A science fiction writer could not have craft­ ed a more profound conflict. Researchers dis­ cover a revolutionary approach to treating  some of a society’s most devastating illnesses,  but the secret lies in the human embryo,  which is held sacred—untouchable—by sever­ al of that society’s leading religions. America  is living out such a conflict. 

Michele Garfinkel co-authored the American Association for the Advancement of Science’s 1999 report, Stem Cell Research and Applications: Monitoring the Frontiers of Biomedical Research. She argues that the debate over research on embryonic stem cells is framed as moral principle versus research gains. Shunted aside is a balanced assessment of stem cell therapy’s potential for treating specific diseases and saving lives. Will the controversy entirely shut out research on normal human development—without which stem cell therapy may never achieve its real potential? Cerebrum welcomes letters expressing different points of view.

In November 1998, human stem cells fell from the sky—or might as well have, given how apparently unprepared the science, health policy, and legislative communities were for the report of the discovery. Today it seems almost incredible that embryonic stem cells (a special type of undifferentiated cell found in human embryos) were discovered only two years ago. Since then, scientists in laboratories worldwide have reported the previously unthinkable results: to name only two, mice sprout healthy neurons in their incurably diseased spinal cords and monkeys grow new motor neurons. During the same period, government agencies, scientific organizations, and Congress brought about virtual policy gridlock with inconsistent recommendations for regulating stem cell research, as a result of the controversial issue of using public funds to support research using embryonic stem cells.

What are these cells that have created such challenges? Stem cells continue to proliferate without differentiating into any particular organ or cell type. They come in two basic forms. Embryonic stems cells, found in every human embryo and fetus, can grow into virtually any kind of adult tissue and are referred to as pluripotent. Adult stems cells (found in children as well) may have a more restricted range of fates and are referred to as multipotent.

The discovery of stem cells in human embryos by James Thompson and colleagues, announced in November 1998, came near­ly simultaneously with a similar discovery by John Gearhart and his research team of stem cells in human fetuses. These cells could be kept alive for long periods in a petri dish and showed patterns of gene expression characteristic of undifferentiated cells. Under certain conditions that are not yet fully known and cannot yet be con­trolled completely, the cells would undergo differentiation to form internal tissue called endoderm (for example, gut epithelium), mesoderm (cartilage, bone, and muscle), or ectoderm (skin). This shattered one of the abiding certainties of neuroscience: the belief that there was no way to replace damaged or dead cells in the brain and central nervous system.

Suddenly, the grim roll call of irreversible diseases and disorders involving degenerated neurons—from Parkinson’s disease to spinal cord injury—looked dif­ferent. Scientists might well have recalled Keats’ famous description of Cortez and his men, who “looked at each other with a wild surmise...” on his discovery. The headlong pace of private research (publicly funded scientists are de facto banned from the field, caught in policy gridlock) on applying stem cell therapy, wrote the Washington Post (April 19, 2000), “is thrilling patients who hope to see medical benefits in their lifetimes.”

Given this potent blend of hope, scientific excitement, and political sensitivi­ty (not to mention some impressive com­mercial possibilities), it is not surprising that the potential of stem cell therapy has been both exaggerated and dismissed altogether. Many, although not all arguments have framed the research as a trade between a presumed compromise of principles and a possible gain from new therapies. The willingness of some pro-life legislators to entertain the idea that using frozen embryos might be acceptable is a public confirmation of such straight bartering.

What have been lost in many public arguments are reasoned discussions about what the best approaches to treating particular diseases are, and what we really need to know if we are in fact to use stem cell therapies. An amazing roster of brain and other nervous system diseases, and brain injuries, have been discussed in terms of potential stem-cell therapies: Parkinson’s disease, multiple sclerosis, Alzheimer’s disease and other dementias resulting from central nervous system degeneration, the spongiform encephalopathies such as Creutzfeldt-Jakob disease, brain tumors, and traumas. In addition, there is the whole area of normal human development, where scien­tists know relatively little, compared with knowledge of animal development, because of restrictions on human embryo research.

Where is embryonic stem cell therapy most promising? Where may adult stem cells work? Which diseases are likely to yield first to research? Where are stem cell approaches of any kind likely to prove insufficient because new cells would be susceptible to the disease? And where, as is almost certain, will our limited knowledge of human development frustrate advances against specific disorders?

