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Back to Focus on Stem Cells articles

Sorting Out the Confusion - An Update on Stem Cells

Prepared by Ida Chow (SDB Executive Officer, [email protected]) and Gary Radice (SDB Education Committee Member, [email protected]). September 2001

The Dog Days of August have been indeed crazy, especially for the folks at the National Institutes of Health and the U.S. Department of Health and Human Services, trying to answer all the questions from the White House and the Congress about human embryonic stem cells. The hype mainly (but not solely) in the popular media has also given a sense of urgency to the issue that cannot be solved overnight. We hope this piece will help those not directly involved with the subject (including many of us, developmental biologists) to put things in perspective and decide on their own the merits on the use of human embryonic stem cells for research and therapy purposes. We will refer to, and include links to sound documents and articles that we feel are relevant to this discussion, which by no means constitute a complete survey of the literature.

Firstly, the Society for Developmental Biology's positions on:
Now, some fundamental facts:
1. Stem cell research and cloning: the science behind the headlines.
2. Feasibility and limitations in the use of embryonic (ES), fetal (FS) and adult (AS) stem cells.
3. Minimum number of cell lines necessary for therapeutic use.
4. The cell lines on the NIH approval list.
5. Legislative considerations.
6. Ethical considerations.


Lastly, the references and links.

Just Released News!
As this article was being readied for posting, Secretary of Health and Human Services Tommy G. Thompson announced at a September 5 US Senate hearing that a stem cell research agreement has been signed between the National Institutes of Health and the WiCell Research Institute, Inc. As stated in the NIH press release, this Memorandum of Understanding will allow NIH scientists to access the five cell lines held by the Madison-based institution which is affiliated with the University of Wisconsin. It may also serve as a model for research agreements between other research institutions and stem cell providers on the approved list.

1. Stem cell research and cloning: the science behind the headlines
It is generally believed that as an embryo grows, each cell inherits copies of the same set of genes that were present in the fertilized egg. But if every cell has the same genes, then how do these cells ever become different from each other? Somehow as an embryo grows, cells that start off being identical must precisely turn on or off different gene sets to become different cell types in just the right numbers.

This fundamental question about cell differentiation during embryonic development has puzzled and challenged developmental biologists for many years. Learning the answers has been difficult, because typically these decisions are made only once or a few times in a small number of cells inside each embryo at early stages of development. The excitement surrounding stem cell research comes from the opportunity to study these genetic decisions as they occur in large numbers of cells outside the embryo, growing in culture where they can be controlled and studied more easily. The hope is that studying isolated stem cells will finally allow us to learn the exact steps needed to convert an undifferentiated cell into any specific cell type. This knowledge would have extensive therapeutic implications since it could make it possible to grow replacement cells for those damaged by disease.
For detailed explanation and illustrations please see NIH's recent report "Stem Cells: Scientific Progress and Future Research Directions"

"Cloning" is not the same as stem cell research, but can encompass many different technologies, including the use of stem cells. In this context, cloning means creating a new individual by replacing an egg cell nucleus (with only one-half of the genetic complement) with a nucleus from the body cell of a different individual (containing the full genetic complement). This donated nucleus then directs the development of a new embryo, with the same genes as the donor. The donor nucleus potentially could come from another embryo, an adult, or a stem cell growing in culture.
For additional explanation on cloning please see "Cloning: Past, Present and the Exciting Future" by Marie A. Di Berardino.

2. Feasibility and limitations in the use of embryonic (ES), fetal (FS) and adult (AS) stem cells.
Stem cells are characterized by their ability to divide or multiply indefinitely and by their pluripotency, that is, the ability to differentiate (transform) into most of the different cell types in the body. Because of this versatility, these cells present an enormous potential for cell-based therapies, once the molecular and cellular mechanisms essential for directed differentiation are identified. Since the amount of research conducted in this area is still very small, due to limited funding, the progress thus far has been slow, albeit exciting. Unless more qualified scientists have the means to join in this effort the pace of progress will be slow, and the medical benefits will not be realized in a timely manner. One also has to remember that the translation from basic discoveries to actual clinical use is another elaborate step, which has to be followed by the production stage for efficient therapeutic use. Thus, it is important to accelerate this promising path. The sooner we start, the sooner we'll reach that goal.

