Brain Vol. 127 No. 12 © Guarantors of Brain 2004; all rights reserved
Book review |
NEURAL STEM CELLS FOR BRAIN AND SPINAL CORD REPAIR
Tanya Zigova, Evan Snyder and Paul Sanberg, editors.
2002. Totowa (NJ)
Humana Press
Price $149.50. ISBN 1588290034
STILL LIVES—NARRATIVES OF SPINAL CORD INJURY
Jonathan Cole
2004. Harvard (MA): Bradford Books, MIT Press
Price £18.95.
ISBN 0262033151
STEM CELL RESEARCH—NEW FRONTIERS IN SCIENCE AND ETHICS
Nancy E. Snow, editor.
2003. Notre Dame (IN)
University of Notre Dame Press
Price $25.00.
ISBN 0268017786
1 Neurology Unit, Department of Clinical Neurosciences, School of Clinical Medicine and 2 Cambridge Centre for Brain Repair, University of Cambridge, UK
Stem cells, stories and wonderful works
For you created my inmost being; you knit me together in my mother's womb. I praise you because I am fearfully and wonderfully made; your works are wonderful, I know that full well. My frame was not hidden from you when I was made in the secret place. When I was woven together in the depths of the earth, your eyes saw my unformed body. All the days ordained for me were written in your book before one of them came to be.Psalm 139: 13–16
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5 years ago, when bone marrow-derived cells appeared to become neurons. Subsequent replication of this work has been difficult and the original data were reinterpreted as examples of cell fusion. However, in the last few months, this research has come full circle, with a number of groups now reporting definite trans-differentiation of different stem cells using rigorous criteria. If true, then the most innocuous tissues such as autologous skin could generate neural cells. And all ethical dilemmas would melt away.
So why the continued emphasis on embryonic stem cells? Some scientists, like David Prentice in Stem cell research—new frontiers in science and ethics (edited by Nancy Snow), argue that ‘despite twenty years of experiments with mouse embryonic stem cells, ... the claims for embryonic stem cells and their advantages over adult stem cells are unsubstantiated’. We do not agree. The hard fact is that currently the stem cell that has shown to greatest capacity to differentiate appropriately in the brain and to function physiologically and reverse disease behaviour is the embryonic stem cell in mice (Studer et al., 1998
). Ignoring this point is to do bad science and bad ethics. These experimental data mean that, if technical considerations were all that mattered, the stem cells most likely to be taken into humans would be derived from human embryos, probably from redundant blastocysts generated by IVF protocols. This is not an immediate prospect. For in order to drive their differentiation and reduce their tumorigenic potential, such cells have to be taken through a sequence of in vitro manipulations with various growth and differentiation factors, a process called redifferentiation. We judge it will be at least 5 years before redifferentiation protocols in humans will be secured. Furthermore, important clinical issues need to be resolved. The disparate results from trials of transplantation of fetal dopaminergic tissue in Parkinson's disease probably arise as much from variations in the selection of patients as the type of cell and approach adopted. Zigova, Snyder and Sanberg's text fails to engage with such topics as patient selection, timing of treatment and outcome measurement. These are not just scientific issues, for a utilitarian ethical analysis places a heavy burden of procedural correctitude on a trial, so that the clearest possible answers emerge from exposure of the fewest patients to risk.
So the therapeutic use of embryonic stem cells cannot be dodged. And the central ethical question arises: ‘when does the developing fetus acquire the moral status of a live human?’ Theologically reconstructed, this question becomes ‘when does the embryo develop a soul?’ or a societal version might be ‘when does the embryo acquire the rights of personhood?’ or—at its most inflammatory—'when does discarding cells become murdering the innocent?' In the morality of the post-modern Western world, answers to these questions are largely a matter for personal negotiation and public ambivalence, with cynicism for institutional or religious positions. The debate is not helped by the polarized stereotypes of suffering patient, amoral scientist and bleeding-heart ethicist. Just as complex biological problems are solved by the hard labour of multidisciplinary teams working together with mutual respect, so many different voices need to be heard on the difficult issue of the use of fetal stem cells in medicine. For ethicists, the rich resources of philosophical and religious thought over the centuries is so familiar that they need not be stated. At least that must be the reason why none of the classical accounts are retold in Stem cell research—new frontiers in science and ethics. So the opportunity is lost to educate those working on stem cells who may be untrained in moral philosophy. Such people might be surprised by the close historical relationship between ethics and science. To the modern reader, Aristotle's suggestion that there are three phases of ensoulment seems ludicrous at first, with the vegetative life initiated at conception, exchanged after a few days for an animal soul, and the rational soul being infused only at 40 days for males, and at 90 days for females. But it drew upon the embryology of his day and, critically, introduced the doctrine of progressive animation. Thomas Aquinas agreed that humanization is a gradual process: ‘And we must observe a difference between the process of generation in men and animals and in air or water. The generation of air is simple, since therein only two substantial forms appear, one that is displaced and one that is induced, and all this takes place together in one instant, so that the form of