| Two years ago a Public Advisory Group concluded that Canadians would not support xenotransplantation under the current legislation, that the level of risk was too high, the level of knowledge too low and that alternatives should be investigated more. The report 'Animal-to-human transplantation: Should Canada proceed?' was addressed to the former Minister of Health Allan Rock. Nevertheless, animal research was already active in the field. It is no surprise because the financial expectations are substantial.
In 1999, a white paper was presented in Sweden which introduced new rules to guide the development of xenotransplantation. This document resulted from a survey that was conducted among 460 individuals on the national waiting list for a cadaveric kidney transplantation. It concluded that 66% of respondents said they would accept an animal kidney graft if the risks were equal to those of a human transplant. If the risks were higher, only 16% would accept the animal organ. When asked whether xenotransplantation research should continue, 91% on the waiting list were positive whereas 80% were positive in the general population.(1)
So far xenotransplantation has a track record of failure. A few people and many more laboratory animals have died after receiving an organ obtained from another species. The first recorded attempts in the early 1900s by a French surgeon, who transplanted rabbit kidney pieces into a child, showed that the child passed away two weeks later. Surely, the animal organ that was implanted into the child was rejected due to an acute immune response generated by the host in order to get rid of the foreign tissue.
Another major obstacle to xenotransplantation is the risk of disseminating viral agents in the human population and little is known about this potential risk. Some scientists think this possibility might be one of the greatest threats that humankind will have to face with. Owing to the resilience of donating and due to the poor collection of human parts, animal tissue has been considered an expedient to overcome the shortage of donors.
Initially monkeys were thought to provide organs but this idea appeared unethical. In captivity, monkeys are expensive to breed and harbor potential viruses that could turn harmful if placed into a human being. Calculations showed that it would cost 10 million dollars and up to 7 years to raise a colony of specified-pathogen free baboon per year.(2) On the other hand, little moral consideration has been given to pigs that popular imagery sees as dirty and repulsive animals. Rather economic constraints, some anatomic similarities, and prejudices against pigs have encouraged the enrolment of thousands of those animals in painful experimental xenotransplantation.
Technically, xenotransplantation is an immunological challenge. The tissue is recognized through specific molecules present at the surface of the cells and called antigens. Of the important molecules responsible for the rejection of the graft, alpha 1-3 galactosyl transferase catalyses the formation of alpha 1-3 galactosyl glycoproteins. They were found at the surface of endothelium cells, which are the cells forming the blood vessels. The presence of this glycoprotein on a graft obtained from a pig and transplanted into a baboon is responsible, in part, for the acute rejection that occurs within minutes after surgery. The alpha 1-3 galactosyl glycoproteins are detected by antibodies that trigger a vigorous reaction leading to the necrosis of the tissue.(3)
What can be done to prevent acute rejection? Cyclosporine, an immunodepressant inhibiting T-cell activity, has been used but proven inefficient to reverse rejection. In principle, the mode of action of graft rejection depends on the phylogenetic disparity among species, which means that the closer the animals involved, such as humans and apes, the less the rejection is likely to engender a dramatic destruction of the graft. In this situation, T-cells are responsible for the rejection through direct recognition of the antigens present at the surface of the donor cells.
In the case of species such as humans and pigs where the genetic gap is deeper, the immune response is more complicated and involves antibodies, molecules forming the complement, and T-cell populations intercommunicating with each other. In order to overcome immune rejection, different strategies have been designed such as the suppression of the factors implicated in the process. Immunodepressive drugs are toxic and long-term administration of suppressive drugs is not ideal.
