Advantages and Disadvantages: A Comparison
(1) Embryonic stem cells
Human embryonic stem cells (hESCs) are of interest to researchers because their pluripotency allows these cells to differentiate into any type of body tissue. However, this is their only advantage. By contrast, the disadvantages of embryonic stem cells greatly outnumber, and outweigh, this single desirable feature.
Among other disadvantages, embryonic stem cells are highly unstable. They have not yet been through Mother Nature's test, which is to create a human being. It is a well established fact that 50 to 75% of all human embryos fail to develop into a human being and spontaneously abort, due either to "inborn errors" such as a genetic mutation or to problems implanting. More pregnancies spontaneously abort than result in the successful birth of a child. Even considering the conservative estimate of 50% nonviability, when working in a laboratory with an embryo, it is impossible to know from which 50% any particular embryo has been selected. If embryonic stem cells happen to come from the 50% of embryos that would have proven to be nonviable (if allowed to develop normally), then those same "inborn errors" will be transferred to the patient receiving the stem cells. Clearly, this could cause more harm than good.
Additionally, pluripotent embryonic stem cells often form teratomas (a tumor-like, cancerous mass, resembling a self-fertilized cell, differentiated but not fertilized). Teratomas have been shown to form when embryonic stem cells are injected into animals. Originally, in the early days of stem cell research, this was the criterion, and indeed the "gold standard", by which pluripotent stem cells were recognized: by their ability to form teratomas. If cells were unable to form teratomas, they were identified as being something other than pluripotent stem cells. Indeed, this ability of pluripotent stem cells to form teratomas is still part of the formal definition of a teratoma, as stated by NIH:
Teratoma: "A tumor composed of tissues from the three embryonic germ layers. Usually found in ovaries and testes. Produced experimentally in animals by injecting pluripotent stem cells, in order to determine the stem cells' abilities to differentiate into various types of tissues." (From "Stem Cells: Scientific Progress and Future Research Directions," available at http://stemcells.nih.gov. Please see "Glossary").
Indeed, as recently as 2002, researchers in China published their findings in which they referred to the successful formation of teratomas from stem cells. In an article announcing the establishment of the first human embryonic stem cell line in China, He et al. wrote,
" The suspension of stem cells subcultured for 5 months were inoculated to the legs of severe combined immunodeficiency (SCID) mice subcutaneously to observe the teratoma formation. Results: Six weeks after inoculation of the 3 cell lines, teratomas were formed in all mice. Histological examination revealed that they contained various tissues derived from all three embryonic germ layers. Conclusion: Human embryonic stem cell lines were successfully established in China." (He et al., 2002, "Human embryonic stem cell lines preliminarily established in China." Zhonghua Yi Xue Za Zhi, 82(19):1314 - 1318).
Subsequently in China, a man with Parkinson's disease was treated with human embryonic stem cells which developed into a cancerous tumor (teratoma) in his brain. The man died from this tumor, even though the treatment was intended to help him, not kill him. As an increasing number of researchers have observed, the power of embryonic stem cells is also the source of their potential peril. (Bohlin RG, "The Continuing Controversy Over Stem Cells," 2005, online publication).
Further risks and problems associated with using human embryonic stem (hES) cells include:
- Genetic instability: "There are reports of high differentiation rates of hES cells (which destroy their stem cell status) and genomic instability after prolonged culture. For example, some hES cell lines display a certain level of aneuploidy (gain or loss of chromosomes) including the gain of chromosome 17q, chromosome 12, trisomy 20 (3 copies of chromosome 20) or abnormal X chromosome."
- Epigenetic errors: "These are frequent in hES. These include differences in the expression of SSEA-4, in telomere length, in the down regulation of collagen, in STAT4, a lectin and 2 genes involved in TGFb signalling, which have been described in different hES cell lines derived in the same laboratory and cultured under feeder free conditions."
