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Journal of the Academy of Hospital Administration

Statement of Specific Principles for Research in Transplantation Including Fetal Tissue Transplantation

Author(s): Editors

Vol. 15, No. 1 (2003-01 - 2003-06)

Key Messages:

In continuation with the earlier issue the present issue provides an insight into the principles/guidelines for research in Transplantation including fetal tissue transplantation.

Editors

Introduction

The practice of transplantation is in its infancy in India. The exceedingly high cost restricts its application, and also reduces the interest in research into this field. The same reason makes it imperative that Indian scientists should devise means of reducing the cost and improving the success rate, to make it feasible to increase the number of Indians who can benefit by this treatment.

At present the protocols devised in the West are followed which are not necessarily ideal. The ethical principles of research in human subjects have been well enunciated in the Declaration of Helsinki adopted by the World medical Association in 1964, and amended in 1975, 1983, 1989 and 1996. Transplantation, however, raises some peculiar aspects, and these will have to be weighed in that light. The problem has been considered with special reference to the following points:

  • I. Transplants from live or cadaver donors
  • II. Embryonic and fetal tissue and organ transplantation
  • III. Xeno-transplantation
  • IV. Transplantation for cosmetic purposes.

I. Transplants from live or cadaver donors

Definitions

Cadaver: A dead body. For purposes of this document, the term refers to a dead human body.

Death: This was originally defined as entire and continuous cessation of respiration and circulation. It has since been recognized that the heart could continue beating for a time, even for days, though the brain lacked the ability to maintain respiration and sustain life. Death of the brain stem, also called brain death, has since been recognized internationally, and in the 'Indian Transplantation of Human Organs Act', 1994.

Brain death: This is as specified in 'Transplantation of Human Organs Act, 1994' with 'Transplantation of Human Organs Rules, 1995'. Salient features are described below:

Entire, permanent, and irreversible cessation of functions of he brain stem-this is synonymous with brain-stem death, since the centers for the control of essential body functions such as consciousness, respiration, and blood pressure are situated within the brain stem. In many countries strict criteria for diagnosis for brain death have been established. These include the presence of deep coma, the absence of any brain-stem functions such as spontaneous respiration, pupillary reactions, eye movements, gag and cough reflexes, and the exclusion of low body temperature and drugs as relevant to the comatose state. The EEG is a useful (but not essential) confirmatory test. Brain death is when 'Damage is judged irremediable' based on its context, the passage of time, and the failure of all attempts to remedy it. Secondly, all possible causes of reversible brain-stem dysfunction, such as hypothermia, drug intoxication, or severe metabolic upset, must be excluded. Finally, the absence of all brain-stem reflexes must be demonstrated, and the fact that the patient cannot breathe, however strongt he stimulus, must be confirmed.

When testing the brain-stem reflexes, the following normal responses must be looked for:

  1. constriction of the pupils in response to light,
  2. blinking in response to stimulation of the cornea,
  3. grimacing in response to firm pressure applied just above the eye socket,
  4. movements of the eyes in response to the ears being flushed with ice water, and
  5. coughing or gagging in response to a suction catheter being passed down the airway.

All responses have to be absent on at least two occasions with an interval of six hours between them. Apnoea, which also must be confirmed twice, is assessed by disconnecting the patient from the ventilator, (prior to this test, the patient is fully oxygenated by administering 100% oxygen for several minutes to ensure that the patient will not suffer serious oxygen deprivation while being disconnected from the ventilator). The purpose of this test is to establish the total absence of any inspiratory effort as the carbon dioxide concentration in the blood (the normal stimulus to breathing) reaches more than sufficient levels to stimulate any respiratory center cells they may still be alive.

