Humane Charities List 

"Primum  non  nocere"  (Latin)  -  Hippocrates.  "First, do no harm."

Humane Charities Australia's submission to the NH&MRC on

Draft Guidelines and Discussion Paper on Clinical Xenotransplantation Research

Humane Charities Australia welcomes this opportunity to provide comment on the draft guidelines and discussion paper on xenotransplantation.

First, by means of introduction, Humane Charities Australia was established in June 2002 and is currently in the process of being incorporated.  Its purpose is to provide a source of information on health charities that do not fund animal experiments, so that vital funding can be redirected towards more ethical and scientifically-valid research.  At the onset, I should stipulate that our position is of total opposition to the use of non-human animals for the purpose of medical research into human health, including xenotransplantation.  This is on both ethical and scientific grounds.

We understand that with xenotransplantation being a relatively ‘unconquered’ area of medical science there may be much prestige to be gained in discovering key elements to its process and that major funding is therefore being injected into this area through powerful vested interests. We hope that these would not be the key motivating factors to continue further studies in this area, and that the overall objective would be to achieve the highest level of health care and the least amount of suffering. We do not consider that proceeding with research into xenotransplantation would be the most appropriate and practical way to achieve this end goal.

Ethics

Humane Charities Australia feels it is important first to dispute the right to use non-human animals as tools for research and indeed to be farmed for ‘spare parts’.  Because of this view, it may be noted that we refer to the use of source animals rather than donor animals throughout this document. This is due to the fact that they are not providing consent and are therefore not donating their organs.

Generally speaking, humans regard their own lives as having greater value than non-human animals - presumably because of our supposed higher level of intelligence, communication skills and ability for reasoning.  If however, another species were to emerge (hypothetically) that demonstrated a higher intelligence and social structure than that of humans, would we then concede acceptance and allow ourselves to be utilised for their benefit? Presumably we would not, yet because non-human animals are unable to defend their own rights we use them to our advantage, as if their right to life is of no significant value.

We would also like to raise the question; would those researchers involved in clinical studies of xenotransplantation be prepared to carry out the same procedures on severely mentally retarded orphans (ie low level of intelligence and no family ties) as they would on non-human animals? If the response to this question is no, then this would illustrate a clear case of speciesism.

The words of Jeremy Bentham best summarise the ethics of animal use:

“ The day may come when the rest of animal creation may acquire those rights which never could have been withholden from them but by the hand of tyranny. The French have already discovered that the blackness of the skin is no reason why a human being should be abandoned without redress to the caprice of a tormentor. It may one day come to be recognised that the number of the legs, the villosity of the skin, or the termination of the os sacrum are reasons equally insufficient for abandoning a sensitive  being to the same fate.  What else is it that should trace the insuperable line? Is it the faculty of reason, or perhaps the faculty of discourse? But a full grown horse or dog is beyond comparison a more rational, as well as a more conversable animal, than an infant of a day or a week or even a month old. But suppose they were otherwise, what would it avail? The question is not, Can they reason? nor Can they talk? but, Can they suffer?”[1]

Even Dr Christian Barnard, a pioneer in organ transplantation was later opposed to the use of animals. “...I had bought two male chimps from a primate colony in Holland.  They lived next to each other in separate cages for several months before I used one as a donor.  When we put him to sleep in his cage in preparation for the operation, he chattered and cried incessantly. We attached no significance to this, but it must have made a great impression on his companion, for when we removed the body to the operating room, the other chimp wept bitterly and was inconsolable for days.

The incident made a deep impression on me. I vowed never again to experiment with such sensitive creatures.”[2]

How Far Will it go?

The transplantation of animal organs or cells into a human body raises another angle of ethical concern.  The cells produced by the implanted organ will not remain in the organ but instead will migrate throughout the entire body.  The organs will also produce animal rather than human proteins and other factors which will circulate further.  This ‘chimerism’, or creation of hybrids raises the following questions:

•     Where does the human end and the animal begin?

•     Will the individuals be afforded human or animal rights?

•     Will we in effect be creating a ‘sub-species’ of human?

•     Maybe future generations will farm the ‘sub-species’ for their own replacement organ supply?

This may all sound like science fiction, but the consideration of clinical studies of xenotransplantation means that the process has already begun!

