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Interstate Alliance on Stem Cell Research Chimeras John Gearhart James W Effron University Professor Professor of Medicine and Veterinary Medicine Director, Institute for Regenerative Medicine University of Pennsylvania September 10, 2008 University of Maryland Biotechnology Institute Baltimore, MD Definitions (as relates to mammals) Mosaic: The occurrence in an animal of two or more cell populations of different chromosomal constitutions or chromosomal function developed from a single zygote or conceptus Chimera: an animal that is composed of cells derived from two or more conceptuses Hybrid: an offspring of parents from different species through ‘crossbreeding’ Clone: an animal derived from a single individual Transgenic: an organism whose genome has been altered by the transfer of gene sequences from another species Human Chimera Prohibition Act of 2005 (Introduced in Senate) 109th CONGRESS 1st Session S. 1373 To amend title 18, United States Code, to prohibit human chimeras. IN THE SENATE OF THE UNITED STATES, July 11, 2005 Mr. BROWNBACK introduced the following bill; which was read twice and referred to the Committee on the Judiciary July 6, 1996 – February 14, 2003 ARCH DERMATOL/VOL 144 (NO. 3), MAR 2008 Microchimerism 1st introduced in the 70’s to describe long term donor cell survival in a small proportion relative to the host cells following bone marrow grafts in mice Sources: blood transfusions (and bmt’s) twinning (and loss of twin) organ transplants bidirectional trafficking during pregnancy Fetal origin of cells in maternal tissues Fetal cells are transferred to the maternal circulation during all human pregnancies Persisting cells are found in a wide range of tissues Fetal cells persist in maternal blood and tissue decades after pregnancy Fetal cells with stem cell-like properties are transferred: Pregnancy-associated progenitor cells (PAPCs) What are the consequences of fetal cells in maternal tissues following pregnancy? Hypotheses: Bad microchimerism Autoimmunity Good microchimerism Rejuvenation/repair Associations between fetal cell microchimerism and maternal autoimmune disease Systemic sclerosis: blood and affected tissues Significantly increased Polymorphic eruption of pregnancy: skin Significantly increased Systemic lupus erythematosus: many tissues Variable Hashimoto’s disease: thyroid Significantly increased Primary Chimeras Secondary Chimeras (Secondary) Human Chimeras Anyone who has received a blood transfusion, a bone marrow transplant, a pig heart valve, an organ transplant Future: non-autologous stem cellderived therapies Animal/Human Chimeras (aka part-human animals or manimals) Any animal receiving human cells, tissues or organs ‘Humanized’ animals (genes as well) Animals with human immune system, organs (including brain?!) Stem cells and chimeras How much will the transplanted cells contribute to an animals body or organ functions? Focus on two issues: Germ cells Brain Factors to be considered with the possible ‘humanizing’ of the brain of chimeras Stage of development when the cells are introduced The proportion/number of human cells introduced Site of graft Relatedness of host to the human Why do we want to make animal/human chimeras? In stem cell research, human cells are the therapy. The fate and function of these cells must be assessed in vivo to determine their efficacy and safety. Must also appreciate that this paradigm is not w/o inherent concerns. The FDA requires animal testing before they are tested in humans. Opposing views and concerns with humanizing animals Animal welfare issues Respecting the boundaries of species Respecting human ‘dignity’ Regulations and Oversight with Stem Cells and Chimeras Medical Research Council of Canada Select Committee on Science and Technology, UK Parliament National Academy of Sciences Recommendations US