Guidelines on Live Donor Transplants

  1. Donation from a live donor should be restricted to renewable tissues like bone marrow, or to a paired organ whose removal will not greatly alter physiological functions, like the kidney. Since the removal of an eye will compromise binocular vision and produce disfigurement, it should not be permitted in a live donor.
  2. Surgery on the donor inflicts bodily harm on him or her, the extenuating circumstances being the saving of another human life. It is imperative that no risk be imposed on the donor beyond that inherent in surgery and the loss of a vital organ. Any manner of experimentation, though it may be intended to improve the survival of the graft, should be prohibited if there is the slightest extra risk to the donor. Examples are pre-treatment of the donor with immuno-suppressives or anticoagulants.
  3. Every such research project should be preceded by careful assessment of predictable risks and compared to foreseeable benefits and improvement in the success rate of transplantation.
  4. The interests of the donor should always take priority over those of the recipient of the transplant.
  5. In view of the risk involved, the voluntary consent of thedonor is absolutely essential. Further, the donor should be informed of all possible risks in a manner easily understood by the subject before the consent is taken.
  6. It follows that the donor should have the legal capacity to give consent and be in a position to exercise free power of choice without the slightest element of force, duress, or coercion, and should have sufficient knowledge and comprehension of the subject to be able to make a decision with full understanding of the consequences. Children and mentally incompetent adults as also individuals with restricted autonomy should not be used as organ donors or as subjects for such experiments.
  7. Since the experiment would have consequences for the recipient too, the donor must be fully informed of the nature of the procedures and the possible effects on the recipient before consent is taken.
  8. The responsibility of providing the above information to the donor, and of making sure that he/she understands fully the implications of the what is to be done and what he or she consents to, rests entirely on the individual who directs the research project.
  9. The experiment should be such as to yield fruitful results for he overall good of the donee without any risk to the life of the donor. The experiment should be undertaken only if there is not other method available of finding the answer to the question raised.
  10. The experiment should be so planned and conducted as to avoid all unnecessary risks to the donor, to the organ to be transplanted, and to the recipient of the organ to be transplanted, and to the recipient of the organ. Proper precautions should be taken and adequate facilities should be available to protect the donor from the most remote possibility of harm.
  11. The donor should be at liberty to withdraw from the experiment and to abrogate the consent given earlier, with no requirement to offer any explanation of the reasons for his or her doing so.
  12. If at any time during the course of the experiment the investigator comes to know that there is risk to the donor or to recipient as a result of the procedure, it is his or her responsibility to terminate the experiment forthwith.
  13. This does not preclude any treatment or procedure done on the organ or tissue after removal from the donor's body, aimed at reducing its antigenicity and improving graft survival.

Creating of Human being for transplantation purposed should be banned.

Guidelines on Cadaver Donor Transplants

  1. Every one should give a thought to the need for organ donation after death. In such an event one should make a decision and inform the next of kin, and register oneself with an appropriately constituted authority. Where one is opposed to donating his or her organs, this too, should be made known to the next of kin, so that this wish of the deceased may be respected after death. Such a "Living Will" is in vogue in a number of countries in the world.
  2. In the absence of such prior directions from the deceased, the person in lawful possession of the body will make the decision to use the organs or not, as he may think fit, after consultation with the family.
  3. It is important that the medical team uses the body only for the purpose for which consent has been given.
  4. Remaining tissue and organs should be treated with the respect due to a human body, and will not be used for any purpose to which explicit consent had not been given.
  5. Under no circumstances should financial gain be made from any such procedure.
  6. There shall be no coercion and no monetary inducements offered to the family of the prospective cadaver donor.
  7. Confidentiality of the donation must be maintained on both sides: the recipient and his or her family will not be informed of the identity of the donor, and the family of the donor will equally be kept unaware of who receives the donated organ. This is essential to avoid any form of exploitation by the donor's family.

