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The ethics of fetal tissue transplants.

The Ethics of Fetal Tissue Transplants

Heretofore, damage to the brain or spinal cord, whether from injury or disease, has been considered irreversible. There is no satisfactory cure for Parkinson's or Alzheimer's disease, for paraplegia resulting from spinal cord injury, for certain forms of epilepsy, or for a host of other less common but equally grave neurologic disorders. This situation may soon change. Over the last ten years, animal experiments have demonstrated that transplantation of appropriate fetal brain tissue to an impaired adult brain can in certain cases restore normal function. Human fetal brain tissue recently was used in transplants for patients with Parkinson's disease in Mexico and Sweden, and similar procedures are planned or underway in China, Canada and elsewhere. Future uses of fetal tissue may not be restricted to neurosurgery but might include transplanting of fetal pancreas to treat diabetes mellitus or fetal liver for certain blood and metabolic disorders.

The prospect of therapeutic use of human fetal tissue has aroused strong emotions. Objections have been raised on several grounds:

* The requisite killing and dissection of the fetus both are an abuse to the developing human being and brutalize those who perform them. Further, the therapeutic use of fetal tissue will encourage abortion, may motivate conception with the express intent to abort, and might even lead to the sale of fetuses and fetal material.

* Collection of fetal tissue in a medically useful form exposes the mother to unnecessary risk, while transplantation of such tissue exposes the recipient to unacceptable risk.

* The medical use of human fetal tissue has unacceptable social consequences.

* The legal safeguards necessary to overcome these objections are either undesirable or unenforceable.

Such objections raise important issues for the most immediate practical application of fetal tissue, the transplantation of human fetal dopamine-secreting neurons to the brains of patients with medically unresponsive Parkinson's disease.

Scientific Grounds

Parkinson's disease is a devastating neurologic disorder that occurs when neurons degenerate in the region of the midbrain called the substantia nigra. Normally, fibers from these cells secrete the chemical dopamine in forebrain regions important for regulating movement. In the absence of normal dopamine secretion, the patient suffers from a variety of impairments including rigidity, difficulty initiating movements, and tremor. The underlying causes of the disease are unknown and there is currently no cure. Existing drug treatments inevitably lead to unacceptable side effects, and as the disease itself progresses the patient becomes unable to carry out the essential activities of daily life.

Animal experiments over the last decade have demonstrated that fetal dopaminergic neurons can be grafted to the brain, restoring normal movement to rats and monkeys with experimentally induced Parkinson's disease. Similar grafts of tissue from adult adrenal glands, which also produce dopamine have been shown to have beneficial effects in animal experiments. Such a procedure has been performed in at least one hundred patients with Parkinson's disease in Mexico, China, Sweden, and the United States. While it would be premature to draw definitive conclusions about the therapeutic value of this procedure, there appear to be no significant adverse effects. Nonetheless, based on animal experiments, it is likely that grafts of fetal human dopamine-secreting neurons will be substantially more effective than adrenal grafts. Procedures for transplanting human fetal neurons are under development in a number of laboratories, and at least five operations have been performed in Mexico City, Stockholm, and Birmingham, England. [1]

Numerous factors influence the success of neuronal transplantation to the brain. Among the most important are the age of the tissue, the manner in which it is prepared, and the method by which it is transplanted. The ability of neurons to survive transplantation appears to be greatest if they are taken from the brain while still immature, after they have ceased to divide but before they have begun to grow their long, fibrous axons. If they are taken at later stages of development, the inevitable cutting of these axons during tissue preparation may be fatal to the cells. However, if grafts are prepared from much earlier tissue, when cells of the brain primordium are still actively dividing, the effect of subsequent transplant growth may resemble that of a brain tumor; moreover the dopamine-secreting cells will be diluted by other irrelevant cell types derived from the same early tissue. In the case of the dopamine-secreting cells of the human substantia nigra, cell division appears complete by the eleventh week after conception; human midbrain cells have been most effective in restoring normal movement to rats with experimental Parkinson's disease when derived from fetuses of less than twelve weeks of age. [2]

