According to current statistics, close upon a quarter of a million patients afflicted with a range of disorders are being restored to active life thanks to the science and art of organ transplantation. But on the other side of the coin, we see quite a range of problems of moral, legal and social nature. Perhaps the most acute of them, encountered in allotransplantation - the transplantation of donor organs and tissues - is a shortage of "donor material". This shortage is the main reason why doctors resort to transplantations of kidneys, the heart or the liver only as the last resort when the potential of drug therapy or conventional surgery has been exhausted and the patient is practically doomed.

Another look at the current statistics will tell us that in the leading economically advanced countries no less than 150 thousand people are now on the waiting list for organ and tissue transplants from donors. As for the world demand, the figures are really staggering and have been doubled since 1988 with the annual growth rate of no less than 15 percent. Only 5 to 6 percent of this demand is met and only for people under 65 years of age.

Another, and no less important limiting factor, comes from the staggering expenses involved. In the United States, for example, a kidney transplant costs close to 90 thousand dollars. Add to that the mean annual spendings of some 7 thousand dollars on drugs which a transplant patient must take for the rest of his or her life in order to prevent transplant rejection. In Russia now a kidney transplant operation costs no less than 250 thousand rubles and that does not include the money one has to pay for the very expensive imported medical drugs. In the face of this grim reality the bulk of kidney transplants here rely on the financial backing of our medical authorities besaddled with budget problems of their own. Needless to say, there has been a marked drop in the numbers of kidney transplants in this country in recent years.

And as with most other acute shortages on the market, the demand generates all sorts of supply, including that by criminal gangs eager to make money by hook or by crook. In practice that means that each of us here can be targeted as a "donor" for some wealthy patient. And on a less "criminal", but no less dramatic side of this coin we see advertisements on display at the entrance of the Institute of Transplantation and Artificial

Organs of the Ministry of Health of the Russian Federation. The desperate people placing these ads are offering their own body organs for sale with total disregard for, or ignorance of, the law which bans organs sales and under which only relatives of a patient can donate their organs.

With all that in mind, it would be no exaggeration to say that the problem of donor organs and tissues for transplantations has assumed truly global proportions.

One of the promising solutions consists in replacing ailing human organs with those from certain animals - what is called xenografting, or heterografting. Until very recently this has been only a matter of medical theory because doctors had no ways of preventing animal organs rejection by human recipients. Indeed, even with man-to-man transplants (except between twins) the threat of organ rejection is practically always there so that the recipient is practically "doomed" to what we call suppressive drug therapy for the rest of his life. As medical experts point out, even if and when an animal transplant does "take root" in a human patient, there is absolutely no telling for how long it will continue to function.

And yet medical science does have a record of some more or less

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successful attempts of this kind in recent years. In 1963, for example, Dr. K. Rimstma transplanted to a human patient a kidney from a chimp which functioned for the whole nine months. And there have also been attempts to replace human heart and liver with those taken from primates. But the results of all of these experiments were not very encouraging. In all such transplants the immunological response in the human recipient starts right after the surgery and continues from several minutes to several hours. This involves complicated morpho-physiological changes in the transplant which manifest themselves in the form of edemas, hemorrhages and/or occlusions of blood vessels; all that destroys the "alien" organ.

The process of rejection is triggered by antibodies contained in human blood whose function is to protect the host from any "alien" matter. And there is also a group of nine proteins (a complement so-called) which are normally present in blood in the form of inactive enzymes. When "alien" substances (antigens) get into the host system - as is the case with animal organ transplants - these antibodies bind to them, forming an antigen-antibody complex which produces an uncontrolled activation of the complement. As a result a conjugated protein complex is formed on the surface of alien cells precipitating some irreversible changes and leading to the ultimate destruction of these cells.

One of the "targets" for the above complement in the tissues of a xenotransplant are the endothelial cells which line up the inner walls of minor blood vessels. In healthy tissues they act as a barrier that prevents proteins and blood cells from escaping into the surrounding body tissues on the one hand, and that precludes intra-vascular thrombosis on the other. Under the impact of these processes, and because of the secretion into blood of certain other pathological factors, endothelial cells are modified, loosing their barrier function and stimulating the formation of thromboses which plug blood vessels.

Needless to say, the closer the donor animal and the human recipient are related evolutionally, the better are the chances of success. Yet for a number of reasons there are certain constraints on the use of anthropoid apes for xenografting: the limited population of such apes, problems of their breeding in large numbers in captivity, and the threat of dangerous infections from donors of this kind to say nothing of the "Greenpeace" ethics with regard to the deliberate killing of living beings.

With all that, it has been possible to find a fitting "substitute" for chimp donors and this substitute are pigs. They are bred in sufficient numbers and their organs are similar to human ones in size and physiology.

The prospect of using pigs as donors for organ transplants for human patients gave an impetus to the immunological, virological and molecular-biological, including genetic engineering, studies of these animals. Research scientists have been able to identify the mechanism of rejection of such transplants in humans and to map out ways of overcoming this effect. The next stage was the breeding of special - transgenetic - donors whose cells contain, in addition to their own ones, genes "alien" to this particular species. The organism of such animals produces proteins which protect a transplant from attacks by the human immune system. How does it work in practice? By using genetic engineering (transgenetic) techniques scientists alter the genetic apparatus of a pig embryo. This modified embryo is then implanted into the womb of a surrogate "mother" pig which becomes pregnant. The progeny born in this way has tissues which match human ones in many parameters and are not so readily rejected.