Guidelines on Recipients of Transplants

  1. The patient with failure of a vital organ is at a particular disadvantage in developing countries due to the enormous cost involved for the available interventions. If the organs involved are the kidneys, most Indians cannot afford to maintain themselves on dialysis. Similarly ventilators are available at very few centers. There are no artificial supports for other organs like the heart, the lungs and the liver, so death is imminent and no means is available to keep the individual alive short of replacing the organ concerned. Thus a measure of urgency is introduced into the search for a donor organ.
  2. A desperate patient may consent to procedures which put him or her at risk. It is all more important that every research protocol for transplantation should be carefully reviewed by an appropriate committee of suitably qualified scientists, jurists and other eminent members of society, so that its scientific and ethical basis may be impartially evaluated.
  3. The transplant research team should have high technical expertise.
  4. Adequate data management, tissue storage facilities, and surveillance procedures should be available in center before it is authorized to conduct research into transplantation.
  5. If, at any time, a patient should refuse to take part s a subject for a research project, it should in no way interfere with his or her right to receive treatment of the best quality, which the team is capable of providing.
  6. Under no circumstances should there be a conflict between scientific content of a study and the best interests of the patient. Should there be need to choose, the experiment should be abandoned and the patient should receive the best treatment possible.

II. Embryonic and Foetal Tissue and Organ Transplantation

Introduction

Human foetal tissue has been used in research for a wide range of purposes over decades. The thought of using foetal cells as transplants was first occasioned when scientists attempted to find ways of treating patients with loss of nerve cells in the brain and spinal cord. Since damaged nerve cells do not regenerate, repair to damage in the brain and spinal cord is serve rely limited. Attempts to trick the neurons into repair and re-growth have yet to bear fruit. That was when the attempts to transplant healthy neural tissue into damaged areas of the brain were started in an effort to allow the re-establishment of damaged neural circuits. The immunological complications that result, whenever any foreign tissue is transplanted into a human, proved a barrier.

The use of foetal tissue is one of the means to minimize the chances of rejection. In the early weeks after conception, foetal cells multiply rapidly and show very little antigenicity because many surface antigens would not yet have developed. These cells are not fully differentiated and adapt easily to the signals received from surrounding tissue in a host. They grow and differentiate in such a manner that they are integrated to form part of the host organ. Foetal cells can also be successfully preserved by cooling and be reanimated. As the technology for developing immortal foetal cell lines for study of gene regulation, pattern formation in embryogenesis, as models of cell interaction and function, for vaccine development and study on cell growth and regulation, cancer and immune response was perfected, hopes for the use of these cells as transplants strengthened.

Non-neural foetal tissue transplantation has included injection of immune cells from the thymus and liver of aborted fetuses into the umbilicus of a 30 week old foetus with bare lymphocyte syndrome, a rare and always fatal immuno-deficiency disorder. Success has also been reported on the use of foetal thymus in the reconstitution of a servere combined immuno-deficient (SCID) child in Italy who survived 17 years exhibiting normal immune responses even through his T cells were of foetal donor origin. Other potential uses of foetal tissue include treatment of diabetes, genetic retinal abnormalities, optic nerve and spinal cord injury, alzheimer's disease, aplastic anaemia, acute leukaemia/lymphoma and liver failure.

Definitions

Embryonic state: Between 15 days and 8 weeks post-conception of a pregnancy. In the absence of more precise information (i.e. menstrual cycle length), conception is presumed to have taken place two weeks after the beginning of the woman's last menstrual period. The distinction of the 15 day stage as the beginning of the embryonic stage is not arbitrary: the pre-embryo is not isomorphic with the later developmental stages, since cells cannot yet be defined as contributing to the embryo is not isomorphic tissue, and complete implantation has not yet been accomplished. At 8 weeks, the rudiments of nearly all the main structures have been laid down giving a general appearance of a mammal-to-be with four limbs and a head.

Foetal stage: Subsequent period between 8 weeks and the time the baby is born, at approximately 38 weeks post-conception (40 weeks post-last menstrual period).

  1. Live aborted foetus: If an aborted foetus is alive, it is a person, no matter how short the period of gestation, and using it for an experiment would, in law, be considered an assault upon it.
  2. Dead foetus: An expelled or delivered foetus that exhibits not heart beat or spontaneous breathing. Some organs, tissue and cells remain alive for varying periods after the moment of death of the foetus.
  3. Neonate state: Newly born live individual of any gestation period.