While grafts of skin or kidneys between unrelated animals of the same species ordinarily are promptly rejected, grafts of fetal neurons generally are not. [3] This is apparently because the molecules that distinguish tissue from different individuals of the same species are absent from the surface of fetal neurons. The molecules that distinguish tissue from different species, however, are present; thus grafts of fetal neurons between members of different species generally are rejected unless the immune system is suppressed. Since immuno-suppressive drugs may have undesirable side effects, animal fetuses are inferior sources of neural tissue for transplantation to human patients. In contrast, there appear to be no serious immunological obstacles to the use of unrelated human fetal tissue.

The Abortion Question

Procurement of fetal tissue for transplantation could lead to abuse of the fetus if it were the sole reason for abortion, or if it required dissection of needed tissue from a living fetus. However, the force of these objections would be greatly reduced if, as seems likely, tissue from the current (independently motivated) caseload of routine terminations of pregnancy furnished a sufficient supply for transplantation.

Each year in the United States, over 1.3 million pregnancies are voluntarily terminated. In 1981, 78 percent of induced abortions were performed between the sixth and eleventh weeks of gestation--that is, at stages appropriate for neural transplantation. Of these, 94 percent were performed by what is generally considered the safest method, suction curettage. [4] Uniform criteria for fetal death are not at issue in the case of abortion by suction curettage: the fetus is invariably fragmented by its passage through the vacuum cannula. Cells within these tissue fragments may remain alive and can be collected aseptically. In approximately one case in ten, the fragment containing the fetal midbrain can be identified.

Thus each year, in principle, tissue from approximately 90,000 appropriately aged fetuses could be available for transplantation. Currently, much of this tissue is discarded. (There are in addition a large number of spontaneous abortions. However, the probability of fetal pathology in these cases and the indeterminate delay between death of the fetus and its expulsion from the uterus make spontaneously aborted fetuses an unsatisfactory source of neural tissue for transplantation. Surprisingly, this was the source used for the first procedure performed in Mexico City.) Requests for the release of fetal tissue for research use are not required by law, but are already a feature of abortion consent forms in some centers; such requests could be modified to include therapeutic use.

The annual incidence of Parkinson's disease in the United States is approximately twenty per 100,000 population, so that fewer than 60,000 new cases are diagnosed each year. [5] Not all of these patients would be satisfactory candidates for transplantation surgery. On the basis of animal experiments, dopaminergic neurons from a single fetal midbrain seem sufficient for effective transplantation to one Parkinson's disease patient. Thus it would appear that the potential supply of fetal neural tissue from legal abortions would substantially exceed anticipated demand.

But the fact that tissue may be obtained from voluntary legal abortion does not exempt fetal tissue transplantation from moral questioning. Rather, it focuses ethical concern on the antecedent abortion. As Richard Wasserstrom has written:

If an abortion has been performed and if the fetus is still nonviable, then experimentation upon the fetus in no way affects the fetus's ability, or lack thereof, ever to realize any of its existing potential. On this view especially, abortion, not experimentation upon the nonviable fetus is the fundamental, morally problematic activity. [6]

Here, however, I wish only to identify one consequence of our society's decision to permit voluntary abortion: dissecting and transplanting fetal tissue cannot constitute an abuse to the dead, fragmented fetus, and should be no more problematic than dissecting and transplanting organs from cadavers.

If collection, dissection, and transplantation of fetal tissue fragments do not constitute an abuse to the fetus, might these procedures nevertheless brutalize the men and women who perform them? Sissela Bok has argued that in part because early fetal cells "cannot feel the anguish or pain connected with death...words such as 'harm' or 'deprive' cannot be meaningfully used in the context of early abortion and fetal research." Nor, Bok maintains, "is such an early abortion and consequent research brutalizing for the person voluntarily performing it, or a threat to society." [7] We cannot rule out the empirical possibility that procedures like fetal tissue transplantation or abortion may brutalize those who participate in them, but there are no indications that doing so desensitizes these scientists, physicians, or nurses to the value of life. It is nevertheless clear that no one should be compelled to participate against his or her will.

