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Embryonic Stem Cells
An Overview for the Non-Scientist

Ground-breaking research, particularly in the biomedical fields, is often associated with controversy, both from within and without the scientific community; at times, scientists face outright opposition to their work. A topic that has recently raised public concerns—among religious leaders, politicians, celebrity spokespersons, and many others—is research on embryonic stem cells (ESC), primitive cells found in the early embryo that can differentiate into any adult tissue. Although the great promise of ESC therapy is widely accepted, vociferous debate continues as to the ethical validity of ESC harvesting, which presently cannot be done without destroying a potentially viable human embryo. This summary will not attempt to address directly the important ethical issues surrounding ESC research, but rather will outline current understanding of ESC development and progress towards ESC therapy.

Definition and Identification

All types of stem cells are capable of asymmetric division, in which a parent cell divides into one daughter cell identical to the parent and a second daughter cell capable of further differentiation, or maturation. The identical daughter cell contributes to the self-renewing population of stem cells, while the second daughter differentiates along a given lineage to form cells of a particular tissue. These differentiated cells lose the ability to multiply and therefore cannot by themselves regenerate a damaged tissue. An example of such terminally-differentiated, or mature, cells is a nerve cell, which cannot do much self-repair and often dies if damaged. Most organs in the adult body contain a population of stem cells that serve as sources of cell replacement throughout life. Red blood cells, for example, are constantly replenished from hematopoietic stem cells residing in the adult bone marrow. (These stem cells are the important part of a bone marrow transplant.) 

Embryonic stem cells are harvested from a blastocyst, which is a hollow ball of cells that has formed by the fifth day after a sperm fertilizes an egg. One week after fertilization, the developing embryo is then called a gastrula and is composed of three distinct layers of cells. All cell types in the adult body were ultimately derived from one of these three germ layers. The ectoderm forms the skin, brain, and spinal cord; the mesoderm forms the muscles, blood vessels, kidneys, and genitals; and the endoderm forms the lungs, stomach, gut, and liver. Adult stem cells are constrained to produce cells along given lineages—for example, skin stem cells make skin cells, and gut stem cells make gut cells—within just one of the three embryonic germ layers. Embryonic stem cells, however, are from the primitive blastocyst (which has not yet divided into three layers) and can therefore differentiate into cells of any lineage within any germ layer. Adult stem cells are termed multipotent for their ability to differentiate along several lineages, whereas the more primitive ESC are called pluripotent for being able to recreate tissues from all three germ layers. Pluripotency is what causes such great enthusiasm for ESC; if properly manipulated, these cells should be able to grow or regenerate any organ in the adult body. (A totipotent stem cell is one that can create any human cell; ESC are not totipotent because they cannot make the placenta, which is not derived from any of the three germ layers.) The figure below illustrates the fate of ESC and the blastocyst:

How can a researcher test whether a group of cells contains healthy ESC? One way is to measure for certain proteins inside or on the surface of the cells and see if the cells look like ESC. Some proteins—such as an important one named Oct-4—are only made by primitive cells like ESC. Other proteins are markers of mature cells, like muscle cells and blood cells; ESC should not express any of those. A better test is to ask if the cell can act like an ESC: can it differentiate into any type of adult cell? An easy way to do this test is to transplant a few of the cells into a mouse with SCID disease. A mouse with SCID, or severe combined immunodeficiency, has no immune cells (like “The Boy in the Plastic Bubble”) and therefore cannot reject any transplant, even one from another species. Free to grow in a SCID mouse, true ESC will make a teratoma, a tumor made up of cells from all three germ layers—muscle, fat, skin, hair, even teeth! The ability to grow a teratoma in a SCID mouse is considered the best proof that a cell is pluripotent like ESC.

Therapeutic Potential

Patients that could potentially benefit from ESC therapy include those with any disease that results from damage to or destruction of tissue. Type 1 diabetes is a failure to produce insulin (a hormone that controls blood sugar) after the body’s own immune system mistakenly destroys part of the pancreas. Parkinson disease causes tremors and muscle rigidity because of a loss of specific brain cells that make the signaling molecule dopamine. Damage to nerve cells from trauma can result in spinal paralysis, because nerve cells in the adult do not regenerate well. After suffering a myocardial infarction (heart attack) a patient is at risk of not circulating blood well because heart muscle dies and is replaced by scars. Hospital patients undergoing surgery or childbirth frequently need blood transfusions to replace their lost red blood cells and clotting factors. In each of these cases, researchers would like to be able to replace the damaged or missing cells with tissues made from ESC. Not only can stem cells grow new tissues, but they also tend to migrate to damaged areas, so stem cell therapy may one day be both more effective and less invasive than whole organ transplants. Despite the popular excitement surrounding the field, however, many challenges remain to be met before such regenerative medicine is a reality.