- Genetic and epigenetic heterogeneity among hES lines: "3 different hES cell lines in the same laboratory expressed 52% of genes examined in common, but the expression of 48% of the genes was limited to just one or two of the cell lines. Not all of the hES cell lines maintain their pluripotency under the same culture conditions, their potential for large scale culture and growth under feeder free protocols, or their ability to form teratomas after injection into SCID (severe combined immune deficiency) in mice. Their capacity to differentiate spontaneously into different cell types under in vitro conditions is variable. It is of concern that application of genetically and epigenetically unstable hES cells in transplantation therapies could be detrimental. Quality control becomes difficult."
(Quoted from www.i-sis.org.uk).
According to the London based Institute of Science in Society, researchers have drawn the following conclusions:
- "Due to the number and severity of the technical challenges remaining to be solved before the initiation of large scale clinical trials, embryonic stem cells are not likely to be part of routine clinical practice in the foreseeable future."
- "The technical difficulties in derivation and culture of hES cells could be expected to involve high costs, especially when these cell lines and procedure can attract patents. It is difficult, therefore, to justify allocation of such large amounts of public funds in supporting hES cell research and in maintaining hES cell banks, that could be much better deployed elsewhere; as, for example, in supporting research and development of adult stem cells (including cord blood cells)."
- "Exacerbating health inequalities: another objection to hES cell research is that it will be a very costly procedure, even if it succeeds, and will exacerbate the global inequalities in access to healthcare. Populations in developing countries have more urgent diseases to fight, and they will be that much more disadvantaged if large portions of the available funds are diverted towards developing hES cell technology by the hype and misinformation surrounding it."
Many of the wondrous claims for embryonic stem cells have been found to be unsubstantiated. There remain many current as well as potential future problems surrounding human embryonic stem cell therapy, and Dr. David Prentice enumerates some of these problems in the following points:
- Currently, there have been no clinical treatments performed from human embryonic stem cells.
- In animal models, the success rate has been dismally low.
- There exists great difficulty in obtaining pure dish cultures in the laboratory.
- There remain many unanswered questions regarding the functional trans-differentiation of the stem cells.
- The cell lines are difficult to establish and maintain.
- There remains the problem of immune rejection.
- There remains the potential for tumor formation (teratomas) and tissue destruction.
- There remains the problem of genomic instability and genetic incompatibility.
- Due to the required destruction of an embryo in order to cull the stem cells, the entire field remains ethically contentious.
"Yet," Dr. Prentice explains, "defective embryos are routinely used to produce ES cells, and positively recommended by some researchers, who have stated, 'Perhaps genetically deficient cells may be entirely suitable for somatic cell replacement.' This is a large assumption fortunately not shared by other researchers. We suggest that the wide range and high incidence of epigenetic defects in nuclear transfer embryos will preclude safe use of this approach [of creating hES cells] until the procedure is dramatically improved."
According to The Institute of Science in Society,
"If epigenetic reprogramming error is inherent to the somatic nuclear transfer procedure, as pointed out by some researchers, then it is a blind alley as far as tissue replacement is concerned, even if the ethical concerns are set aside. Yet China, Singapore, the U.K. and the U.S. have already legalized therapeutic cloning, and Korean scientists reported the first hES cell line created using this procedure in February of 2004."
Instead of using hESCs, many researchers advocate the support of adult stem cell research instead:
"Adult stem cells, in particular, bone marrow cells and cord cells, already have well established clinical histories, and cannot be patented. They have shown great promise and potential in treating a variety of diseases, including, more recently, brain and spinal cord repair in animal models. Adult stem cells can be harvested directly from the patients requiring transplant, and used without culture or after only brief periods of culture, thereby avoiding immune rejection and all other technical problems and risks arising from prolonged cell culture. Adult stem cells appear to have all the developmental potential of ES cells, even though the precise mechanisms are debated, without the risks of cancer. On account of the ease of harvesting, handling and use, and the lack of patents, costs are minimal, and hence the treatments developed are likely to be widely available to all. Finally, there is little or no moral objection to using them." (Quoted from The Institute of Science in Society, London, www.i-sis.org.uk)
(2) Postnatal stem cells
Placental and umbilical cord stem cells offer pluripotency, world wide availability, lack of contamination, ease of isolation and maintenance, lack of immune rejection by the host, and they are ethically and politically noncontroversial.