Animal Welfare

In a Victorian radio interview on 3AW with Stan Zemanek, Dr Kerry Breen, Chairperson of the Australian Health Ethics Committee, estimated that the number of animals to be used in clinical studies would probably be in the hundreds.  However, what of the many animals including rats, mice, rabbits and dogs that would be used in pre-clinical studies of genetic modification? What of those used in the development of the improved immunosuppressant drugs that will be required? What of the number of pigs and baboons to be used in the pre-clinical procedures? And what of the pigs to be used in the actual clinical transplants?  We envisage that these animals would constitute a significantly higher number than that indicated by Dr Breen.

Importation of Primates

It has been suggested that, due to the small supply of primates available for pre-clinical studies, an extensive breeding program be established in Australia. However, due to the gestation period of primates, many will need to be imported from overseas to satisfy the immediate need.  No primates had been imported into Australia for research for over 10 years, until July 2000 when 20 pig-tailed macaques were imported from Indonesia for HIV research.

During long distance air travel many animals have suffered and died from heat, cold, hunger, thirst and the stress of being confined in small crates.  Animals sold are usually 10 months old and still dependent on their mothers. Removal of offspring can cause distress to both parent and offspring as well as the rest of the colony due to their advanced social structure.  Young primates form a close bond with their mothers and would suffer from extreme deprivation if reared in isolation.

Animals are often taken from the wild and resumption of a trade in CITES-listed species could put wild populations at risk of exploitation.[3]

Housing and Handling

Special husbandry and housing conditions required for transgenic source animals is a major welfare concern. Adherence to strict levels of hygiene and disease control will reduce access to the outside environment and minimise human contact.[4]  Will the pathogen-free housing mean that pigs will not have access to nesting and rooting materials - important requirements for their environmental enrichment?

Pigs will be born by caesarean section with their mothers being killed and the piglets will therefore never have the opportunity to suckle and bond with their parent.

Baboons, it has been mentioned, [page 59] are “very difficult to work with and usually require an anaesthetic for even simple examinations or blood sampling”.  This would suggest that they find the procedures stressful and would therefore be traumatised by the ordeal.  They would also suffer the consequences of being dosed with immunosuppressive drugs leaving them vulnerable to infection, or suffer rejection of the transplant organ over days or weeks.

Surgical Procedures

In the creation of transgenic source animals, animals suffer from the processes of surgical embryo retrieval and embryo transfer.

During the microinjection process for example, the host mother must be injected with hormones to ensure she is at the right stage of ovulation.  The significant manipulation of the animals ovulation and oestrus cycle that takes place to ensure the availability of adequate embryos can lead to over-stimulation of the ovaries causing painful ovarian cysts or enlarged ovaries.

Animals can also become considerably stressed from the exposure to additional hormones, collection of eggs and implanting of the fertilised eggs.

Due to a lack of efficiency in the microinjection process, genes can often fail to reach the right target cells within the embryo and can cause painful abnormalities or even death.

Further examples of how animals have suffered during the actual xenotransplant process:

Cynomolgus monkeys were implanted with hearts from transgenic pigs.  They survived up to 62 days, but received such high doses of immunosuppressive drugs that they were ‘sacrificed’ due to gastrointestinal complications.[5]

In a similar experiment, five monkeys who received transgenic hearts had to be killed due to “gastrointestinal toxicity, resulting in severe diarrhoea.”[6]

Behavioural Problems

The presence of a transgene may also affect the animal’s ability to perform normal behaviour.  Beltsville pigs for example (genetically modified to express additional growth hormones), experienced such extreme welfare problems that normal behaviour was impossible for them. They suffered from lethargy, lameness, lack of coordination, thickened skin, gastric ulcers, severe synovitis, degenerative joint disease, pericarditis and endocarditis, cardiomegaly, paraketosis, nephritis and pneumonia.[7] It is suggested in the discussion paper [page 42] that the genetic modification will involve “major changes to the source animal”.

Ethics Committees

The presence of ethics committees, and in particular inclusion of a category C member (animal welfare representative) is often used by researchers to promote a ‘clean’ image of the industry to the public - as an assurance that the care and use of animals is sanctioned by those with a concern for their welfare and/or rights.  However this is not the case. Most category C persons serving on an ethics committee are opposed to the use of animals in research. Their presence is to ensure that the animals are protected as much as possible but only within the scope of the Code of Practice. The committees are dominated by institutional members.  In 1998 a survey of category C members was conducted by Animals Australia.[8]  The responses received revealed that:

•     One third of respondents are “not happy with the way decisions are made” on their AEC;

•     Half stated that “researchers failed to adequately answer the most crucial questions on the proposal forms, particularly those dealing with justification for the research and the availability of alternatives or refinements”;

•     Half the respondents indicated that they had experienced “animosity or aggression from researchers on the AEC during decision making”; and

•     Almost that number also indicated that “pressure is brought to bear on them to go with the status quo”.