ES cells: Embryonic stem cells are derived from the inner cell mass of a human blastocyst, a stage of very early development, when the embryo is still a microscopic ball of about 100 dividing cells. When cultured in plastic dishes under appropriate conditions they are capable of dividing indefinitely and differentiating into almost all the more than 200 cell types of the body. The pluripotency of these ES cells has been repeatedly demonstrated in mouse and other laboratory mammals in the past twenty years. However, these cells from the inner cell mass will not normally form the placenta, which is formed by cells coming from the outer cell (trophoblastic) layers of the blastocyst. Thus, ES cells will not give rise to a fetus even if implanted into a woman's womb.

FS cells: The fetal stem cells may be isolated from germ cells or other developing organs of fetuses. When cultured in dishes they behave similarly to the ES cells. FS cells derived from germ cells have also been shown to be pluripotent, while less is known about the cells derived from other fetal tissues.

AS cells: In an adult, the tissues that normally turn over and replace themselves, such as the skin, the lining of the stomach and intestines and the blood cells, contain undifferentiated cells called stem cells. These adult stem cells undergo cell division, thus preserving the undifferentiated cell population, and some differentiate into the appropriate cell types to replace those that died in their natural life span. For a long time it was believed that these stem cells would only differentiate into cells of the same tissue, that is, skin stem cells into skin and blood stem cells into blood. It was also believed that some cell types, such as the neurons and the heart muscle cells do not have these precursor cells, and that once the neurons and the heart cells died they could not be replaced. These concepts are now being reevaluated.

In the last two years, several reports have revealed the ability of cells obtained from adult tissues in mouse and human to differentiate into cell types that belong to other tissue types. For example, cells from the bone marrow have been shown to be capable of transforming into muscle and other cell types. In addition, precursor cells obtained from adult mouse central nervous system have been reported to transform into neurons and other support cells when cultured under specific conditions.

These unexpected findings have opened new hopes for AS cells. Since these reports are very recent and still largely unconfirmed by different research groups, the pluripotency of the AS cells remains to be explored by more studies. In addition, little is known about the properties of these AS cells, including their life span, genetic diversity and stability of the derived cell lines. The number of divisions these AS cells can undergo remains undetermined. Whether these undifferentiated, precursor cells derived from adult mammals (including humans) are truly stem cells with indefinite cell division capability and pluripotency remains to be elucidated.

3. Minimum number of cell lines necessary for therapeutic use
Currently, this number is still in dispute among specialists in the field. Interestingly, it has grown from a dozen to one hundred or more in the past two years, as a result of additional findings in the fields of immunology and gene regulation. Recent studies in mice have shown that the initial suggestion of a dozen "universal" donor cell lines that could be used for all patients without causing tissue rejection is untenable. This means that proper tissue matches between recipients and transplanted cells are still essential, as we now see with organ transplant patients. Advances in the fields of immunology and transplantation biology will certainly enhance the therapeutic benefits of the ES cells.

One possible way to overcome this mismatch is to extract adult stem cells from the patient, and then to coax them to multiply in large numbers and to differentiate into the cell type of interest.

Another means is to use the technique of somatic cell nuclear transfer to produce a blastocyst, by injecting the nucleus from a body cell of the patient into an egg whose own nucleus has been removed, and then triggering the egg to divide by applying an electrical current. Embryonic stem cells derived from the inner cell mass can then provide cells of the patient's exact match for therapeutic use.

Both these approaches depend on further understanding of the cellular and molecular mechanisms regulating the cell differentiation processes, and on technologies to produce large numbers of desired cells. In addition, the success of adult stem cells can only be realized if identification and extraction from the person can be done effectively.

We don't yet know what the effective and minimum number of stem cell lines is, to order to cover all the human genetic variations. We are, however, optimistic that answers will be available when more studies are carried out with current cell lines.

4. The cell lines on the NIH approval list
The criteria allowing embryonic stem cell lines to be used for NIH-funded research, based on President Bush's August 9 announcement are that:
- the cell lines were derived before August 9, 2001;
- they were derived from excess embryos after infertility treatments, and not from embryos produced for research purposes;
- the embryo donors' consent was obtained;
- there was no financial inducement for this donation.
Several issues need to be addressed by individual scientists who search for use of these cell lines:
- Whether all the cell lines are pluripotent remains to be determined for individual lines. Some of these cell lines were obtained very recently and have yet to be tested for pluripotency.
- Whether all the cell lines have shown infinite replication property has to be shown, since some of the cell lines are from recent derivations and have only gone through a few cell generations, instead of the hundreds of generations of a well-established cell line derived one or two years ago.
- Whether there is full disclosure and agreement between providers and users.
- The restrictions in the material transfer agreements, including future uses and patents, need to be carefully considered and agreed upon between each provider and user.
Some future issues to be addressed when clinical trials phase is reached:
- The genetic variation of the cell lines may still be limited, although they seem to have come from a variety of sources.
- The exposure of most of the cell lines to mouse fibroblast feeder layers means that specific tests must be conducted (such as for detection of mouse viruses and other agents) before clinical trials can be carried out, in order to meet US Food and Drug Administration's approval.

