Monday, August 2, 2004

Answers to stem cells questions

Frequently asked questions on stem cell research, prepared by the International Society for Stem Cell Research. The answers to the following questions were written and reviewed by a panel of scientists who specialize in stem cell research.

QUESTION: What are stem cells?

ANSWER: Stem cells are the foundation cells for every organ, tissue and cell in the body. They are like a blank microchip that can ultimately be programmed to perform any number of specialized tasks. Stem cells are undifferentiated, "blank" cells that do not yet have a specific function. Under proper conditions, stem cells begin to develop into specialized tissues and organs. Additionally, stem cells are self-sustaining and can replicate themselves for long periods of time.

These unique characteristics make stem cells very promising for supplying cells to treat debilitating diseases like Alzheimer's disease, cancer, Parkinson's disease, type-1 diabetes, spinal cord injury, stroke, burns, heart disease, osteoarthritis and rheumatoid arthritis. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing transplants far exceeds the number of organs available. Stem cells offer the potential for supplying cells and tissues, which can be used to treat these various diseases.

Q: Where do stem cells come from?

A: Human beings start their lives from a single cell, called the zygote, which is formed after fertilization. The zygote divides and forms two cells; each of those cells divides again, and so on. About five days after conception, there is hollow ball of about 150 cells called the blastocyst. The blastocyst is smaller than a grain of sand and contains two types of cells, the trophoblast and the inner cell mass. Embryonic stem cells are the cells that make up the inner cell mass. As embryonic stem cells can form all cell types in an adult, they are referred to as pluripotent stem cells.

Stem cells can also be found in very small numbers in various tissues in the adult body. For example, bone marrow stem cells are found in the marrow of the bone and they give rise to all specialized blood cell types. Adult stem cells are typically programmed to form different cell types of their own tissue; they are called multipotent stem cells. Adult stem cells have not yet been identified in all vital organs. In some tissues like the brain, although stem cells exist, they are not very active, and thus do not readily respond to cell injury or damage. Scientists are now also exploring ways in which they can induce the stem cells already present to grow and make the right cell types to replace the damaged ones.

Stem cells can also be obtained from sources like the umbilical cord of a newborn baby. This is an accessible source of stem cells, compared to adult tissues like the brain and bone marrow. Although scientists can grow these cells in culture dishes, they can do so only for a limited time. Recently, scientists have also discovered the existence of stem cells in baby teeth and in amniotic fluid-the "water bath" that surrounds an unborn baby-may also have the potential to form multiple cell types. Research on these cells is very promising but at a very early stage. These cells will have to be characterized and studied further.

Q: What are the potential uses of human stem cells?

A: Most of the body's specialized cells cannot be replaced by natural processes if they are seriously damaged or diseased. Stem cells can be used to generate healthy and functioning specialized cells, which can then replace diseased or dysfunctional cells.

Replacing diseased cells with healthy cells, called cell therapy, is similar to the process of organ transplantation only the treatment consists of transplanting cells instead of organs. Some conditions or injuries can be treated through transplantation of entire healthy organs, but there is an acute shortage of donors. Stem cells can serve as an alternate and renewable source for specialized cells. Currently, researchers are investigating the use of adult, fetal and embryonic stem cells as a resource for various, specialized cell types, such as nerve cells, muscle cells, blood cells and skin cells, that can be used to treat various diseases.

For example, in Parkinson's disease, stem cells may be used to form a special kind of nerve cell, a kind that secretes dopamine. These nerve cells can theoretically be transplanted into a patient where they will re-wire the brain and restore function, thus treating the patient.

Q: What are the obstacles that must be overcome before the potential uses of stem cells will be realized?

A: One of the first obstacles that must be overcome is the difficulty in identifying stem cells from adult tissues, which contain numerous mixtures of various cells. The process of identifying and growing the right kind of stem cell, usually a very rare cell in the adult tissue, involves painstaking research.

Second, once stem cells are identified and isolated, the right conditions must be developed to cause these cells to differentiate into the specialized cells. This too will require a great deal of experimentation.

In general, embryonic and fetal stem cells are believed to be more versatile than adult stem cells. However, scientists are still working on developing proper conditions to differentiate embryonic stem cells into specialized cells. As embryonic stem cells grow very fast, scientists must be very careful in fully differentiating them into specialized cells. Otherwise, any remaining embryonic stem cells can grow uncontrolled and form tumors.

Assuming that the above obstacles can be overcome, new issues arise when the specialized cells (grown from stem cells) are implanted into a person. The cells must be integrated into the patient's own tissues and organs and "learn" to function in concert with the body's natural cells. Cardiac cells that beat in a cell culture, for example, may not beat in rhythm with a patient's own heart cells. And neurons injected into a damaged brain must become "wired into" the brain's intricate network of cells and their connections in order to work properly.

