[Paleopsych] SW: On Human-Non-Human Primate Neural Grafting

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Science Policy: On Human-Non-Human Primate Neural Grafting

     The following points are made by M. Greene et al (Science 2005
     1) If human neural stem cells were implanted into the brains of other
     primates what might this do to the mind of the recipient? Could such
     grafting teach us anything of value for treatment of neurological
     injury and disease? Could we change the capacities of the engrafted
     animal in a way that leads us to reexamine its moral status? These
     questions have gained significance since publication of research
     involving grafting human neural stem cells into the brains of fetal
     monkeys [1]. In 2004, the authors formed a multidisciplinary working
     group; two plenary meetings over 12 months provide the basis for this
     2) There is considerable controversy (reflected within the discussion
     group) over the likely value of interspecies stem cell work for
     progress toward therapies [2]. We cannot graft human neural stem cells
     into human beings solely for experimental purposes, even if they will
     lead to human therapies. Group members arguing for the value of
     research on human cells in non-human primates (NHPs) pointed out that
     because the aim is to learn about human neural stem cells it makes
     most sense to use human lines. The fact that available NHP lines are
     few and poorly characterized [3] is an additional reason to use human
     lines. Another consideration is the need to assess candidate human
     cell lines for viability, potential to differentiate, and safety with
     regard to such possibilities as tumor formation. NHPs may be
     appropriate for in vivo screening.
     3) Skeptics argued that differences between humans and NHPs could
     render results uninterpretable and that the preferred path for many
     questions is to study NHP neural stem cells in NHPs. Assessments of
     the scientific merit of the research must form and develop along with
     the field itself.
     4) The authors unanimously rejected ethical objections grounded on
     unnaturalness or crossing species boundaries [4]. Whether it is
     possible to draw a meaningful distinction between the natural and the
     unnatural is a matter of dispute. However, stipulating that research
     is "unnatural" says nothing about its ethics. Much of modern medical
     practice involves tools, materials, and behaviors that cannot be found
     in nature but are not unethical as a consequence
     5) Another concern is that human to non-human primate (H-NHP) neural
     grafting is wrong because it transgresses species boundaries [5].
     However, the notion that there are fixed species boundaries is not
     well supported in science or philosophy. Moreover, human-nonhuman
     chimerism has already occurred through xenografting. For example, the
     safety and efficacy of engrafting fetal pig cells has been studied in
     people with Parkinson's disease and Huntington's disease without moral
     objection. Indeed, some have suggested that porcine sources may be
     less morally contentious than the use of human fetal tissue. Merely
     because something has been done does not prove it right. However, the
     authors see no new ethical or regulatory issues regarding chimeras
     6) The central challenge is whether introducing human cells into NHP
     brains raises questions about moral status. A variety of reasons have
     been given for according different moral standing to humans and NHPs.
     In the Abrahamic traditions, humans are set apart by God as morally
     special and are given stewardship over other forms of life (Genesis
     1:26-28). For Kantians, human capacities for rationality and autonomy
     demand that we be treated as ends in ourselves. Mill finds, in the
     richness of human mental life, an especially fecund source of utility.
     Singer, although strongly defending equal consideration of nonhuman
     interests, argues that self-awareness affects the ethically allowable
     treatment of a creature by changing the kinds of interests it can
     7) In conclusion: The authors support the National Academy's
     recommendation that H-NHP neural grafting experiments be subject to
     special review. The authors agree that such review should complement,
     not replace, current review by animal-use panels and institutional
     review boards. The authors further recommend that experiments
     involving H-NHP neural grafting be required, wherever possible, to
     look for and report changes in cognitive function. Explicit data
     collection on cognition and behavior will help to ensure that ethical
     guidelines can be developed appropriately as the field advances.
     References (abridged):
     1. V. Ourednik et al., Science 293, 1820 (2001)
     2. J. S. Robert, Bioessays 26, 1005 (2004)
     3. K.-Y. F. Pau, D. Wolf, Reprod. Biol. Endocrinol. 2, 41 (2004)
     4. P. Karpowicz, C. B. Cohen, D. van der Kooy, Nat.Med. 10, 331 (2004)
     5. F. Fukuyama, Washington Post, 15 February 2004, p. B04
     Science http://www.sciencemag.org
     Related Material:
     The following points are made by A.E. Wurmser et al (Science 2004
     1) The ability of stem cells to both self-renew and differentiate into
     many different cell types enables these versatile cells to generate
     and repair tissues and organs. Yet studies of the fruit fly Drosophila
     and of mammalian skin, intestine, bone marrow, and brain reveal that
     these inherent stem cell features are tightly regulated by the cells
     and proteins that constitute the extracellular environment (or
