Arches. Photo by Daniel Chia
Jun
26
2010

Stem Cells

In the last few years, stem cell research has become the latest buzz in the popular media as well as the scientific world. It was the subject of President George W. Bush’s first prime-time television address. It is continuously on the cover of popular news magazines. So what is all the fuss about?

Stem cells hold the potential to treat or even cure many of the diseases that continue to mystify scientists today, such as Parkinson’s Disease, Alzheimer’s Disease, diabetes, and Huntington’s Disease (HD). However, stem cell research is controversial, as most of the stem cell lines available today are derived from embryos or fetuses.

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The following chapter aims to explain the science behind stem cells and their potential to treat HD.

Stem Cell Basics^

What is a stem cell?^

Most of the cells that make up the organs and tissues of the body are highly specialized for their specific jobs. The red blood cell, for example, is specifically crafted to carry oxygen from the lungs to the tissues. A comparison can be made with today’s society where most workers are trained to perform a specific trade. The days of the generic fix-it man are gone; instead, the electrician, the plumber, and the cable guy fill specific niches.

Likewise, in the human body, most cells are specialized for certain jobs. In fact, most cells lead very standard lives – they grow up, do the same job every day, and then eventually retire and pass away. These cells, such as nerve cells or skin cells, are called specialized cells. They are mature cells that have characteristic shapes and are committed to performing specific functions (See Figure 1). Once these cells have matured, they are usually incapable of reproducing themselves. They essentially remain “childless” for their whole lives.

If mature specialized cells cannot leave “children” behind when they die, how does your body make new cells? For example, when you cut your skin, how do you grow new skin cells? When you get blood drawn, how do you make new blood cells?

It turns out that stem cells solve this unique problem. A stem cell can reproduce itself over and over again (a special trick known as “self-renewal” or “self-replication”). With every replication, the stem cell produces one new stem cell and one new specialized cell. Stem cells can often give rise to a number of different cell types. For example, blood stem cells can produce both red blood cells and white blood cells. In this way, stem cells are not committed to produce a single cell type. Instead, a stem cell remains uncommitted until it receives a specific signal to divide and produce one of the various specialized cells.

In more formal terms, a stem cell is a special kind of cell that has the ability to divide for indefinite periods of time and to give rise to the mature, specialized cells that make up an organism. A stem cell is uncommitted and remains uncommitted until it receives a signal to differentiate (become a specialized cell). (See Figure 2).

What are the different kinds of stem cells?^

There are three main types of stem cells under scientific study today:

  • Embryonic stem (ES) cells: ES cells are taken from the very early stages of embryo development and can give rise to all of the cells of the human body, except the placenta and other supportive tissues in the womb.
  • Embryonic germ (EG) cells: EG cells are taken from the later stages of embryo development and are slightly less “powerful” in their ability to divide.
  • Adult stem cells: Adult stem cells are found in the tissues of a fully developed child or adult and can only produce a limited number of cell types.

These three types of stem cells are easiest to understand in a discussion of human development. Human development begins when a sperm fertilizes an egg and creates a single cell, known as a zygote, which has the potential to form an entire organism. This single cell is said to be totipotent, meaning it has the “total” potential to give rise to all types of cells. About 24 hours after fertilization, the zygote divides into two identical totipotent cells, and is now known as an embryo. About five days after fertilization and after several cycles of cell division, these cells begin to specialize and form a hollow sphere, called a blastocyst. The blastocyst has an outer layer of cells that make up the shape of a sphere and a cluster of cells, known as the inner cell mass, inside the sphere. The outer layer of cells will eventually form the placenta. The inner cell mass will eventually form all the tissues of the human body. The inner cell mass cannot form an organism on its own, however, because it is unable to produce the placenta and the other supporting tissues necessary for development in a woman’s uterus. Therefore, the inner cell mass cells are said to be pluripotent, meaning they have the potential to give rise to most of the tissues required to produce an organism. In other words, they can give rise to all the cells of the human body, excluding the supportive tissues used in the womb. (See Figure 3).

Embryonic stem cells, which are also pluripotent, are isolated directly from the inner cell mass at this blastocyst stage. In 1998, researchers first isolated ES cells from human embryos that were obtained from in vitro fertilization clinics. Although these embryos were originally intended for reproduction, they were in “excess” and were headed for the trash. Instead of being disposed, however, they were donated to research.

Five to 10 weeks after fertilization, the growing embryo, now called a fetus, develops a region known as the gonadal ridge. The gonadal ridge contains the primordial germ cells, which will eventually develop into eggs or sperm.

Embryonic germ cells are isolated from these primordial germ cells of the 5- to 10- week old fetus. Like ES cells, EG cells are also pluripotent.