(3) Adult stem cells
Like postnatal stem cells, adult stem cells are also ethically and politically noncontroversial. Additionally, adult stem cells exhibit greater "plasticity" and pluripotency than previously suspected, and they pose no risk of immune rejection by the host (if the donor and recipient are the same person). Adult stem cells also pose no risk of teratoma formation (unlike embryonic stem cells).
In the past, multipotency and monopotency were considered to be the major drawbacks of adult stem cells, since this limited their ability to transdifferentiate. However, now that a wider capacity for transdifferentiation has been demonstrated in adult stem cells, with some of them exhibiting pluripotency, this previously perceived disadvantage no longer exists.
Since a certain amount of genetic damage is normal with aging, the older an adult stem cell is, the greater the odds that it may have incurred some genetic damage. Additionally, if the donor and recipient are not the same person, there may exist the possibility of immune rejection of the cells by the host.
In the debate between proponents of adult stem cells versus proponents of embryonic stem cells, it has been said that while both are of merit, adult stem cells by themselves are "not sufficient." Now, however, there is evidence that such a claim is incorrect. With growing proof of their pluripotency, and without the danger of forming teratomas, adult stem cells actually offer a greater possibility for successful clinical therapies than do embryonic stem cells.
Until recently, it was thought that adult stem cells are, at best, multipotent, and in many cases only monopotent. For example, it was thought that adult neural stem cells are only capable of becoming neural cells, and that adult heart stem cells are only capable of becoming heart cells, and that adult blood stem cells are only capable of becoming blood cells, etc. This type of cell is monopotent. Adult blood stem cells have been very useful for treating patients who need blood regeneration, but adult blood stem cells have not been used (until recently) to treat patients who need heart, brain, lung or liver regeneration. This lack of pluripotency, or a lack of transdifferentiation (the ability to change from one stem cell type into another) has made adult stem cells seem less attractive than embryonic stem cells to researchers.
Now, however, these previously held beliefs are changing.
The measure of "plasticity" of any particular type of stem cell, which is the extent of its ability to exhibit transdifferentiation, is now known to be greater in adult stem cells than previously thought. For example, adult bone marrow stem cells have been found to differentiate into skin, lung epithelium, kidney epithelium, liver parenchyma, pancreatic tissue, skeletal muscle, heart muscle, endothelium, and nerve cells in the cortex and cerebellum of the brain. Perhaps more surprising, however, is the discovery that immature skeletal muscle stem cells have also been successful in regenerating cardiac tissue. Examples of such diverse transdifferentiation by adult stem cells shall be described in further detail below.
Even in the very early years of stem cells research, scientists knew that adult stem cells derived from human bone marrow are capable of transdifferentiation. In the 1960s, researchers first discovered that bone marrow contains at least two distinct types of stem cells. One population, the hematopoietic stem cells, forms all the types of blood cells found in the body. A second population, called bone marrow stromal (or mesenchymal) cells and discovered a few years later, are a mixed cell population that generates bone, cartilage, fat and fibrous connective tissue throughout the body. In the 1990s, scientists then discovered in humans what they had known to be true about rats since the 1960s, namely, that the adult human brain contains stem cells capable of generating the 3 major cell types found in the brain: astrocytes, oligodendrocytes (non neuronal cells), and neurons (nerve cells). In other words, human neural tissue may be naturally and continually regenerated. This discovery contradicted previously held beliefs.
The following is a partial list of various differentiation pathways of adult stem cells that have now been identified:
- Hematopoietic stem cells give rise to all the types of blood cells: red blood cells, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, macrophages, and platelets. Additionally, hematopoietic stem cells may differentiate into 3 major types of brain cells (neurons, oligodendrocytes, and astrocytes), as well as skeletal muscle cells, cardiac muscle cells, and liver cells.
- Bone marrow stromal cells (mesenchymal stem cells) give rise to a variety of cell types, including bone cells (osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), as well as muscle, liver, blood, brain and nerve cells, and connective tissue cells such as those found in tendons. Additionally, bone marrow stromal cells are also capable of differentiating into cardiac muscle cells and skeletal muscle cells.
- Neural stem cells in the brain give rise to its three major cell types: nerve cells (neurons), and the 2 categories of nonneuronal cells, namely, astrocytes and oligodendrocytes.
