreas of animals. Tissue xenotransplants could include skin grafts for burn victims, corneal transplants for the visually impaired or bone transplants for limb reconstruction. Cellular xenotransplants may be a way to treat people who have diabetes or Parkinson’s disease.
Xenotransplantation raises a number of issues that call for informed public discussion.
Issue #1: Is xenotransplantation needed?
The current demand for healthy cells, tissue and organs for medical transplants exceeds the available supply. Novartis, a biotechnology company, estimates that 180,000 people around the world are waiting for organ transplants but only one-third will receive one.1 Aside from patients suffering from organ failure, xenotransplantation could potentially treat those with hemophilia, AIDS, diabetes, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.2
In Canada, up to 30 percent of people waiting for organ transplants die on the waiting list.3 In 1999, there were 3,544 people on waiting lists for donated organs (or 115.9 per million population). Most patients needed kidneys (78%); the rest needed livers (10%), hearts or hearts and lungs (4%), lungs (4%), and kidney-pancreas or pancreas (3%).4 The need for organs in Canada is expected to increase by almost 200 percent by 2020.5
Canada’s donor rate of 14.4 per million population is among the lowest of all developed countries. By way of comparison, Spain is reported to have the highest human donation rate worldwide with 33.6 per million in 1999.6 Canada’s low organ donation rate is partly due to its low death rate from car accidents and gun shots, a major source of donated organs in other countries.7 However, there is little doubt Canada’s organ donation rate could be increased – some say by as much as 80 percent – by ongoing efforts to promote donation through public education campaigns and by more efficiently requesting, collecting and distributing organs.8
Another way to increase the number of donations is by adopting a policy of “presumed consent.” This means that it is assumed people agree to donate their organs upon death unless they have indicated otherwise. Several countries have adopted a “presumed consent” policy. Governments adopting presumed consent would have to launch massive campaigns to make people aware of the policy. However, some people who do not want to be a donor would not get around to opting out, which could raise ethical concerns as their organs could be removed after death.9
Other approaches to overcome this shortfall have been considered.
Disease Prevention
One approach is to prevent disease in the first place through exercise, healthy eating and lower alcohol and tobacco consumption. However, preventive therapies are unlikely to have an impact on organ failure rates for at least a decade.10
Many experts believe that the demand for organs will never be met by prevention efforts combined with human donations.11
Living Donors
The donation of kidneys and livers by living donors is now accepted as generally safe and effective. Almost a third of the kidneys transplanted in the United States last year came from live donors. The liver, unlike other organs, can regenerate. Therefore, someone can donate a portion of his liver and his liver can still function. Living donations of lungs, pancreas and intestinal segments are generally considered risky for the donors.12
Organ Markets
A controversial method for increasing donor rates involves permitting a legitimate market for human organs. A worldwide market for human organs currently exists and an estimated 200 to 300 Americans a year buy organs from poor people in developing countries.13 However, many people believe an organ market is unethical and would mark the end of the current organ donation system in which organs are donated as an act of generosity for strangers in need.14
Artificial Organs
There have been significant improvements in mechanical and artificial hearts, but most are designed to only be temporary transplants, keeping patients alive until a human organ becomes available or until their own organs recover. Much more work is still needed to develop artificial devices that can last as long as donated human organs.15
Other Novel Approaches
Human stem cell therapy is a promising treatment for Parkinson’s disease and Huntington’s disease.16 Human embryonic stem cells can develop into any type of tissue, including internal organs. For example, some researchers believe that stem cells could be cultured to grow unlimited supplies of human tissue for transplant.17 However, these approaches are just starting to be investigated and are still theoretical.
Issue #2: Is xenotransplantation viable?
The concept of xenotransplantation, in particular whole organ transplants, is not new and the procedure has largely been unsuccessful. The main scientific challenges to xenotransplantation are immune rejection and infection. While drugs have been available for some time to sufficiently suppress the immune system for human-to-human transplants, they have not been successful in animal-to-human transplants. To date, survival times for recipients of xenotransplants have been poor although some cellular xenotransplants seem better able to resist immune rejection.
