Regenerative medicine

Regenerative Medicine
“ Hottest” area in medicine
Focus of HHS and NIH planning
Worldwide interest
Biotechnology companies entering field

Target Diseases
Spinal cord injury
Parkinson’s disease
Stroke
Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)

Myocardial infarction (heart attack)
Congestive Heart Failure

Diabetes mellitus (juvenile form)

Why all the recent attention?
James Thompson (University of Wisconsin) established human embryonic stem cell line in 1998

Flurry of reports showing plasticity of adult stem cells (1998-
Degeneration and Regeneration of the Nervous System (Ramon y Cajal, 1913)
“ 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
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)

Slaying of Dogma

No new neurons in brain in adulthood (in man)

No crossing of germ layers in adults
Cell Therapy: How it works
Replace damaged cells

Stimulate recovery by secreting growth factors -“Trophic factory”
Cell Therapy: sources
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

Problems with embryonic stem cells
Rejection (seen as foreign by host)

Form teratomas

Problems with cloning (nuclear transplantation)
Usually fails (requires many oocytes)

Faulty genetic reprogramming of cell (born clones have obvious or subtle abnormalities)

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)
Fundamental obstacle to cloning of primate cells

It is almost as if someone “drew a sharp line between old world primates-including people-and 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

Cloning “Alamogordo”
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
August 9, 2001 President Bush allowed federal funding for “pre-existing” human embryonic stem cell lines

Federal and State legislative agreement that reproductive cloning should be banned and criminalized
Cloning Legislation
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

Similar bill introduced into Senate by Sen Brownback (S 245)

Hatch Bill
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
Germany, Austria, Ireland, and Italy forbid destruction of embryos

Great Britain, Sweden, Israel, Singapore allow (encourage)
European Union
July 9, 2003 European Commission proposed rules that allow EU research funds to derive new ES lines from embryos “left over” from fertility clinics

EU Council of Ministers will have final say in Fall 2003
Recent developments
June 2003 AMA endorses human cloning for “research”

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
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
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
“ 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
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
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
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
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

Adult Stem cells
Blood, bone marrow
Skin
Neural (brain)
Bone marrow and blood as a source of stem cells
“ The blood is the life” Deut 12:23

Regenerative effect of blood

Bone marrow- the “fountain of youth”?

Multipotent adult progenitor cells
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
Umbilical cord stem cells
Multipotent Adult Progenitor Cells
Marrow stromal cells
CD34, CD133 cells mobilized into peripheral blood

Advantages of adult stem cells
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
Some “plasticity” or “transdifferentiation” may be simply a result of cell fusion

Not as “pluripotential” as embryonic stem cells

Counter to criticism
Not all results can be explained by cell fusion. Fusion does occur in liver but liver cells are often multinuclear

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
Published small trials of bone marrow cells in patients with myocardial infarction (heart attack)

Ongoing trial of bone marrow cells in patents with heart failure
Aims of ethical research
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