Unstable Promises of Embryonic Stem Cells

By Dr. David A. Prentice

Editor's note. An article in the July 6 edition of the prestigious journal Science reported on research into the question of why cloned animals rarely survive and, when they do, are cursed with horrible defects. However, rather than using a skin cell as the source of the genetic material, these mice were created using embryonic stem cells as the source.

The import of the study Science was caught in the first few paragraphs of a detailed story that appeared in the Washington Post ["Clone Study Casts Doubt on Stem Cells"]. It read,

"Mice cloned from embryonic stem cells may look identical, but many of them actually differ from one another by harboring unique genetic abnormalities, scientists have learned."

According to the Post's Rick Weiss, "The work also shows for the first time that embryonic stem cells - - which are at the center of an escalating political and ethical debate as President Bush decides whether federal funds should be spent to study them - - are surprisingly genetically unstable, at least in mice."

Weiss noted, "If the same is true for human embryonic stem cells, researchers said, then scientists may face unexpected challenges as they try to turn the controversial cells into treatments for various degenerative conditions."

We asked Dr. David A. Prentice to explain the study in layman's language and to examine its importance to the whole debate over human embryonic stem cells.

A recent report from the Whitehead Institute, published July 6 in the journal Science, may explain not only why there are so many problems with cloning, but also foreshadows serious problems with using embryonic stem cells to treat human diseases.

The researchers cloned mice, starting not with a skin cell as the donor of the clone's genetic material, but instead with mouse embryonic stem cells.

In cloning, the genetic material is removed from an egg, and genetic material from the individual to be cloned is inserted into the egg; this forms the clone, and development can proceed from there. Researchers previously had seen a higher cloning success rate using embryonic stem cells as the donor of the genetic material, though clones still showed abnormal development and a high death rate.

Embryonic development requires a complex orchestration, a ballet of cells being at the right place at the right time, reading their individual gene recipes in the correct sequence and dancing in concert with one another. The scientists from the Whitehead Institute analyzed expression of various genes during development and after birth (for those clones that survived), and found that there were wide variations and significant instabilities in how different genes were "turned on and off" in the mice.

It's important to understand that the instabilities that were found were not mutations in the DNA--the "basic blueprint." The genetic material was the same in all of the mice. The genetic material, however, is only a "recipe book" which must be "read."

During development, one cell reads some pages of the genetic material, another cell reads others. These differences in what's being "cooked up" by the cells, as well as the timing and sequence of the recipes, is essential to get all of the normal cells and tissues of the body.

Since the mice had been cloned from mouse embryonic stem cells, researchers went back and analyzed the gene expression in the starting material - - the stem cells themselves. The answer was startling: the gene expression "of the embryonic stem cell genome was found to be extremely unstable."

This may answer why the clones themselves were unstable, but it has more far-reaching implications.

Proponents of embryonic stem cell research in humans make extravagant promises of cures for a multitude of diseases, based on the assumption that they will be able to form any of the 210 tissues of the human body from a starting dish of human embryonic stem cells. In point of fact, they have had very few successes along those lines, even in the culture dish or in mice.

Instead, the cells tend to just grow, form tumors when injected into mice, or form a mixed collection of partially formed tissue. While the potential may be there to form any tissue (or certainly is there if the cells are left in the intact embryo!), in practice it has been difficult to get the cells to "perform" in the laboratory.

And as yet there are no cases of embryonic stem cell therapies even being attempted in human patients. The results of the Whitehead Institute study again may point to the reason for this - - the extremely unstable state of the embryonic stem cell genome. More and more it is looking like it will be difficult for embryonic stem cells to make good on their promises of therapeutic benefits for human patients.

Contrast the relative lack of success using embryonic stem cells with the avalanche of recent successes using adult stem cells and other non-embryonic sources such as umbilical cord blood.

Adult and cord blood stem cells are already being used successfully to treat patients with cancer, multiple sclerosis, lupus, rheumatoid arthritis, anemias, and immune deficiencies. They have also been used to grow new corneas to restore sight to legally blind patients, and even to begin repair of cardiac damage after heart attack.

In animal experiments, adult and cord blood stem cells have been used successfully in experimental treatments for stroke, Parkinson's disease, heart damage, liver damage, and to reverse diabetes in mice. The adult and cord blood stem cells are already making good on what now seem to be unstable promises of embryonic stem cell research.

Dr. David A. Prentice is a professor of life sciences at Indiana State University, adjunct professor of medical and molecular genetics at the Indiana University School of Medicine, and a founding member of Do No Harm: The Coalition of Americans for Research Ethics (www.stemcellresearch.org).