Xenotransplantation: Playing God Because At Least Somebody Should

According to the United Network for Organ Sharing (UNOS) statistics, there are about 114,600 people in need of an organ transplantation in the US. About 20 die waiting each day. This year over 24,200 transplant have been performed and over 11,600 donors took part, but the shortage of organs and tissues is apparent. This problem is of course not endemic for the US.

There are certain solutions to the situation and by all means the problem is multi-faceted, but the one we are focusing on in this article is what’s called xenotransplantation.

What Is Xenotransplantation?

Basically, xenotransplantation is transplantation of organs, tissues, or cells between organisms of different species. Typically, it means that grafts are taken from animal donors and planted into human patients.

“Xenotransplantation, animal to human, defined as living cells, tissues or organs of animal origin and human body fluids, cells, tissues or organs that have ex vivo with these living, xenogeneic materials, has the potential to constitute an alternative to material of human origin and bridge the shortfall in human material for transplantation,” reads the respective section of the World Health Organization website.

The concept itself is not new and dates back to the late 17th century, to the first known report by Dutch surgeon Job Janszoon van Meekeren about using a fragment of a dog bone to mend Russian soldier’s skull. Since then blood transfusion from different species was administered to patients with a whole range of pathologies and since 19th century  doctors began to transplant animal skin to humans. Yet, the results of such operations were mixed.

A somewhat more modern stage in xenotransplantation development started in the 20th century, in part thanks to the work of the French experimental surgeon Alexis Carrel who developed surgical techniques for connecting blood vessels.

In the 1960s an American transplant surgeon Keith Reemtsma began working on the idea of using nonhuman primate kidneys to save patients with kidney failure. He carried out 13 transplants, but most of them failed in 4–8 weeks because of the graft rejection or infectious diseases, as the immunosuppressive needed to avoid rejection were underdeveloped and left patients susceptible to diseases. One of Reemtsma’s patients survived 9 months after the surgery and returned to normal life, but died from an acute electrolyte disturbance, which could be indirectly related to the transplant. Thomas E. Starzl and several other specialists predominantly from the US and France had also worked with xenotransplants from nonhuman primates, but didn’t achieve reliable long-term patient survival.

Subsequently, scientists and surgeons shifted focus from primates — human closest genetic kin — to pigs bred in vast numbers to be slaughtered and eaten. There were multiple reasons to disregard said genetic resemblance. Organs from adult chimpanzees and baboons were too small for adult humans, the genetic similarities between primates implied higher risk of spreading infectious diseases, pigs were easier and faster to breed than primates and were more favorable in terms of ethics. Currently pigs are the most promising donor species.

The bulk of preclinical trials on the matter is performed from pigs to nonhuman primates, as the latter are still close enough to humans for the results to be representative. As an example, animal patients with Parkinsonian symptoms are reported to be getting better after unilateral implantation of genetically modified pig neuronal cells. As for the clinical trials involving humans, one is under way in Argentina and the other in New Zealand, where non-immunosuppressed recipients receive implants of intraperitoneal alginate-encapsulated porcine islets. In human language it means that people receive clusters of porcine pancreas cells that produce hormones and are very important in dealing with sugar.

Aside of that, the World Health Organization notes that there are multiple cases of unregulated xenotransplantation being advertised and carried out across the world. These instances, however, have no credible evidence of efficacy and are “ignoring the requirements expressed in the Changsha Communiqué and run contrary to the spirit and letter of most guidance documents governing xenotransplantation clinical trials.” To be fair, the WHO also mentioned that “no specific health risks or suspicious pandemic or epidemic syndromes have been detected in association with these xenotransplantation activities, or been reported from the jurisdictions where they are known to be occurring.”

Scientists are confidently moving towards viable and safe ways of xenotransplantation and preclinical trials involving nonhuman primates are promising. However, there is a number of concerns to be addressed before it becomes a real practical solution adopted far and wide.

How Is It Still Not Ubiquitous?

There are two primary reasons to be cautious about xenotransplantation: rejection of grafts by the recipient’s immune system and the possibility of transmitting infectious diseases from donor animals.

When it comes to implanting grafts from pigs into humans, there is a significant chance that the recipient’s immune system will detect alien tissues and start fighting it, resulting in graft rejection. In case of pig tissues, scientists have found out specific compounds present on the membranes of pigs’ cells that are triggering the immune response. However, thanks to genetic engineering, by 2020 scientists bred a generation of transgenic pigs without said compound. This advance gave rise to the new wave of xenotransplantation research and now numerous groups are working on transplantation of genetically modified pig grafts into nonhuman primates to see if it is good enough for human patients. Another method of avoiding harsh immune response in the recipient is called the tolerance approach. This method basically makes the recipient’s immune system recognize the graft as its own self. The key part of it is to introduce pig bone marrow containing progenitor immune cells into the recipient and let those cells develop into mature immune cells that will not attack the pig graft.

The second problem is the diseases human recipients may get from the grafts originating from other species, namely, the Porcine Endogenous Retrovirus (PERV). This virus is able to infect human cells and can possibly lead to epidemic in human populations. In fact, it was the reason why most of the biotech companies stopped their research and closed labs in the early 2000’s. The promising solution came in form of so-called gnotobiotic pigs. Gnotobiotic animals are the specimen born and raised in a sterile environment. Scientists know every strain of microorganisms present in such specimen, hence the name. A company called eGenesis managed to create 37 healthy gnotobiotic piglets that were completely free of PERV.

“This work provides a promising first step in the development of genetic strategies for creating strains of pigs where the risk of transmission of retroviruses has been eliminated,” said professor Ian McConnell from the University of Cambridge.

Yet, while these fundamental concerns are being solved step by step, there are other things to overcome before xenotransplantation becomes readily available to patients in need.