Private Enterprise

The sale of farmed animals as a private enterprise is another cause for concern. As with other farmed animals used for agricultural purposes it is often difficult to ensure that private owners are adhering to Codes of Practice and that welfare of the animals is given sufficient priority.  It is a well known fact that the housing and treatment of battery hens, meat chickens and breeding sows is hugely detrimental to the animals whose worth is only for the end products they supply. The battery egg, chickenmeat and pig industries are policed by the relevant codes of practice and the Prevention of Cruelty to Animals Acts yet their welfare is seriously compromised.  It can be assumed that transgenic pigs or any other source animals may be subject to the same shortcomings, and considered products or supplies rather than sentient animals.

Science

Danger of Animal-Based Research

The use of animals in medical research has a very shady history. Inter-species variation ensures that results from animal tests when extrapolated to humans are extremely unreliable. This has been acknowledged extensively within the discussion paper, and demonstrated throughout history as having disastrous effects on humans.  Thalidomide is probably the most infamous example, however there have been many others over the years which have shown that this an ongoing concern and not just an occasional error on the part of researchers and drug developers.

Whilst we acknowledge that medical knowledge has grown over the years, there will ALWAYS be variables that can affect the results of animal tests and render them inappropriate to extrapolate to human conditions.

Only recently, Premarin, believed to be a safe treatment for menopausal women, has been found to greatly increase the risk of breast cancer, heart disease, strokes and blood clots in the lungs.  Over nine million women worldwide have been prescribed Premarin as a hormone replacement therapy and in Australia alone, 300,000 have been urged to seek advice from their doctor.
One can wonder how far we may have progressed had it not been for the delays and deviations caused by animal-based research.

The problems with inter-species variation become even more apparent when applied to organ transplants.  Consider for example, the four most commonly transplanted organs - the liver, kidneys, lungs and heart.

The Liver - Variations exist in the liver enzymes that activate or detoxify drugs or chemicals, meaning that an animal liver recipient may be more susceptible to the toxic effects of chemicals or may under- or over-react to normal doses of medicines.  There are also differences in protein production, hormone activity and bile composition which may result in toxic effects on body tissues.  Patients can also suffer from blood clotting and problems with formation of red blood cells.

Kidneys - Due to the higher level of uric acid in the bloodstream than that in pigs, recipients can be susceptible to major problems with waste levels of uric acid in the blood, causing kidney stones or kidney failure.  Pig kidneys do not have the mechanism for controlling levels of medicine in circulation which is particularly of concern as xenotransplant recipients are likely to be more dependent on drugs.  Pig kidneys may also be incapable of stimulating red blood cell formation.  The differences in enzyme production and hormone activity can also affect blood pressure, hydration and fluid balance.

Lungs - The size of lungs is of great importance, If too small they may cause persistent leakage of gas and fluid, and if too large they can then collapse.  Obtaining the exact size can be difficult as they vary greatly among different pig breeds and their growth rate is unpredictable.

Heart - Size mismatches of hearts can cause life-threatening blood clots. A pigs heart normally pumps lower amounts of blood than is required by humans which can lead to organ failure and death.[9]

The problem with inter-species variation has been further exemplified on page xxxix of the discussion paper:” In rodents, diabetes has been successfully treated by transplanting pancreatic islet cells but this has not yet been successful in primates or large animal models. Nor has it been successful for approximately 12 participants who have received fetal pig islet tissue to date. A few patients have been treated with pig brain cells to treat Parkinson’s disease, with mixed results.”  [emphasis added] And again on page 54 “Although pancreatic islet xenotransplantation has been successful in rodents, there are no convincing data that pig islets can control blood sugar levels in large animal models or primates.”  These discrepancies raise the question of why non-human animals are being used in the first place?

Risk to the Wider Community

The uncertainty of risks of disease transmission, particularly across the species barrier, has already been acknowledged by researchers.  Clearly, this is not just a theoretical possibility but a very possible outcome.  AIDS is already believed to have been contracted from chimpanzees. BSE and Ebola viruses originated from cross-species contamination.  Some of the major flu epidemics from the start of last century were believed to have originated from pigs.  Porcine Endogenous Retrovirus (PERV) has already been discovered in the animals intended to be used as a source for organ donors. With continued emergence of new zoonoses from unexpected sources, the inability to diagnose potential xenozoonotic viruses with current tests and their unknown pathogenic behaviour, the chances of cross-species infection seems to be exceedingly and unacceptably high.  Even more alarming is that, even if detected, the viruses are largely untreatable.