The most obvious challenge for a researcher who has ESC is how to make the ESC grow into the right tissue. In the blastocyst, ESC receive a complex combination of signals to multiply and differentiate into the germ layers and become various organs. The researcher must replicate some of those conditions in a dish to make the desired cell type. Successes so far include nerve cells, bone cells, heart muscle cells, and platelets. Once all the right signals have been discovered, the researcher must tweak the combination in order to grow cells that are both pure (no bone cells contaminating a heart cell mixture) and functional (heart cells are worthless if they do not contract to pump blood). This process involves a lot of painstaking trial-and-error, but some success has been met.

Once a researcher knows how to induce ESC to grow a particular tissue, the next challenge is making sure the transplant behaves properly once it is put inside the patient. Preliminary research suggests that ESC transplants may fail to stimulate the immune system as does an unmatched whole-organ transplant or a mistyped blood transfusion. If this data is replicated and proven true, then it will represent a major advantage of ESC therapy over therapy with adult stem cells, which must be matched like any other transplant. A disadvantage of ESC, however, is their propensity to form tumors, such as the teratoma in the SCID mouse. ESC come from a stage of development during which rapid growth is crucial in order to make a fetus out of a ball of cells. In the adult, such rapid growth causes a tumor and can lead to cancer. Some researchers have experimented with suppressing ESC genes that cause rapid growth, though this is tricky to do while still maintaining the pluripotency that makes ESC useful. Another strategy is to induce enough differentiation in the dish that by the time the transplant enters the body of the patient it has lost its growth potential. The challenges of rejection and tumor formation remain to be fully addressed before ESC therapy can be used.

Last but certainly not least are the technical difficulties and ethical dilemmas surrounding the harvesting of ESC. So far, the only techniques that have successfully harvested human ESC have involved destroying a blastocyst that otherwise—if it had been successfully implanted into a uterus—might have matured into a fetus and eventually a human baby. A new harvesting technique, which shows promise but has not yet been successful, is based on diagnosis procedures currently used during in vitro fertilization. When a couple is at high risk for genetic disease, each embryo is genotyped before the expensive task of implantation is attempted. A single cell is removed from the 8-cell zygote for analysis, and this tiny loss does not seem to affect the health of the embryo. If this one cell could be expanded in vitro, then this routine biopsy could be used both to diagnose the zygote and to generate a new ESC line. A different solution to the harvesting problem is to find another versatile stem cell type that is easier to access and use that cell instead of ESC. Some researchers have described pluripotent cells that resemble ESC in the placenta and in the amniotic sac, both of which could potentially be harvested without harming the fetus or newborn. If these cells prove to be as useful as ESC for the purposes of research and therapy, then most of the ethical controversy surrounding ESC use will be sidestepped.

Availability

On 9 August 2001, President George W. Bush approved US federal funding (through NIH, The National Institutes of Health) for research on certain previously-derived ESC lines, in order to better investigate the exciting therapeutic potential of these cells. Not all ESC lines were approved, but only those derived from a donated embryo that was originally created for reproductive purposes, i.e., embryos created but unused for in vitro fertilization. In order to discourage the creation and destruction of more embryos, President Bush restricted funding only to those lines already in use as of his announcement, which at the time was estimated to be at least sixty viable lines. This decision was hailed as a great compromise between the practical need to fund promising science and the ethical imperative to prevent further destruction of embryos.

Unfortunately, most of the lines approved in 2001 are now unusable for research or therapy; at most 21 viable lines remain. Since these lines were created early in the history of research on human ESC, they were not cultured under conditions now known to be ideal. The most prevalent problem is a result of the common practice of growing ESC in a dish with mouse cells, which at the time was the only way to make the ESC proliferate. Many cell lines grown this way now express a mouse protein on their surface, a protein that human transplant recipients would recognize as foreign. These cells will never work for therapy, because they will be rejected by any human patient.

Newer human ESC lines are available that were not grown with animal cells, but research on those lines cannot be connected in any way to US federal funds. State governments, other countries, and private organizations offer funding, but none can match the size of NIH grants, nor do non-NIH sources all require reporting of research results to the public.

Conclusion

Given the passion and tension permeating debates over ESC use, everyone involved in the discussion must take care to learn the truth about these intriguing cells, their potential as well as their limitations. The magnitude of the possible benefits from ESC therapy precludes a simple ban on all research, so we must find ethically acceptable ways to move forward with ESC. At the same time, work on adult stem cells and possible ESC alternatives should be pursued with equal vigor, because the hurdles of ESC harvesting and use may prove too great to overcome without disrespecting the human life we are trying to enrich.

 

This overview was written by Tim Kreider in 12/2006 and reviewed by Dr. Pranela Rameshwar.