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…the sovereignty of man lieth hid in knowledge…

BIOMEDICAL ETHICS SEMINAR Embryonic Stem Cell Chimera Research: What is it? What are its benefits? What concerns does it raise?. Mark Mercola, Ph.D. Professor, Stem Cell and Regeneration Program, The Burnham Institute, and Department of Pathology (adjunct), UCSD School of Medicine

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…the sovereignty of man lieth hid in knowledge…

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  1. BIOMEDICAL ETHICS SEMINAREmbryonic Stem Cell Chimera Research: What is it? What are its benefits?What concerns does it raise? Mark Mercola, Ph.D. Professor, Stem Cell and Regeneration Program,The Burnham Institute, and Department of Pathology (adjunct), UCSD School of Medicine March . 17 , 2004

  2. …the sovereignty of man lieth hid in knowledge…

  3. Heritage of Experimental Biology Leading to Research Using Chimeric Embryos • 17th-18th centuries: • Initial experiments challenging spontaneous generation and demonstration that sperm activate eggs (Redi, Spallanzani) • Regeneration in amphibians, worms, snails (Spallanzani, Tremblay) • 19th and early 20th Centuries: • Concept of a germ cell as set aside distinct from somatic cell (August Weismann) • Wilhelm Roux: hot needle killing one blastomere of frog embryo -> mosaic embryos • Driesch, isolation of sea urchin blastomeres and McClendon, isolated frog blastomeres -> regulative development • Horstadius, Speman: inductive interactions between blastomeres

  4. Hans Spemann and Hilde Mangold • Organizer experiment • Transplantation of cells from one (pigmented) to another (unpigmented) embryo • Evaluated ability of transplanted tissue to induce/organize structures in host tissue

  5. Potency of Individual Cells in Mammalian Embryos • Potency tested by dispersion and reaggregation with different embryo to make chimeric embryos, tracking the donor cells within the host embryo • Totipotency of individual cells probably persists until implantation • Nuclear potency persists longer, perhaps in many somatic nuclei remain totipotent or can be “re-booted”.

  6. Embryonic Stem Cells • Derived from pre-implantation embryos; cultures of inner cell mass cells maintained in a totipotent state in culture • Totipotency demonstrated by chimeras • Regenerative potential is only beginning to be explored and requires understanding how to direct differentiation to target tissues

  7. Spontaneous Cardiomyocyte Formation in Aggregate Cultures of hES Cells How to channel this ability to differentiate to produce target tissues?

  8. Examples of Tissues for which Interspecies Chimeras have helped define Potency, Fate, and Function • Neural crest • Somites • Brain • Tumors These experiments do not elicit much ethical concern

  9. A Few Possible Reasons for Minimal Concern of Grafting Experiments • Adult, so no chance of germline transmission • Non-human host • No involvement of human CNS function • Degree of mosaicism is poor - e.g. large bits of tissues generally transplanted

  10. Mouse Embryonic Stem Cell-based Chimeras • Introduction of ES cells into pre-implantation blastocyst • Mix with host cells • Generate high degree of mosaicism • Contribute to germline = sperm and egg • Basis for gene knockout technology, which underlies a substantial national research effort • Most people do not voice ethical concerns about this technology

  11. Human ES cell lines • Derived similarly to mouse ES lines • Pluripotency is assumed from teratoma assays • Pluripotency makes them advantageous for tissue regeneration • Many people voice ethical concerns • Restrictions on use with federal funding • Relatively few restrictions with private funding

  12. Pros and Cons: Pro: Test potency of human ES cell Pro: Create disease models for research Con: Widely available hES cell lines probably will not incorporate effectively Con: Fear that might contribute to germline Con: Moderate ethical unease Consider: Similar issues with other cell types, except germline potential; therefore a large debate is looming on horizon How to establish mechanisms to ensure ethical practice at research institutions? Human ES Cell Line -Mouse Embryo Chimera

  13. What Makes a Procedure Ethically Challenging? • Example 1: Human ES cells into human embryos • Consider hES cells placed into preimplantation embryos, even if to cure a genetic disease? • What if cells are differentiated first, so that they rescue a defect but cannot contribute to germline? • Example 2: Human hematopoietic stem cells into primates to generate animals that could donate blood • What makes people uneasy? • How to draw line between ethical and unethical? • If chimeras are to be permitted, is there a tissue that must remain free from donor cells?

  14. Ethical Advisory Board • Distinct from animal use and human subject IRB committees • Consists of lawyers and ethicists • Reduces risk of performing a procedure that might be illegal, unethical or otherwise engender adverse publicity

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