Not only would clinical trials be exposing the organ (or tissue) recipient to major health risks, but these risks would also be extended to the recipient’s carers and families and the wider community.  Considering that viruses may initially show no obvious signs of disease and may spread beyond the recipient into the general population before they become evident, at what stage will researchers deem their patients as no longer carrying any risk?  And during that period before the disease is identified or acknowledged, how many people are likely to have been exposed to that disease?  We do not consider that the general public would be prepared to accept the risk of introducing another potentially untreatable human epidemic such as HIV/AIDS or bovine spongiform encephalopathy (BSE).  Certainly an individual has the right to expose themselves to any risks involved in scientific research but to further expose that risk to the wider community, who have NOT given consent, is highly unethical.  Indeed the number of individuals that could suffer and die from a new epidemic could greatly exceed those potential lives which xenotransplantation was supposed to have saved in the first place.

Also of particular concern is the containment of those who decide to withdraw from trials. Whilst we would consider that containment of an infected person against their will would likely be a breach of their human rights, to do otherwise would be exposing the wider community to the risk of contamination.

Finally, to quote Dr Tony D’Apice, vice president of the International Xenotransplantation Association, “At present, the risks are greater than the benefits, because we don’t know what the benefits are.” And Prof. Ian Macreadie, bioethicist at RMIT University (who incidentally also is supportive of xenotransplantation research) “We are likely to see some problems with infectious diseases emerge in time. There are things we don’t know or understand yet.”[10]

Other costs to the community

It has been mentioned briefly in the discussion paper that funding for xenotransplantation studies may likely divert resources from other medical services, however it was also mentioned that this is not within the scope of the discussion paper.  We would consider this issue to be of major relevance to the community.  How could funding research into an uncertain and risky subject, which is likely to benefit only a select few (if any), possibly be justified when other medical procedures are likely to be sacrificed in order for it to proceed?  There have already been concerns by the public in the past that hospital funding is insufficient to meet our current needs - eg a shortfall in hospital beds, operation waiting lists, outbreaks of disease due to insufficient staffing/cleaning.  We do not consider that the public would agree to further cutbacks to allow research into xenotransplants and believe that this issue would need to be explored in full to determine the real financial costs.

Alternatively, if funding is provided by the private sector (ie pharmaceutical companies) then there is a vested interest involved and then the best interests of the public may not be the main priority.

Survival rates amongst recipients of human organs are not particularly high.  25% of human heart recipients die within a year.  Half of all human lung recipients die within two years.[11]  Considering the  much higher compatibility and lesser health risks of using human organs there seems to be little hope of xenotransplantation being of any success.  Investing funding into such research therefore appears futile and a waste of valuable resources.

Alternatives

When we consider the high risks of disease and the ethical implications, it is inconceivable that clinical trials of xenotransplantation could be even considered to proceed when there are already a number of alternatives that are in various stages of development and/or use. Humane Charities Australia would certainly prefer to see the alternative options explored further.

Researchers have already acknowledged that allotransplantation is far safer than using materials from a different species. This eliminates the risk of zoonosis and also reduces the chance of the organs being rejected by the recipients body.  Clearly this is the best option for those in need.  The urgency to proceed with exploring xenotransplantation however, is due to the extreme shortage of organ donors within Australia.  As research into xenotransplantation will involve a great deal of time and money, we consider these resources would be of greater value if used to address the problem of human organ shortage.  There are a number of options:-

Greater availability

In Australia in 2000, 196 deceased people became organ donors.  They made up 0.15% of all people who had died during the year.  However it is estimated that up to 1% of people who die in a year might have the potential for organ donation.  This would indicate a potential increase of almost 670% in availability. 

According to the Australian Bureau of Statistics[12], there are a number of reasons that may account for the small number of donor organs available.

1.         Doctors do not ask that organs be donated after a patient has been determined to be brain dead.

2.         Relatives of the deceased have refused consent.

3.         Insufficient hospital procedures/equipment available. 

In South Australia, intensive care clinicians play an important role in maintaining intensive care patients and requesting donation, and emergency department procedures are also said to have contributed to the highest organ donation rate within Australia.[13]

In contrast to Australia’s low donation rate (10.2 per million population), Spain has the highest donation rate (33.9 per million population). This has been attributed to procedures introduced by a national transplant organisation set up in 1989, which included having donation coordinators in hospitals, training medical staff in requesting donation, and closely monitoring potential and actual donation.[14]  Spain, Belgium, France, Austria and Norway have also adopted a ‘presumed consent’ system of organ donation. Whilst this has been considered an unethical approach in the U.S. it should be an acceptable practice considering that everyone has the option of not allowing consent for their organs to be used if they so desire, and also considering the possibility of saving the lives of others.  The ‘presumed consent’ system also negates the need for doctors to intrude on the relatives grievance process - a time at which they may refuse removal of the deceased organs due to their emotional subjectivity.