5. Legislative considerations
Different countries are introducing legislation to fit respective constitutions and cultural-historic backgrounds. The United Kingdom has had, since the mid 1980's, the most open, yet regulated system, which has allowed research using human embryos up to 14 days after fertilization. In December 2000, the British Parliament approved the use of somatic nuclear transfer technology to produce human embryos for research purposes, but not for reproductive purposes. It also allows in vitro fertilization for production of human embryos, with subsequent derivation of stem cells for research purposes. All scientists and physicians using these procedures are licensed by the Human Fertilisation and Embryology Authority (HFEA), and all the human embryos used are registered. Strict guidelines are also imposed. Other countries such as Canada, Australia, Japan, Singapore, Israel, Spain, Italy, Sweden and Finland either have approved, or will soon approve derivation and use of ES cells from excess human embryos left from infertility treatments.

One characteristic of the American legislation is that some restrictions are applied to federally funded activities, whereas the same activities may not have any limitation if carried out with private funds. This is especially significant in the areas of medical practice, in regards to the assisted reproductive technologies (in vitro fertilization, for example) and biomedical research, as we see now with the human embryonic stem cells. Currently, investigators funded by private organizations may derive cells from, and conduct experiments with human embryos; whereas those receiving federal monies such as from the NIH cannot. This disparity, added to the inherent "proprietary" rights of private companies and extensive public expression of their opinions by activist groups, complicates the matter even more in this country.

Bills on stem cells (and other issues) introduced in the US Congress can be found at: http://thomas.loc.gov

6. Ethical considerations
The popular media's attention to the human ES cells and cloning has raised the awareness of the public on these particular topics, and in general concerning the ethics of biomedical research aiming at clinical benefits. We see this as a healthy opportunity for learning and for open discussions about both the science and the life philosophy each of us live by. Since we live in a free country, we need to listen to each other, to open the doors to science in order to provide us with the hard data, and to help us make the right decision.

Due to the fact that these issues touch upon many sensitive areas; including political, traditional, cultural and religious concerns, there will likely never be complete agreement in all areas. Perhaps, the best that can be hoped for, is a general consensus to work toward the greater good, that being the most beneficial results for the greatest number of people.

References and links

On SDB Website Basic science and clinical implications
  • July 2001 report by NIH on stem cell research. A detailed report downloadable as PDF files, with chapters on the basic science, potential therapeutic uses, and references of published research.
  • NIH's web site that includes updated press releases, federal guidelines, text of testimony to Congress, and other information about NIH policy and proposals.
  • The general science magazine New Scientist maintains an excellent web site with recent articles explaining various aspects of stem cells and cloning, including updates on recent research and good explanations of some of the technical and conceptual problems encountered by researchers working in this area.
  • "Stem cell Research: Medical progress with Responsibility," the June, 2000, report from the UK's Chief Medical Officer's Expert Group reviewing potential therapeutic applications of stem cell research. British law allows experimentation with human embryos until the time when they can no longer form twins (i.e., when the embryo becomes an individual) at day 14.
Human Embryonic Stem Cells: Bioethics Human Embryonic Stem Cells: Reports and Legislations Articles of related interest
  • "What Only the Embryo Knows" - An opinion article by Stephen Jay Gould published in New York Times, on August 27, 2001, giving a historical perspective.
  • "Cloning: Past, Present and the Exciting Future" - An article written by Marie A. Di Berardino for the Breakthroughs in Biosciences series published in 1999 by the Federation of American Societies for Experimental Biology giving the history, the technology and ethics of cloning. Available as PDF file.
  • 1999 article in Science magazine by Davor Soltor and John Gearhart in which they propose several strategies for therapeutic uses of nuclear cloning. Enhanced links take the reader to footnotes and further references.

 

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