(In the 1990s, researchers began to focus on cell transplants, which in some cases are easier for a patient to tolerate.18 Several hundred cell transplants took place during the 1990s in Russia, the United States, Poland, Czech Republic, Switzerland, Sweden and New Zealand. Most were to treat patients with diabetes, Parkinson’s or Huntington’s disease, although one case involved a baboon bone marrow transplant to a patient with HIV in the United States, and six patients with ALS (Lou Gehrig’s disease) received hamster cells in Switzerland.)19
Scientists are trying to overcome immune rejection by adding human genes to animal cells to make them more acceptable to a patient’s immune system. Genetically modified animals are called “transgenic” animals. Transgenic pigs have been developed in various countries and shipped to researchers in Canada. The National Post recently reported on pre-clinical (animal-to- animal) studies by a researcher at the Robarts Research Institute in London, Ontario, who transplanted the kidneys of more than 20 genetically modified pigs into baboons.20 These pre-clinical studies indicate the extent of progress being made towards clinical studies involving humans.
In December 2000, the International Society for Heart and Lung Transplantation said that “current experimental results indicate a clinical trial [animal-to-human] at present would be premature” and that these trials should be undertaken only when the risks have been shown to be minimal (see Issue #3). The Society said that clinical trials would be justified and should be encouraged when researchers achieve acceptable results in animal studies, but only if there is little potential for the spread of animal viruses to humans. The Society says that pig-to-human heart transplants could be feasible within a few years.21
Some experts believe that moving to clinical trials is the only way the uncertainties surrounding xenotransplantation can be answered. Others say it is too early to consider clinical trials. And there are those who believe that even if animal-to-human transplants become a safe procedure, it does not necessarily mean we ought to do it.
Issue #3: How far should we go to save a human life?
Xenotransplantation raises a number of ethical issues. For example, how far is it acceptable to interfere with nature in order to try to prolong human life? Would crossing the species barrier have an impact on what it means to be human? Similar questions were raised 40 years ago when human-to-human transplants were being considered. Then, questions were about crossing the frontier between self and non-self.22
Critics of xenotransplantation say the procedure goes beyond medical innovation, crossing the very boundaries that define us as human.23 While few of the world’s major religions have made formal pronouncements on xenotransplantation, some religious believers are willing to accept it in principle provided unnecessary animal suffering is avoided. Others find it unacceptable, perhaps because of their relationship with the natural world.
Some people are opposed to altering the genetic makeup of animals, a procedure that would probably be necessary to prevent the human immune system from rejecting the xenotransplant. They argue that the boundaries that exist between species are for their protection and that tampering with the integrity of a species will have unpredictable repercussions.24 Others say that the boundaries between the species are not fixed but change with evolution. They argue that genetic modification is an extension of selective breeding that has gone on for centuries and, in any event, it would happen on a small and limited scale to benefit humans.25 Opponents argue that evolution has no direction and for humans to arbitrarily use artificial means to control life is like ‘playing god.’ Attitudes to xenotransplantation could well change over time and it is difficult to say how different cultures and societies will respond.26
Issue #4: Is the risk to the public acceptable?
It is impossible to fully understand or predict all the risks associated with xenotransplantation because scientific knowledge is lacking.27 However, the most serious risk appears to be transferring undetected animal diseases to patients that could, in turn, be transmitted to the general public. The worst-case scenario would be a major new epidemic.
Early clinical attempts at xenotransplantation were conducted with limited consideration of animal-to-human (or “zoonotic”) infection. Although there is no evidence that these attempts resulted in zoonoses, most patients died soon after treatment and did not have time to develop any symptoms. Much of the discussion around zoonoses began in 1996 when 40 scientists wrote a letter concerning xenotransplantation guidelines proposed by the American Public Health Services.28 In this letter, they pointed out the dangers of infection from non-human primates, noting that HIV almost certainly originated as an ape or monkey virus that infected humans.29
Scientists now have a better understanding of viruses and infections. They know that “retroviruses” contained in animal cells can infect human cells and can exist for many years before any symptoms are displayed. With xenotransplantation, these animal infections could quickly become deadly because the human recipient’s immune system would be suppressed.30
(Some animal viruses have jumped the species barrier and infected humans. The AIDS-causing HIV-1 and HIV-2 viruses are now known to have originated from non-human primate viruses31 and jumped from monkeys to people after infectious events up to 60-some years ago.32 Two human leukemia viruses have also been shown to originate with non-human primates. These examples all involve transmissions from non-human primates to humans.)