Guidelines for research on foetal tissue or organs for transplantation

  1. Every transplantation or research project involving the use of embryonic or foetal tissue must be approved by the local scientific and ethics committees and referred to National or Central Ethical Committee for final approval.
  2. All members of the hospital or research staff - medical and paramedical - directly involved in any of the procedures will be fully informed of the purpose and implications of the research project.
  3. The researcher shall not be a party to deliberate conception and/or subsequent abortion for the sake of obtaining tissue or organ for research or saving the life of a family member or for the purpose of commercialization.
  4. No research is permitted on the live aborted foetus.
  5. Tissue for transplantation or research may be obtained from dead embryos or fetuses, their death resulting from legally induced or spontaneous abortion. Death of an intact embryo or foetus is defined as absence of respiration and heart beat.
  6. Voluntary, informed, written consent will be obtained from the mother in two stages ? first for the abortion, next for the donation of tissue from the foetus. The mother's decision to donate foetal tissue is sufficient for the use of the tissue unless the father objects in writing. In cases of incest or rape, the father's objection carries no significance.
  7. The mother will not dictate who shall receive the foetal tissue taken for transplantation.
  8. Anonymity of donor and recipient will be maintained so that neither party is aware of the identity of the other.
  9. The procedure of abortion, or its timing, will not be influenced by the requirements of the transplantation activity. These should solely be based on concern for the safety of the mother.
  10. Those participating in termination of pregnancy will not, in any way, be party to the subsequent usage of embryonic or foetal tissue for commercial purposes.
  11. The procurement of embryos, fetuses or their tissue for commercial purposes will not involve profit or remuneration.
  12. Intact embryos or fetuses will not be kept alive artificially for the purpose of removing usable material.
  13. Tissues from aborted foetus can be cultured and banked for use in research on transplantation. If such stored tissue is to be subsequently used for any purpose other than the original objective, a fresh sanction will be obtained from the scientific and ethical committees.
  14. Cells obtained from fetuses will not be patented for commercial considerations for their subsequent usage.
  15. Use of umbilical cord blood from a live foetus or neonate for transplantation: The fundamental principle in any operation on a live foetus or neonate will be to ensure that no harm will occur to the foetus or neonate will be to ensure that no harm will occur to the foetus or neonate. Since the exact timing of the clamping of the umbilical cord has a significant impact on the neonate and early clamping may cause an abrupt surge in arterial pressure resulting in cerebral intraventricular hemorrhage, particularly in premature neonates, normal clamping protocol will be followed when collecting foetal blood for transplantation. There is a risk that the neonate donor may need his or her own cord blood later in life. If the blood has been used for another, he or she might be without blood when it is needed. Parents will be fully informed of the risks of the donation and written consent obtained from them on behalf of the foetus.
  16. Use of tissue or organs from dead anencephalic foetus or neonate (foetus or neonate lacking brain development above the level of the brainstem) is permitted. Physicians may provide anencephalic neonates with ventilator assistance and other medical therapies that are necessary to sustain organs till such time as the diagnosis of death is made on the basis of cessation of cardiac function. Retrieval and transplantation of organs of an encephalic foetus are ethically permissible only after such diagnosis of death is made.
  17. No transplantation of foetal tissue into man will be permitted unless the following criteria have been met:
    1. there will be a detailed scientific basis for such transplantation;
    2. animal experiments must show successful results ? eradication of disease, eliminiation or amelioration of symptoms and signs or successful substitution of deficient chemicals and restoration of normal physiological function by the transplant. These must be documented in one or more indexed journals with good peer review mechanisms;
    3. all records pertaining to animal experiments must be complete and submitted to specialist and general scientific scrutiny. These records must be preserved for a minimum period of five years after the completion of the study preferably on permanent basis as far as possible;
    4. Success in animal experimentation must be shown on a long-term basis. The studies must include investigations on animals receiving the transplants at periodic intervals after the procedure specially with reference to unequivocal demonstration of absence of any transmission of disease through the transplant.
    5. Trails in human patients will commence only on those patients where no other form of treatment is available and where, in the absence of the transplant, the patient is likely to suffer relentless deterioration in his health with fatal termination.
    6. After obtaining her consent, the mother must be screened for transmissible disease. If possible, the material to be transplanted must also be similarly screened.
    7. Trials in human patients will be carried out only at the institutions having clinical and research facilities needed for such trials, including those that may be required to treat complications that may follow such research.
    8. The research group and the institution(s) in which they work will undertake to conduct free of charge the research on their human subjects and also treat completely any complication they may follow their study even if it appears several years after the conclusion of the study.
    9. The research group will provide the human subjects a printed document explaining in simple, non-technical language, the purpose of the study, details of the procedures the human subject is to undergo, complications they may follow these procedures, financial implications, interests of the researchers in the conduct of the study, and a commitment to treat completely and free of cost any complication that may ensue. The human subject must certify in writing that he has studied and understood the contents of this document and that he/she is willing to participate in the study.
    10. Any adverse effects noted will be immediately discussed with members of the ethics committee and the project grounded if these cannot be explained or reasonably corrected in the course of the study.

