topics in (nano) biotechnology stem cell therapy lecture 7 31st march, 2004 phd course
TRANSCRIPT
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TOPICS IN (NANO) BIOTECHNOLOGY
Stem Cell TherapyLecture 7
31st March, 2004
PhD Course
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Stem Cells• Introduction
• Sources and types of Stem Cells
• Main Applications
• Companies in the Field
• Stem Cells for Gene Therapy
• Legal and Ethical Issues
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What is a stem cell?
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What is a Stem Cell?
• Stem cells are undifferentiated cells capable of differentiating into any kind of tissue. This morphing process can occur almost indefinitely.
• Taken from human embryos only days old, stem cells are capable of developing into any of nearly 220 cell types that make up the human body.
• When a stem cell divides, it creates a stem cell that's specialized — one that can create cells that perform specific functions, such as blood cells. It also creates an exact replica of itself.
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• Totipotent: have unlimited capability. Can develop to all postembryonic tissues and organs.
• Pluripotent: stem cells capable of giving rise to most tissues of an organism.
• Multipotent: stem cells that are specialized to give rise to a particular cell type.
Types of Stem Cells
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• Stem cells are characterized by three hallmark properties:– Pluripotent: capable of differentiating into most
cells, but incapable of forming placental tissue so cannot form a fetus
– High Proliferative Potential: theoretically, one cell can give rise to an entire organ system
– Self-Renew: can regenerate themselves so are “immortal”
Stem Cell Properties
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Where Do Stem Cells Come From?
• Stem cells exist in different forms in both the embryo and the adult
• Embryonic stem (ES) cells are taken from blastocyst stage embryos (just a few days old and composed of few cells), of which there are about 200,000 in cryopreservation in IVF clinics
• ES cells are pluripotent and adult stem cells have more limited abilities to differentiate but can form cell types different to their own – a property known as plasticity
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ES cells: - spare embryos
- special purpose embryos
- cloned embryos
Adult stem cells: - adult tissue
- cadavers
Other sources: - aborted fetuses
- umbilical cords
Sources of stem cells
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20 years ago - mouse ES cells
1998 - James Thompson - human ES cells
Stem cell proliferation
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Multiple embryos are produced in vitro for clinical purposes.Donated surplus embryos are used as a source of ES cells.These surplus embryos would otherwise be discarded or remain unused
How are ES Cells Generated?
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Fertilized Embryos Are Allowed to Divide Several Times in Culture
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Harvesting ES Cells
The blastocyst is the stage of development (~1,000 cells) at which the embryos inner cell mass (ICM) forms. It is the ICM that harbors ES cells. Stem cells exist only fleetingly at this stage of development
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Generating an ES Cell Line
The trophoblast is removed from the embryo, the inner cell mass is isolated and, using a micropipette, ES cells are extracted and placed in tissue culture. These cells are passaged for many generations until some spontaneously form “immortal” lines
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Generating an ES Cell Line
In vitro growing
• Growth medium
• Feeder layers
• Spontaneous differentiation
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Differentiation
Growth factor Induces cells from
retinoic acid ectoderm
epidermal growth factor (EGF) ectoderm
bone morphogenic protein 4 (BMP4) ectoderm
basic fibroblast growth factor (bFGF) ectoderm
activin-A mesoderm
transforming growth factor-beta 1 (TGF-B1) mesoderm
hepatocyte growth factor (HGF) three germ layers
nerve growth factor (NGF) three germ layers
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Stem Cell Therapy
• Using replacement cells to cure disease may prove to be one of the most significant advances in medicine
• Unlike current treatments that rely on surgery or drugs to modulate activities, stem cells provide a replacement for dysfunctional or degenerating tissue
• In the future, stem cells could enable the means to create entire organs that fail due to aging or disease
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Sources
Plasticity
- Adult Central Nervous System (CNS)
- Bone marrow and blood stem cells
- Other tissues
Adult Stem Cells
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What tests are used for identifying adult stem cells?
