Transcript Stem Cells and Cloning

Stem Cells and Cloning
David C. Hess M.D.
Professor and Chairman
Department of Neurology
Medical College of Georgia
Advances in medical
treatment and health
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Sanitation, clean drinking water
Infectious diseases: vaccinations,
antibiotics
Advances in coronary heart diseasestatins, blood pressure control; cancer
treatment
Regenerative medicine
Regenerative Medicine
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“Hottest” area in medicine
Focus of HHS and NIH planning
Worldwide interest
Biotechnology companies entering field
Regeneration in urodele amphibians
Target Diseases
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Spinal cord injury
Parkinson’s disease
Stroke
Amyotrophic Lateral Sclerosis (Lou
Gehrig’s Disease)
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Myocardial infarction (heart attack)
Congestive Heart Failure
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Diabetes mellitus (juvenile form)
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Why all the recent attention?
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James Thompson (University of
Wisconsin) established human
embryonic stem cell line in 1998
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Flurry of reports showing plasticity of
adult stem cells (1998-
Degeneration and Regeneration of the
Nervous System (Ramon y Cajal, 1913)
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“In adult centres, the nerve paths are
something fixed, ended, immobile.
Everything may die, nothing may be
regenerated.”
“It is for the science of the future to
change, if possible, this harsh decree.”
Neurogenesis in human brain
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Old dogma was “no new neurons”
Study in cancer patients treated with
BrdU showing neurogenesis in dentate
gyrus in late adulthood (Eriksson, Nat Med
1998;4:1313)
Erikkson P, Nat Medicine 1998;4:1313
Slaying of Dogma
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No new neurons in brain in adulthood
(in man)
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No crossing of germ layers in adults
Cell Therapy: How it works
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Replace damaged cells
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Stimulate recovery by secreting growth
factors -“Trophic factory”
Cell Therapy: sources
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Marrow stromal cells
Multipotent adult progenitor cells (MAPC)
Human umbilical cord stem cells
Hematopoietic stem cells
Neural stem cells
Embryonic stem cells
Nuclear transplantation/embryonic stem cells
NEJM 2003;349:283
NEJM 2003;349:272
Problems with embryonic
stem cells
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Rejection (seen as foreign by
host)
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Form teratomas
NEJM 2003;349:280
Problems with cloning
(nuclear transplantation)
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Usually fails (requires many oocytes)
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Faulty genetic reprogramming of cell (born
clones have obvious or subtle abnormalities)
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Issue of mitochondrial DNA (not a perfect
match-some mitochondrial DNA comes from
mother or oocyte)
Biological roadblock to human
cloning (Science 2003;300:297)
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Fundamental obstacle to cloning of primate
cells
It is almost as if someone “drew a sharp line
between old world primates-including peopleand other animals saying, ‘I’ll let you clone
cattle, mice, sheep, even rabbits and cats, but
monkeys and humans require something
more.’”- Gerald Schatten, Univ Pittsburgh
Biological obstacle to primate cloning
Simerly et al Science 2003;300:297; Science 2003; 300:225
Cloning “Alamogordo”
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South Korean scientists publish “recipe”
for human cloning (isolate embryonic
stem cell line from a human clone)
Effort applauded by scientists
U.S. Legislative and Executive
Action
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August 9, 2001 President Bush allowed
federal funding for “pre-existing” human
embryonic stem cell lines
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Federal and State legislative agreement
that reproductive cloning should be
banned and criminalized
Cloning Legislation
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Human Cloning Prohibition Act of 2003
(Rep Weldon H.R 534) passed House
on Feb 27, 2003 with vote of 241-155.
Outlaws therapeutic cloning
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Similar bill introduced into Senate by
Sen Brownback (S 245)
Hatch Bill
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The Human Cloning Ban and Stem Cell
Research Protection Act of 2003
(S.