This is where the "wonder" transgenic pigs come into play. Pigs are engineered to carry human genes so that the human body eventually does recognize the pig organ as its own. For example, pig cells expressed specific proteins that inhibit autoimmune reactions when the body starts destroying itself. Molecules such as decay accelerating factor (DAF or CD55) prevent exacerbated immune reactions due to the activation of the complement by inactivating it. White and colleagues have produced transgenic pigs expressing CD55 by microinjecting 2443 embryos. Only 45 (2%) were transgenic; a few were selected for screening and the rest discarded. The CD55 inactivated the complement in pig hearts and in the primates transplanted. The mean survival of neural graft was 1.6 day whereas the mean survival of the transgenic pig heart was 5.1 days in the monkeys without immunosuppression and 40 days in immunosuppressed monkeys.(4)
These figures would suggest some encouraging improvements. The apparent problem lies in the fact that very young monkeys were used in this study and it is known that their immune system is not fully mature. Since the soldiers are missing, there is no battle and the graft can live on but only for a short time as long as the immune system remains underdeveloped. Other transgenetic pigs have been manipulated to suppress the expression of alpha 1-3 galactosyl glycoproteins but inactivation of these molecules is not enough to prevent the cascades of cellular disasters that preclude the elimination of the graft.
The search for a satisfactory piglet has prompted pharmaceutical companies, such as Novartis, to invest a great deal of money. Despite the serious technical challenges and the ethical hindrances to the continuation of xenotransplantation, companies have seen the opportunities to make money. However, the cost of transplanting animal organs in patients will be enormous. Donation of organs, which is considered as an altruistic gift until now, will not be free any longer and the drugs to suppress the immune attack even less.
Let us think about it; raising animals in sanitized and highly monitored facilities, along with safety control measures, highly trained staff, laboratory tests, and the necessary security devices, cameras and staff to scare away those who ask questions, will the cost be passed to taxpayers? Not to mention the legal battles that the companies will have to wage if they want to spread their technologies and settle the predictable lawsuits with the government agencies, the medical institutions and the victims in the public.
From a humane point of view, we know that laboratory animals experience boredom, fear, pain and isolation and despite the concerted efforts to hide animal suffering in the basements of highly secured facilities some information may leak. The following story started in November 2000, when the Daily Express reported shocking animal experiments conducted by a Cambridge-based company, Imutran. (5) For some unknown reasons, confidential documents fell into the hands of journalists and analysis of the papers revealed that 'horrific animal suffering' had become evident in the words of some British officials.
At that time, thousands of pigs and baboons had been killed in the past 5 years preceding the termination of the research, and published papers excluded critical information relative to the scientific data. The unofficial data showed that suffering was underestimated, deaths were not reported properly, and experiments were sloppy and over one-quarter of the animals died within a few days due to technical problems. The documents reported that one particular monkey had to be killed because the surgeon realized that the organ, that was about to be transplanted in that animal, was mistakenly frozen. Another monkey had a pig heart implanted in the neck and the animal was observed holding it while the transplant was "swollen" and "seeping yellow fluid."
The company's best achievement was the survival of a transplanted monkey (Baboon X201M) for 39 days after surgery. Imutran had been using the service of Huntingdon Life Sciences (HLS), a research center based in the same area to perform 400 transplants on primates. Imutran's parent company is the Swiss drug giant Novartis. A few days later, reactions started to flow. The British government shut down the project and Imutran announced the relocation of its activities to a country where vivisection is more welcomed. According to Novartis's head of global research, Paul Herrling, Imutran was packing while Novartis was continuing pumping money to reestablish its subsidiary in co-operation with Biotransplant, another company, in the United States.
- 1. Thomas Brevig et al. "Xenotransplantation for CNS repair: immunological barriers and strategies to overcome them." Trends In Neuroscience (23), 8: 337-344 (2000)
- 2. Daar A.S. "Ethics of xenotransplantation: Animal issues, consent, and likely transformation of transplant ethics." World J Surg, 21: 975-982 (1997)
- 3. Malassagne B. et al. "La xenotransplantation, physiopathologie du rejet suraigu et différé, et perspective thérapeutiques." Pathol Biol, 48: 377-382 (2000)
- 4. Cozzi E. and White D. "The generation of transgenetic pig as potential organ donors for humans. Nature Med 1:964-966 (1995)
- 5. Lucy Jonhson and Jonathan Calvert. "Terrible despair of animals cut up in the name of research." Daily Express, 21. 09 (2000)
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