On February 4, 1999, The Islet Foundation had a chance to present its case in favour of xenotransplantation to the Standing Committee on Health in the Canadian House of Commons in Ottawa. The committee consists of select members of parliament who have been charged with improving the organ and tissue transplantation system in Canada. TIF had an opportunity to make its case for a timely completion of xenotransplantation guidelines, and to demand that only science and consistent ethical principles should be part of the process.

Several of the Members of Parliament within the committee raised the issue of xenotransplantation even before the TIF presentation. In every case, xenotransplantation was discussed in a positive light as a potential contributor to solving the organ supply problem. After the presentation, the members asked excellent questions, and were generally unsympathetic to the rhetorical and unscientific attacks on xenotransplantation carried out by its various opponents. 

Both the speech and the accompanying brief are presented below.

Xenotransplantation, the transplanting of tissue and organs from pigs to people, may be the most important development for solving the accelerating gap between supply and demand for transplanted organs. Diabetes is responsible for 29 percent of kidney transplants. Soon, xenografts of insulin-producing islets from pigs may be able to reverse diabetes, and prevent the kidney damage that inevitably leads to an organ transplant. 

In the longer term, whole organs from clean, purpose-bred pigs could result in a disease-free source of organs that are available on demand and safer than human-to-human transplants. 

Xenotransplantation can deliver life-saving health benefits to Canadians, save billions of dollars in health costs, and dramatically improve the safety and availability of transplanted organs. Yet, xenotransplantation is being opposed by a vociferous group that includes well-meaning individuals, political activists, and various extremists. This opportunity will be lost to Canada unless rational xenotransplantation guidelines based on science and on consistent ethical principles are put in place to allow clinical trials to proceed immediately. Children and adults must not be denied these life-saving advances in order to appease groups opposed to the humane use of animal products for human health.

To assure that Canada plays a leading role in the emerging field of xenotransplantation, our government must show leadership. Our government must demand scientific evidence from groups resisting xenotransplantation, and reject any arguments that cannot be supported by reason and by consistent ethical principles. 

As the government drafts its xenotransplantation guidelines, it will hear arguments and even threats from various groups who wish to prevent advances in this area. It is worth taking a moment to consider the merits of their various arguments.

The specter of widespread disease transmission presented by the opponents of xenotransplantation is utterly without merit, and yet almost every media story on xenotransplantation raises this fear. To date, thousands of people have received living pig tissue, including skin to treat burns, liver cells to treat liver disease, islets to treat diabetes, and neurons for Parkinson’s disease. In the 1920s and 1930s, people with diabetes injected non-sterile pig insulin. In all these thousands of so-called opportunities for transmission of pig disease to humans, not a single case of infection has emerged. 

Animal rights groups have stated that it is unethical to use animal tissue to treat human disease. Yet, can a society that uses pigs for suede, bristles and bacon, prohibit using the same animal to save a child from the horrors of diabetes? 

Xenotransplantation must not face an unrealistically higher test of public safety than everyday medical procedures. Today, we do not deny medical care to people with AIDS despite the very real and demonstrated risk of disease transmission to medical staff and ultimately to the general public. Based on fears that are purely speculative and have never once been demonstrated, how can we deny medical advancement to people with diabetes and other diseases that may only be treatable using xenografts? Such a selective and unscientific prohibition would be both discriminatory and unconstitutional.

Xenotransplantation, like any medical practice, must be regulated. If Canada creates regulations that are overly restrictive or delayed, we will face the prospect of desperate Canadians becoming unregulated "transplant tourists" in less vigilant jurisdictions. 

At the advent of any new medical development -- including water fluoridation, blood transfusions, animal insulin, organ transplants, and genetic engineering – there were people making dire predictions and calling for prohibition. If their wills had prevailed, many of us would not be alive for this debate. Our government must be unmoved by the voices of hysteria and fear of change, and listen only to arguments that can be supported by science and by consistent ethical principles.

Thank you.