Legislation could also be changed that currently allows objections from relatives, when the donor has previously registered as an organ donor, to prevent the organs from being used. Clearly if a person has given consent prior to their death then there should be no right for another to overturn that decision.

Reducing the demand

The estimate that demand for organs in developed countries is growing at 15% per year raises the question, why?[15]  Many of today’s health problems are generated by our choice of lifestyles.  Smoking, lack of exercise and consumption of animal products have all been acknowledged as being major contributing factors to such conditions as heart disease, stroke, cancer, diabetes and a range of other ailments.  By using our resources to promote healthier lifestyles we would be reducing the number of people who are in need of organ or tissue transplants.  Whilst we acknowledge that not all those on transplant waiting lists are there as the result of unhealthy lifestyles, with a healthier population, and thus fewer people waiting for transplants, the lower demand for organs and tissue would ensure that those people suffering from genetic ailments have a better chance of receiving a transplant.

Use of organs from ‘non-heart-beating donors’.

Doctors at University Hospital Zurich have discovered that kidneys transplanted from “cardiac death” donors are just as successful (in some cases more successful) than those transplanted from “brain dead” donors. They have estimated that the use of such organs could increase the availability of donor kidneys by up to 30%. Research currently underway on the liver, pancreas and lungs indicate that these too may be transplanted from a donor shortly after the heart has stopped beating.[16]

Living donors

Donation of organs from living persons is another option for kidneys and (partial) livers. This may also be promoted further by surgeons suggesting this option to patients and their relatives, and by hospitals having the required surgical equipment to perform such operations.

Development of artificial organs

Whilst this may be in the very early stages of development and is not likely to be used for some years - so too is xenotransplantation.

Artificial organs do not carry the risk of zoonosis and are considered less likely to cause rejection from the recipient’s body, thus eliminating the need for immunosuppression.

The above examples of alternatives to xenotransplantation illustrate that there ARE realistic, safer, less costly (in terms of health risks and finance) and more humane ways to address the current shortage of available human organs. Whilst Humane Charities Australia acknowledges the high cost of instigating and/or expanding the above alternatives, we would consider them to be less costly than to proceed with clinical studies of xenotransplantation - a procedure which would possibly benefit only a select few, carries dangerous health risks and has no guarantee of success.

Conclusion

Referring back to the principles of the (draft) guidelines [page xxi] the concerns raised in this submission, suggest that the following principles cannot be met:

•     the research must serve the common good;

A proportion of the community will always be opposed to xenotransplantation and will therefore not benefit from any favourable results. Many will also be unable to afford such procedures.  This, together with the number of animals to be used and the number of people that may be affected by any zoonosis or who suffer from the lack of other medical procedures (due to funding being redirected) would not qualify clinical studies of xenotransplantation as serving the ‘common good’.

•     the research must be scientifically sound;

•     the research must be based on relevant efficacy data from preclinical studies;

Data obtained from animal-based research cannot be considered either efficacious or scientifically sound when extrapolated to humans.

•     the benefits must justify any risks;

The perceived extension of lives of a select few cannot justify the risk of exposing the entire population to a potentially untreatable human epidemic.

•     the research must respect the dignity of participants.

The non-human participants involved in this research are not granted any dignity. Their use only encourages an ethically regressive view of animals and provides for commercial degradation of their lives.

In summary, based on the high risk of transmission of retroviruses and particularly the exposure to the wider community; the ethical and welfare issues concerning the use of animals; the limited level of acceptability by the public; the high cost in funding and resources; the probability of public funding being re-directed away from other urgent medical procedures; and considering the alternative and safer options that are already available, Humane Charities Australia cannot agree to clinical studies of xenotransplantation proceeding.

We therefore urge you to ensure that further research into the use of non-human animals for the purpose of organ transplants be abandoned immediately.  To continue with such research will merely be opening a Pandora’s box wrought with hidden dangers and untold cruelty.  Instead we hope that the NHMRC will encourage only humane and scientifically valid options such as those alternatives mentioned above.

Helen Rosser, National Coordinator, Humane Charities Australia Inc.         30 August 2002

Copyright © 2004 AAHR
Last modified: June 23, 2005