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  • 1. BIOMEDICAL ETHICS SEMINARBIOMEDICAL ETHICS SEMINAR Embryonic Stem Cell Chimera Research: What is it? What areEmbryonic Stem Cell Chimera Research: What is it? What are its benefits?its benefits? What concerns does it raise?What concerns does it raise? Mark Mercola, Ph.D. Professor, Stem Cell and Regeneration Program,Mark Mercola, Ph.D. Professor, Stem Cell and Regeneration Program, The Burnham Institute, and Department of Pathology (adjunct), UCSD SchoolThe Burnham Institute, and Department of Pathology (adjunct), UCSD School of Medicineof Medicine March . 17 , 2004March . 17 , 2004
  • 2. ……the sovereignty of man lieth hid in knowledge…the sovereignty of man lieth hid in knowledge…
  • 3. Heritage of Experimental Biology Leading toHeritage of Experimental Biology Leading to Research Using Chimeric EmbryosResearch Using Chimeric Embryos  17th-18th centuries:17th-18th centuries:  Initial experiments challenging spontaneous generation andInitial experiments challenging spontaneous generation and demonstration that sperm activate eggs (Redi, Spallanzani)demonstration that sperm activate eggs (Redi, Spallanzani)  Regeneration in amphibians, worms, snails (Spallanzani, Tremblay)Regeneration in amphibians, worms, snails (Spallanzani, Tremblay)  19th and early 20th Centuries:19th and early 20th Centuries:  Concept of a germ cell as set aside distinct from somatic cell (AugustConcept of a germ cell as set aside distinct from somatic cell (August Weismann)Weismann)  Wilhelm Roux: hot needle killing one blastomere of frog embryo ->Wilhelm Roux: hot needle killing one blastomere of frog embryo -> mosaic embryosmosaic embryos  Driesch, isolation of sea urchin blastomeres and McClendon, isolatedDriesch, isolation of sea urchin blastomeres and McClendon, isolated frog blastomeres -> regulative developmentfrog blastomeres -> regulative development  Horstadius, Speman: inductive interactions between blastomeresHorstadius, Speman: inductive interactions between blastomeres
  • 4. Hans Spemann and Hilde MangoldHans Spemann and Hilde Mangold  Organizer experimentOrganizer experiment  Transplantation of cells from one (pigmented) toTransplantation of cells from one (pigmented) to another (unpigmented) embryoanother (unpigmented) embryo  Evaluated ability of transplanted tissue toEvaluated ability of transplanted tissue to induce/organize structures in host tissueinduce/organize structures in host tissue
  • 5. Potency of Individual Cells in MammalianPotency of Individual Cells in Mammalian EmbryosEmbryos  Potency tested by dispersion and reaggregationPotency tested by dispersion and reaggregation with different embryo to make chimeric embryos,with different embryo to make chimeric embryos, tracking the donor cells within the host embryotracking the donor cells within the host embryo  Totipotency of individualTotipotency of individual cellscells probably persistsprobably persists until implantationuntil implantation  Nuclear potency persists longer, perhaps inNuclear potency persists longer, perhaps in many somatic nuclei remain totipotent or can bemany somatic nuclei remain totipotent or can be “re-booted”.“re-booted”.
  • 6. Embryonic Stem CellsEmbryonic Stem Cells  Derived from pre-Derived from pre- implantation embryos;implantation embryos; cultures of inner cell masscultures of inner cell mass cells maintained in acells maintained in a totipotent state in culturetotipotent state in culture  Totipotency demonstratedTotipotency demonstrated by chimerasby chimeras  Regenerative potential isRegenerative potential is only beginning to beonly beginning to be explored and requiresexplored and requires understanding how tounderstanding how to direct differentiation todirect differentiation to target tissuestarget tissues
  • 7. QuickTime™ and a Video decompressor are needed to see this picture. Spontaneous Cardiomyocyte Formation inSpontaneous Cardiomyocyte Formation in Aggregate Cultures of hES CellsAggregate Cultures of hES Cells How to channel this ability to differentiate to produce target tissues?How to channel this ability to differentiate to produce target tissues?