Xenotransplantation, the transplanting of tissue and organs from pigs into people, may be the most important development for solving the accelerating gap between supply and demand for transplant organs. Diabetes is responsible for 29 percent of kidney transplants. Soon, xenografts of pig islets may be able to reverse diabetes, and prevent the kidney damage that inevitably leads to an organ transplant. In the longer term, whole organs from clean, purpose-bred pigs could result in a disease-free source of organs that are available on demand and much safer than human-to-human transplants. This opportunity will be lost to Canada unless rational xenotransplantation guidelines based on science and consistent ethical principals are put in place to allow clinical trials to proceed. Children and adults must not be denied these life-saving advances in order to appease extremist groups opposed to the humane use of animal products for human health.

 

Contents

Introduction

Diabetes is a disease that has profound implications for Canada's organ procurement and transplantation system. In 1996, diabetes alone accounted for 29 percent of all transplanted kidneys from brain dead donors. In the United States as of January 9, 1999, 40,545 people with renal failure were waiting for kidney transplants. On the supply side, in all of 1997 a total of 11,458 kidney transplants were performed. For people and their families awaiting organs, these statistics mean suffering, anxiety, and all too often, death. Proportionally, the picture for Canada is similar.

What if the massive demand for organs created by diabetes could be eliminated? What would this mean for closing the accelerating gap between organ supply and demand? Today, there is the possibility of restoring normal blood glucose control to people with diabetes, and thereby to end the destruction of their kidneys and the other devastating complications of this disease.

Ironically, the best hope for restoring normal blood glucose control involves transplantation, yet has no impact on existing organ demand. Xenotransplantation, the grafting of animal tissue into humans, is one of the best hopes for curing diabetes. Diabetes is a disease in which a person's immune system erroneously destroys the insulin-producing islets. The only cure lies in replacing those dead islets with living islets. Just as people with diabetes have attempted to crudely control their blood glucose through the injection of pig insulin for 77 years, it may be possible to transplant the islets that produced that insulin in the first place. The recipient would again enjoy normal blood sugar control, with insulin production precisely adjusted on a second-to-second basis in response to changing physiological conditions. Eliminating the wild swings in blood sugar that are a part of all externally administered insulin regimens will reduce or eliminate the inevitable consequences of diabetes, including the destruction of kidneys.

Pig islets have the potential to cure diabetes, and to thereby relieve the organ procurement and transplantation system of the massive load imposed by this disease.

Allotransplantation, the grafting of organs from human donors, has been a victim of its own success.  The transplanting of organs such as kidneys, hearts, livers, lungs, pancreases, and lungs has saved so many lives that the demand for human organs is outstripping the supply by an accelerating margin. More people are dying each year while waiting for a suitable organ donor.  Even Spain and Austria, with the highest organ donation rates in the world, are unable to control the growing gap between supply and demand.

To bridge the gap between organ supply and demand, xenotransplantation is the only real hope.  Not only can xenotransplantation of islets reduce the demand for kidneys, but in the future, pigs may also provide an on-demand source of life-saving tissue and organs for dying adults and children. In addition, xenotransplantation offers the possibility of treating diseases, such as diabetes and Parkinson's disease, that were hitherto not considered treatable through transplantation. 

The Xenotransplantation Spectrum

Xenotransplantation, like any new medical technology, comes with enormous promise and some unknowns.  The one risk identified is zoonotic infection resulting from a virus or other pathogen that crosses the species barrier and infects the human host, specifically the Pig Endogenous Retrovirus, or PERV. The remote chance of an infection that causes disease only in the new host would not necessarily create any ethical concern, since the recipient was deriving benefit from the transplant.  The ethical issue centres on the possibility that the zoonotic infection could be spread to other humans who did not derive the same benefit as the recipient. 

Some observers of xenotransplantation have expressed concern about the use of non-human primates, especially baboons and monkeys, as organ donors, as well as the fact that the recipient would be heavily immunosuppressed.  It is important to realize that xenotransplantation is not a monolithic body of science, uniform in its risk and benefit.  In fact, xenotransplantation reflects a whole spectrum of activity, ranging from pig islets without immunosuppression at the safest end of the spectrum, to baboon heart transplants with immunosuppression at the riskiest end of the spectrum.  The difference between those two extremes of xenotransplantation is greater than the difference between xenotransplantation and allotransplantation. To regulate and practice these extremes as if they shared the same risk/benefit profile would squander a unique opportunity to safely deliver demonstrable benefit from xenografts in the near term. 