As the human fetus continues to develop, pluripotent stem cells specialize into stem cells that are geared for specific tissues. For example, they become blood stem cells (which produce blood cells) or skin stem cells (which produce skin cells). These specialized stem cells are said to be multipotent, meaning they can give rise to many, but not all, types of cells.

While all three types of stem cells discussed above (ES cells, EG cells, and multipotent stem cells) are found in the developing human, only multipotent stem cells are found in children and adults. Therefore, multipotent stem cells are often referred to as adult stem cells. Unlike other stem cells, adult stem cells are only found in specialized tissues and can only give rise to the specialized cell types that make up that tissue. Currently, adult stem cells have been found in the bone marrow, blood, blood vessels, skeletal muscle, skin, lining of the digestive track, dental pulp of the tooth, liver, pancreas, cornea and retina of the eye, and brain.

Stem Cell Research^

What kind of research is being conducted?^

Stem cells are being investigated in various areas of scientific research. The most notable research areas are described below:

I. Basic Research
On the most fundamental level, stem cells are used to study the early events of human development. This research may one day explain the cause of birth defects and help devise new approaches to correct or prevent them. Also, research on the genes and chemicals that control human development may help researchers manipulate stem cells to become specialized for transplantation or genetic engineering.

II. Transplantation Research
Stem cells may hold the key to restoring many vital bodily functions by replacing cells lost in various devastating diseases. Many diseases and disorders, such as Huntington’s disease, disrupt specific cellular functions or destroy certain tissues in the body. The goal, therefore, is to coax stem cells to develop into the desired specialized cells, which can then be used as a renewable source of replacement cells or tissues. This process could possibly treat HD and other conditions such as Parkinson’s and Alzheimer’s diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

III. Genetic Engineering Research
Stem cells could be used as a vehicle for delivering genes to specific tissues in the body. The goal is to add genes to stem cells that would then coax the stem cell to differentiate into a specific cell type or force the stem cell to produce a desired protein product. Currently, researchers are trying to use specialized cells derived from stem cells to target specific cancer cells and directly deliver treatments that could destroy them.

IV. Drug Testing and Toxin Screening
Currently, animal models are used to test drug safety and efficacy and to screen potential toxins. Animal models, however, cannot always predict the effects that a drug or toxin may have on human cells. Therefore, if human stem cells can be used to generate cells that are important for certain drug or toxin screenings, these cells may offer a safer, more reliable test by mimicking a more realistic human environment.

V. Chromosomal Abnormality Testing
Stem cells might also be used to explore the effects of chromosomal abnormalities in early human development. As a result, we might be able to understand and monitor the development of early childhood tumors, many of which are embryonic in origin.

What are the advantages and disadvantages of using embryonic stem cells, embryonic germ cells, and adult stem cells for research?^

At first glance, embryonic stem cells, embryonic germ cells, and adult stem cells all present similar possibilities for scientific research. They are all stem cells, after all, and therefore share some key characteristics and hold similar potential. For example, they all have the ability to self-replicate for indefinite periods of time in the human body and can give rise to specialized cells. The overall purpose behind research with all types of stemm cells, therefore, is very similar. It has also been shown that all three cell types can be isolated from other cells and kept in a specific laboratory environment that keeps them unspecialized. This is crucial for controlled scientific research. Upon experimentation, it has also been shown that all stem cell types will replicate and specialize when transplanted into an animal with a lowered immune system. The cells then undergo “homing,” a process where the transplanted cells are attracted to and travel to an injured site when transplanted into an animal that has been injured or diseased. Homing provides hope that the transplantation of stem cells will be a clinically useful procedure.

Despite these general similarities, there are some important differences between embryonic stem cells, embryonic germ cells, and adult stem cells. The origins of these three cell types define their differences: ES cells are derived from the inner cell mass of the blastocyst in a developing embryo, EG cells are obtained from the primordial germ cells of a fetus, and adult stem cells are found in developed, specialized tissues. The differences between ES, EG, and adult stem cells result in different advantages and disadvantages for each stem cell type in scientific research and development.

ES and EG cells have some clear advantages over adult stem cells concerning research and clinical usefulness. For example, ES and EG cells are pluripotent, meaning they have the potential to give rise to all types of cells in the body. Adult stem cells are multipotent, meaning they only have the potential to give rise to a limited number of cell types. So far, no adult stem cells have proven to be pluripotent. This means that ES and EG cells could potentially provide a renewable source of replacement cells for any tissue in the human body. Adult stem cells, however, would only be clinically useful for the specific adult tissue that the stem cells came from. ES and EG cells are also relatively abundant in the developing organism, especially compared to adult stem cells, which are scarce in the adult body. As a result, ES and EG cells are much easier to identify, isolate, and purify compared to adult stem cells, which are very difficult to identify, isolate and purify in the lab. This makes research with ES and EG cells all around easier than research with adult stem cells.