Redeeming Abortion

There is also much concern that medical and scientific use of fetal tissue may provide new reasons for abortion. A decade ago in the Hastings Center Report, Mary Anne Warren argued that a "surgeon ought to agree to [a] woman's plan to provide her husband with kidneys of a fetus conceived for that purpose [i.e., transplantation] and aborted at five or six months." [8] More recently, The New York Times reported that the daughter of a man suffering from Alzheimer's disease asked to be inseminated with her father's sperm to provide him with fetal tissue for a therapeutic neural transplant. [9] Concern that the use of fetal tissue for transplantation in such cases could become an incentive for abortion thus appears well grounded.

Nonaltruistic financial motives could also impel a woman to conceive solely to provide fetal tissue for transplantation. The sale of human embryos for cosmetics production has been reported, and kidneys for transplantation from live donors in Brazil and India have been advertised for sale to physicians in Germany. [10]

While in the United States the sale of human organs is prohibited, their donation, particularly to a closely related individual, is generally condoned or even praised. How then are we to respond to proposals to conceive and "donate" fetal tissue? Is the freedom of choice exercised by a woman who does so different from that exercised by a woman for whom abortion is the preferred method of birth control?

It is important to distinguish between ethical and legal perspectives. Thus, while we may fault a person with a rare blood type who denies crucial blood to a hemorrhaging patient, a law compelling the blood donation would be unacceptable. To protect individual autonomy, we may prefer not to prevent rational people from mutilating themsleves or extirpating their organs. But if we hold it wrong to treat persons only as means, we may prohibit commerce in body parts. If, by extension, we consider it wrong to treat human fetuses only as means, we may condemn conception with the intent to abort, whatever the ultimate purpose. Successful therapeutic use of fetal brain tissue, once widely available, may indeed influence a woman's abortion decision, but it is impractical to ascertain motives, and it would be improvident to legislate against them. We should, however, prohibit the sale of human fetal tissue, as well as the "donation" of fetal tissue to any specific recipient, and implement acceptable legislation for these purposes.

Risks and Clinical Trials

Is the mother exposed to unnecessary risk by the procurement of fetal tissue for transplantation? Suction curettage using laminaria (rather than rigid dilators) for cervical dilatation is the safest available procedure for terminating pregnancies at the stage of fetal development optimal for tissue procurement. [11] Since the supply of fetal tissue by this procedure exceeds the anticipated demand, at the moment there is no justification for exposing the mother to riskier procedures to obtain transplantable tissue.

This situation could change however. Mary B. Mahowald, Jerry Silver, and Robert A. Ratcheson have considered the possibility that as a result of future developments, "gestation may need to be prolonged and the method of abortion may need to be altered to increase the chances of therapeutic success for the recipient." Holding that prolonging pregnancy "is comparable to maintaining vital functions of a cadaver donor through mechanical support," they indicate that "a woman who would otherwise undergo abortion during the first trimester might be asked to continue her pregnancy until the second trimester." On this account, it is morally appropriate to solicit the pregnant woman's free and informed consent to alternative, riskier abortion procedures less damaging to the fetus than suction curettage. [12]

Prolonging pregnancy differs from maintaining vital functions of a cadaver donor in the important sense that the fetus will in the meanwhile continue developing, perhaps to a stage where it may feel pain. Moreover, it is doubtful that coercive aspects can be absolutely excluded from such solicitation. The pregnant woman should not be asked to accept greater risk just to increase the chance of successful transplantation: the termination of her pregnancy ought, as a matter of course, to be performed by the safest available method. Medical decisions regarding abortion should be made without regard to potential subsequent use of fetal tissue. Physicians involved in any such use must remain distinct from those involved in the abortion.