Xenotransplantation offers greater opportunity to reduce the gap between demand and supply of organs than just about any other medical or procedural advance. In the short term, up to 29 percent of kidney transplants could be eliminated. In the longer term, organs such as hearts, livers, and kidneys could be immediately available to patients as soon as they are needed.

The following table compares the extremes in xenotransplantation.  The wide range of risk profiles clearly demonstrates that one set of guidelines targeting the worst case will never work. 
 

Based on actual testing of people who have received living pig tissue over the past decade,  as well as historical evidence of safety, the risk of PERV infection is now generally seen as much smaller than the risks inherent in many everyday medical practices. Most regulatory agencies, including the US Food and Drug Administration, are now supportive of xenotransplantation under conditions of reasonable testing and archiving.
 

The First Xenotransplant Trials

Xenotransplantation is a relatively new science with great promise.  The question arises: What should the first clinical trials of xenotransplantation be?  Just as nobody started selling tickets to cross the Atlantic immediately after the Wright brothers managed 20 seconds of bumpy flight at Kitty Hawk, the first xenografts should be selected for the maximum chance of success and the minimum risk of an adverse outcome.  There can be a strong case made that islet xenografts are the logical first choice.  Although whole organ xenografts will provide tremendous life-saving potential, they represent a greater challenge and more unknowns than islet xenografts.  By demonstrating success and safety in the least challenging end of the xenotransplantation spectrum, both governments and the public will be more supportive of whole organ xenografts. 

The following table compares islets to whole organ xenografts in terms of challenge, risk, rejection potential, efficacy, track record, compatibility, and public response.  The whole field of xenotransplantation would benefit from an early success, such as reversing diabetes. 
 

It now appears that clinical trials of xenotransplantation will be allowed to proceed in most countries under guidelines that assure adequate record keeping, reporting of adverse events, archiving of donor and recipient biologic samples, safe and humane animal management, long-term monitoring of recipients, and other procedures intended to reduce or eliminate risks

The Xenotransplantation Debate - Science or Superstition?

Xenotransplantation is a new field of medicine. Like many new advances, from organ transplants to powered flight to genetic engineering, fear of the unknown has lead to vociferous opposition from small, but effective, groups. Such opposition has been active against xenotransplantation. As recently as one year ago, these voices had gained the spotlight and were exerting a significant influence on government regulatory bodies. Today, their arguments have been thoroughly examined in the United States and elsewhere, and it appears that the medical opportunities presented by xenotransplantation will be supported and pursued.

No doubt, these voices will be heard as Canada develops its regulatory framework for xenotransplantation. It is important to examine each of the arguments used, and to see if they represent a rational and defensible case against this life-saving opportunity, an opportunity that may do much to alleviate the tragic problems inherent in our organ procurement and transplantation system.

Xenotransplants have a clean track record…
In 1998, sensitive assays were performed on people who had received living pig cells. The objective was to see if there was any evidence of infection by pig viruses. The New Scientist (8 August 1998 Vol. 159 No. 2146) reported the results of this study. Below are excerpts from the article: 

Transplants of pig islets into a number of humans in the United States, New Zealand, and Sweden have produced no adverse effects from pathogen crossover, despite the fact that many recipients were immunosuppressed, and hence much more susceptible to infection. Dr. Anthony Sun at the University of Toronto has successfully reversed diabetes in monkeys, our primate cousins, using microencapsulated pig islets.  Even though these islets were harvested from slaughterhouse pigs under non-optimum conditions, the monkeys experienced no adverse effects as a result of the transplants. 

Similarly, pig skin has been used for graft purposes on serious burns in many thousands of cases, and there has been no evidence of pathogen transmissibility. 

Another comforting body of evidence lies in the thousands of lab animals that have been transplanted with pig tissue, with a total absence of retroviral transfection. Laboratories around the world have been implanting pig tissue into mice, rats, rabbits, dogs, monkeys and other animals for decades.  Many of these animals were severely immunosuppressed and some, such as SCID mice, had no immune system at all.  Yet even given these ideal opportunities, porcine retroviruses produced no infection. If retroviral infection were to be a real issue, then we would have seen infection not only in the animals themselves, but likely also in their human handlers who suffer periodic bites and other opportunities for transfection. 