The Ethics Behind Xenotransplantation

The ethical concerns behind xenotransplantation mostly focus on the issues of religion and animal rights. In some cultures and religions, such as Islam or Judaism, pigs are seen as unclean animals, so the question of transplanting a heart from a pig to a person who adheres to those views may be questionable from the point of view of said person’s beliefs.

The issue of animal rights may be questionable as there is a very thin line between breeding animals for food and breeding them for organs. Either way, the animal has to die in order to deliver the necessary goods. So, if a person is a vegetarian or a vegan, they may see it as the main ethical obstacle for accepting this practice.

The most complex problem here, however, is the issue of self-realization. Some people may just feel very uncomfortable knowing they literally have a heart of the pig. This also may dilute the line between humans and animals. Even though, technically speaking, any human being is an animal just because he or she is not a fungus or a tree, some people may find it hard to accept someone with animal organs as a “real human”, which in turn infringes on the question of what actually makes human a human, and may entail even some elements of xenophobia.

The issue of ethics is sometimes covered by professional codes of conduct. For instance, the American Medical Association has its own code of ethics when it comes to xenotransplantation. Among other things, it encourages the members of the association to act as follows:

• Encourage education and public discussion of xenotransplantation
• Ensure that research in which they participate is well designed and adheres to institutional review board requirements, applicable national guidelines, and ethical standards
• Ensure that research in which they participate is adequately funded
• Ensure that recruitment is restricted to patients with serious or life-threatening conditions for whom no adequately safe and effective alternative therapies are available unless there is documented, very high assurance of safety.
• Ensure that if participation by individuals who lack decision-making capacity is contemplated, appropriate measures are taken to safeguard their interests
• Ensure that participants are informed about and consent to the unique risks and burdens posed by xenotransplantation
• Ensure that high standards of care and humane treatment of all animals used in research are upheld.

The matters of religion are also involved in the widespread criticism of xenotransplantation which is often branded as “playing God.” However, as it is a part of a centuries-long debate on whether there is any God, and neither point of view is universally accepted and provable, the ethical debate may turn philosophical, which can hardly solve the problem that originated it.

Legal Issues

Basically, as the entire method is not widespread, there is not much regulations to govern it. However, xenotransplantology has undergone preclinic testing and proved efficient under those conditions. So, as a result, there are some general guidelines in some jurisdictions that focus on some general matters without much delving into any specific issues.

First of all, the World Health Organization, which is a part of the UN, has issued a resolution in 2004 that urges the member states to allow any xenotransplantation practices only when a proper regulation is developed for their national level. This requirement is among the most popular in most legal documents related to the issue.

In 2008, the Changsha Communique of the WHO has expanded the list of recommendations, which now included:

1. Member States should review their laws to determine whether they have adequate authority to regulate xenotransplantation, ban unregulated xenotransplantation and provide appropriate sanction for failure to comply.
2. Member States should assess whether they have the resources and capacity to regulate xenotransplantation effectively. If they do not have such resources and capacity, they should ban xenotransplantation in their territories.
3. If a Member State has the capacity to regulate xenotransplantation and believes xenotransplantation should be carried out, it should ensure there is an effective national registry and regulatory process in place.

In 2011, the Second Global Consultation confirmed that those recommendations remain in force.

The developments on national levels also took place. Thus, in the US the xenotransplantation matters are regulated by the FDA, which includes the investigational use of extracorporeal hemoperfusion for patients with fulminant liver failure, and the transplantation of fetal pig neuronal cells into patients with serious neurological ailments, such as refractory Parkinson’s disease.

In the EU, the authorities were very cautious about xenotransplantation and the infection risks it may create, so they issued certain recommendations as to how the EU member states should proceed in this area. Those recommendations by the Committee of Ministers include, among other things, the following:

• No xenotransplantation should be carried out in a member state that does not provide regulation for xenotransplantation activities in conformity with the provisions of this recommendation.
• No xenotransplantation activity should be carried out in a member state unless authorization is given by a body officially recognized as competent for this purpose
• No xenotransplantation should be carried out unless it is undertaken by an accredited team in an authorized center.
• Member states should have a plan in place to address any events, in particular of infection, possibly related to a xenotransplantation which could compromise public health.
• Patients participating in a xenotransplantation should be adequately informed in a comprehensible manner of the nature, objectives, possible benefits, potential risks and consequences of the procedure, as well as of any constraints that may be linked to it
• No xenotransplantation should be carried out without the documented, specific, free and informed consent of the patient
• The husbandry and care for all animals used in xenotransplantation should take account of their physiological, social and behavioral needs and should be designed to ensure their well being, particularly where breeding animals are maintained for long periods. The pain, suffering or distress and the number of animals used should be minimized.

Additionally, the Committee called the member states to actively ensure all issues associated with xenotransplantation are properly discussed by the public, which should be well informed about all relevant medical, psychological, cultural, ethical, legal, social, and economic implications involved in those matters.

Conclusion

The biggest challenge for xenotransplantology, if it ever kicks off, is not tackling purely medical and scientific issues, but to overcome the general prejudice against it. Whether it is based on religious or ethical views or just a somewhat understandable unwillingness to “be partially a pig,” this distrust to the prospects of xenotransplantation eventually leads to regulatory problems.

Currently, there is no detailed regulatory framework in this regard, if we don’t count several resolutions that have no legally binding power and simply outline the general recommendations as to the matter. They point out to somewhat obvious things like the need to do everything properly, to establish national regulations, to prevent possible complications, and to make sure the general public duly understands what xenotransplantation is all about.

So, even though scientifically it wouldn’t be too much of a problem to create and maintain a working system for xenotransplantation, should the need for that arise, it’s the public opinion and regulatory vacuum that actually stop this promising medical area from being thoroughly developed.

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