HUMAN EMBRYONIC STEM CELL RESEARCH - WHERE DOES IT STAND NOW?
August, 1999

Since the first report posted in February much has taken place on the issue of federal funding for human embryonic stem cell research. There is optimism that the Department of Health and Human Services (DHHS) general counsel Harriet Rabb's ruling to authorize federal funding of projects using pluripotent stem cells derived from human embryos (see Feb. 1999 report on this site) will go ahead. But there is still the possibility that a "rider" will be added to the Labor-HHS appropriations bill by opponents at the Congress which would prohibit this ruling from being carried out. More meetings have been held by the National Bioethics Advisory Commission (NBAC) and patient groups, as well as information sessions for the Congress staff by SDB, ASPET (American Society for Pharmacology and Experimental Therapeutics) and ASCB (American Society for Cell Biology). NIH also has established an advisory committee to the Director on setting guidelines for the future applications.

More papers have since been published on the potentiality of embryonic and adult stem cells to differentiate into several cell lineages. Here we have a summary of these events and references are listed at the end of the article.

NBAC final report

It is expected that NBAC will send its final report on the ethics of research with human embryonic stem cells to the President within a few weeks. Since the deliberations and hearings on this subject have to be conducted in public, as legally mandated, the media have published portions of discussions among the commissioners, as well as passages from the several versions of the drafts of the report. Unfortunately, on several occasions these passages and some candid comments by the commissioners were reported as "decisions" of the Commission creating unwarranted confusion, even leading to the release of official White House statements (see Websites below). On the other hand, these open meetings and hearings offered an opportunity for the public to hear about the issue of pluripotent embryonic stem (ES) cell research and think about the ethics and rationale for using human ES cells for cell-based therapies.

Currently, transcripts of several NBAC meetings and a brief statement on the status of the report are available on the Commission's Website, http://bioethics.gov/. The final version of the report will be posted on the Website shortly after its delivery to President Clinton, expected before the summer ends.

NIH

A 13-member advisory panel was formed by NIH Director Harold Varmus to formulate the guidelines for NIH funding of projects using human embryonic stem cells that have been derived by investigators who receive private funding. This panel co-chaired by Shirley Tilghman (SDB member) of Princeton University and Ezra Davidson of Charles R. Drew Univ. of Medicine and Science will submit a draft of the guidelines in early fall; and the public has 60 days to comment before the guidelines are reviewed by another advisory panel to the NIH Director and implemented. The guidelines will include standards on donors' consent, and source of the stem cells, in addition to the usually required scientific validity for the particular proposal. Until then, no proposal using human pluripotent stem cells will be accepted by NIH.

As a result of Senator Specter's request to Dr. Varmus, each NIH institute has issued a statement listing the potential benefits from human ES cell research. Unfortunately this document has not been posted on NIH Website yet, but it has been delivered to Senator Specter's office.

Are ES cells really more promising than adult stem cells?

Since the publication of J. Thomson's and J. Gearhart's papers on human ES cells last November, original research reports on multilineage potency of stem cells originating from adult human bone marrow mesenchyme (Science 284:143-147, 1999), liver (Hepatology 29:1193-1198, 1999) and skeletal muscle (Am. Surg.65:22-26, 1999) have been published. In addition, a study showing cross tissue type differentiation (stem cells from the nervous system into blood cells) has been reported in rodents (Science 283:534-537, 1999).

This led to the question of why ES cells are necessary if adult stem (AS) cells are available and there is no legal ban in their use, in addition to the existence of established guidelines for use of human adult cells and tissues. This question, in fact, has been consistently raised by opponents to human ES cell research and use of ES cells for therapeutic purposes.