In the early decades of using pig insulin to treat diabetes, many people received daily injections of insulin that was not completely sterilized. Neither these people nor their intimate contacts exhibited any evidence of new disease not found in the general population.

Thus, not only has retrovirus infection of humans never been demonstrated through centuries of intermingling, but actual xenografts have failed to infect any recipient. 

Human infection by pigs has never been a public health issue…
The risk of infection of human beings by pig viruses such as Pig Endogenous Retrovirus (PERV) has been present for hundreds of years.  Humans have butchered pigs over the centuries, with literally millions of opportunities for viruses to enter human bodies through wounds and lesions.  Even in the massive industrial meat packing operations of this century, with each worker butchering hundreds of pigs every day, PERV infection of a human being has never been a public health issue.  In other words, there have been millions of inadvertent experiments seeking adverse clinical outcomes as a result of PERV infection on many millions of people.  If PERV could infect humans, it would have done so by now. 

AIDS was not caused by xenotransplantation…
Those opposing islet xenotransplantation frequently talk about the scourge of AIDS.  It is important to remember that AIDS was not caused by the transplantation of animal tissue into people.  The Human Immunodeficiency Virus (HIV) found its way into humans through existing pathways. Islet xenotransplantation is not some new pathway where none existed before, and to use the specter of AIDS as a bogeyman against this procedure is irresponsible scare-mongering without any scientific integrity. 

Mad Cow Disease…
Some opponents of xenotransplantation have cited Mad Cow Disease as an example of animal diseases infecting humans with disastrous consequences.  Once again, the pathway through which this disease was spread was not xenotransplants, but was the feeding of diseased animal protein to cows.  Such an infection pathway has absolutely no relevance to xenotransplants, since the cost of islets is insignificant compared to their benefit, and there will be no economic pressure to use diseased donors. 

Medical science is all about risk and benefit…
Every medical advance and procedure carries both risk and benefit.  When the benefit outweighs the risk, we progress. To deny islet xenotransplantation to people with diabetes is to ignore the profound benefits while irresponsibly exaggerating the undemonstrated risks. 

Consider medical practices that are performed every day.  Normal organ transplantation -- even a blood transfusion -- carries the risk of infecting the recipient with every pathogen present in the donor, including infectious HIV and hepatitis.  Today, people with AIDS are routinely treated at hospitals, despite the risk of infection to medical staff and their intimate contacts  These are not some abstract theoretical risks, but real dangers that have unfortunately been demonstrated many times.  Yet even this public health danger does not stop us from performing organ transplants or providing medical care to people with AIDS.  As a society, we have made the rational decision that the benefits outweigh the risks, however real those risks may be.

The last significant advance in the treatment of diabetes was the discovery of insulin over 75 years ago by Banting and Best.  Their practice of "injecting the filthy juices of dogs and pigs into children" was ridiculed and opposed back in 1921.  Fortunately, science prevailed, and animal insulin saved hundreds of thousands of children from a merciless death.

We should all be grateful that voices like the present xenotransplant opponents' were not heeded at the introduction of animal insulin or blood transfusions or organ transplants or water fluoridation or any number of other medical advances.  If they had been, many of us would not be alive for this debate. 

Pigs are cleaner than people…
As organ donors, pigs are a much safer source than human cadavers.  Pigs can be bred in a specific-pathogen-free environment to optimize the safety of their tissue for transplants.  We have no control over the lives led by human donors, or the safety of their organs after brain death. There are very few viruses that can cross from pigs to humans, and only pig tissue that is free of such viruses will be used.  Because pig tissue is so plentiful and cheap, it is possible to test extensively and to accept only the most pathogen-free sources. 

Islet xenotransplant recipients retain a healthy immune system…
In most cases of organ transplant, the recipient is required to take life-long immunosuppressant drugs to prevent rejection of the transplanted tissue.  As a result of a weakened immune system, the recipient is much more prone to infections and to certain types of cancer.  Many of the concerns expressed about xenotransplantation are based on the expectation that the recipient will be immunosuppressed, whereas this is not the case.  Because islet xenotransplantation uses immunobarriers to protect the islets from rejection, the recipient retains a normal healthy immune system.  Therefore, any later infections are as controllable as in the general population and no additional public health risk is created. 