In 1997, the British government reviewed the current scientific knowledge and decided to ban experiments with humans and non-human primates. The United States decided not to ban experiments with non-human primates but recommends that proposals for clinical trials using non-human primates “should not be submitted to the FDA [Federal Drug Administration] until sufficient scientific information exists addressing the risk posed by non-human primate transplants.”33
Because of the high risk of infection from non-human primates, pigs are the current animal of choice for xenotransplantation. But non-primates can also cause zoonotic infections. For example, tissues and cells of animals, including pigs, can act as a reservoir for various infectious agents that may then infect humans.34 In an effort to reduce the risk, pigs for xenotransplantation are being bred in germ-free environments. However, scientists are not able to produce pigs without any viruses.
Pig endogenous retroviruses (or “PERVs”) can be found in all tissues of most pigs.35 In 1998, scientists discovered a PERV virus that can replicate in human cells.36 This discovery raised questions about other as yet unidentified infectious agents in pigs and other animals that could cause disease in human cells. It appears to be impossible to breed PERV-free pigs because it is in their genetic material.37 However, in 1999 a scientific paper considered 160 patients who had been treated with living pig xenotransplants of one kind or another over the previous 12 years, and the authors concluded that there was no evidence of a long term PERV infection in any of the patients.38
It is impossible to fully understand or predict all the risks associated with xenotransplantation because scientific knowledge is incomplete. Certainly, no technology or medical procedure is risk free and some say that in order to assess the risks, researchers should be allowed to conduct carefully controlled clinical trials. However, there is no consensus about the level of safety that would be necessary and the degree of risk that would be acceptable for clinical trials to occur.
The “precautionary principle” says that when an activity threatens to harm the environment or human health, precautionary measures should be taken even if some information is not established with certainty from scientific studies.39 However, the precautionary principle has been hotly debated and if taken to the extreme it could be argued that little or no scientific research would take place. It is therefore difficult to weigh the risks and benefits of xenotransplantation in the face of uncertain information and it is unknown what level of risk the public would be prepared to accept.
Issue #5: Are there legal issues that should be considered?
Xenotransplantation raises several legal issues. One of these issues is informed consent. It is generally agreed that those who participate in clinical trials would have to agree to a number of unusual restrictions on their freedom. Several countries are developing guidelines for research and clinical trials, and patients may be required to consent to some or all of the following:
- restricted travelling activities,
- never having children,
- identifying all their sexual partners to authorities,
- never donating blood,
- submitting to life-long surveillance, and
- agreeing to a post-mortem after death.40
Since it could take years for an infectious disease to develop, it is unlikely that patients would be permitted to exercise the traditional right to withdraw their participation. New public safety laws might have to be created in order to enforce the strict monitoring requirements.41 Some analysts believe the proposed monitoring would never survive a challenge based on the Canadian Charter of Rights and Freedoms.42 Because of the potential risk of viruses to society at large, close contacts of xenotransplant patients might have to agree to life-long monitoring and would also have to give informed consent.
Researchers both in academic institutions and biotechnology companies are the driving force behind xenotransplantation. Issues around business ethics, such as transparency, accountability and conflict of interest need to be considered. There are other issues such as liability and fair access to medical resources that would need to be explored.
Issue #6: What animal issues need to be considered?
Non-human primates (e.g., apes, monkeys, chimpanzees, and baboons), pigs, dogs, rabbits and rodents (e.g. mice, rats) are being used in large numbers for xenotransplantation research all over the world. Currently, pigs are the source animals of choice.
