Human Embryonic Stem Cells:The Controversy, and

Innovative Applications

By,

Kelli Kalvesmaki

ISAT 351

April 21, 1999

Outline Derivation Techniques

– Blastocysts– Embryonic Germ (EG) Cells

Controversy of Human Embryonic Stem Cells– Legal Issues– Ethical Issues

Future Applications

University of Wisconsin

Derived pluripotent hES cells from blastocysts

Take hES cells from the inner cells mass of a blastocysts

Donated from an in vitro fertilization clinic

University of Wisconsin (continued) The hES cells are

cultured in a petri dish, and the team established five independent cell lines

Cells differentiated into the primary lines: endoderm (gut epithelium), ectoderm neural epithelium), and mesoderm (striated muscle).

Disadvantages of Deriving hES Cells from Blastocysts

Extremely difficult to manipulate

Involves the couples who donated the blastocysts (informed consent)

John’s Hopkins University Derived human Embryonic Germ (hEG) cells from aborted

fetuses hEG cells are from formed eggs and sperm from human fetal

tissue The hEG cells are cultured on feeder layers and media

containing nutrients and growth factors While in culture, the hEG cells developed into pluripotent hES

cells. The hES cells also differentiated into the three germ layers

(endoderm, mesoderm, and ectoderm) The hES cells are distinguished by:

– identifiable surface markers– normal chromosomal structure– the cell’s ability to replicate and differentiate

Telomerase Activity

Both teams noticed telomerase activity within the hES cells.

Telomerase: An enzyme made up of two molecules (one is RNA and one is a protein). It lengthens the telomeres, the end of a linear strand of DNA, thus extending the replicative life span of cells.

Significance:

– Suggests that hES cells are immortal

– Indicates the possibility of an unlimited supply of undifferentiated hES cells

– Proposes notion that new genes can be inserted into specific sites on the chromosome in order to enhance expression or control expression of a particular gene or genes.

Legal Issues

Ethical Issues

Controversy of hES Cells

Controversy of hES Cells: Legal Issues

It is illegal to federally fund all research involving human embryos.

It is feared that with the science of biotechnology emerging, the sharp distinction between stem cells and other cells no longer exist.

Controversy of hES Cells: Legal Issues

Federally Funding hES Cell Research:– Bayh-Dole Act – Stevenson-Wydler Technology Innovation Act of 1980 – Federal Technology Transfer Act of 1986 (FTTA)– Series of governmental acts that provide incentives for

scientists to develop new therapies and techniques in order to promote economic development, increase the U.S.’s competitiveness in the pharmaceutical industry world wide, and to specifically benefit the public.

– Obligation that scientists have in order to receive a patent when governmental funds are involved is to ensure:

• Utilization• Commercialization• Public Availability

Federally Funding hES Cell Research (Continued):– When research is not funded by the government, there is no

obligation to make intellectual property available to others for either commercial or research purposes

– When a patent holder exercises their rights through licensing that is not consistent with the overall advancement of basic research it can:

• limit product development• restricts further progression in research• does not benefit the general public• disrupts the balance between exclusivity and accessibility

Controversy of hES Cells: Legal Issues

Federally Funding hES Cell Research (Continued):

– This is the case with Geron, since all of the research has been restricted to private funds

– This greatly concerns the NIH, especially since hES cells can act as a research tool for learning about the fundamental biological processes of cellular growth and differentiation in human development

– Therefore federal funded hES cell research will actually benefit the general public, and provide regulations that can control hES cell research

Controversy of hES Cells: Legal Issues

Federally Funding hES Cell Research (Continued):– Further investigation on the distinction between embryos and

hES cells:• Formal definition of an embryo is an organism derived by

fertilization and other means.• An organism is characterized as an individual constituted

to carry out all life functions.• Stem cells cannot be defined as an embryo, since hES

cells cannot survive on their own, and will not develop into a fetus if simply placed in a woman’s uterus. (Since hES cells are pluripotent and not totipotent)

On January 15, 1999, the Department of Health and Human Services decided to provide federal funding towards research utilizing human ES cells.– The NIH will not use the federal funding until formal

guidelines and procedures to oversee the research is developed.