• There is not a general agreement on the criteria that should be used to identify and test adult stem cells. One of the following three methods is generally used:• Labelling cells in living tissue with molecular
markers and determination of the type of cells they specialise
• Remove cells, carry out cell culture and label, transplant into different animal to see if tissues reform cells of tissue of origin
• Isolate the cells, manipulate them (growth factors/new genes) – determine what potential cells can be formed
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Embryonic vs Adult stem cells
Embryonic Stem Cells Embryonic Stem Cells
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Stem Cell Therapy for Tissue Replacement
Stem cells are the parent cells of every cell in the body. Under the right conditions, ES cells can be transformed into a variety of cells that make up the bone marrow, brain, muscle, skin, pancreas, and liver
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Clinical Applications
When transplanted into an injured tissue (eg. damaged cardiac muscle following heart attack) heart cells derived from ES cells in culture can contribute to tissue regeneration in vivo
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Other Sources of Stem Cells• Spare Embryos: leftover from IVF clinics• Special Purpose Embryos: created by IVF for the sole
purpose of extracting stem cells• Cloned Embryos: embryos can be cloned in the lab by
somatic nuclear transfer in order to harvest their stem cells
• Aborted Fetuses: can be used as a source of stem cells early in development (5-11 weeks of gestation)
• Umbilical Cords: this normally discarded tissue holds great promise as a source of blood-forming (hematopoietic) stem cells
• Adult Tissues or Organs: stem cells can be isolated from tissues of living adults during surgery (eg. hematopoietic stem cells from bone marrow)
• Cadavers: neural progenitor cells have been isolated from human brain tissue up to 20 hours after death
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Comparing Embryonic and Adult Stem Cells
Advantages• Flexible: have the potential to make any cell• Immortal: one ES cell line can potentially supply endless
cells with defined characteristics• Easily Available: embryos from IVF clinics
Disadvantages• Difficult to Culture: the conditions for inducing tissue-
specific differentiation are poorly understood• Immunoreactivity: ES cells from another donor may be
rejected after transplantation into an incompatible recipient• Ethically controversial: embryonic sources of stem cells
are opposed by people who believe that life begins at conception even if donors give consent
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Comparing Embryonic and Adult Stem Cells
Advantages• Already Somewhat Specialized: inducement may be simpler• Not Immunogenic: recipients who receive the products of
their own stem cells will not experience immune rejection• Mixed Degree of Availability: some adult stem cells are easy
to harvest (skin, muscle, marrow), while others may be dangerous to the donor (brain stem cells)
Disadvantages• Limited Quantity: difficult to obtain in large numbers• Finite: don’t live as long as ES cells in culture• Less Flexible: may be more difficult to reprogram to form
other tissue types• Genetically Unsuitable: may carry genetic mutations of
disease or become defective during culture
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How do we turn on stem cells?
The recent discovery of molecular switches that help determine whether stem cells will become muscle cells or other cell types might pave the way for effective treatments of muscular dystrophy (MD).
Rudnicki believes Pax7 acts as a switch that tells muscle stem cells to become satellite cells instead of blood cells. If turning on Pax7 can force the cells to make this choice, it could be used to devise treatments for MD that effectively combine gene therapy with stem cell transplantation.
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Target Diseases for Stem Cell TherapyBlood Diseases• Bone marrow transplants (BMT) are a well known clinical
application of hematopoietic stem cell (HSC) therapy• HSCs can regenerate all of the different cell types in blood• BMT is used for the treatment of blood cancers like leukemia
and lymphoma, as well as breast cancer and any other disease requiring immune system regeneration
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Target Diseases for Stem Cell TherapyHeart Disease• ES cells can be induced to form cardiac muscle cells that
actually beat in culture• When transplanted into damaged hearts, these cells can form
gap junctions and contract in unison with surrounding cells• HSCs can also be grafted into damaged heart muscle and, in
this new environment, are reprogrammed to produce heart cells instead of blood cells
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Target Diseases for Stem Cell TherapyBrain and Spinal Cord Injury• Neural stem cells can be isolated from
adult brains or generated from ES cells in culture
• HSCs can also be transplanted into the brain where they are reprogrammed to generate neurons and glial cells
• Potential applications include Parkinson’s disease, ALS, Huntington’s disease, stroke, Alzheimer’s disease, paralysis
• Animal and early human trials are underway
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Target Diseases for Stem Cell Therapy
Type 1 Diabetes• Patients lack pancreatic beta cells
and cannot produce insulin• Insulin-producing structures similar
to pancreatic islets have been generated from mouse ES cells in culture
• It may also be possible to isolate pancreatic stem cells from adult tissue
• Early stage of development
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Target Diseases for Stem Cell TherapySkin and Hair Replacement• Skin (keratinocyte) stem cells reside in the hair