This preference for pigs stems largely from the more serious risks of infection from non-human primates.43 Non-human primates are also expensive to raise and breed slowly.44 Pigs, on the other hand, are not seen as being as developed as non-human primates, are easy to breed, and their organs are about the right size for humans (although it is not known how their organs will function in humans).
Opinions about the rights of animals vary considerably. In general, there is growing concern about the use of animals in experiments, particularly for testing cosmetics, pharmaceuticals, pesticides, chemicals and household products. People for the Ethical Treatment of Animals (PETA), one of the largest animal rights organizations in the world, operates under the principle that animals are not ours to eat, wear, experiment on, or use for entertainment.45 On the other side are those who say humans have an absolute right to life that overrides any rights of other creatures because humans rank highest in the natural order.46 According to most opinion surveys, the majority of respondents agree that animals should be used in a controlled and regulated way, with due regard to their welfare, if there is a direct benefit to humans.47
The need to produce disease-free animals may have an impact on their welfare. In an effort to reduce the risk of infection in humans, pigs for xenotransplantation research are being bred and raised in sterile laboratory environments. The Canadian Council on Animal Care48 oversees the use of animals in publicly-funded biomedical research.
Issue #7: What costs need to be considered?
It is difficult to estimate how much xenotransplantation would cost if it becomes an accepted medical treatment. The costs associated with xenotransplantation, at the clinical trial, post-clinical trial and implementation stages, would be borne by industry and federal and provincial governments.
It is likely that a xenotransplant would be at least as expensive as other transplants.49 The cost of a kidney transplant in British Columbia is approximately $20,000 with an additional yearly cost of about $6,000 for anti-rejection medication.50 The average cost of a heart transplant is reported to be $80,000.51 In Ontario, organ transplants cost about $47 million a year and that figure is predicted to increase to more than $121 million by 2005.52 Additional costs for xenotransplants would include the actual cost of the animal organ (breeding, feeding, housing, slaughter, disposal of the rest of the body), long term surveillance of the patient and close contacts, mandatory autopsy on death and possible quarantine costs.
Costs associated with xenotransplants may be balanced by the cost of treatments for people waiting for organ transplants. For example, about 700,000 patients around the world suffer from kidney disease and must undergo regular dialysis treatment at an annual cost of about $19 billion. It costs about 60 percent less to transplant a kidney than to keep the patient on life-long dialysis.53
Since any disease treated by human-to-human transplants could potentially be treated by xenotransplants, the demand for xenotransplants could be high if it becomes an accepted procedure. Some fear this increased demand could drive health costs up or divert monies from other health initiatives. Others say that in the long term, because of the ability to plan and coordinate transplantations, xenotransplantation may become an economical alternative to human transplantation.54
Issue #8: If Canada proceeds with xenotransplantation, what regulations would need to be in place to manage it?
The following is an outline of Federal legislation and regulations (or the absence of them) concerning xenotransplantation.55 It should be noted that provincial regulations may also address some of these areas.
Pre-clinical Trials
Currently in Canada, xenotransplantation studies are being carried out using laboratory animals. These pre-clinical or experimental trials do not involve human patients and are not regulated by Health Canada.
Clinical Trials
Xenotransplants are considered to be therapeutic products (a drug or medical device) and are subject to the requirements of the Food and Drugs Act and Regulations and Medical Device Regulations. In clinical trials, human patients are required to provide consent prior to taking part in authorized research under very controlled conditions.
A physician or sponsoring company can submit a request to Health Canada to conduct a clinical trial. The decision on whether to approve a clinical trial is based on safety, quality, effectiveness and a benefit/risk evaluation. There are no explicit regulations covering clinical trials involving xenotransplants.
The Minister of Health has the authority, under Division 8 of the Food and Drug Regulations and in the Medical Device Regulations, to prohibit the use of xenotransplants in clinical trials if it is in the interest of public health to do so.