While it is unlikely that more mature fetal brain tissue will be advantageous for foreseeable applications, it is true that accurate dissection of the relevant portion of fetal brain would be simplified by use of an intact fetus removed from the uterus by hysterotomy. Such a method would face difficulties in determining fetal death, and objections on grounds of inflicting harm by operating on a living (even if nonviable) fetus. Nevertheless, in the future, a woman undergoing abortion might offer freely, without solicitation or remuneration and with full awareness of the increased risk to her health from complications of surgery, to have her pregnancy terminated by such surgery to provide tissue for transplantation to an anonymous recipient. A rational individual's status as patient should not compromise her autonomy; certainly we vouchsafe a cancer patient the right to choose between surgical and medical treatment, though the two may carry unequal risks. Thus it seems to me that the woman's choice would be ethically acceptable, but would not obligate a dissenting physician to perform the operation.

But would transplantation of fetal tissue expose the recipient to unacceptable risk? While the adult brain can sustain transplanted neurons, it cannot support the long-distance growth of their fibers. Fetal dopaminergic cells have not restored impaired movements when grafted to the site of the host's degenerated dopamine-containing cells in the substantia nigra. At present, the cells must be grafted to the forebrain regions normally reached by their dopamine-secreting fibers. When large pieces of neural tissue are transplanted, neurons in their interior generally die before sufficient blood vessels can grow in from the host brain. Simple diffusion of nutrients and wastes may suffice for smaller grafts. Small tissue pieces can be transplanted to surgically prepared cavities in the brain under direct visual observation, a technique used in most of the adrenal grafts that have been performed. Yet there is less damage to the brain and better graft survival if the tissue is taken up in a syringe and transplanted as a slurry using finebore needles; in the future, transplantation procedures in humans will probably use this method. Neurosurgical techniques for accurately inserting such needles under computed-tomographic guidance in the awake patient are well-established.

Improvement of the patient's symptoms as a result of transplanting fetal neurons in this manner is expected on the basis of a large number of similar procedures carried out in rats and several species of monkey. Human fetal neural transplantation is, however, an experimental procedure and an unsatisfactory outcome is possible. The grafts may be without effect, or their excessive growth could compress the forebrain regions in which they are placed, further compromising brain function and exacerbating symptoms. Infection or inflammation as a result of the surgery could be fatal. Concern that transplanting brain tissue "would alter the identity of the recipient" [13] is without factual basis, but excessive secretion of dopamine or other neurochemicals by the grafts, or brain damage from their excessive growth could possibly lead to imbalances of mood or personality.

Some suggest that a clinical trial of neural transplantation is premature: technical questions remain concerning optimal graft volume and site and method of implantation, and the mechanisms by which the grafts exert their therapeutic effects are controversial. [14] Many of these questions can only be answered in the clinic, and the risks associated with such experimental procedures must be considered in light of the progressive and terminal course of Parkinson's disease. There is currently no adequate alternative therapy for these patients. The risks of transplantation may be acceptable above all because success would most benefit the patients themselves. The decision should be theirs, without coercion and after thorough discussion of the procedure and its foreseeable risks. While further animal experimentation is urgently needed, a clinical trial of fetal neural transplantation restricted to patients who no longer respond satisfactorily to existing medication is ethically warranted.

What is less clear is whether such a trial can or should be restricted initially to a limited number of rigorously controlled studies or allowed to proceed at the discretion of individual researchers, patients, and hospital ethics committees. The current enthusiasm for intracranial adrenal transplantation in Parkinson's disease when the value of this risky procedure has yet to be established suggests that restrictions might be appropriate. However, while guidelines may suffice to restrain scientists who depend on the favor of granting agencies, it is less likely that independent neurosurgeons could be as easily controlled.

Social Barriers

That these are matters for the whole of society to decide--not simply the individuals directly involved--follows from an appreciation of their larger consequences. But how are we to know what these social consequences will be? Will the therapeutic use of fetal tissue have brutalizing effects upon our society that outweigh the advantages of resulting medical progress? This is an empirical question that we are asked to consider before the fact. In the absence of evidence, the question may be rejected as "an inflammatory toying with human fears." [15] But fear of a biological "slippery slope," or of the "thin edge of the wedge," is not ungrounded. Reflecting on the barriers that prevent people and states from performing atrocities, philosopher Jonathan Glover has observed that the "barriers must be at least as much emotional as intellectual... Can we be sure that fetal research could be kept in a separate emotional compartment? .... Perhaps the risk that these barriers will be weakened is a small one, but even a small risk of a great disaster should not readily be dismissed... [W]e have reasons, to do with ourselves rather than them, for not treating [fetuses] as merely disposable." [16]