water remains during the whole period preceding the induction of the form of air. On the other hand, in the generation of an animal various substantial forms appear: first the semen, then blood and so on until we find the form of an animal or of a man’ (Summa Theologiae, Ia, q. 119, a. 2). From these roots, the modern doctrine of ‘delayed humanization’ has emerged, in which the value of a fetus grows with its physical development. This argument has been used to suggest that the fetus becomes human at implantation when the chances of its survival are much increased and the subsequent possibility of twinning is very low, so the embryo can be considered a distinct individual. Such considerations led to the current maximum limit of 14 days of experimentation on human embryos in the UK. The implication is that this ethical process will adapt to changes in biological understanding. This is institutively sensible, but potentially dangerous as uncertainty about biology may lead to subversion of ethics. The start of life or ensoulment may be informed by empirical studies, but cannot be proved by them. Here, perhaps, lies the source of the disabling ambiguities of the Anglican position on stem cell research. The reformers, Calvin and Luther, were not explicit in their understanding of ensoulment, but their exegeces of Psalm 139 (above) and Exodus 21:22–23 (in which the consequences for hitting a pregnant women are discussed, with a different punishment depending upon whether the fetus survives or not) suggest they viewed conception as the start of life: as Calvin writes in Commentaries on the Last Four Books of Moses ‘for the foetus, though enclosed in the womb of its mother, is already a human being, and it is a monstrous crime to rob it of the life which it has not yet begun to enjoy’.
Nancy Snow, who works in a Catholic University, drew together a panel of scientists and ethicists for a conference on stem cell ethics in 2001 sponsored by her university, the Archdiocese of Milwaukee and the Wisconsin Catholic Conference. Out of this meeting emerged Stem cell research—new frontiers in science and ethics which largely speaks to a Roman audience. Whilst noting in passing the shocking lack of representation of other denominations and faiths to the debate on stem cell morality, it is nonetheless useful to sample the current anxieties of Catholic commentators. The timing of ensoulment is acknowledged to be difficult, and so the teaching of Donum Vitae, that the ‘human being is to be respected and treated as a person from the moment of conception’ (I, 1) arises as a prudent response to uncertainty. As Lisa Cahill's important essay shows, this position derives from a tradition of probabilism within Catholic thinking. In its light, she assesses the impact of restrictions on fetal stem cell medicine on: patients, the fetus itself and the integrity of the doctrine of respect for life. She places these considerations in the context of the current pontiff's emphasis on distributive justice. Her analysis, satisfyingly broad in its scope, concludes rather lamely that embryos ‘left over’ from IVF protocols, whose future is either destruction or frozen animation, might be used in medicine, but embryos should not be created expressly for therapeutic purposes. Lamely, because she does not allow the possibility that IVF protocols should be changed to ensure that embryos are not ‘left over’; nor does she consider the wonderfully creative suggestion of embryo adoption (www.snowflakes.org). Karen Lebacqz—the one Protestant contributor—would certainly challenge this uncritical acceptance of IVF. She draws a challenging parallel between IVF and fetal stem cell use, as both procedures create—and destroy—fetuses to satisfy the needs of a third party.
If the conclusion from these analyses is that the embryo is partly or wholly human, then the next ethical question is: ‘is it right to destroy a human life for research intended to treat illnesses?’ Healing is after all fundamental to Christ's witness on earth and ‘central to God's identity’ as Therese Lysaught emphasizes. A fine dissertation follows on the circumstances in which killing might be morally acceptable, using Thomas Aquinas' arguments on self-defence and the just war tradition. Physicians will be more familiar with the ‘double-effect’ argument in medical ethics (derived from Aquinas on self-defence) that permits a harmful effect—within careful limits—if the primary goal is good. In this way, for instance, are justified those treatments that alleviate great suffering but which might also shorten life (such as opiates in cancer pain). This raises the question: ‘what is the harm of diseases which might be treated by embryonic stem cells?’ Here most ethical accounts, including Snow's book, are weak, pre-supposing much about the suffering of people with neurodegenerative diseases. It is widely assumed—by the media certainly—that hordes of patients with disabling neurological diseases are clamouring for stem cell treatment. But the truth, as portrayed in Still lives, is complex and more subtle. Jonathan Cole narrates the lives of 12 people with spinal cord injuries, typically acquired early in life and traumatic in nature, in order to answer the ‘simple question of what it is like to live in a wheelchair, without sensation and movement in the body’. Many sustained their injury by diving or swimming in shallow water, exposing the fragility of the spinal cord. At the moment of injury, many knew what had happened, even if its enormity was not at first acknowledged. There followed rehabilitation in specialist spinal units, where one sensed the amazing sense of camaraderie that exists amongst this patient group. Then the accounts fragment, as people try to refashion their lives. This is the strength of the book, rather than the author's philosophical speculations on, for instance, what makes us interactive people in society.