As researchers and policymakers consider the resources needed to vigorously attack diseases of the brain and nervous system and ask how critical questions about stem cell research apply to these conditions, let us look briefly at the political context in which research is proceeding.

STEM CELLS: FROM WHERE? FOR WHAT?

Appearance of the reports from Thomson’s and Gearhart’s laboratories seemed to take policymakers by surprise, instigating a flurry of activity. President Clinton charged the National Bioethics Advisory Commission (NBAC) to “conduct a thorough review of the issues associated with…human stem cell research, balancing all medical and ethical issues.”¹ The American Association for the Advancement of Science (AAAS), together with the Institute for Civil Society (ICS), undertook a project to outline recommen­dations for research on human stem cells and their eventual clinical use.² The National Institutes of Health (NIH) began to assemble guidelines that would be required for federally funded researchers; those are still under review.³

NBAC and AAAS/ICS made recom­mendations concerning many aspects of the research and eventual applications. But, as reflected in the spareness of the NIH draft guidelines, two issues stand out as being of most immediate concern—whether public funds can be used to isolate embryonic stem cells and for subsequent research, and what kind of oversight is necessary. On these two pivotal matters, there is no agreement among the bodies that have thus far issued their recommendations:

• The NBAC’s guidelines allow for public funding for deriving the cells (and thus destroying embryos) and research on these cells; it calls for oversight at national and local levels.
• The NIH bases its suggested guidelines on an interpretation of Public Law 105­277, section 511, 112 STAT. 2681-386. That law prohibits using appropriated funds “for the creation of a human embryo or embryos for research purposes; or research in which a human embryo or embryos are destroyed, discarded or knowingly subjected to risk of injury or death…” The legal office of the Depart­ment of Health and Human Services since advised NIH that this means feder­ally funded researchers cannot participate in isolating cells from embryos because this destroys the embryo. Because stem cells themselves are not embryos, however, publicly funded scientists could use the cells once they were isolated (if this were done without using public funds). The guidelines specify allowable sources of cells: embryos created outside the body during in vitro fertilization proce­dures “in excess of clinical need.” The NIH calls for national oversight in addition to local institutional review boards. Presumably this approach will include a way to monitor adherence to ethical guidelines in the private sector component of the process.
• AAAS recommendations suggest funding for experiments on previously isolated cells only, a policy decision recognizing the potential stumbling blocks of allowing public funding to derive cells. For those eager to see publicly funded research under way, even if publicly funded researchers cannot derive the cells themselves, the correctness of this reasoning is at least somewhat apparent. In contrast to NBAC and NIH, however, AAAS recommendations suggest no national oversight at this time, noting that there are no new research ethics concerns and that existing bodies can best deal with stem cell experiments. It does not preclude national-level oversight should new issues arise.
• Senators Arlen Specter (R-PA) and Tom Harkin (D-IA) introduced a bill calling for federal funding for isolating embryonic stem cells and subsequent research. The timing of any major debate on the bill is likely to depend on political considerations.

By comparing other recommendations of these groups, one sees obvious hope that the moral and political dilemmas of stem cell research can be avoided by concentrating research on adult stem cells rather than on those isolated from embryos. The key feature distinguishing adult stem cells from embryonic stem cells, at least in terms of clinical applications, is the more limited range of fates they are thought to be able to achieve with appropriate stimulation. Certainly in some applications multipotent adult stem cells will work very well, and may even be preferable to pluripotent embryonic cells. But there is no way to make this decision in the absence of data on the various kinds of cells.

For example, adult stem cells have long been known to exist in blood; this feature has been exploited for bone marrow transplants. In contrast with old convictions of the field, stem cells have been found in differentiated tissue, including neural tissue, long thought to undergo no new growth. Genuinely surprising was the discovery that adult multipotent stem cells could differentiate into tissue types distinct from the one they were originally isolated from: for example, “brain into blood.” ⁴ Whether this is because entirely different types of stem cells co-exist in mature tissue or because one kind of multipotent stem cell can, in fact, achieve decidedly different fates is one in a long line of questions that need to be answered before the promise of the enterprise can be reasonably evaluated. It may turn out that adult cells are more versatile than our earlier understanding indicates. But it is unfair to make this evaluation in the absence of further research on adult and embryonic stem cells.  