- Epithelial stem cells in the lining of the digestive tract occur in deep crypts and give rise to several cell types: absorptive cells, goblet cells, Paneth cells, and enteroendocrine cells.
- Skin stem cells occur in the basal layer of the epidermis and at the base of hair follicles. The epidermal stem cells give rise to keratinocytes, which migrate to the surface of the skin and form a protective layer. The follicular stem cells can give rise to both the hair follicle and to the epidermis.
- Brain stem cells may differentiate into blood cells and skeletal muscle cells.
- Bone marrow, skeletal muscle, and adult blood cells have also been shown to differentiate into cardiac cells.
- Stem cells from fat are capable of differentiating into bone, cartilage and muscle.
- Peripheral blood stem cells can differentiate into bone marrow, blood, and nerves.
- Stem cells taken from hair follicles may differentiate into skin, brain, smooth muscle, and fat.
- Gastrointestinal stem cells may differentiate into esophageal, stomach, small intestine, and large intestine/colon tissue.
- Placental stem cells may differentiate into nerve, cartilage, skeletal, muscle, tendon, bone marrow, and blood vessel tissue.
- Skeletal muscle stem cells may differentiate into smooth muscle, bone, cartilage, fat, and heart cells.
- Brain stem cells may differentiate into nerves, blood cells, muscle, and all tissue.
- Umbilical cord and placental blood cells may differentiate into all types of bodily tissue.
The precise mechanisms underlying adult stem cell "plasticity", or pluripotency, are not yet fully understood. However, researchers are investigating such mechanisms, as the ability to control or regulate these processes could be key to the repopulation and repair of diseased tissue.
Bone marrow stem cells are particularly versatile, and an especially exciting discovery is the ability of bone marrow stem cells to be transformed into cardiac cells. Recent results of such a discovery were published in the journal Circulation by Dr. Noel Caplice, a cardiologist at the Mayo Clinic. In a study that he conducted, he found that bone marrow progenitor cells naturally "home in" on damaged heart tissue and begin repairing the tissue. Autopsies were performed on 4 female patients with leukemia who had died between one month and 2 years after receiving bone marrow transplants from male donors; a small percentage of the heart cells in the women were found to contain male chromosomes, indicating that the cells originated from the bone marrow transplants. Similar findings were also reported by researchers in New York and Italy, who published their results in the New England Journal of Medicine.
As mentioned above, stem cells from immature skeletal muscle have also been used to regenerate cardiac tissue. In Brazil, 4 out of a group of 5 heart failure patients no longer needed heart transplants after being treated with their own stem cells, derived from their skeletal muscle. As Hans Fernando Rocha Dohmann, the principal investigator, explained, "This finding has a significant social relevance since there isn't a single heart transplant program anywhere in the world which is able to treat all the patients who need it," he told reporters at the annual meeting of the European Society of Cardiology.
Heart tissue is the first tissue created when an embryo begins differentiating. This fact is believed to be partly responsible for the ability of various types of adult stem cells to transdifferentiate into cardiac tissue.
At a conference entitled, "Stem Cells: Shaping the Future," held in London on September 15th of 2003, Prof. John Martin described a study involving stem cells derived from bone marrow that will be used in a large, double blind, controlled clinical trial to be conducted in 30 hospitals across Europe. Patients will receive stem cells separated from their own bone marrow and delivered through the coronary artery to the damaged areas of their hearts. If successful, this will become an inexpensive and practical method of regenerating cardiac tissue after damage.
A report from M.D. Anderson is particularly noteworthy. It has previously been shown that stem cells derived from bone marrow and umbilical cord blood can regenerate cardiac tissue, but this study demonstrated that adult stem cells already circulating in adult blood can also repair heart tissue. Stem cells taken from a patient's own blood have been found to regenerate heart muscle cells as well as artery tissue in the hearts of mice. Says Edward T.H. Yeh, M.D., professor and chair of M.D. Anderson's Department of Cardiology, "Taking stem cells from blood is a lot easier, and a lot less painful, than taking it from bone marrow. For patients, it would be as simple as donating blood. We would then isolate these potent cells and give them back to the patient where the damage has occurred." The research corroborates the idea of adult stem cell "plasticity", or pluripotency, which states that even adult stem cells are able to transform themselves into different organ systems and tissue as needed to repair injury. The theory conflicts with previous dogma which held that specific types of tissue may only be formed from the same type of monopotent stem cell. This study from M.D. Anderson has demonstrated that new cardiac muscle cells (myocytes) and several layers of new blood vessel tissue (endothelial and smooth muscle cells) can be formed from blood derived stem cells.