The different personal strengths and weaknesses of the subjects of Still lives mould how their injury affects their lives and their relationship to the world. Thus, some have used spinal cord injury to champion the cause of people with disabilities, whilst others have retreated into worlds of their own, seeking explanations as to how and why they carry on. So Colin remarks of his spinal cord injury that ‘the only thing to look forward to is the fact that it is going to get progressively worse. To manage that is very difficult’, whilst Ian feels that ‘being with spinal cord injury is a different world with different rules; I just wish I knew what the rules are’. and Nasser feels that you ‘just have to get on with it. No cure, just get on with it’. Some seek cures and even embark on long courses of experimental therapy, for instance Julie Hill's experience with the lumbosacral anterior root stimulator implant to simulate paralysed muscles. These accounts are inspiring and upsetting, richly conveying the range of problems experienced by people with spinal cord injury. Such injuries are usually thought of by neurologists in terms of negative symptoms, with weakness, wasting and sensory loss. Time and again though the narratives remind us of the important positive symptom of pain, which may be the single most influential factor preventing work or social interactions (see for example Bob in Chapter 11). The devastating impact of spinal cord injury on sexual dysfunction is also mentioned repeatedly, inducing a sense of not being wholly male or female. If the only immediate candidate for cellular repair is the embryonic stem cell, then those arguing against its use on ethical grounds must confront the possibility they are denying a potential relief of this physical, psychological and spiritual pain.
However, the range of human responses to injury is complex. There were some surprises. Some would not wish to have their old lives back. One person (Mike) described his injury as ‘he best thing that ever happened to me’, redirecting his meandering life into sharp focus and purpose. And we heard from perhaps the most neglected group, relatives and carers. Kevin, husband of Julie Hill, makes it clear that one of the positive turning points in their relationship was having to work together, and with professionals, on her experimental therapy. The complexity and breadth of the physical, psychological and social consequences of spinal cord injury makes one realize the enormous challenges for reparative strategies. It is not sufficient to implant cells, but vital to ensure they wire up correctly and help disability, whilst not exacerbating symptoms such as pain. If cellular therapies are to work, then it will be necessary to retrain the patient to use their spinal cord, possibly taking them back into the units where they have spent some of the most traumatic months of their lives. If this is not difficult enough, the hopes raised by the prospect of treatment and dashed by any setbacks would place vulnerable people under considerable psychological strain which should not be underestimated.
If, in some years from now, fetal stem cells become routine therapies, a new ethical problem will arise. Professionals with moral objections to fetal stem cell use might find themselves drawn into compromising situations. Would it be morally acceptable to refer a patient for fetal cell transplantation? To participate in follow-up? To advise on concomitant medication? Or perhaps the dissenting lab technician would get asked to prepare stem cells, or provide the media in which they are grown, or order the necessary consumables; at what point is his or her involvement complicit in the offending act? Here the principles of ‘cooperation’ in moral philosophy are genuinely helpful. Edward Fulton deftly guides the reader through some tortuous terminology (‘formal explicit cooperation’, ‘material proximate cooperation’) to conclude that Catholics should not generate embryonic stem cell lines nor use them for research, but may use the products of such research: a position similar to acceptance of vaccines generated by cell lines derived from abortions. Interestingly, Fulton allows that an individual may wish to make a strong statement against the destruction of embryonic life by refusing even these acceptable practices: ‘such an action would go beyond what is morally necessary and would be heroic’.
The biology and ethics of human embryonic stem cells are both complex. They stretch our technical and intellectual resources, and challenge our notions of life and personhood. They expose our society's ambiguous attitude to the fetus and our ignorance of the plight of those with neurodegenerative disease. And they confront our moral and religious beliefs. Much in the debate is uncertain and some is unknowable. Our response should be not to retreat into dogma but to proceed cautiously, compassionately and humbly, with an ear for all voices. Therese Lysaught catches this spirit in her concluding paragraph:
I do not know what I would do if one of my children needed the products of human embryonic stem cell research. But I know that what I ought to do should be illuminated by the story of the Trinitarian God, whose story is one of peace, healing and compassion—the difficult activity of suffering with those who suffer precisely because, want as we might, we cannot eliminate that suffering.
Reference
Studer L, Tabar V, McKay RD. Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1998; 1: 290–5.[CrossRef][Web of Science][Medline]
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