In some cases stem cell therapy may not even be the best approach. Where it is, the best starting material— adult or embryonic stem cells—might depend on the disease. If promising therapies work less than perfectly, we will be thrown back on questions about human embryos themselves—on our need to understand more about basic human development.

BRAIN DISEASES: FIRST IN LINE FOR TREATMENT?

Diseases and injuries of the brain and central nervous system rank among the most frightening and overwhelming of all human afflictions. When acute, they impinge on our sense of self and the capacities that make us social beings. These diseases are frequently complex in their pathologies, complicated by underlying genetics, and poorly understood in terms of diagnosis, progression, and treatment. They cry out for intense research programs, but the research is itself complicated and expensive.

Patients, families, and friends should be told forthrightly that although a few classes of neurodegenerative brain disorders may be particularly responsive to stem cell therapies, many prove more resistant— at least to the most straightforward types of therapy—and require much more research. Yet much of what is understood about potential applications for stem cells in disease as a whole does come from the nervous system. Despite the vast complexity of that system, the hope is that these diseases may be the first for which robust treatments will become available. Many stem cell transplant experiments on animals were for brain and central nervous system research and showed great promise. Even absent positive results for particular diseases, however, there are pressing reasons to choose the brain as a focus for stem cell early research. These reasons, like the brain itself, are complex, but a brief explanation is in order.

Although scientists are beginning to find exceptions, there are long-standing observations to the effect that brain cells cannot regenerate themselves after damage and that individual brain cells lose the ability to grow and divide to produce new cells. At the same time, brain structure is almost inconceivably complex, with connections between cells and regions that are remarkably specific. This suggests that a mechanical approach to correcting brain lesions (for example, with some sort of electronic device) is unlikely to work. Now scientists have new evidence that stem cells exist in tissues that, like the brain, were assumed to have none. Scientists do not know if regeneration fails in the brain because there are too few stem cells, because these cells after a certain stage of development no longer can respond to signals to regenerate, or for some other reason. But if a high-concentration, high-quality source of stem cells (for example, human embryonic stem cells) could be introduced into the brain, they might respond to signals that already existed in the brain and thus grow and integrate properly with existing structures. There is evidence this approach might work. The experiments are discussed below.

The brain and nervous system are subject to more than 100 different disorders and diseases. It is impossible here to evaluate specific potential therapies for each, so we will examine possibilities for certain major diseases based on results in animal studies and tantalizing hints from human research. The diseases represent various classes of brain disorders, but it is well to remember that we know relatively little about the mechanics of most brain dysfunction. In several instances discussed below, the apparent success of experiments seems to have depended on the ability to respond to stem cell therapies in a mouse of stem cells to migrate and differentiate in model. Although molecular mechanisms appropriate ways with little intervention are not completely understood, in the initial by researchers. This approach may work progression of diabetes only islet cells die, well for many diseases and injuries. But in some cases, which we cannot now predict, the ability of the cells to differentiate and develop properly may depend on the nature of the lesion. Doctors may have to treat stem cells before transferring them to the patient with particular growth factors or other reagents to prompt the cells to differentiate and function as they must for therapy to work.

PARKINSON’S DISEASE exemplifies a type of disorder that could prove miraculously tractable to stem cell therapies. Even early studies that injected crude human fetal tissue extracts (presumably containing stem cells) appear to have had some long-term benefits, although those results are continually re-evaluated. Unfortunately, this approach has daunting drawbacks, including how much tissue is needed for each treatment and a lack of uniformity in tissue extracts used for each individual treatment.

There are parallels between Parkinson’s and another disease—diabetes—that appears to respond to stem cell therapies in a mouse model. Although molecular mechanisms are not completely understood, in the initial progression of diabetes only islet cells die, and therefore only one kind of cell needs regeneration. In research in mice, scientists took cells from the pancreas and grew them in culture. Unable to characterize stem cells visually, they simply took all the cultured cells and transplanted them. The mice seemed to grow normal islet cells and their diabetic condition seemed to reverse (long-term results are pending).⁵ An islet cell transplant protocol is being developed for diabetes, but—as in Parkinson’s—this approach is limited by the availability and consistency of the cells.