Ethics Review
There is no federal legal obligation for ethics review and approval for research involving humans. However, in reviewing clinical trial submissions, Health Canada requests that the sponsor certify that a research ethics board approval of the protocol be approved before initiating the trial.
A condition for receiving funding from one of the three Federal Research Councils is that any type of research involving human subjects be reviewed and approved by the institution’s Research Ethics Board. It is further required that all researchers working within an institution that receives public research funds submit their protocols for review and approval by the research ethics board.56
Animal Protection
There is no explicit legal framework in Canada that applies to the protection of animals used for xenotransplantation. There is no federal statute in Canada regulating the use of animals for experimental or other scientific purposes.57
The Canadian Council on Animal Care (CCAC) is the national organization responsible for setting and maintaining standards for the care and use of animals in publicly-funded research, teaching, and testing in Canada. In these publicly-funded institutions, no pre-clinical xenotransplantation research may be conducted unless it has been approved by an animal care committee. The CCAC’s authority does not extend to non-academic institutions (e.g. private industry) that do not use public funds.
If xenotransplantation becomes a recognized medical practice, there currently is no legal protection of animals that would be used, other than the general offences involving cruelty to animals and the general conditions governing the treatment of animals while they are transported.
Section 446, Cruelty to Animals, of the Criminal Code, creates a number of offenses involving cruelty to animals. In particular, it forbids willfully “causing unnecessary pain, suffering, or injury to an animal or bird.”
The federal Health of Animals Act (June 1990, revised March 1992) is aimed at protecting Canadian livestock from contagious diseases (e.g. tuberculosis) and keeping out foreign diseases. The Act provides for Regulations on the general conditions governing the care, handling, and treatment of animals within, into, or out of Canada.
Environmental and public health protection
The Canadian Environmental Protection Act (CEPA) aims to protect the environment and human health. Under its Regulations, all substances new to Canada (manufactured in, sold in, or imported into Canada), including new products of biotechnology, are assessed for health and environmental impacts. This assessment would apply to the pre-marketing phase of xenotransplantation (i.e. prior to the sale of xenotransplants in Canada), but would not necessarily apply to the pre-clinical and clinical stage of xenotransplantation (i.e. prior to the conduct of human studies involving xenotransplants in Canada).58
Importation and exportation of organs, tissues or cells specifically designated for xenotransplantation
There are no explicit regulations covering the importation/exportation of organs, tissues, or cells specifically designated for xenotransplantation. In the absence of explicit regulations, xenotransplants are considered to be therapeutic products (drugs or medical devices) and are subject to the requirements of the Food and Drugs Act and Regulations and Medical Device Regulations.
Basically, the Food and Drugs Act and Regulations apply to the sale of all drugs or medical devices in Canada, whether manufactured in Canada or imported. There are no explicit requirements for importation.
Importation and exportation of genetically modified animals, organs, tissues or cellsThe importation of animals into Canada is governed primarily by the Health of Animals Act and Regulations. The aim of this legislation is to prevent the introduction of animal diseases into Canadian livestock. Controls over the importation of genetically modified animals are only imposed at this level.
Infection risks controls
There is currently no explicit federal legislation in Canada addressing xenotransplantation infection risk controls.
Indemnity, responsibility and compensation rights in the event of a xenozoonosis
There is currently no federal legislation in Canada addressing indemnity, responsibility and compensation rights in the event of xenozoonosis.
Framework to deal with xenotransplantation research
There is currently no explicit legislative framework to deal with xenotransplantation research in Canada.
Framework to deal with clinical xenotransplantation protocols
There is currently no explicit legal framework in place to deal with clinical xenotransplantation protocols.
The draft Proposed Canadian Standard for Xenotransplantation defines the steps that should be followed in order to review xenotransplantation and to determine the safety, efficacy and ethical standards. The Proposed Standard has not yet been adopted by government.
Measures in the event of a cross species infection or a xenozoonosis epidemic
There is currently no legal framework in place to deal with the event of a cross-species infection or xenozoonosis epidemic. However, methods for infection control and safety are described in the draft Proposed Canadian Standard for Xenotransplantation (see above).