LE Magazine March 2002
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Adult stem cell research
|Until a couple of years ago, it was believed that you could only make blood cells from bone marrow stem cells, skin from skin stem cells and so on. Today it is recognized that adult stem cells can be derived from multiple sources such as the central nervous system, the heart, skeletal muscle, the pancreas, even from fat. Moreover, scientists have been able to isolate and culture adult stem cells more easily than previously thought possible.|
Another argument used against therapeutic cloning research is that it is unnecessary. According to this view, the promise of stem cells for medicine can better be achieved via adult stem cell research, while the compatibility of cloned tissues can be achieved by other means. An organization called "DO NO HARM: The Coalition of Americans for Research Ethics" takes this position and issues reports on adult stem cell research to support it.
Recent advances in adult stem cell research have indeed been impressive. Until a couple of years ago, the prevailing dogma was that adult stem cells could only be used to develop the same type of tissue the stem cells were taken from. Thus, it was believed that you could only make blood cells from bone marrow stem cells, skin from skin stem cells and so on. It was also believed that adult stem cells could only be derived from a very limited number of sources and that adult stem cells are difficult to isolate and grow in tissue culture.
Today it is recognized that adult stem cells can be derived from multiple sources such as the central nervous system, the heart, skeletal muscle, the pancreas, even from fat. Moreover, scientists have been able to isolate and culture adult stem cells more easily than previously thought possible. In fact, Dr. Fred Gage and colleagues at The Salk Institute's Laboratory of Genetics in La Jolla, California have been able to derive and grow adult stem cells from various regions of human post-mortem brains taken from dead patients.
Recent advances in adult stem cell research:
Recent studies have demonstrated that bone marrow stem cells can be transformed into other types of tissue than blood cells and that they have the potential for the treatment of a variety of conditions.
In one study, researchers at the Baylor College of Medicine transplanted purified bone marrow stem cells from adult donor mice into the bone marrow of lethally irradiated mice. The transplanted cells regenerated the hematopoietic system in the recipients and then migrated into cardiac myofibers, where they helped to regenerate the heart, which was suffering from ischemic damage caused by coronary artery occlusion and reperfusion. In another study at New York Medical College, scientists injected bone marrow cells from donor mice into the contracting wall of the hearts of recipient mice, which had been damaged by ischemia. After nine days, they found newly-formed heart tissue in 68% of the infarcts.
In France, doctors implanted skeletal muscle stem cells back into a patient from whom they were taken after he suffered a heart attack. They found encouraging improvement of the patient's condition after eight months' follow-up. Clinical trials are underway in Europe and the U.S. to determine the value of this new type of therapy for heart disease.
At Humboldt University in Germany, scientists found that transplanted bone marrow cells in mice could generate fully developed, functional Purkinje neurons in the brain. Purkinje cells are large neurons that secrete the neurotransmitter GABA in the cerebellum, an area of the brain involved in movement and coordination.
Scientists at the Yale University School of Medicine derived several types of mouse somatic cells from a single transplanted bone marrow stem cell. Among the types generated were cells of the GI tract, lung and skin. It was speculated that the derived cells may have been "summoned" to sites of injury by factors secreted from these sites.
Adult vs. embryonic stem cells
The recent advances in stem cell research are very exciting. Further research in the field could lead to major advances in medicine. But there are still fundamental advantages that embryonic stem cells have over adult cells that have been recognized by most leading scientists in biology and medicine. Among the supporters of embryonic stem cell research (and cloning as a method of generating ESCs) are the National Institutes of Health (NIH), the National Academy of Sciences (NAS), the Federation of American Societies for Experimental Biology (FASEB) and many Nobel laureates.
Human embryonic stem cells are unique in the history of medical research. They are totipotent (or pluripotent), which means they stand near the base of the developmental tree and can branch out to form any type of cell needed in medicine. In contrast, adult stem cells are merely multipotent. They stand further out on the branches of the tree, which only enables them to form a limited number of cell types.
Nobel laureate David Baltimore summed it up as follows:
"It has been suggested that adult tissues might provide an alternative source of stem cells. This is simply false. Adult tissues are not known to have cells with the potential to become all parts of the body. In adults, certain tissues (e.g. skin, blood and brain) do contain specialized types of stem cells, but they are not generic stem cells with the same properties as those derived from embryos."