Parkinson’s disease is similar mechanically to diabetes. While the exact mechanism of cell killing is unclear, only one type of cell is affected. The neurons of a single region, the substantia nigra, are damaged or destroyed, resulting in the loss of production of the neurotransmitter dopamine. Thus, as with diabetes, only one kind of cell would have to be restored.

MULTIPLE SCLEROSIS is a disease in which nerve fibers lose the insulation, myelin, that helps conduct nerve signals. Medical research has found no cure and no consistently effective, safe treatment. Multiple sclerosis occurs twice as often in women as in men. Onset, which occurs as early as the mid-teens, peaks in the 20s and 30s. MS does not cause acute fatalities but reduces life span by about five years, results in huge economic losses from lost time during peak work years, and can take a tremendous toll on sufferers’ day-to-day lives. It may be eminently treatable with stem cells. Again, looking at animal research, one group of researchers showed that shiverer mice (a mouse mutant used in research) exhibited some decrease in tremors following injection of neural stem cells.⁶ Similar experiments in other labs reinforce this promising outcome. With some refinement, the approach seems a reasonable candidate for a clinical trial.

What is notable in Parkinson’s and multiple sclerosis is that apparent improvement came from the injection of otherwise undifferentiated neural stem cells, which seem to act the same way natural neural stem cells do. They differentiate properly in the appropriate place, apparently responding to normal guidance and cues for differentiation. If these results hold up in further testing in animals and eventual testing in people, this will be an extraordinary advance in treating neurodegenerative diseases with a specific tool, and in the relative ease of treatment.

There need not be battles in all cases over which diseases should have priority in research. For example, the leukodystrophies, a broad class of diseases including adrenoleukodystrophy, Canavan disease, Zellweger syndrome, and Refsum disease, are rare compared with, for example, multiple sclerosis. Because each results from different genetic lesions and different mechanisms, but all lead to demyelination of the nerves, it is not unreasonable, based on the shiverer model, to think that remyelination by simple injection of stem cells could be a robust clinical approach. The next important step will be to reconfirm results with the shiverer mouse in other experimental models for demyelination diseases.

ALZHEIMER’S DISEASE is more complex  and its causes poorly understood. This form  of dementia is becoming more common  as people live longer; although the exact  number is difficult to estimate, one out of  ten Americans over age 65 may be afflicted.  The exact mechanism of Alzheimer’s is not  understood; there may be several genetic  lesions involved, complicating treatment.  Alzheimer’s affects neural connections deep  in the brain (in the hippocampus, affecting  short-term memory) and in the cortex  (disrupting language and reasoning). It is  not immediately apparent if an undifferenti­ ated neural stem cell would improve the  defective connections and signaling between  neurons that seem to be the basis of the  disease, although there is certainly a need  to restore healthy neurons simultaneously  to treat other aspects of the disease.^*   

These questions could apply to other  diseases where dementia results from  CNS degeneration. These include Leigh’s  disease, which targets a specific component  of neurons; Pick’s disease, which causes  degradation of the frontal and temporal  lobes and is a dementia like Alzheimer’s;  and Binswanger’s disease, an extremely  rare condition causing lesions in the brain’s  deep white matter. Again, even if the  mechanisms of progression of these diseases  are not well understood and may result  from different genetic or environmental  insults, if introduced stem cells act as they  do during early normal development, the possibility exists for curing even the rarest disorders.  

 ^* See “Rescuing Aging Memory: Stem Cells and Other Rising Stars” by John H. Morrison in the Spring 2000 issue of  Cerebrum. 

The SPONGIFORM ENCEPHALOPATHIES, whether transmissible or inherited, are especially insidious. This group includes illnesses such as Creutzfeldt-Jakob disease and Gerstmann Straussler disease, associated with abnormal functioning of a normal protein (although the link between that protein and the death of cells leading to the spongy appearance of the brain is not clear). If stem cells would act to replace dead cells, these could be powerful treatments. But, perhaps more so than with the other diseases discussed here, there would be concern that even the introduction of new cells would not be sufficient and that the new cells could themselves be susceptible to disease, or that the stem cells would have to be continually reintroduced. Here, more understanding of the disease mechanism is needed.