Having said that, there are reasons to believe that such transgenetic technologies and xenografting have a promising future. It should be possible to preserve an implanted xenograft for the rest of a patient's life even without regular therapy. With this in view, British experts predict having more than 300 pig-breeding farms worldwide in the near future geared to the transplantation program.

But the problem of transplant rejection entails other snags too. Some time ago two teams of medical researchers in London reported on the presence of what they called retroviruses in pig tissues which can infect human cells after transplantation and cause malignancies. Usually the threat of infections from donor organs can be overcome by selecting non-pathogenic

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animals. In this particular case, however, the retroviruses are present in fetal DNA and can provoke a disease when an implant is already in the human body. And it is also true that humans have protective factors (blood serums and other immune systems) which can combat such pathogenes as retroviruses. But in the conditions of immunodeficiency when immune-suppressor drugs are administered to prevent transplant rejection, the level of natural body defenses is sharply reduced producing a real threat of retroviral infection with subsequent malignancies. On the other hand, there is no denying the fact that even with transplants from human donors accompanied by lifelong anti-rejection therapy, there is a high risk of viral infections (such as HIV, or AIDS) or microbial infections and a threat of subsequent malignancies. That is why in manipulations with animal organs and tissues donor animals have to be closely inspected for any viral infections and the patient has to be vaccinated accordingly.

In view of the above, there has been a split among medical scientists on the issue: some call for a ban on xenografting, while others maintain that the risks involved will be eliminated with the progress of medicine. The World Health Organization and the US Department of Nutrition and Drugs have been in favour of xenografting experiments, but banned for several years clinical transplants of animal organs to humans. But, say what you may, no formal bans can stop scientific research, and so xenografting is making progress on both the theoretical and the practical level. To give just one example, the Diacrin and Genzyme Tissue Repair firms in the United States have developed and are applying in practice the method of administration of pig nerve cells to patients in the treatment of some chronic disorders of the central nervous system which cannot be dealt with by any conventional methods (such as Parkinson

and Huntington diseases). Two other US companies - Neocrin and VivoRx - have been successfully treating sugar diabetes by the transplantation of pig pancreas cells to chimps and humans. Firms like Circe Biomedical and Nextran in the United States, and the British Immutran have launched clinical trials to test the transplantation of liver and liver cells in cases of acute liver deficiency. And although the details on most such cases are missing, positive results are reported in 42 out of 94 such cases after the introduction of liver cells. In this country, scientists of the Research Institute of Transplantology and Artificial Organs have achieved some positive results in the treatment of sugar diabetes and acute liver deficiency with the help of animal cells.

But even with the most positive assessment of the prospects of xenografting, the practical introduction of this method involves a whole range of serious ethical and legal problems. In deciding on the applicability of any therapy for human patients the general rule should obviously be: The risk of a failure, even by accident, should not be higher than that resulting from the disease. The legal rights of a recipient under the law of the Russian Federation "On Transplantation of Organs and/or Human Tissues" are summed up in Section I, Article 5- "Medical Conclusion on the Necessity of Transplantation of Human Organs and/or Tissues" and Article 6 "Consent of the Recipient on Transplantation of Human Organs and/or Tissues". These declare that human organ or tissue transplantations can take place only with the patient's consent in writing. The recipient must be warned in advance of the likely complications from the proposed therapy.

Genetic engineering techniques involving pigs or monkeys give rise to some obvious ethical problems. How should we treat the " human -ization" of animals through the administration of human genes?

One of the leading experts on animal organ transplants to humans, Prof. A. Rao of the Department of Cell Transplantation of the Pittsburgh University (USA), is quoted as saying that any ethics committees will oppose attempts to modify monkeys by bringing them closer to man. Barriers must be placed in the way of development of superhumans. In other words, the American scientist is urging stringent control over any and all genetic engineering experiments. The really important thing is not to develop some unwanted animal species under the excuse of cultivating scarce donor organs.

Pig transplants, no doubt, will run into what one can call Islamic opposition, to say nothing of the ban on all human organ transplants in various Arab countries.

The problem of animal organ transplants to human patients has so far received no formal assessment from the Orthodox Church. All we know is its generally tolerant stand on transplantology in general as something that does not run counter to church canons.

As for ourselves, we fully share the stand on the problem taken by the World Health Organization which favors the development of research in xenografting while imposing a moratorium for several years on any major operations involving animal organ transplants to humans until we have the final confirmation of the safety of any such medical procedures. The Bioethics Committee of the Council of Europe is now working on an additional protocol to the Convention on Human Rights and Biomedicine which will be dealing with the problems of xenografting and transplantology.

V.I. Shumakov, A.G. Tonevitsky, "Xenotransplantology: Scientific and Ethical Problems ". Chelovek, No. 6, 1999

Prepared by Vladimir GOLDMAN

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