In addition to bone marrow, adult stem cells have also been harvested from adipose tissue, as well as from the brain, peripheral blood, blood vessels, skeletal muscle, skin and liver cells. Studies involving such stem cells are now being reported with increasing frequency. In the past, most human trials involving stem cells have been conducted in Europe and South America, with a "lag time" before such news would filter down into the U.S. popular media.
Possible therapies involving adult stem cells now include replacing the dopamine producing cells in the brains of Parkinson's patients, developing insulin producing cells for type I diabetes, and repairing damaged heart muscle following a heart attack.
Discoveries about the pluripotency of adult stem cells are continually being made. Meanwhile, some questions about adult stem cells still remain unanswered, such as:
- How many kinds of adult stem cells exist, and in which tissues do they reside?
- What is the origin of adult stem cells in the body? Are they "leftover" embryonic stem cells, or do they arise in some other way? Why do they remain in an undifferentiated state when all the cells around them have differentiated?
- What are the signals that "trigger" and regulate the proliferation and transdifferentiation of stem cells?
- Is it possible to manipulate adult stem cells to enhance their proliferation so that sufficient tissue for transplants can be produced?
- Does one, single type of stem cell exist, possibly in the bone marrow or circulating in the blood, that can generate the cells of all other organs and tissue?
- What are the factors that stimulate stem cells to relocate to sites of injury or damage?
- There exists a stem cell "homing factor", which allows the stem cells to "zero in" on an area of damaged tissue, which is not yet fully understood.
- Some adult stem cells have exhibited a capacity for "dedifferentiation", which is the return from a multipotent state to a more pluripotent, early state. The process by which this phenomenon occurs, or is "triggered", has also not yet been fully elucidated.
The "plasticity" of adult stem cells is particularly applicable to the field of "tissue engineering." From a report entitled "Allogenic transplantation of human mesenchymal stem cells for tissue engineering purposes: An in vitro study," by Niemeyer et al., at the Universitatsklinikum Freiburg, the following abstract describes this promising new field:
"Due to their plasticity and high proliferation capacity in vitro, human mesenchymal stem cells (MSC) are promising candidates for tissue engineering approaches of mesenchymal tissues like bone, cartilage, or tendon. Undifferentiated MSC do not express immunologically relevant cell surface markers. They inhibit the proliferation of allogeneic T cells in vitro and elicit no immune response after allogeneic or xenogenic transplantation. Thus, MSC ought to be seen as immunoprivileged or immunomodulating cells. Our results support the hypothesis that MSC are immunoprivileged cells which are potentially at disposal for HLA incompatible cell replacement therapies."
Adult stem cells offer distinct advantages which embryonic stem cells do not offer. A partial list of such advantages of adult stem cells include:
- There already exists a well established clinical history in the use and handling of such cells, particularly bone marrow cells and umbilical cord blood cells.
- Neither these cells nor the procedures employed for isolating and maintaing them attract patents, so associated costs will be kept low.
- These cells are developmentally as flexible as embryonic stem cells.
- There have been numerous promising studies demonstrating the ability of these cells to repair tissues and organs, including brain and spinal cord cells, which previously have been among the most difficult types of injuries to treat.
- These cells are easy to obtain and easy to use.
- These cells can be harvested from the same patients who require the treatment, thereby avoiding immune rejection by the host.
- These cells can be used directly without expansion, although they may still be expanded in culture if necessary.
- The genomic stability of these cells is maintainable in culture (unlike with embryonic stem cells).
- The growth and differentiation of these cells is controllable.
- These cells do not pose a risk of cancerous teratomas (unlike with embryonic stem cells).