follicle and can be removed when a hair is plucked
• These cells are bipotent, forming hair and epidermis in culture
• Provide tissue for autografting, without problems of immune rejection
• Clinical trials underway for venous ulcers, burn injury, and hair transplants
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HOW STEM CELLS AND GENE THERAPY MIGHT WORK TOGETHER
1. A sample of bone marrow is removed.
2. Stem cells are isolated and allowed to multiply in culture.
3. Cells are treated with a modified virus containing a therapeutic gene
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HOW STEM CELLS AND GENE THERAPY MIGHT WORK TOGETHER
1. The virus is taken up by individual cells and the therapeutic gene goes into the cell's nucleus.
2. Treated ("corrected") cells are injected into the bloodstream.
3. Treated cells respond to injury signals from degenerating muscle or other tissues and migrate out of the bloodstream.
4. Treated cells patch damage and build healthy tissue
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Stem cells for Gene Therapy
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Commercial Opportunities in Stem Cell Research
• Devices: manufacture of equipment and materials needed to isolate stem cells from adult tissues (e.g. Antibodies, affinity beads and flasks, columns, cell sorters, etc.)
• Isolation: novel “processes” are patentable • Composition: the make-up of the isolated stem cell
product is patentable, irregardless of how it was obtained
• Manipulation: novel methods of culturing or reprogramming stem cells are patentable
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• Aastrom
• Advanced Cell Tech.
• BresaGen
• Cryo Cell
• Curis
• Diacrin
• Geron
• ReNeuron
• StemCells
• Incara
• Nexell
• NeuroNova
• Novartis
• Genzyme
• Others
Biotechnology Companies in the Stem Cell Field
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Biotechnology Companies in the Stem Cell Field
Nexell
Isolex 300i Magnetic Cell Selection System. The only FDA approved device for clinical scale isolation of hematopoietic stem cells from blood
Aastrom
Manufacture a “bioreactor” that allows the growth of many hematopoietic stem cells from the small number that can typically be harvested from adult or umbilical cord blood
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Biotechnology Companies in the Stem Cell Field
StemCells Inc.
Have parallel programs in pre-clinical development for the isolation and characterization of neural, liver and pancreatic stem cells. Primarily process and compositional patents
Geron
Own the intellectual property used to clone “Dolly” the sheep. Funded the University of Wisconsin research that generated the first human ES cells. Parallel programs in directing the development of ES cells into neural, liver and cardiac cells for transplantation
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Biotechnology Companies in the Stem Cell Field
Diacrin
Developing xenotransplants using fetal pig cells in chronic stroke patients
NeuroNova
Strategy is to isolate adult brain stem cells, induce them to form dopaminergic neurons in culture, and then transplant these cells into the brain of patients with Parkinson’s disease
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Biotechnology Companies in the Stem Cell Field
ReNeuronHas developed neural stem cell lines from different
regions of the human brain. Can be grown in large numbers for transplantation.
Also examining the genes and proteins expressed in neural stem cells to identify novel targets for drug discovery
NovartisThrough its acquisition of SyStemix, Inc., now owns the
composition patent on human hematopoietic stem cells
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Ethical debate
• Harvesting ES cells destroys the blastocyst
• “This is murder”
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Ethical debate
• ES cell research requires human cells
• Could create a commercial market for human cells
• “This devalues life”
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Ethical debate
• “If excess IVF embryos are being discarded anyway, they should be put to good use”
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Ethical debate
• “Therapeutic cloning is a slippery slope - it will lead to reproductive cloning”
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Governing ES cell research
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Legal & Ethical IssuesReNeuronHas developed neural stem cell lines from different
regions of the human brain. Can be grown in large numbers for transplantation.
Also examining the genes and proteins expressed in neural stem cells to identify novel targets for drug discovery
NovartisThrough its acquisition of SyStemix, Inc., now owns the
composition patent on human hematopoietic stem cells