ES_bkgd

ES Cells - background

Laurel F. Appel, Wesleyan University

What are Embryonic Stem Cells? Stem cells are cells that can divide to become more than one different kind of cell. Embryonic Stem Cells (ES cells) are special because they have the potential to make any cell type of the body. There are also various stem cells found in adults, but they all appear to be more limited in the kinds of cell types they can produce. ES cells have been worked with most extensively in mouse, and but have also been derived from other mammals, including humans.

Where do Embryonic Stem Cells come from? Embryonic Stem Cells are derived from early mammalian embryos created by in vitro fertilization (IVF). After a 5-6 days of divisions, the embryo has a few hundred cells forming two major parts: the outer layer, or trophoblast, which will go on to form the outer membranes that attach to the mother's uterus (part of the placenta), and the inner layer, or Inner Cell Mass (ICM), which will go on to form the embryo proper. Embryonic Stem Cells are cells taken from the ICM, and then grown in culture.

What might they be used for? Embryonic Stem Cells are pluripotent: they can form all of the cell types of the embryo proper. Using the proper signals of hormones and growth factors, ES cells could be directed to generate specific cells or tissues needed by patients suffering from all sorts of serious conditions, such as diabetes, Parkinson's, or organs needed for transplant.

Why are they such a politically hot topic? Separating the ICM from the trophoblast destroys the potential of the blastocyst to implant in a uterus and develop all the way into an infant and be born. This is similar to very early abortion. For those that find any form of abortion unacceptable, this procedure is unacceptable, and anything that could be derived from it would be morally tainted. For others, the respect accorded to a fertilized human egg does not prevent its use to treat other humans already born and living with debilitating or life-threatening conditions. For dying patients and their families, the ethical issues are of whether and when doctors and scientists will be allowed to pursue this research. For the Congress, it is partly a question of which groups to risk alienating.

What is the source of the embryos? The original lines of human ES cells were derived from leftover embryos from fertility treatments. Because fertilized eggs can be stored more successfully than unfertilized eggs, all of the eggs that are ripened and removed from woman for IVF are usually fertilized right away with sperm. Then, some are implanted to try to acheive a pregnancy, and the rest are frozen away for later attempts or additional children. Once a couple decides their family is complete, some opt to donate the rest of the embryos for research. Others choose to keep them frozen away indefinitely, donate them to other prospective parents, or allow them to be thawed and destroyed. The most recent headlines (July 11, see below) were from a clinic in Virginia that created embryos specifically for ES cells for research, opening up yet another ethical can of worms.

Is this cloning? No, but the two get confused a lot, and might both be used for cell therapies. Dolly, the cloned sheep, was made by putting a nucleus from an adult sheep into a donor egg whose nucleus had been removed. By specially treating this new nucleus/egg combination, it was induced to go about normal development and become a new lamb, Dolly, whose nuclear DNA was identical to a previously-existing sheep, the nuclear donor. There is no theoretical reason this could not be done with humans, though most people and most scientific organizations have come out against human cloning for reproduction for ethical reasons. But this sort of cloning, also called Somatic Cell Nuclear Transfer (SCNT) might be combined with ES Cell techniques to generate tissues that would be immunologically identical to a patient, so the patient would not need lifetime immune-suppression to avoid rejecting the transplant.

What's the latest news on cloning animals from ES cells? It is possible to use Dolly-like techniques to turn ES cells back into embryos that can be implanted into the uterus of a foster mother. The latest results show that although some animals have been born, there are problems with this technique. Some of the problems seem to be related to improper growth regulation by genes that usually modulate operation in the placenta or embryo based on which parent the came from (imprinting), but no longer have that information.

Epigenetic Instability in ES Cells and Cloned Mice (Science, Volume 293, Number 5527, 6 Jul 2001, pp. 95-97.) David Humpherys, Kevin Eggan, Hidenori Akutsu, Konrad Hochedlinger, William M. Rideout III,1 Detlev Biniszkiewicz, Ryuzo Yanagimachi, Rudolf Jaenisch
[Abstract] Cloning by nuclear transfer (NT) is an inefficient process in which most clones die before birth and survivors often display growth abnormalities. In an effort to correlate gene expression with survival and fetal overgrowth, we have examined imprinted gene expression in both mice cloned by nuclear transfer and in the embryonic stem (ES) cell donor populations from which they were derived. The epigenetic state of the ES cell genome was found to be extremely unstable. Similarly, variation in imprinted gene expression was observed in most cloned mice, even in those derived from ES cells of the same subclone. Many of the animals survived to adulthood despite widespread gene dysregulation, indicating that mammalian development may be rather tolerant to epigenetic aberrations of the genome. These data imply that even apparently normal cloned animals may have subtle abnormalities in gene expression.

For More Reading:

Stem Cells: A Primer (National Institutes of Health, May 2000) http://www.nih.gov/news/stemcell/primer.htm

Current Status of Human Embryonic Stem Cell Research (FASEB Q&A on NIH guidelines, March 2001) http://www.faseb.org/opar/ppp/nih_stem.html

HOUSE CONCURRENT RESOLUTION 17 (107th Congress) Expressing the sense of the Congress supporting Federal funding of pluripotent stem cell research. (January 30, 2001)

Cloning: Past, Present, and the Exciting Future (Marie A. Di Berardino, Ph.D., Federation of American Societies for Experimental Biology, June 1999) http://www.faseb.org/opar/cloning/

Dolly's Legacy: Nuclear transfer--used to clone Dolly and now owned by Geron--may help scientists develop more potent stem-cell therapies (Scientific American, http://www.sciam.com/explorations/1999/062199dolly/

New York Times Articles (available free, but you must sign up for a free personal subscription)

Scientists Create Scores of Embryos to Harvest Stem Cells http://www.nytimes.com/2001/07/11/health/genetics/11CELL.html

Scientist's Stem Cell Work Creates Uproar (Profile of the scientist who first succeeded in growing human ES cells) http://www.nytimes.com/2001/07/10/health/10CELL.html

Bush Weighs Stem Cell Decision Amid Reminders of Suffering http://www.nytimes.com/2001/07/08/politics/08STEM.html

Several G.O.P. Senators Back Money for Stem Cell Research http://www.nytimes.com/2001/06/19/health/19RESE.html

The Recycled Generation http://www.nytimes.com/library/magazine/home/20000130mag-hall6.html

Return to Appel's Chatroom Page