An improbable chain of events...
Before PERV infection from islet xenotransplantation ever becomes a public health issue, a series of conditions must be met.  To endanger the public, all the following questions must be answered with a yes.  Has PERV actually ever infected a human being?  If PERV infection is possible, is PERV replication-competent?  If it is replication-competent, can PERV actually cause disease? If it can cause disease, can the disease spread to other humans?  Considering that science cannot even answer yes to the first question, it is irresponsible to conclude that a prohibitive risk exists in the face of such overwhelming benefit to society. 

Immunobarriers also block retroviruses...
In islet xenotransplants, immunobarriers are used to protect the islets from the recipient's immune system.  These barriers encapsulate the islets and have pore sizes thousands of times smaller than any retroviruses that may be trapped inside, thereby providing an additional, though unnecessary, level of protection against retrovirus infection. 

Pigs are not primates…
Much of the fear of xenotransplantation derives from the proposed use of baboons and other primates as organ donors.  Because humans are also primates, the number of viruses than can cross from a primate donor to a human recipient is similar to a human-to-human transplant.  Pigs, on the other hand, are not primates and the species barrier is yet further protection against infection. 

There is no animal rights issue…
Some have questioned the ethics of sacrificing pigs to cure human disease.  Surely it is more ethical to sacrifice a pig to spare a child the horrors of diabetes, than it is to slaughter pigs for bacon, suede, and paint brushes.

Ethics must be applied consistently …
People with diabetes and other diseases cannot, under the Canadian constitution, be denied treatment on a discriminatory basis. Health risks to the general public are accepted as part of our everyday life. Do we deny Canadians the right to travel to countries where ebola virus is present? Do we deny health care to people with AIDS because of the risk to the general public? Do we enforce lifelong tracking and restrictions on these people? These risks are real, not theoretical. For people with diabetes and other diseases who could benefit from xenotransplantation, we must not take away the rights enjoyed by other Canadians based on fears that are purely speculative and have never once been demonstrated.

Conclusion & Recommendations

All progress entails some risk, and to avoid all risk is to kill progress.  We know the risks of diabetes – blindness, kidney failure, heart disease, amputation, birth defects – as well as the staggering healthcare costs (over C$12 billion per year in Canada and US$100 billion per year in the US) and productivity losses.  We know the tragedy of an organ transplant system that all too often depends on the death of a young, healthy person to extend the life of a sick person. Clinical trials of islet xenotransplantation are such a small and manageable risk compared to these horrible and near certain outcomes.

Islet xenotransplantation has the potential to reduce the demand for kidney grafts by 29 percent, and to provide considerable relief to the organ management system. Xenotransplantation of other tissue and organs may some day eliminate the agonizing delays, tragic deaths, and disease transmission that inevitably result from human-to-human organ transplants.

To assure that all Canadians enjoy the benefits of well-regulated xenografts, our government must:

1. Adopt a regulatory framework for xenotransplantation that addresses only real and demonstrable risks, and is not hobbled or delayed by a perceived need to appease extremist groups, especially those who threaten violence and harassment;

 
2. Start with the xenotransplantation guidelines of another country, such as the United States, as a springboard to assure we do not "re-invent the wheel" and allow unnecessary death and suffering to continue;

 
3. Avoid the specter of desperate Canadians becoming unregulated "transplant tourists" in less restrictive jurisdictions by (1) harmonizing guidelines with other countries, especially the United States, and (2) eliminating bureaucratic delays in creating the guidelines; 

 
4. Assure that people who can benefit from xenotransplantaion are not denied treatment on an unconstitutional and discriminatory basis as a result of guidelines that apply an unrealistic test of public safety compared to everyday medical practice enjoyed by others; and

 
5. Provide federal tax incentives and funding for xenotransplantation research, especially cellular xenografts such as islet and liver cells, both of which have the potential to deliver enormous benefit in the near term.