Fetal tissue transplantation for treatment of Parkinson's disease, as here described, poses no risk of eroding these barriers. The risks posed by future developments will have to be considered in their turn. Whenever and wherever we approach a slippery slope, we shall have to erect new barriers that will inevitably seem arbitrary in the details of their placement. [17] It will be unfortunate if in erecting these barriers, legislatures and society at large are preempted by the pace of research.


[1] Ignacio Madrazo et al., "Transplantation of Fetal Substantia Nigra an Adrenal Medulla to the Caudate Nucleus in Two Patients with Parkinson's Disease," New England Journal of Medicine 318 (January 7, 1988), 51; Olle Lindvall et al., cited in Georgina Ferry, "New Cells for Old Brains," New Scientist (March 24, 1988), 54-58; "British Fetal Cell Implants," New York Times (April 19, 1988), 27.

[2] Patrick Brundin et al., "Behavioural Effects of Human Fetal Dopamine Neurons Grafted in a Rat Model of Parkinson's Disease," Experimental Brain Research 65 (1986), 235-40; Ingrid Stromberg et al., "Human Fetal Substantia Nigra Grafted to the Dopamine-denevated Striantum of Immunosuppressed Rats: Evidence for Functional Reinnervation," Neuroscience Letters 71 (1986), 271-76.

[3] Massimo S. Fiandaca et al., "Immunologic Response to Intracerebral Fetal Neutral Allografts in the Rhesus Monkey," Brain Research 74 (in press, 1988).

[4] Centers for Disease Control, Abortion Surveillance 1981 (Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1985), 51.

[5] Fletcher H. McDowell and Jesse M. Cederbaum, "The Extrapyramidal System and Disorders of Movement," Clinical Neurology, Volume 3, A.B. Baker and Robert J. Joynt, eds. (Philadelphia: Harper and Row, 1987), ch. 38, 18-41.

[6] Richard Wasserstrom, "Ethical Issues Involved in Experimentation on the Nonviable Human Fetus," in Appendix: Research on the Fetus, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (Washington: 1975), 9-3.

[7] Sissela Bok, "Fetal Reseach and the Value of life," Appendix: Research on the Fetus, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, (Washington: 1975), 2-7.

[8] Mary Anne Warren, Daniel Maguire and Carol Levine, "Can the Fetus be an Organ Farm?" Hastings Center Report 8:5 (October 1978), 23-25.

[9] Temar Lewin, "Medical Use of Fetal Tissue Spurs New Abortion Debate," The New York Times (August 16, 1987), 1.

[10] Debra MacKenzie, "Third-World Kidneys for Sale," New Scientist (March 28, 1985), 7; "Embryos to Lipsticks?" New Scientist (October 10, 1985), 21.

[11] Centers for Disease Control, Abortion Surveillance 1981, 14-15.

[12] Mary B. Mahowald, Jerry Silver, and Robert A. Ratcheson, "The Ethical Options in Transplanting Fetal Tissue," Hastings Center Report 17:1 (February 1987), 9-15.

[13] Mahowald, Silver, and Ratcheson, 12.

[14h Robert J. Joynt and Donald M. Gash, "Neutral Transplants: Are We Ready?," Annals of Neurology 22 (1987), 455-56.

[15] Bok, "Fetal Research," 2-13.

[16] Jonathan Glover, "Matters of Life and Death," New York Review of Books (May 30, 1985), 19-22.

[17] Jonathan Glover, Causing Death and Saving Lives (Middlesex, England: Penguin, 1977), 167.

Alan Fine is assistant professor of physiology and biophysics in the Faculty of Medicine, Dalhousie university, Halifax, Nova Scotia.
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Author:Fine, Alan
Publication:The Hastings Center Report
Date:Jun 1, 1988
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