303) allows nuclear transfer but outlaws
the implantation of the products into “a
uterus or the functional equivalent of a
uterus”
Laws throughout the world
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Germany, Austria, Ireland, and Italy
forbid destruction of embryos
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Great Britain, Sweden, Israel,
Singapore allow (encourage)
European Union
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July 9, 2003 European Commission
proposed rules that allow EU research
funds to derive new ES lines from
embryos “left over” from fertility clinics
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EU Council of Ministers will have final
say in Fall 2003
Recent developments
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June 2003 AMA endorses human
cloning for “research”
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July 17, 2003 New England Journal of
Medicine articles and Editorial
encouraging “therapeutic cloning” and
plan to seek out embryonic stem cell
studies to publish
New Jersey cloning law S1909
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Permits therapeutic cloning
Forbids “reproductive cloning” or
bringing a clone to “term” but does not
forbid clone to be implanted in a uterus
and developed for “parts”
Funding of human embryonic
stem cells and cloning
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New Jersey Governor plans to fund
California planning taxpayer funding
Harvard University: 100 million
Stanford University
Univ of California San Francisco 10
million donation
Respect for Life (Donum Vitae) 1987
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“To use human embryos or foetuses as the
object or instrument of experimentation
constitutes a crime against their dignity as
human beings having a right to the same
respect that is due to the child already born
and to every human person.”
“The practice of keeping alive human
embryos in vivo or in vitro for experimental or
commercial purposes is totally opposed to
human dignity. “
Donum Vitae 1987
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Human embryos obtained in vitro are
human beings and subjects with rights:
their dignity and right to life must be
respected from the first moment of their
existence. It is immoral to produce
human embryos destined to be
exploited as disposable "biological
material".
Donum Vitae, 1987
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Also, attempts or hypotheses for
obtaining a human being without any
connection with sexuality through "twin
fission", cloning or parthenogenesis are
to be considered contrary to the moral
law, since they are in opposition to the
dignity both of human procreation and
of the conjugal union.
Declaration of Helsinki and
Nuremberg Codes
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Protect human research subjects
Forbid doing deadly harm to a human
Minimize risks to humans
Alternatives always sought before risk
to human incurred
Human cloning: why it is
wrong
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Creation of embryo with intent to
destroy; “strip mining” of stem cells;
“commodification” of human life
“Therapeutic” cloning will lead inevitably
to reproductive cloning
Problem with oocyte supply
Clones may be defective because of
incomplete reprogramming of genome
The ALTERNATIVE
Adult Stem cells
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Blood, bone marrow
Skin
Neural (brain)
Bone marrow and blood as a
source of stem cells
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“The blood is the life” Deut 12:23
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Regenerative effect of blood
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Bone marrow- the “fountain of youth”?
Putative bone marrow populations involved in repair after stroke
MAPC differentiate into endoderm, mesoderm, and ectoderm
Multipotent adult progenitor
cells
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Isolated form human bone marrow
A subpopulation of marrow stromal cells
Differentiate into virtually every cell type
in vitro and in vivo
All the positive attributes of embryonic
stem cells
Do not form teratomas
Bone marrow/blood sources
of stem cells
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Umbilical cord stem cells
Multipotent Adult Progenitor Cells
Marrow stromal cells
CD34, CD133 cells mobilized into
peripheral blood
NIH Stem Cell Website
Adult stem cells home to area of injury
NEJM 2003;349:273
Cell and Restorative Therapy of Stroke Patient (Lancet 2002;359:1047-54)
Advantages of adult stem
cells
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Autologous (in some cases)
No tissue rejection
No ethical concerns
No teratoma formation
Easy to obtain (bone marrow
aspirate)
Widely available
Disadvantages (criticism) of
adult stem cells
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Some “plasticity” or “transdifferentiation”
may be simply a result of cell fusion
Not as “pluripotential” as embryonic
stem cells
Counter to criticism
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Not all results can be explained by cell
fusion. Fusion does occur in liver but
liver cells are often multinuclear
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MAPCs can give rise to cells of all germ
layers and appear to have same
potential as embryonic stem cells (and
do not form teratomas)
Clinical trials of adult stem
cells
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Published small trials of bone marrow
cells in patients with myocardial
infarction (heart attack)
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Ongoing trial of bone marrow cells in
patents with heart failure
Aims of ethical research
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Reprogram an adult cell to become a “stem
cell” without step of becoming a human
embryo
Isolate the “universal” stem cell from adult
(MAPC?)
PROPOSE “ethical” regenerative medicine