     "niche") that stem cells inhabit (1). For example, Shen et al. (2)
     have demonstrated that endothelial cells (ECs) that are enriched in
     the niche occupied by neural stem cells (NSCs) regulate NSC
     proliferation and induce these stem cells to become neurons in vitro.
     2) It is well established that NSCs are not randomly distributed
     throughout the brain, but rather are concentrated around blood vessels
     (3-5). This location places NSCs in close proximity to the ECs that
     line blood vessels, facilitating communication between these two cell
     types (3-5). To test the degree of intercellular communication between
     NSCs and ECs, Shen et al (1) cultured NSCs and monitored changes in
     their behavior when ECs were brought into close proximity (2). These
     investigators maintained cultures of mouse embryonic NSCs (derived
     from the cerebral cortex of 10- to 11-day-old mouse embryos) by adding
     fibroblast growth factor-2. Under these conditions, NSCs proliferated
     slowly and many of them exited the cell cycle, choosing to
     differentiate instead (2). However, when NSCs were cocultured with ECs
     their proliferation rate doubled, resulting in the formation of large
     interconnected sheets of undifferentiated cells.
     3) One aspect of the Shen et al strategy was to introduce ECs into NSC
     cultures by means of transwell inserts. The pores of the transwells
     were too small to allow cell-cell contact between NSCs and ECs, but
     were large enough to enable signaling factors secreted by ECs to
     diffuse into the NSC cultures. Remarkably, the removal of transwells
     containing ECs triggered the coordinated differentiation of
     proliferating NSCs into neurons. Only 9% of NSCs unexposed to ECs
     expressed mature neuronal markers, compared with 31 to 64% of NSCs
     exposed to the EC transwells. This trend also was observed with
     cultured NSCs derived from the subventricular zone of adult mouse
     brain (2). Thus, signaling molecules secreted by ECs induced a shift
     in the mixed population of proliferating and differentiating NSCs,
     pushing them toward self-renewal while simultaneously priming them for
     the production of neurons.
     References (abridged):
     1. E. Fuchs et al., Cell 116, 769 (2004)
     2. Q. Shen et al., Science 304, 1338 (2004)
     3. T. D. Palmer et al., J. Comp. Neurol. 425, 479 (2000)
     4. A. Capela, S. Temple, Neuron 35, 865 (2002)
     5. A. Louissaint et al., Neuron 34, 945 ( 2002)
     Science http://www.sciencemag.org
     Related Material:
     The following points are made by Pasko Rakic (Nature 2004 427:685):
     1) Neural stem cells are a focus of strong interest because of the
     possibility that they could be used to replace neurons that have been
     damaged or lost -- perhaps as a result of injury such as trauma or
     stroke, or through neurodegenerative disorders such as Parkinson's
     disease. These stem cells can give rise to neurons and their
     supporting cells (glia) and it is hoped that something akin to neural
     stem cells in the adult human brain could be stimulated to generate
     replacement neurons.
     2) Non-mammalian vertebrates, such as the salamander, can regenerate
     large portions of their brain and spinal cord, but humans have
     evidently lost this capacity during evolution. Therefore, most
     research on neural stem cells is carried out on mammals such as
     rodents, which are genetically closer to humans. However, although
     mammalian genomes may be similar, this similarity masks vast species
     differences in the way the brain is organized and in its capacity for
     regeneration and susceptibility to environmental insults. The failure
     of brain repair in clinical trials based on the promising results seen
     after the use of similar procedures in rodents is sobering testimony
     to the importance of such species-specific distinctions.
     3) Human neural stem cells behave differently from their rodent
     equivalents in culture(1), but direct study of human brain tissue by
     Sanai et al(2) demonstrates additional significant and clinically
     relevant species-specific differences. A large number of postmortem
     and biopsy samples reveal two basic findings. First, neural stem cells
     that can potentially give rise to neurons, as well as to two types of
     glial cell (astrocytes and oligodendrocytes), are situated in a region
     of the forebrain known as the subventricular zone. Second, a pathway
     known as the rostral migratory stream -- which in adult rodents
     contains neurons that migrate from the subventricular zone to the
     brain region concerned with sensing smell -- is absent in humans.
     4) In adult mammals, including humans, the subventricular zone (more
     commonly known as the subependymal zone[3-5]) contains cells that have
     the characteristics of glial cells and that can generate neuronal
     cells in culture. Sanai et al(2) show that in adult humans these
     "glial progenitor cells" form a prominent layer, or ribbon, that is
     restricted to a specific region in the brain that lines the lateral
     cerebral ventricle. This region is also present in non-human primates,
     but it is thinner and less well delineated than in humans(4).
     References (abridged):
     1. Ginis, I. & Rao, M. S. Exp. Neurol. 184, 61-77 (2003)
     2. Sanai, N. et al. Nature 427, 740-744 (2004)
     3. Lewis, P. D. Nature 217, 974-975 (1968)
     4. McDermott, K. W. & Lantos, P. L. Brain Res. Dev. Brain Res. 57,
     269-277 (1990)
     5. Weickert, C. S. et al. J. Comp. Neurol. 423, 359-372 (2000)
     Nature http://www.nature.com/nature

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