  • 8. Examples of Tissues for which InterspeciesExamples of Tissues for which Interspecies Chimeras have helped define Potency, Fate, andChimeras have helped define Potency, Fate, and FunctionFunction  Neural crestNeural crest  SomitesSomites  BrainBrain  TumorsTumors These experiments do not elicit much ethical concernThese experiments do not elicit much ethical concern
  • 9. A Few Possible Reasons for MinimalA Few Possible Reasons for Minimal Concern of Grafting ExperimentsConcern of Grafting Experiments  Adult, so no chance of germline transmissionAdult, so no chance of germline transmission  Non-human hostNon-human host  No involvement of human CNS functionNo involvement of human CNS function  Degree of mosaicism is poor - e.g. large bits ofDegree of mosaicism is poor - e.g. large bits of tissues generally transplantedtissues generally transplanted
  • 10. Mouse Embryonic Stem Cell-basedMouse Embryonic Stem Cell-based ChimerasChimeras  Introduction of ES cells intoIntroduction of ES cells into pre-implantation blastocystpre-implantation blastocyst  Mix with host cellsMix with host cells  Generate high degree ofGenerate high degree of mosaicismmosaicism  Contribute to germline = spermContribute to germline = sperm and eggand egg  Basis for gene knockoutBasis for gene knockout technology, which underlies atechnology, which underlies a substantial national researchsubstantial national research efforteffort  Most people do not voiceMost people do not voice ethical concerns about thisethical concerns about this technologytechnology
  • 11. Human ES cell linesHuman ES cell lines  Derived similarly to mouse ES linesDerived similarly to mouse ES lines  Pluripotency is assumed from teratoma assaysPluripotency is assumed from teratoma assays  Pluripotency makes them advantageous forPluripotency makes them advantageous for tissue regenerationtissue regeneration  Many people voice ethical concernsMany people voice ethical concerns  Restrictions on use with federal fundingRestrictions on use with federal funding  Relatively few restrictions with private fundingRelatively few restrictions with private funding
  • 12. Human ES Cell Line -Mouse Embryo ChimeraHuman ES Cell Line -Mouse Embryo Chimera  Pros and Cons:Pros and Cons:  Pro: Test potency ofPro: Test potency of human ES cellhuman ES cell  Pro: Create diseasePro: Create disease models for researchmodels for research  Con: Widely available hESCon: Widely available hES cell lines probably will notcell lines probably will not incorporate effectivelyincorporate effectively  Con: Fear that mightCon: Fear that might contribute to germlinecontribute to germline  Con: Moderate ethicalCon: Moderate ethical uneaseunease  Consider:Consider:  Similar issues with otherSimilar issues with other cell types, except germlinecell types, except germline potential; therefore a largepotential; therefore a large debate is looming ondebate is looming on horizonhorizon  How to establishHow to establish mechanisms to ensuremechanisms to ensure ethical practice at researchethical practice at research institutions?institutions?
  • 13. What Makes a Procedure EthicallyWhat Makes a Procedure Ethically Challenging?Challenging?  Example 1: Human ES cells into human embryosExample 1: Human ES cells into human embryos  Consider hES cells placed into preimplantation embryos, even ifConsider hES cells placed into preimplantation embryos, even if to cure a genetic disease?to cure a genetic disease?  What if cells are differentiated first, so that they rescue a defectWhat if cells are differentiated first, so that they rescue a defect but cannot contribute to germline?but cannot contribute to germline?  Example 2: Human hematopoietic stem cells intoExample 2: Human hematopoietic stem cells into primates to generate animals that could donate bloodprimates to generate animals that could donate blood  What makes people uneasy?What makes people uneasy?  How to draw line between ethical and unethical?How to draw line between ethical and unethical?  If chimeras are to be permitted, is there a tissue thatIf chimeras are to be permitted, is there a tissue that must remain free from donor cells?must remain free from donor cells?
  • 14. Ethical Advisory BoardEthical Advisory Board  Distinct from animal use and human subject IRBDistinct from animal use and human subject IRB committeescommittees  Consists of lawyers and ethicistsConsists of lawyers and ethicists  Reduces risk of performing a procedure thatReduces risk of performing a procedure that might be illegal, unethical or otherwise engendermight be illegal, unethical or otherwise engender adverse publicityadverse publicity

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