Another advantage of embryonic stem cells is that they can be modified more easily than adult cells. One type of modification is "gene targeting," which could enable these cells to "heal" mutations in genes that cause diseases and contribute to aging. Other potential applications of stem-cell-mediated gene therapy could be to provide resistance to chemo- and radiation therapy, enhance immune response to tumors, and induce tolerance to the transplantation of tissues and organs from other species.
A third advantage of embryonic stem cells is that they multiply far more easily in tissue culture than adult cells. Dr. Ronald McKay of the National Institute of Neurological Disorders points out that, because of the proliferative power of embryonic cells, they will likely be used to produce large numbers of cells for use in clinical medicine. Dr. John Gearhart of Johns Hopkins Medical Center adds that the ability of embryonic cells to divide in the lab makes them a vital tool for learning how cells differentiate,  which is one of the major questions in biology. Insight into cell differentiation could provide us with clues about why we grow old and how we can reverse the process.
Embryonic stem cells derived from cloned embryos provide another important advantage over adult cells. Cells, tissues and organs generated from cloned stem cells will be almost identical immunologically to the cells of the donor from which the embryo was created. This should enable doctors to transplant them into donors without rejection problems.
Today's transplants usually require the lifelong administration of toxic, expensive drugs such as cyclosporine to stop the recipient from rejecting the tissue or organ being transplanted. Although it may become possible to grow tissues from adult stem cells derived from specific patients, which could then be transplanted into these patients without rejection, this is not likely to work as well as with cloned embryonic stem cells. Companies such as BioTransplant in Boston are working on methods of tricking the immune system into accepting "foreign" transplants, but success in this area may be years away. Moreover, using such tricks may never be as effective as transplanting tissues developed from cloned embryonic stem cells.
Revolutionary advances in medicine
Research with embryonic stem cells is about a decade behind adult stem cell research. The isolation of embryonic stem cells was first reported by Dr. James A. Thomson and colleagues at the University of Wisconsin in 1998, and scientists at Advanced Cell Technology are only now beginning to close in on the isolation of stem cells from cloned human embryos. Yet, there have already been major breakthroughs in embryonic stem cell research, which promise revolutionary advances in medicine.
Mouse embryonic stem cells have been induced to develop into hematopoietic cells, heart cells, insulin-secreting pancreatic cells and neural progenitor cells, which have aided in brain development and recovery after spinal cord injury. Recently, scientists at Hadassah University in Jerusalem developed neural progenitors from human embryonic stem cells, which were then induced to develop (in vitro) into mature neurons, astrocytes and oligodendrocytes. When these cells were transplanted into the brains of newborn mice they migrated into various brain regions in response to normal developmental cues.
When Thomson, et al at the University of Wisconsin transplanted neural precursors from human embryonic stem cells into the brains of 22 newborn mice, they found, one-to-four weeks later, that new mature neurons and glial cells had been incorporated into various brain regions in 19 of the mice. The new human cells were indistinguishable morphologically from the recipients' cells. They could only be detected through the use of human-specific markers.
Scientists at the Hebrew University in Jerusalem found that retinoic acid (a vitamin A analog) and beta nerve growth factor both induced the growth of neurons in vitro from embryonic stem cells. They also showed that retinoic acid promoted the growth of mature neurons with receptors for the neurotransmitters dopamine and serotonin. The results of this study suggest new methods for the production of large numbers of neurons in culture for the possible replacement of neurons lost from trauma or degeneration to the central nervous system in humans.
These advances represent the first wave of a revolution in medicine. The development of compatible cells, tissues and organs grown in the laboratory will eventually enable us to replace almost every diseased, injured or aging cell in our bodies with young, healthy cells. The only cells that won't be replaceable are the brain cells that determine our identity, which will have to be rejuvenated rather than replaced. One possible method of rejuvenation for key brain cells, or for the organism as a whole, will be the use of stem cells for therapies to raise or lower the expression of genes involved in aging and degenerative disease.
In fact, new studies suggest that cloned embryonic stem cells, which are extremely young cells, may even be younger than their chronological age. After the cloning of Dolly, the sheep, it was reported that Dolly might have inherited the shortened telomeres of her nuclear donor (a six-year-old ewe), suggesting that she might be biologically older than she should be. (Telomeres are DNA segments at the ends of chromosomes that become shorter when cells divide). More recent studies, however, have come to the opposite conclusion about cloned animals.