In spite of the optimism generated by these recent articles on the pluripotentiality of human AS cells, many scientists, including those who conduct AS cell research support the continuation and expansion of human ES cell research, and not to limit research to AS cells only. Several reasons explain the need to support human ES cell along with AS cell research:

1. It appears that the natural shortening of the chromosome length due to aging is not repaired even when the mature cell is reversed into embryonic stage and allowed to differentiate into a new individual. This was reported to be the case with cells of the two-year old sheep Dolly, who was cloned from a six-year old ewe's udder cells (Nature 399:316-317, 1999). Other studies have connected activation of enzymes that prevent this shortening to carcinogenesis in adult cells. This raises the question of possibility of early programmed apoptosis (cell death) and appearance of other unwanted properties in cells derived from AS cells. Epigenetic changes in the genome may also be more difficult to reverse in older adult cells than in embryonic cells.
2. Unlimited self-renewal, a characteristic of ES cells which allows them to divide and propagate indefinitely, thus providing large numbers of identical cells for further differentiation studies and eventual therapeutic use. This number is further augmented with the larger number of stem cells present in embryos. Conversely, the search of stem cells in adult animals, including humans, has been elusive as these cells are difficult to be identified and the number is estimated to be minimal. In addition, accessibility and isolation of AS cells have been dismal to say the least. For example, the rare neural stem cells so far isolated from adult rodents (rats and mice) have been found in the deepest regions of the brain, not the easiest site to reach.
3. The pluripotentiality of AS cells has not been widely confirmed, especially in the situation of stem cells of one embryonic origin (ectodermal, mesodermal or endodermal) differentiating into cells of a different origin. To date, there is only one published report (Science 283:534-537, 1999) of this cross-over where adult neural stem cells (of ectodermal origin) from one donor mouse were injected into another host mouse's blood. Several months later, cells were isolated from the host mouse bone marrow were cultured in dishes and blood lineage cells (usually of mesodermal origin) carrying markers of the donor cells were identified. Whether this occurs in other mammals including humans remains to be determined.
4. Based on the knowledge we currently have of the molecules and factors that promote growth and differentiation in the embryo, the use of these molecules on ES cells to drive differentiation into desired cell types is more likely to succeed than in AS cells maintained in culture, where initial studies remain to be carried out.

5. Human ES cells offer a window for studying the earliest events in human development and answer basic questions that may lead to a better understanding of mechanisms causing birth defects, pregnancy loss, infertility and adult tissue regeneration.
6. The dilemma posted by the large number (in tens of thousands) of frozen in-vitro fertilization (IVF) embryos that are left-over (and sometimes unclaimed) from fertility procedures: to discard them or to use them for studies to increase our understanding of human development, to provide means for cell-based therapies to promote better quality of life and life expectancy of other humans with metabolic or degenerative diseases.

Conclusion

At the present moment, it seems to be advantageous to keep both stem cell sources available so that answers to the questions as well as advances to actual application to medicine can be achieved more quickly. Evidently, serious considerations must be given to both scientific and ethical aspects regardless of the cell source. Only the best scientific projects should be allowed; thus the importance of increasing the pool of scientists capable of conducting such research by allowing federal funding for ES cell research. The harvest, derivation and use of ES cells must follow strict ethical guidelines, especially the aspects of informed consent from the donors and respect for the donors' decision and believes.

Website References:

- NIH's Fact Sheet of Stem Cell Research: http://www.nih.gov/news/pr/apr99/od-21.htm

- NIH Director's Congressional testimonies:

http://www.nih.gov/welcome/director/120298.htm

http://www.nih.gov/news/stemcell/statement.htm

- NBAC's Statement: http://bioethics.gov/statement.html

http://www.senate.gov/~appropriations/labor/Varmus.htm

http://www.senate.gov/~appropriations/labor/Meslin1-26-99.htm

http://www.senate.gov/~appropriations/labor/Melton.htm

http://www.senate.gov/~appropriations/labor/Doerf1-26-99.htm

http://www.senate.gov/~appropriations/labor/Dickins.htm

http://www.senate.gov/~appropriations/labor/caplan2.htm

http://www.senate.gov/~appropriations/labor/thomson2.htm

http://www.senate.gov/~appropriations/labor/Goldste.htm

http://www.ninds.nih.gov/WHATSNEW/PRESSWHN/1999/freed.htm

- ASCB: http://www.faseb.org/ascb and click on Public Policy

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