BRAIN TUMORS are malignant cancers dreaded because they are often far advanced when diagnosed; it is difficult to remove them without damaging the brain; and post-operative treatments are frustrated by the natural barrier between the blood system and the brain and other built-in protections of the brains. One recent experiment took advantage of the ability of neural stem cells to graft into existing tissue.⁷ Researchers made mouse neural stem cells that produced a protein called interleukin-4, which previ­ously had been shown to fight some brain tumors in rats. The scientists injected the modified mouse neural stem cells directly into a tumor (a brain glioblastoma), where the stem cells apparently grafted properly and expressed interleukin-4. Following treatment, few of the experimental mice died. The result needs to be replicated in this and other model systems because there are reasonable questions about whether or not laboratory-induced tumors are good models for naturally occurring tumors. Still, this is the sort of therapy that, if successful, could radically change approaches to treating brain and other tumors.

One potential advantage to using stem cells instead of cells that are differenti­ated and transplanted is that stem cells may act as cells do during normal early develop­ment, homing by responding to specific signals, then differentiating into neurons (grey matter) and glia (white matter). This appeared to happen in at least one experi­ment where human neural progenitor cells were transplanted into an adult rat brain and migrated along appropriate routes, appearing to differentiate properly by type (neural vs. glial) and location.⁸

If, in fact, these stem cells turn out to be as consistently compliant as they appear to be in the above experiments, they could be the miracle that sufferers of these terrible diseases eagerly await. Meanwhile, however, scientists, policymakers, and patients must keep in mind that these are very early days for this research. Obstacles are bound to appear. 

TANTALIZING HINTS, DAUNTING HURDLES

Note that the successful experiments with animals described above and the human fetal tissue involved in treating Parkinson’s used multipotent rather than pluripotent stem cells. We do not know the full range of pluripotent stem cells, but we know they have drawbacks. One is that because these cells are so plastic they can, and often do, differentiate into undesired tissues, as multipotent cells apparently do not. This is important because differentiated embryonic stem cells, when transplanted, could possibly begin to form a tumor. Even if this were a benign growth, the situation would be less than ideal. By the same token, we do not know if multipotent (adult) stem cells will prove easy to isolate on demand. Nor do we know if enough of them can be isolated for any given treatment. Scientists need to study stem cells from all sources, including embryos, to discover the best approach for any disease.

Before we even begin to ask in any consistent way what stem cells can do, how much research is needed on normal early development in humans?

 Would results be even more dramatic using embryonic pluripotent stem cells? Are neural stem cells special in this ability? Will the results we have reviewed hold for other neurodegenerative diseases and traumas to the brain and nervous system?

 We just don’t know how various approaches will compare and, as the framework for research in this area is now constructed, we won’t know any time soon. The results from animal experiments are promising, but may not translate directly to humans. Those results do mean, however, that good clinical trial protocols can be designed.

Even if the successes in animals carry over to people, obstacles will arise in the case of certain diseases. This has happened frequently. A recent example that made news was the shrinking of tumors in mice by treatment with angiogenesis inhibitors. It is an extremely promising approach but, as is normal in research, there have been ups and downs. It is not clear how the results will translate from animals to human beings; the leap can be long. There are two prime considerations.

First are the classical concerns of bioethics that attend every human clinical trial. Informed consent is most obvious, but there are whole layers of concerns that distinguish clinical trials from animal experiments.⁹ Second, and crucial, is: Before we even begin to ask in any consistent way what stem cells can do, how much research is needed on normal early development in humans? 

THE VEIL OVER HUMAN DEVELOPMENT

Virtually all discussion of research on human stem cells, particularly from embryos, has centered on their potential for treating diseases that occur after birth. Certainly the stakes in that arena are high; and it almost certainly will be necessary to understand normal early human development as a prologue to fashioning useful stem cell therapies for certain diseases. Unfortunately, restrictions on research on human embryos have left early human development relatively poorly understood. At this time, we cannot even imagine what information about human development might be useful in creating therapeutics.

Most research articles do not make the point explicitly, but it is assumed that failures in experiments on animals (whether the research is basic or clinical) are viewed through a filter of knowledge about normal development in those animals. That knowledge of development becomes a powerful aid in refining experiments and therapeutic approaches. In human clinical trials, by contrast, if an approach fails there is often little to fall back on. For example, it seems possible that multiple sclerosis and Canavan disease, although they have different initial lesions and outcomes, can be treated with identical approaches because the affected tissue is the same. But this may turn out to be a complete misunderstanding of the nature of such diseases. It may, in fact, be necessary to understand much more about the normal development of myelin before distinctions in response to treatment are understood.