The local ethics committee must ensure report-back measures at every stage of research and confirm that a detailed report on the procedures, findings and conclusions is submitted to an indexed journal for publication even when the results are of a negative nature. The National/ Central Ethics Committee should be kept informed.

As with therapeutic transplantation, constantly updated local (metropolitan), regional or national lists of available tissues and organs should be maintained to ensure that optimal use is made of all available donations. These lists should be made freely available to all authorized research workers.

III. Xeno-Transplantation

Introduction

Paucity of organs from humans for transplantation into other humans has led to the search for other sources such as animals. Initially the focus was on the great apes, as they appear to be nearest to man in the evolutionary scale. It was soon realized that unbridled use of simians would lead to possible extinction of their species. Attention has thus turned to other animals.

Definitions

Primates: The most highly evolved of animals. Includes simians and homo-sapiens.

Simians: The monkey species, including the great apes.

Species: Group of individuals sharing similar biological characteristics and who can breed within the group to produce fertile offspring.

Source animal: Animal from whom tissues or organs are removed for transplantation in humans. The term 'donor animal' has been discarded as the animals cannot give consent.

Tissue: A collection of similar cells, all of which perform the same function. An example is neural tissue within the brain.

Transgenesis: The introduction of a foreign gene into an animal or organism. The transferred gene is called transgene.

Xeno-transplant: Transplant of cells, tissue or organ from one species to another. This principally concerns transplant from animal to man.

Zoo noses: Diseases peculiar to animals in the normal course of events that can, under special circumstances - as after xeno-transplant-be transferred to man.

Ethical considerations

Transmission of disease from animal to man:

There has been considerable apprehension that tissues or organs transplanted from animal to man may convey infection or unwanted genetic abnormalities. This anxiety has prompted most countries, to ban all research on transplanting animal organs to human beings till this issue has been satisfactorily addressed. Measures proposed include the breeding of successive generations of animals and studying them for all known and possible unknown organisms that can cause disease. Only those animals certified free from disease could be considered for transplantation.

Our immune responses are likely to reject all foreign tissue and organs transplanted into us. The chances of rejection are minimized if the source animal is genetically similar to man. This is the reason for considering the great apes as likely source animal.

Once the apes were ruled out in order to preserve their species, attention turned to cattle, sheep and pigs. In each of these species, transplant of unaltered tissue or organ will certainly lead to rejection.

Pigs are currently the animals of choice as the size of their organs and the anatomical and physiological loads they must carry are similar to those in man. Besides, pigs breed easily and are maintained without much difficulty. Experimental studies have been carried out on kidneys, liver, heart, heart valves and bone marrow, islet cells of the pancreas and nerve cells obtained from pigs with encouraging results.

Attempts are on so that pigs be engineered to possess genetic material similar to that in man. This can be achieved by replacing porcine genes by human genes into the ell that will form the pig embryo. Tissues and organs from such transgenic pigs will, it is hoped, stand the scrutiny by the immune systems of the patients into whom they are transplanted and will be left unmolested. However, there are possible problems in using porcine tissue or organs in human transplantation. The average pig survives for only twenty years. Will transplanted tissues function efficiently in man with a life span of three score years and ten, or will they fail after two decades, necessitating further transplants?