Yet another challenge is the phenomenon of tissue rejection. Just as in organ transplants, the body's immune cells will recognize transplanted cells as "foreign," setting off an immune reaction that could cause the transplant to fail and possibly endanger the patient. Cell recipients would have to take drugs to temporarily suppress their immune systems, which in itself could be dangerous.

Thus, research on stem cells and their applications to treat various diseases is still at a preliminary stage. However, results from animal models are very promising and many researchers believe that it is only a matter of time before the same results can be achieved with human stem cells.

Q: What is a stem cell line?

A: A stem cell line is composed of a population of cells that can replicate themselves for long periods of time in vitro, meaning out of the body. These cell lines are grown in incubators with specialized growth factor-containing media, at a temperature and oxygen/carbon dioxide mixture resembling that found in the mammalian body.

Embryonic stem cell lines, both human and mouse, can be grown indefinitely in vitro if the correct conditions are met. Importantly, these cells continue to retain their ability to form different, specialized cell types once they are removed from the special conditions that keep them in an undifferentiated, or unspecialized, state.

A limited number of human embryonic stem cell lines have been approved for use by scientists receiving federal funds in the United States. In August 2001, President Bush mandated that if scientists were using federal funds, research could only be conducted on the cell lines that were already in existence, grown from fertilized eggs that were to be discarded at in vitro fertilization clinics.

This regulation stated that no additional human stem cell lines could be generated from additional blastocysts. In the long term, this will place severe restrictions on the scientific process in this field and will limit the ability of scientists to compare the potential of human embryonic stem cell lines for tissue repair, to that which can be accomplished from other sources, such as adult stem cells.

Q: What is an embryonic stem cell?

A: Embryonic stem cells are derived from the cells that make up the inner cell mass of the blastocyst. Both mouse and human embryonic stem cell lines exist. Mouse embryonic stem cells are capable of generating any and all cells in the body, under the right conditions. Therefore, they are said to be pluripotent and have unlimited potential as far as growth and differentiation. The cells divide continuously in tissue culture dishes in an incubator, but at the same time maintain the ability to generate any cell type when placed into the correct environment to cause their differentiation.

Human embryonic stem cell lines are currently being studied and several research teams are working to determine whether or not they possess the same properties as mouse embryonic stem cells. Because human embryonic stem cells were isolated relatively recently, and therefore we know less about them, it is currently more difficult to work with human systems than mouse. However, scientists are making remarkable progress that could ultimately lead to therapies to replace or restore damaged tissues using these human cells.

Q: What is an adult stem cell?

A: Adult stem cells are distinct from cells isolated from embryos or fetuses and are found in tissues that have already developed, as in animals or humans after birth. These cells can be isolated from many tissues, including brain. However, the most common place to obtain these cells is from the bone marrow that is located in the center of some bones. The marrow is harvested from human donors at the iliac crest (the back of the upper hip bone).

There are different types of stem cells found in the bone marrow, including hematopoietic stem cells, endothelial stem cells, and mesenchymal stem cells. It has long been known that hematopoietic stem cells form blood, endothelial stem cells form the vascular system (arteries and veins), and mesenchymal stem cells form bone, cartilage, muscle, fat, and fibroblasts.

Recently a theory of "stem cell plasticity" has been put forth, which suggests that some adult stem cells may have a broader potential to form different cell types than was previously suspected. That means cells from the bone marrow, originally thought to be purely blood-forming cells, may contribute to regeneration of damaged livers, kidneys, hearts, lungs and other organs.

Although this field is extremely exciting, it is highly controversial in the scientific community and needs additional carefully documented research to understand the full potential of the adult stem cells, and in particular how they compare to embryonic stem cells.

Q: What is unique about stem cells from baby teeth or umbilical cords?

A: Stem cells from umbilical cord blood or the pulp under baby teeth are "younger" stem cells than those obtained from adults. They are able to divide for longer times in cell cultures than most adult stem cells, and may give rise to different tissues. Their potential to form many different cell types is currently being explored.

Umbilical cord blood stem cells are used for stem cell transplantation to reconstitute blood cell formation (the hematopoietic system) in patients that have been irradiated or treated with specific drugs for cancer or leukemia. Also, in some genetic diseases, where patients have a problem forming normal blood cells, a transplantation of matched umbilical cord blood cells can give them a new blood-forming system.

The new cells are infused into the vein of the patient and then they are able to find their way into the bone marrow, in a process called "stem cell homing."

Q: Do stem cells come from aborted fetuses?