This is one concern about the lack of understanding of human development. Another is the need for general understanding of human development that is (at least partially) divorced from disease per se. Access to human stem cells and human embryos will offer scientists an unprecedented opportunity to do that research. This has been recognized, at least in passing, by the NIH, NBAC, AAAS, and others, but there is scant discussion of a concerted research effort. Yet the results of such an effort would improve disease treatments that use stem cells, and lead to better treatments and prevention based on insight into normal vs. aberrant development. Understanding early development also could lead to more sophisticated prenatal care. 

How is this optimistic outlook affected by the debate over stem cell research?

TREATMENT VERSUS UNDERSTANDING?

The social and ethical questions raised by stem cell research cannot be ignored in our national dialogue. The difficulty, as we have seen, is that the conflict is framed in terms of social/ethical concerns against concerns about curing disease. On one side is the sense that, as a society, we want to move slowly, ensure that doing this researchis right, and invoke proper oversight (the NIH approach). On the other is a feeling of urgency because of the resounding roster of diseases that supposedly could be cured with the products of this research—and pleas from individuals and groups embattled with specific diseases. What the discussion has glided over is what exactly we will get from the research.

 To say that one is destroying an embryo as a step in a research program directed at curing a disease may mute the ethical controversy, but what happens to scientists who use stem-cell research to study development? Implicit in virtually all biomedical research is an assumption that eventually its discoveries will result in a palliative or cure for some affliction. The key term is eventu­ally. Stem cell research is in its infancy, and investigation targeted to clinical applications may turn out to suffer from the dearth of deep understanding of normal human development. Unfortunately, insisting that stem cell research will result in cures not only casts that argument in a way that makes taking sides almost unavoidable, it raises obstacles to those who wish to carry out more basic research on human development. In other words, to say that one is destroying an embryo as a step in a research program directed at curing a disease may mute the ethical controversy, but what happens to scientists who use stem-cell research to study development and other non-disease ques­tions? Their research is no less important, but making their case becomes much harder.

Of course, political controversies of this kind are often outstripped by science’s advance. For example, even scientists and policymakers with no strong qualms about using human embryos for research are concerned that it may prove more difficult than it now seems to maintain embryonic stem cells (or other stem cells) in a culture medium. True, several scientists have reported maintaining stem cells in culture for several years, with no unwanted differ­entiation or tumor-producing qualities, but this experience is with a small number of independent lines of cells. As additional independent stem cell lines are isolated and maintained, it is conceivable we will discover that, on average, these are harder to maintain than we thought—perhaps so difficult that it will not be worthwhile from a clinical perspective to continue research.

Admittedly, this seems unlikely, based on early reports; in fact, the opposite situa­tion may prevail. That is, a small number of embryos may have to be destroyed to start a few cultures, but these cultures may be infinitely maintainable and expandable, pro­viding high quality cells for transplantation. In that hopeful scenario, those opposed to embryo destruction still may not want to use these therapies, but a continuous supply of cells from a few initial sources may be enough to alleviate concerns. Again, science would have outstripped politics.

Alternatively, the controversies may grow if it is only in the private sector that research continues and applications begin. For example, critics point to the situation in assisted reproduction clinics, where oversight is often minimal. Stories about commerce in eggs have become common (it is illegal to buy and sell human tissues, but there is no regulation of additional payments to the donor for time and effort). Another problem is the lack of any mecha­nism for regulating research that takes place in these laboratories in contrast to those in the public sector. Note, however, that the Food and Drug Administration has oversight over the private sector for drugs and biologics that will undergo clinical trials and be marketed.

Larger concerns are raised about the public availability of stem cell therapies, especially because early research in animals was paid for with public funds. Should the use of stem cell therapies be distributed differently from any other new technology developed in the private sector? One answer is that we, as a society, might believe that because of their source and their potential power the cells are indeed special. These are reasonable beliefs to take into account in designing guidelines about royalties and allocating funds for research.