Equally worrying is the possibility of transferring germs and viruses peculiar to pigs into man through transplanted tissues. We are aware of species-specific infective diseases that limit themselves to that species. Under special circumstances - as after transplantation - such organisms may make the leap from one species to another and cause untold havoc in the new species, which has no immunity against them. Some of the most deadly viruses currently devastating individuals and groups in some African countries - that causing Lassa Fever, the Marburg virus and the Ebola virus are such examples. They appear to have spread from bats or other animals to man. The human immunodeficiency virus (HIV) also appears to fall into this category. These questions are still unresolved.

Apart from the known bacteria, fungi and viruses, there is concern for those hitherto unknown and undetected, especially so with slow viruses, that produce manifestation of the disease years-often decades - after they gain entry into our systems. Equally disquieting is the fact that once an infective organism makes a jump across species, it may spread like wildfire in the new species - in this case, man.

It is also proposed that extensive research, with long-term follow-up studies by carried out on animal-animal transplants so that we may learn of possible pitfalls and develop measures to avoid them before undertaking the first experiment involving man.

Guidelines on Xeno-transplantation

  1. Experimental xeno-transplantation must only be permitted between different animal species. Animal - to man transplants must not be permitted at the present level of knowledge which may be referred to the Central/ National Ethical Committee on Human Research.
  2. Institutional scientific and ethics committees must approve of such research studies, with special attention being paid to their relevance, availability of facilities for extensive, sophisticated and long-term studies for transmission of disease through transplantation.
  3. An advisory committee consisting of reputed scientists in the field, medical professionals, veterinary experts and microbiologists must oversee all such transplants.
  4. Records on all research studies must be detailed, scrupulously maintained and kept available for a long period of time, perhaps decades.
  5. Safeguarding the interest of the pioneer human recipients when such transplants are permitted in future, it is proposed that each and every animal - to - man transplant be very carefully vetted and sanctioned on a case-by-case basis. In each instance, extensive studies on the animals to ensure freedom from infection must be made mandatory. The human recipients of tissues or organs must be carefully followed up over a long term.

IV - Transplantation for cosmetic purposes

  1. Research on transplantation for cosmetic purposes (such as the creation of a new ear after transferring tissue from the patient on to a mould which is later implanted into the subcutaneous tissue of a transgenic mouse) will be governed by the same principles as those in using donation of tissue or organ from a live donor.
  2. Donation of tissue should be restricted to renewable tissues like skin to an extent where such removal will not greatly alter the normal functions of such tissue.
  3. It is imperative that no risk be imposed whilst removing tissue beyond that inherent in surgery. Any manner of experimentation, though it maybe intended to improve the survival of the graft, should be prohibited if there is the slightest extra risk to the donor. Examples are pre- treatment of the donor with immuno-suppressives or anticoagulants.
  4. Every such research project should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits and improvement in the success rate of transplant in a manner easily understood by him, before his consent is taken.
  5. The patient must be informed of all possible risks, including those of failure of the transplant in a manner easily understood by him, before his consent is taken.
  6. if follows that the donor should be competent to give consent; should be in a position to exercise free power of choice without the slightest element of force, duress, or coercion; and should have sufficient knowledge and comprehension of the subject to be able to make a decision with full understanding of the consequences. Children and mentally incompetent adults so also persons with limited autonomy should not be subjected to such surgery.
  7. The experiment should be such as to yield fruitful results for the good of patients who need transplantation without having the donor. The experiment should be undertaken only if there is no other method available of finding the answer to the question raised.
  8. The experiment should be so planned and conducted as to avoid all unnecessary risks to the donor, to the tissue to be transplanted, and to the recipient site.
  9. Where tissue is to be temporarily transferred to an animal, all necessary precautions should be taken, and adequate facilities should be available, to protect the patient from the most remote possibility of harm.
  10. The subjects should be at liberty to withdraw from the experiment and to abrogate the consent given earlier, with no requirement to offer any explanation of the reasons for his or her doing so.
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