Peter Rathjen Stem cell therapies – and the future of medicine

Mammalian embryogenesis

Embryonic Stem (ES) Cells Blastocyst ICM (stem cells) Isolate ICM Culture in vitro (+LIF) ES Cells

Properties of ES cells in vitro Blastocyst ES Cells Immortal Pluripotent Differentiate Unlimited numbers, of any kind of cell Differentiated Cells

Cell Therapies “An unlimited supply of any kind of cell with any genetic modification” Cell replacement:Parkinson’s disease (nerves) Stroke (nerves) Heart disease (muscle) Diabetes (pancreas) Immune system (blood) Blindness (Retinal cells) Gene therapies:Thalassemias (blood) Dystrophies (muscle)

Cell Therapy with ES cells: how it will work Somatic cell biopsy Master cell bank ES cell + + Transplant into patient Cell product Differentiation Nucleus Enucleated oocyte Enucleated ES cell Patient Donor embryo

∂ ∂ Human neurons from human ES cells Differentiation Human ES Cells Neurons

Cell Therapy with ES cells: how it will work Somatic cell biopsy Master cell bank ES cell + + Transplant into patient Cell product Differentiation Nucleus Enucleated oocyte Enucleated ES cell Patient Donor embryo

ES cell-derived neurons in vitro Neurons identified by expression of the neural marker, tubulin-  III

neurectoderm ICM MesodermEndoderm Origin of Ectodermal Lineages in Mammals 6.5 d.p.c. ectoderm primitive ectoderm PNSCNS neural plate neural tube 4.5 d.p.c. 5.5 d.p.c. PLURIPOTENT ECTODERMAL surface ectoderm hair skin +BMP4

Cell Therapy with ES cells: how it will work Somatic cell biopsy Master cell bank ES cell + + Transplant into patient Cell product Differentiation Nucleus Enucleated oocyte Enucleated ES cell Patient Donor embryo

Integration of ES cell-derived neural precursors in the adult brain ES cell derived cells in the rat striatum, 16 weeks after injection

Correction of disease models Drug induced Parkinsonian model (neural precursors/neurons) Spinal cord lesions (neural precursors) *Immune deficiency (bone marrow/gene correction) *genetically modified stem cells Insulin deficiency (insulin producing cells)

Cell Therapy with ES cells: how it will work Somatic cell biopsy Master cell bank ES cell + + Transplant into patient Cell product Differentiation Nucleus Enucleated oocyte Enucleated ES cell Patient Donor embryo

Oocyte donor (Scot. Blackface) Animal Cloning Enucleation

Natural Birth CLONED ANIMAL Oocyte donor (Scot. Blackface) Animal Cloning Enucleation Surrogate “mother” (Scot. Blackface) Surrogate Mother Nucleus donor (Finn Dorset) Insert Mammary Gland Nucleus

Oocyte donor Enucleation Somatic cell biopsy ES cell + + Nucleus Enucleated ES cell SCNT/Therapeutic Cloning: Overcoming Rejection Somatic Cell Biopsy

Fibroblast‘pluripotent’ cell Inject into mouse blastocyst Contribution to all germ layers Inject under mouse skin Cell Dedifferentiation: Overcoming Rejection KLF4 Sox2 c-myc Oct4

Cell Therapy with ES cells: how it will work Somatic cell biopsy Master cell bank ES cell + + Transplant into patient Cell product Differentiation Nucleus Enucleated oocyte Enucleated ES cell Somatic cell biopsy Nucleus + Enucleated oocyte + Enucleated ES cell nuclear reprogramming

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