Research will continue in the private sector; as a society we may decide this is sufficient. There is so much work to be done, however, that progress equivalent to what could occur with all hands participating will be denied us if research is prohibited in the public sector. I believe that if the public sector is to become involved, we should face with absolute honesty and openness what actually has to transpire for this research to pay off. Embryos will be destroyed, although the hope is that eventually cells will be maintained continually in culture and be of high enough quality to be used for transplantation. We also should face the fact that therapeutics will be unequally available to patients at first because of the cost, although we expect that progress in time will make stem cell therapies affordable to all.

How does a single mammalian cell turn into the being of unparalleled complexity that is a person? 

BEYOND ATTACKS: UNDERSTANDING A UNIQUE SPECIES

Beyond all practical arguments for adding an understanding of human development to the portfolio for stem cell research lies a larger vision. After all, there may never be a truly complete model of human brain development, encompassing all aspects of growth and maturation, and our ability to treat diseases and injuries to the brain and CNS may always have limits.

Human development, however, especially brain development, is of boundless intrinsic interest to our species. We are unique. Individuals and organized religions (among other groups) have a stake in understanding that uniqueness, including human development. How does a single mammalian cell turn into the being of unparalleled complexity that is a person? Brain development proceeds for decades after birth, perhaps throughout life, but most invasive procedures for probing it cannot be carried out ethically in humans. These procedures could be used in early embryonic tissue, however, particularly in the stem cell component.

In the name of treating the fertilized egg and early embryo as if they were people, although they cannot develop unless transferred into a woman’s uterus, certain religious traditions would block the only research that can enable us to understand human development, and thus our uniqueness. Most scientists (and many others) see the fertilized egg or embryo as one part of a totality, including the mother, leading to the generation of a human being. The embryo alone can never turn into a human on its own; only by considering it part of this continuum does its humanness make any sense. Its humanity is potential, not actual, and in law as well as morality, our obligations toward the two are enormously different.

Whether this view will prevail is unclear. We take democracy seriously and must take various viewpoints seriously when crafting public policy. Technologies that enable us to make meaningful progress in understanding human development and disease are rapidly emerging. The stem-cell debate may shift as new knowledge is attained, but for now, at least, that debate seems mired in near-cliches about the needs of real, live patients versus the putative moral rights of embryos. We must move beyond these entrenched positions if we are to make any real progress in resolving the best uses of stem cell therapies.

As we go to press...

1. Letter from the President to the National Bioethics Advisory Commission, 14 November 1998.
2. Chapman, AR, Frankel, MS, and Garfinkel, MS 1999. Stem Cell Research and Applications: Monitoring the Frontiers of Biomedical Research. American Association for the Advancement of Science, Washington, DC.
3. Department of Health and Human Services, National Institutes of Health. 2 December 1999. Draft: National Institutes of Health Guidelines for Research Involving Human Pluripotent Stem Cells. Federal Register 64: 67576-67579.
4. Bjornson, CRR, Rietze, RL, Reynolds, BA, Magli, MC, and Vescovi, AL. 1999. Turning Brain into Blood: A Hematopoietic Fate Adopted by Adult Neural Stem Cells in Vivo. Science 283: 534-537.
5. Ramiya, VK, Maraist, M, Arfors, KE, Schatz, DA, Cornelius, JG, and Peck, AB. 2000. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nature Medicine 6: 278-282.
6. Yandava, BD, Billinghurst, LL, and Snyer, EY. 1999. “Global” cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Proceedings of the National Academy of Science. USA 96: 7029-7034.
7. Benedetti, S, Pirola, B, Pollo, B, et al. 2000. Gene therapy of experimental brain tumors using neural progenitor cells. Nature Medicine 6: 447-450.
8. Fricker, RA, Carpenter, MK, Winkler, C, Greco, C, Gates, MA, and Björklund, A. 1999. Site-specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain. Journal of Neuroscience 19: 5990-6005.
9. For more information on the ethical issues surrounding stem cell research particularly, see: http://bioethics.gov/pubs.html (National Bioethics Advisory Commission); http://www.aaas.org/spp/dspp/sfrl/projects/stem/main. htm (American Association for the Advancement of Science/Institute for Civil Society Stem Cell Project); http://www.nuffield.org/bioethics (a view from Britain: The Nuffield Council on Bioethics Stem Cell Therapy Ethical Issues paper.)