August 10, 2001

Commentary

Stem Cell Grafting for Epilepsy: Clinical Promise and Ethical Concerns

By James Santiago Grisolía, MD
Section of Neurology, Scripps-Mercy Hospital
Department of Neurosciences, UCSD School of Medicine

(Editors Note: In light of all the discussion on the Ethical question regarding stem cell research, we asked Dr. James Santiago Grisolía to provide us with his perspective on this issue. It should be noted that President George Bush should have made his decesion on federal funding for stem cell research Thursday evening the day before publication and too late for our comments.)

 

The recent explosion of research on stem cells and neural grafting holds great promise for many neurological conditions, including epilepsy. Potential roles for cell grafting in epilepsy include remodelling dysfunctional neuronal circuits and local delivery of neuromodulatory or neuroprotective factors. While many basic questions remain to be answered, initial human trials are underway in epilepsy as well as Parkinson's, Alzheimers, stroke and other conditions. There is also the question of ethics in regards to the dynamic new field.

Donor cells are often derived from human embryos, raising scarcity concerns as well as opposition from anti-abortion forces. Alternative donor sources are being actively developed. Safety concerns, adequate consent and equitable access to care will also become important issues. Ethical issues most unique to neural grafting will revolve around redefining self-identity when personality and cognition may be alterred by therapy. Views of selfhood and of being human have evolved in a historically contingent process, so that neural grafting and other consequences of the genetic revolution fall within a series of reductionist scientific developments which lead to an increasing instrumentation of our self-image.

Neuroscientists and clinicians must interact with other cultural, religious and academic groups to promote mutual understanding and richer, but scientifically accurate, views of what it means to be human.

Some years ago, early human experiments with transplanting autologous adrenal medullary cells into the caudate nuclei of Parkinson's sufferers captured the world's imagination. Unfortunately, these early grafted cells failed to survive in clinically relevant quantity, but this audacious beginning stimulated much subsequent investigation, including study of embryonic stem cells or other transformed or dedifferentiated cell sources as possible transplant materials.

The discovery of multipotential cells within the adult human nervous system offered a potential source of donor cells, while supporting the hope that transplanted cells might successfully enter and interact with existing neuronal circuits within the human CNS. While clinical benefit for any neurologic disease as yet remains unproven, the explosion of basic research in this area, along with early human studies in neurologic conditions including epilepsy, should prompt ethical reflection on this dynamic field.

 

ETHICAL ISSUES

Technical developments in stem cell grafting open new vistas of possible benefit to humanity, but with these new technologies come new ethical issues. Within the United States, the most immediately controversial aspect has been the use of aborted fetal tissue as a source of stem cells. While guidelines have been developed to maintain ethical use of fetal tissue, shifting political currents constantly imperil U.S. government support and funding for research based on this tissue source. Development of new sources of precursor cells, for example by clonal expansion of stem cells from mature tissue, or even from fibroblasts or other tissues of the intended host, could avoid this ethical problem. However, artificially dedifferentiated adult precursor cells may not offer the same functional potential, at least for some transplantation purposes, as embryonal stem cells.

Beyond this issue, the complex, highly technical nature of stem cell grafting guarantees that it will be available only on a limited basis, at least initially. The ethical management of scarce health resources has been extensively analyzed in the past, with little about grafting to make it different from other innovative technologies. Ideally, when a grafting technique is found to be safe and effective for a given condition, it should be made widely available, so that clinical factors rather than financial barriers determine its use.

If neural grafting is used responsibly and with well-recognized success, its very success could impact our societal view of the brain and the self. Overall, definition of the self is a complex, historically determined process, with scientific, religious and other viewpoints interacting in a series of metaphors, nicely outlined in several articles within "The Enchanted Loom," including reminders of the historical newness of our now unquestioned view of brain as the organ of mind. Only 250 years ago, Julien Offroy de la Mettrie was hounded from Paris and then from Amsterdam for publishing this radical idea.

Currently, Western societies hold multiple, divergent, even contradictory views of the self, based on diverse concepts from religion, philosophy, neuroscience, computer science, literature, and popular culture. These contradictory views may dwell together within each of us. For example, most neuroscientists view the mind as an emergent property of brain function, arising as the brain develops and ceasing with death. At the same time, multiple polls confirm the majority of Americans believe culturally in an afterlife. It is possible to find American neuroscientists who hold both views simultaneously, with varying attempts to reconcile or ignore these implicit contradictions.

As another example, a long Western tradition views the self as an independent, internally-reliant being. This conception dates back at least to the Enlightenment, and informs legal, economic and political traditions throughout Europe and the United States. Increasing emphasis on the importance of social interaction in the construction of the self forms an important cultural countercurrent, whether arising from postmodern theory, ecologically-based critiques, or indigenous folk and cultural traditions of many sorts.

Neural grafting represents only one development in a long, historical process whereby reductionist, scientific advances have led to an increasing mechanization and instrumentation of our self-image. Anxiety regarding this process can certainly be traced back at least to Mary Shelley's "Frankenstein," but has been further fueled by subsequent scientific and technical developments. Popular culture continues to express anxieties regarding our mechanization and the loss of an integrated self, as in such late 20th century movies as "Blade Runner" or "The Matrix". A persistent sense that something important is imperiled or lost underlies many contemporary concerns about technology, whether couched in appeals to the sacred, or to the complexity and integrity of nature.

Today, the human genome project may be read as reducing humanity to the "simple" result of 30 to 50 thousand gene products, what Walter Gilbert has referred to as "shallow genetic reductionism." The genetic revolution and its spin-offs, including neural grafting, will have major impact on our view of the self. As neuroscience increasingly dissects brain function into component functions governed by discrete brain circuits, holistic or integrated visions of the mind and self will be more difficult to maintain. Neural grafting, with the unlikely but vivid implication that brain circuits could be subbed in or out like circuit boards, potentially contributes to this process.

Traditionally, revealed religion, literature and other cultural institutions create meaning and values and logically will modify this simplistic view of the human. Our obligations as neuroscientists and as clinicians will include interacting with these other traditions and institutions, including dialogue with philosophy, cultural criticism and classical ethicists.

Narrative forms the fundamental basis for case histories in medicine, ethics and the law. Our efforts to cross-pollinate science with the "other humanities" may begin with the stories of real patients, transmitting the richness of human lives and the impact of illness and cure. Nothing has returned the field of epilepsy back to the density of lived experience like the "Brainstorms" series, and communicating such stories with the larger culture may be most valuable for assessing the human impact of disease and of new possibilities for cure, including cell grafting. If we hope to use neural transplantation and other novel technologies to enrich rather than impoverish our patients' lives, we must start by re-examining the meaning of what it is to be human in the light of our burgeoning, still tentative knowledge in the neurosciences.

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