A: One potential source of stem cells comes from early fetal tissue recovered during a narrow window of development. In development, an embryo is called a fetus at about 7-8 weeks following fertilization. At about 4-5 weeks of development, embryonic germ cells, the precursors to the egg and sperm cells, are found in the developing ovary or testis, structures only about 2 mm long.

In 1998, the isolation, culture and partial characterization of embryonic germ cells were reported. The cells were derived from human aborted tissue. When isolated and cultured, these germ cells were shown to have properties similar to stem cells isolated from the inner cell mass of blastocysts.

However, some evidence has suggested that embryonic germ cells may be more limited in their ability to become many different cell types because they are isolated from tissue that is further along in development (several weeks as opposed to only 4-5 days). More research will be required to understand the properties and behavior of these cells to determine their usefulness for future cell therapies. Because of various discrepancies in federal regulations, stem cells taken from fetuses are subject to different rules that stem cells derived from embryos.

Q: Are stem cells currently used in therapies today?

A: Hematopoietic stem cells (HSCs), present in the bone marrow and precursors to all blood cells, are currently the only type of stem cells commonly used for therapy. Doctors have been transferring HSCs in bone marrow transplants for more than 40 years. Advanced techniques for collecting or "harvesting" HSCs are now used to treat leukemia, lymphoma and several inherited blood disorders.

The clinical potential of stem cells has also been demonstrated in the treatment of other human diseases, including diabetes and advanced kidney cancer. However, these new therapies have been offered only to a very limited number of patients using adult stem cells.

New clinical applications for stem cells are currently being tested therapeutically for the treatment of liver diseases, coronary diseases, autoimmune and metabolic disorders (amyloidosis), chronic inflammatory diseases (lupus) and other advanced cancers.

Q: Why is stem cell research confused with cloning?

A: Stem cell research is often confused with cloning because both areas involve the use of embryonic cells. The public and the media often equate "cloning" with the manipulation of embryonic cells to produce an organism, and stem cell research was first brought to the spot light when human stem cells were isolated from human "embryonic tissues". Both fields got even more confused when the term therapeutic cloning was introduced as a means to produce embryonic stem cells. But stem cell research does not always involve embryonic stem cells.

While reproductive cloning (the production of a whole new individual from one original cell by cloning technology) and therapeutic cloning (the use of cloning for the isolation of stem cells) both use techniques involving embryos, stem cell research involves the use of several different types of cells besides embryonic stem cells, such as adult stem cells from humans or animals, or stem cells from fetuses, umbilical cord or amniotic fluid.

Thus, a clear line should be drawn between cloning for the production of a cell or organism with the same nuclear genome as another cell or organism and stem cell research, which is based on the isolation of adult and embryonic stem cells in order to find cures for many degenerative diseases.

Q: What kinds of experiments have been done with stem cells and what still needs to be done?

A: Mouse embryonic stem cells were first described in 1981. The most common types of experiments performed have been to genetically manipulate the DNA within the mouse embryonic stem cells. These experiments have provided a large amount of information on the role that different genes play during mouse development, the formation of different tissues and their role in the adult mouse.

Further, it has been known for years that under the right conditions, mouse embryonic stem cells can contribute to every tissue in the body of the mouse. Experiments that uncovered this phenomenon were conducted by putting mouse embryonic stem cells into a fertilized mouse egg at the blastocyst stage, and examining the mouse that is subsequently generated.

These types of experiments cannot be done with human tissues, thus the potential for human embryonic stem cells must be studied in different ways. The human embryonic stem cells can be studied in vitro (in cell culture conditions) or in special mice that are immune deficient, meaning they will not reject cells from a different species.

Human embryonic stem cells were first described in 1998. The lessons learned from working with mouse embryonic stem cells are rapidly being transferred to human embryonic stem cell systems. Scientists are working hard to understand the properties of these cells and to understand the mechanisms that regulate their differentiation into adult cell types. In addition, many researchers are using these cells to set up models to study early human development and also to provide genetic and cell-based therapies for disease.

To this end, it is hoped to better understand the causes of fetal malformations so they can be treated. It is also hoped that one day we will be able to produce cells in dishes, such as heart, pancreas or brain cells, to replace genetically faulty tissue or tissue damaged as a result of heart attacks, diabetes, spinal cord disorders and Parkinson's disease.

Cell transplantation experiments using mouse models for each of these disorders have been conducted with mouse embryonic stem cells and, in some cases, with human embryonic stem cells. Although it is still in its early days, promising results are emerging.

Hematopoietic stem cells are routinely transplanted following irradiation therapies to treat patients with cancer. Irradiation can destroy the cancer cells, but it also destroys the body's hematopoietic stem cells of the bone marrow leaving the patient without an effective immune system.