One study showed that the telomere lengths in 10 clones created from an aged, 13-year-old female dairy cow were similar to those found in the donor animal. Another study produced similar findings in cloned cattle, whereas two other studies, in cattle and in mice, found that telomere lengths were longer in the clones than in the donor animals.
Some researchers have warned that cloned animals tend to be abnormal but, as cloning research proceeds, the results have been improving. Scientists at Advanced Cell Technology recently reported, for example, that 24 of 30 cloned cows were alive and healthy, one-tofour years after they were cloned. It has also been suggested that the high proliferative capacity of embryonic stem cells might create abnormal cells that might become cancerous. However, in two of the studies in which ES cells were transformed into neurons,[11,12] this did not occur.
Embryonic cell research about to explode
Embryonic stem cell research is on the verge of an explosion, which is likely to lead to unprecedented advances in medicine. Although research with adult cells shows promise, embryonic cell research could be the Rosetta Stone of 21st century medicine. By learning how these early-stage cells are transformed into skin, heart, brain and other organs, we will move closer to learning why we grow old and die while, at the same time, developing therapies to reverse the process.
Cloning is the best way of creating embryonic stem cells for medical purposes. It permits the transplantation of tissues created from these cells without rejection, and makes it unnecessary to use ES cells from any sources other than the patient who needs treatment. If the bill prohibiting therapeutic cloning passes the Senate, as it did the House, it will be a crime of unprecedented proportions.
At the end of this article, we present information about how to influence members of the Senate to vote against the bill to prohibit cloning (S.790) and include a sample letter to illustrate how that might be done.
Urge Senators To Oppose Bill To Ban Human Cloning
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2. Palmer TD, Schwartz PH, Taupin P, et al. Progenitor cells from human brain after death. Nature, 411:42-43 May 3 (2001).
3. Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. Journal of Clinical Investigation, 107:11:1395-1402, June (2001).
4. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature, 410:701-705, Apr. 5 (2001).
5. El Oakley RM, et al. Myocyte transplantation for cardiac repair: a few good cells can mend a broken heart. Annals of Thoracic Surgery, 71:1724-1733 (2001).
6. Priller J, Persons DA, Klett FF, et al. Neogenesis of cerebellar purkinje neurons from gene-marked bone marrow cells in vivo. Journal of Cell Biology, 155:5:733-738, Nov. 26 (2001).
7. Krause DS, Thelse ND, Collector MI, et al. Multiorgan, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 105:369-377, May 4 (2001).
8. Stanworth SJ and Newland AC, Stem cells: progress in research and edging towards the clinical setting. Clinical Medicine, 1:5:378-382, Sep/Oct (2001).
9. Vogel G, Can adult stem cells suffice? Science, 292:1820-1822, Jun 8 (2001).
10. Thomson JA, et al. Embryonic stem cell lines derived from human blastocysts. Science 282:1145-1147 (1998).
11. Reubinoff BE, Itsykson P, Turetsky T, et al. Neural progenitors from human embryonic stem cells. Nat Biotechol, 19:12:1134-1140, Dec (2001).
12. Zhang S-C, Wernig M, Duncan ID, et al. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechol, 19:12:1129-1133, Dec (2001).
13. Schuldiner M, Eiges R, Eden A, et al. Induced neuronal differentiation of human embryonic stem cells. Brain Research, 913:2:201-205, Sep. 21 (2001).
14. Shiels P, Kind AJ, Campbell KHS, et al. Analysis of telomere lengths in cloned sheep. Nature, 399:316-317 (1999).
15. Betts DH, Bordignon V, Hill JR, et al. Reprogramming of telomerase activity and rebuilding of telomere length in cloned cattle. Proc. Natl. Acad Sci USA, 98:1077-1082 (2001).
16. Tian X, Xu J and Yang X, Normal telomere lengths found in cloned cattle. Nature Genetics, 26:272-273 (2000).
17. Lanza RP, Cibelli JB, Blackwell C, et al. Extension of cell life span and telomere length in animals cloned from senescent somatic cells. Science, 288:665-669 (2000).
18. Wakayama T, Shinkai Y, Tamashiro KLK, et al. Cloning of mice to six generations. Nature, 407:318-319 (2000).
19. Lanza RP, Cebelli JB, Faber D, et al. Cloned cattle can be healthy and normal. Science, 294(5548):1893-1894, Nov. 30 (2001).
Urge Senators To Oppose Bill To Ban Human Cloning
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