- These cells pose a very low risk of cross infection with animal viruses and other disease agents.
- Many successful clinical treatments with these cells have already been reported (unlike with embryonic stem cells, which have never been used in any clinical treatment).
- These cells have already been shown to repair damaged organs and tissues in situ, without major surgical intervention.
- Treatment with these cells has been shown to minimize intervention, side effects, health risks, and costs, and hence is potentially widely available to all.
- There are no ethical or political concerns over the use of these cells.
The evidence is clear that adult stem cell research should be supported instead of embryonic stem cell research. As the London based Institute of Science in Society has reported,
"Adult stem cells, in particular, bone marrow cells and cord cells, already have well established clinical histories, and cannot be patented. They have shown great promise and potential in treating a variety of diseases, including, more recently, brain and spinal cord repair in animal models. Adult stem cells can be harvested directly from the patients requiring transplant, and used without culture or after only brief periods of culture, thereby avoiding immune rejection and all other technical problems and risks arising from prolonged cell culture. Adult stem cells appear to have all the developmental potential of ES [embryonic stem] cells, even though the precise mechanisms are debated, without the risks of cancer. On account of the ease of harvesting, handling and use, and the lack of patents, costs are minimal, and hence the treatments developed are likely to be widely available to all. Finally, there is little or no moral objection to using them."(Quoted from www.i-sis.org.uk)
The current clinical uses of adult stem cells include:
- Adult stem cells from the brain and from bone marrow, as well as from umbilical cord blood, have all provided therapeutic benefit after stroke. These cells are capable of "homing in" on sites of neurological damage.
- Adult stem cells are capable of regrowth and reconnection in the spinal cord after injury.
- Liver and pancreatic adult stem cells can form insulin secreting islets, for the treatment of diabetes.
- Stem cells derived from bone marrow and from skeletal muscle are capable of repairing damaged cardiac tissue after a heart attack.
- Neural stem cells can form all neuron types, as they migrate throughout the brain to repair damage and to prevent the loss of neurons associated with Parkinson's disease.
- Using the patient's own adult neural stem cells, a group at Los Angeles Cedars Sinai Medical Center reported a reversal of symptoms in the first Parkinson's patient who was treated by this method. (Reported at a meeting of the American Association of Neurological Surgeons, 4/8/02).
- Certain types of cancer, such as lymphomas, multiple myeloma, leukemia, breast cancer, neuroblastoma, renal cell carcinoma, and ovarian cancer are treatable with adult stem cells.
- Autoimmune diseases, such as multiple sclerosis, systemic lupus, rheumatoid arthritis, scleroderma, scleromyxedema, and Crohn's disease are treatable with adult stem cells.
- Anemias (including sickle cell anemia) are treatable with adult stem cells.
- Immunodeficiencies are treatable with adult stem cells.
- Bone and cartilage deformities (such as childhood osteogenesis imperfecta) are treatable with adult stem cells.
- Corneal scarring is treatable with adult stem cells (through the generation of new corneas to restore sight).
- Neurological damage caused by stroke is treatable with adult stem cells.
- Parkinson's disease is treatable using retinal stem cells or the patient's own neural stem cells.
- Adult stem cells are able to induce the growth of new blood vessels (such as in the prevention of gangrene).
- Adult stem cells are able to induce the growth of new gastrointestinal epithelia (and the regeneration of damaged ulcerous tissue).
- Adult stem cells are able to induce the growth of new skin grafts (grown from hair follicle stem cells, after plucking a few hairs from the patient).
To recap, adult stem cells possess the following characteristics:
- They are able to generate virtually all types of adult tissues.
- They can multiply almost indefinitely, providing sufficient numbers for clinical treatments.
- They have been repeatedly proven successful in laboratory cultures.
- They have been repeatedly proven successful in animal models of disease.
- They have been repeatedly proven successful in current clinical treatments.
- They have the ability to "home in" on, and target, specific sites of tissue damage.
- They avoid any problems with tumor formation.
- They avoid any problems with transplant rejection.
- They avoid any ethical quandaries.
In conclusion, adult stem cells (including placental and umbilical cord stem cells) offer the most promising means of treatment.