Controversy of hES Cells: Legal Issues

Ethical assessment of researching hES cells must distinguish:

– How the hES cells were obtained

– Methods used in the research

– The ultimate goals set forth by the scientists

Controversy of hES Cells: Ethical Issues

Deriving hES cells may destroy the embryo

Religious groups do not support hES cell research since they believe that human life begins when the ovum is fertilized, and the resulting embryo has legal rights to protection just like those of an infant or adult.

In the case of using blastocysts, the embryos will most likely be discarded regardless.

Director of the Ethics Institute at Dartmouth expressed that he “cannot see a logic that would thaw and destroy these embryos rather than using them.”

Controversy of hES Cells: Ethical Issues

University of Wisconsin:

– hES cells derived from from in vitro fertilization blastocysts, had to have the precursor of an informed consent agreement from the couple who donated the blastocysts

– Team went before the Institutional Review Board of the university to have all of the research protocols approved before any of the research was conducted.

– Alta Charo, an ethicist on the Board explained that “the conservative choice is to first protect the born.”

Controversy of hES Cells: Ethical Issues (Continued)

John’s Hopkins University

– All of their research was conducted within the guidelines of the 1994 report by the NIH Human Embryo Research panel

– The fetal tissue obtained was from therapeutic abortions

Controversy of hES Cells: Ethical Issues (Continued)

Geron

– Ensured all of the teams’ goals were clearly stated

– Created an independent Ethic Advisory Board to oversee both teams

– In compliance with the obligations set forth by the conclusions of the NIH Human Embryo Research panel:

• The hES cells will not be used for cloning humans• Will not be transferred to a uterus• Will not be used to generate human-human nor human-

animal chimeras

Controversy of hES Cells: Ethical Issues (Continued)

Federal funding requires the researchers to abide by federal regulation

– The guidelines that the NIH is constructing will hopefully assume some of the ethical concerns

Controversy of hES Cells: Ethical Issues (Continued)

Future Applications

Therapeutic Applications

Pharmaceutical Development

Understanding Complex Events of Early Human Development

Heart Disease Neurological Disorders Type I Diabetes Burn Victims Blood Transfusions Osteoarthritis and Rheumatoid Arthritis Endothelial Cellular Replacement

Future ApplicationsTherapeutic

hES cells can provide a limitless supply of normal human tissue to use in the testing of the toxicity of new drugs

One of the preliminary steps a drug takes in the approval process are the safety and toxicity tests within the pre-clinical trials involving animal models

hES cells can streamline the developmental process by weeding out only the safer drugs that will proceed to be tested on animals.

Many drugs will react differently in animals than in humans, so the hES cells will help in providing information on how the drug will react in humans

Future ApplicationsPharmaceutical Development

Through isolating and differentiating hES cells in culture, research will allow scientists to further understand the fundamental processes that occur during human development

Focusing on how the hES cells differentiated will also identify the genetic and environmental signals that direct specialization, cellular decision making, and cell division

Provide information on how abnormal growth and development occurs– Give rise to new therapies that prevent and diagnose birth

defects and cancer– More clearly defining developmental biology can lead to

innovative treatment of fertility disorders, and the prevention of premature pregnancy loss.

Future ApplicationsUnderstanding Early Human

Development

Conclusions There are many issues and procedures that must be refined or

determined before all of the potential behind hES cells can become a reality:

– An NIH generated set of standardized processes for large-scale production of hES derived differentiated cells for transplantation

– QC criteria for feeder lines, culture media, growth factors, sterility assays, and phenotypic markers for clinical production of hES cells

– Protocols developed and optimized for hES cells that have been genetically engineered

– Studies that examine how to avoid patient immune rejection to transplanted hES cells

– Creation of tissue banks with the most common histo-compatibility profiles for patient in need for cell transplantation

– How to efficiently direct stem cells to differentiate into specific types

– Determine how stem cells derived from fetal germ cells differ from stem cells derived from blastocysts, specifically if there is a fundamental functional difference

Conclusions (Continued)

The End

“The availability of pluripotent, self-renewing hES cells that can be differentiated into bulk-manufactured, functional, youthful cells and tissues will potentially usher in a new era of therapeutic opportunities in transplantation medicine, pharmaceutical research and development, and developmental biology that could positively impact many millions of patients worldwide.”