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The Last Great Invention of the 20th Century

Promega and the BioPharmaceutical Technology Center Institute hosted the 1st Annual International Bioethics Forum: Defining Life, Changing Life, Owning Life in April 2002. The forum, which was open to the general public, focused on those who hold positions that require them to share ideas and information with others: clergy journalists, and teachers. Friday morning featured keynote addresses from four prominent speakers in the field of bioethics: R. Alta Charo, University of Wisconsin-Madison; Kevin FitzGerald, Georgetown University; James Thomson, University of Wisconsin-Madison; and Q. Todd Dickinson, former director of the U.S. Patent and Trademark Office.  This article summarizes some of the information on the topic of stem cells that was presented by the speakers at the morning session.

The second forum will be held the weekend of April 25–26, 2003, and will be organized around the theme "Who Decides?".

This article is divided into several sections:
Politics, ethics, and science
What are embryonic stem cells?
What about adult stem cells, aren't they just as good?
What is the medical promise of stem cells?
How would the production of new drug therapies benefit from ES  cell research?

But, what about isolating the embryonic stem cells in the first place?

By Michele Arduengo, Ph.D.
Promega Corporation


Politics, ethics, and science

Q. Todd Dickinson, former Director of the U.S. Patent and Trademark Office described them as “the last great invention of the 20th Century.” Secretary of Health and Human Services, the Honorable Tommy Thompson, described them as having great potential to alleviate human suffering. 

Dr. James Thomson and colleagues at the University of Wisconsin-Madison isolated the first human embryonic stem cells in 1998. Since then, stem cell research has been the focus of a debate at the edges: the boundaries of science, ethics, religion and philosophy. Stem cell research has generated discussion, protest, argument and hope. 

Dr. Thomson described an embryonic stem cell as a cell that is isolated from the inner cell mass of the blastocyst embryo and has the ability to “replace itself and become something else.” Stated in those terms, stem cells don’t sound particularly controversial. The source of embryonic stem cells is the problem. The first embryonic stem cells were isolated from embryos resulting from assisted reproduction technologies such as in vitro fertilization (IVF). Embryos are destroyed when stem cells are isolated, and this presents a charged ethical dilemma.

In the 1980s and 1990s, the development of techniques such as IVF, which always result in the creation of “extra” embryos, provided a unique opportunity for science to study early human development. Human embryos slated to be discarded, were available in the laboratory for the first time.

The early research on stem cells was not federally funded. Although there was no policy banning federal funding of early embryonic research, in the late 1980s and early 90s, according to Dr. Charo, all requests for funding human embryonic research were “hung up” in a committee that did not exist. Consequently, any research conducted was privately funded with no oversight from federal funding agencies such as the National Institutes of Health.

Today, sweeping promises of cures for devastating neurodegenerative diseases and pictures of embryo farms have inflamed rather than informed the stem cell research debate.

What are embryonic stem cells?

Embryonic stem cells (ES cells) are cells that have the capability of replacing themselves indefinitely (self-renewing) and they can produce other types of cells. Human ES cells have the potential to produce any type of cell found in humans. 

Because of their ability to self-renew, they are considered to be naturally immortal, and they can be grown and expanded in laboratory cultures indefinitely. The only other “immortal” cell lines are cells, such as cancer cells,  that contain mutations that disrupt natural checks and stops for cell division. These other immortal cell lines are useful for some studies, but because they represent an abnormal state, testing drugs against these cells may not always give an accurate picture of what is occurring naturally in the organism.

What about adult stem cells, aren’t they just as good?

Scientists have reported the isolation of cells from adult tissues that appear to self-renew, for a time at least, and then can, in some instances, produce cells with characteristics of different cell types found in adult humans. However, adult stem cells have several limitations:

  1. Adult stem cells cannot tell us anything about the events of early human development or answer questions of cell differentiation and development during early embryogenesis.

  2. Most adult stem cells are not sustainably cultured. Although adult stem cells appear to have some ability to self-renew, this ability is limited. Therefore, adult stem cells cannot provide a continual source of tissues and new cells; they would have to be continually reisolated.

  3. Adult stem cells lose the potential to produce different cell types with time in culture in the laboratory.

  4. Some adult tissues, such as cardiac (heart) tissues, lack adult stem cells. The only way to obtain a large quantity of these tissues would be to create it from ES cells.

  5. There is no compelling scientific evidence that adult stem cells are equivalent in developmental potential to ES cells.

What is the medical promise of ES cell research?

ES cell research holds great promise for new therapies for a number of diseases, but new cures for Parkinson’s and Alzheimer’s Disease are not “right around the corner.” Most of the proposed therapies involve transplantation of tissues grown from differentiated stem cells into the diseased individual. Consequently, methods for successful transplant have to be available, and methods for getting stem cells to differentiate into the appropriate functional tissue must also be available.

One of the diseases that may benefit from stem cell research is juvenile diabetes. Some children have benefited from transplants of pancreatic islet cells isolated from cadavers. However, the source of these cells is extremely limited. Scientists have been able to produce differentiated cells from ES cultures that produce many of the proteins characteristic of pancreatic islet cells, and because of the already successful transplants, a working transplant protocol is available.

A second disease for which a successful cell transplant exists is leukemia. Hematopoietic (blood) stem cells are available from adult bone marrow, although these stem cells are not expandable into large quantities in the lab. If ES cells can be coaxed to develop into hematopoietic cells, they could be used in transplant cultures and would be more readily available.

Other diseases such as Parkinson’s Disease and heart disease will probably benefit from ES cell research in the more distant future.

How would the production of new drug therapies benefit from ES cell research?

One of the biggest promises of ES cells is their ability to produce unlimited quantities of specialized cells, such as cardiac cells or liver cells, that could greatly enhance the safety and efficacy of new drug development.

Drug development requires extensive testing of potential therapeutic compounds before clinical trials can proceed. Still, most of this testing takes place in mice or on tissue culture cells that are immortalized by mutation. This means that a compound can appear not toxic in early testing, but when introduced into humans, can still be an extremely toxic compound. Two antihistamines were shown to cause cardiac problems when used in combination with a particular class of antibiotics. Deaths, drug recalls, and a host of other problems might have been prevented had human cell lines been available for early stages of drug toxicity testing (1). ES cells could provide an economical source of normal human cells for toxicity testing of pharmaceuticals early in their development—potentially saving lives and significantly reducing the cost of new drug development.

But, what about isolating the embryonic stem cells in the first place?

This question is the crux of the debate. Most currently existing ES cell lines were isolated from embryos that were by-products of IVF and other assisted reproduction techniques. Limiting research to currently existing lines or refusing to fund ES research or even banning ES research will not stop the production of embryos that will be discarded as a result of these medical procedures. 

However, for transplantation therapies, the ideal tissues for transplantation would be derived from an embryo that is genetically similar to the patient. This would involve isolating the patient's genomic DNA, from a body cell of some kind, and putting it into an enucleated egg. The egg, with the “donor” genomic DNA, would be stimulated to develop and divide like a natural embryo. At the blastocyst stage, the ES cells would be isolated and used to produce the desired tissue for transplantation. In this case, a created embryo would be destroyed when the stem cells were isolated. 

References  

  1. Sussman, N. et al. (2002) The predictive nature of high-throughput toxicity screening using a human hepatocyte cell line. Cell Notes 3, 7–10.

All quotes were taken from the speakers' presentations at the Bioethics Forum.