In these cases, after irradiation therapy is complete, donor hematopoietic stem cells are transplanted back to the bone marrow to restore the patient's immune system. Experiments involving the transplantation of hematopoietic stem cells to sick fetuses during pregnancy have also been undertaken. These fetuses are generally detected to have genetic defects of their own hematopoietic stem cells. These experiments have been met with some success for the treatment of babies who would have otherwise suffered a range of immunodeficiency disorders, thalassemias and inborn errors of metabolism.

Fetal neural stem cell derivatives have been transplanted to replace damaged cells in experiments aimed at controlling the symptoms of Parkinson's disease. These experiments have been similarly met with some success. Experiments injecting stem cells found in mouse blood vessel walls back into the blood vessels of muscles have been successful in replacing muscle fibers and returning movement to mice with muscle disorders. Mesenchymal stem cells have proven effective in treating mice with genetic liver disease.

Some of the primary experiments that still remain to be performed include those aimed at understanding the factors required to make embryonic stem cells differentiate into the desired cell types; those to understand how to increase the number of stem cells that are accepted by the patient at the correct location in the body during disease; those to reduce host resistance to the new stem cells; and those experiments to ensure that the new stem cells correctly integrate in the body to restore the proper function to the damaged tissue.

Q: Can cord blood or stem cells be stored in a bank?

A: Human cord blood, neural stem cells and human embryonic stem cell banks have been established in various countries and are currently being expanded. Cord blood, like bone marrow, is stored as a source of hematopoietic stem cells for the treatment of specific genetic and acquired diseases in allogeneic stem-cell transplantation therapies.

Neural stem cells, which are derived from aborted fetuses, are stored in banks for the potential treatment of brain specific diseases. Embryonic stem cell banks have also been established for the potential treatment of a wide variety of genetic and acquired diseases, ranging from neural to blood to pancreatic to heart to skin.

Prior to banking, quality control procedures check for: chromosomal abnormalities, the ability of the stem cells to undergo the freeze-thawing processes, the immune compatibility of the stem cells with patients potentially requiring the cells, the presence of viruses within the stem cells that may cause disease, the ability of the stem cells to give rise to the required adult cell types when required, and the ability of the stem cell numbers to be increased to useful amounts.

Q: How many human embryonic stem cell lines are there?

A: The available number of human embryonic stem cell lines is a matter of some debate. Originally, it was stated that there were at least 60 lines. However, most of those were not adequately characterized and only a minority (8 to 10) are currently widely accepted as true human embryonic stem cells. Detailed information on the cell lines that are available through the National Institutes of Health Human Stem Cell Registry can be found at

Q: Why is U.S. federal funding important for stem cell research?

A: Federal funding for research involving mouse embryonic stem cells and adult stem cells (both mouse and human) is currently available and is not restricted. However, federal funding for research involving human embryonic stem cells is limited to research involving only those cell lines that were approved by the Bush administration in August 2001. In contrast, no restrictions in the type of research that can be performed with private funds are in place. There are several reasons why these limitations are problematic.

In the United States, the National Institutes of Health (NIH) provides the greatest amount of federal funding to scientists on a competitive basis, and holds a long-term perspective on biomedical research, where profit is irrelevant and the progress of science for the benefit of public health is critical. The limited amount of funding from private sources will be unable to keep pace with the needs of the stem cell research community. Less restricted availability of federal funds for human embryonic stem cell research would certainly accelerate progress in this field, and improve the health of the American people in the long-term.

As the regulations now stand, any scientist receiving federal funds is precluded from generating additional human embryonic stem cell lines. It is still not clear to what extent the data obtained with the limited set of cell lines now available, can be generalized to the whole human population, especially given the known variability among different mouse embryonic stem cell lines. In addition, the development of efficient ways to generate new cell lines will likely be necessary if embryonic stem cells are ever to be used for therapies.

Although the private sector can conduct research to generate new cell lines, this can lead to several problems. One is that, because of intellectual property issues, the dissemination of knowledge may be slower when the most cutting edge research is done in private companies. The results of any research performed with private funds would be out of public control, and when knowledge is not in the public domain, progress can be slowed.

A second problem is that private companies need to benefit from their investments and at some point, make a profit. Historically, if profit is deemed unlikely, research can be stopped no matter how important it may be for public health or for the progress of science.

It should be pointed out that research on human embryonic stem cells may not only lead to novel therapies for diseases that are currently difficult or impossible to treat, but also to novel insights into human development and into the nature of our species that could never be obtained from work with experimental animals. This type of fundamental scientific inquiry has generally been funded through the extensive federal government grants program.