On the flip side, adult stem cells have some distinct advantages over ES and EG cells. For example, adult stem cells are around for an organism’s lifetime, while ES and EG cells are only found in the developing organism. This allows a longer time frame for adult stem cells to be studied in an individual. Also, removal of stem cells from an embryo will result in the death of the embryo. Removal of adult stem cells, however, does not involve the death of an embryo, and is therefore less ethically complicated. Furthermore, adult stem cells pose no chance of immune rejection after transplantation because they can be transplanted back into the adult that they came from. ES and EG cells are derived from embryos and fetuses, however, and are transplanted into people with different genetic make-ups. Therefore, rejection is an issue only with the use of ES and EG cells.

Finally, ES cells have a strong advantage and disadvantage over the other stem cell types. First, ES cells are able to replicate in the laboratory far better than either EG or adult stem cells. ES cells can self-renew for up to 2 years, doubling up to 300 times. EG cells can only double a maximum of 70-80 times. Meanwhile, adult stem cells only have a limited ability to replicate in the lab. Replication in the laboratory is critical for research to continue. On the other hand, ES cells are the most likely to develop into tumors. If undifferentiated ES cells are taken from the lab and injected into a mouse, a benign tumor can develop. For this reason, scientists do not plan to use undifferentiated ES cells for transplants or other therapeutic applications. EG cells do not form these tumors, however. At this point, it is not known whether tumors will form with transplanted adult stem cells.

The similarities and differences of ES, EG, and adult stem cells are summarized in the chart below:

Tbl Z-1: ES, EG, & Adult Stem Cells - Similarities

Tbl Z-2: ES, EG, & Adult Stem Cells - Differences I

Tbl Z-3: ES, EG, & Adult Stem Cells - Differences II

Which are more useful – pluripotent stem cells or adult stem cells?^

Based on what scientists currently know, it is unclear whether pluripotent or adult stem cells will be more useful for the development of therapies. As far as scientists can tell at this point, neither one is probably better than the other.

Both pluripotent and adult stem cells have their advantages and disadvantages (see chart below). For example, the main advantage of pluripotent stem cells is their ability to produce any specialized cell in the human body. However, because they are derived from human embryos or fetuses, they are also very controversial.

Adult stem cells, on the other hand, are unlikely to be rejected by a patient’s immune system because they can be isolated from a patient, coaxed to divide and specialize, and then transplanted back into the patient. Because stem cells are isolated from an adult, they are also unlikely to cause ethical concerns. However, adult stem cells have not been isolated for all tissues of the body, which limits the types of tissues they can be used for.

Recently, there has been research on adult stem cell plasticity, the ability of an adult stem cell from one tissue to generate specialized cells of another tissue. Thus far, there have been contradicting results. Time will tell whether or not adult stem cells can actually demonstrate plasticity. For more information on cell plasticity, click here.

Many scientists agree that pluripotent and adult stem cells might be better suited for different treatments

Tbl Z-4: Pluripotent vs. Multipotent Stem Cells

What challenges are researchers facing?^

While stem cell research shows great promise, researchers continue to face many biological, technological, and ethical challenges that must be overcome before innovations can be developed and incorporated into clinical practice.

First, more basic research must be done in order to fully understand the events that lead to cell specialization in humans. Currently, scientists are working to produce reliable, reproducible conditions that will direct stem cells to become the specific types of cells and tissues that are needed for transplantation.

Also, before mature cells derived from ES or EG stem cells can be used for transplantation, scientists must overcome the problem of immune rejection. Because these cells are genetically different from the recipient, their incompatibility must be minimized.

Adult stem cell research has also faced many difficulties, including finding, isolating and identifying the cells, growing the adult stem cells in the laboratory and demonstrating plasticity.

In addition to these technological challenges, researchers must also face the ethical controversy surrounding the use of ES and EG cells. If stem cells are used in clinical practice, researchers, doctors, and society at large must agree on acceptable ethical guidelines.

Stem Cell Research and Huntington’s Disease^

What is the potential for using stem cells to treat HD?^

Huntington’s Disease is a neurodegenerative disorder that is characterized by the death of nerve cells in the striatum. (To learn more about the neurobiology behind HD, click here.) Until recently, it was believed that neurons in the adult human brain and spinal cord could not regenerate. Once dead, the neurons were thought to be gone for good. In the mid-1990s, however, researchers discovered that stem cells in the adult brain could give rise to new neurons and neural support cells. With their ability to regenerate and produce new nerve cells, neural stem cells might be able to replace or repair the cells that are destroyed by HD, thus restoring lost function.

In fact, researchers have already discovered how to coax embryonic and adult mouse stem cells to develop into neurons that produce a neurotransmitter called gamma-aminobutyric acid – the type of neurons that are mainly lost in HD.

More research could potentially lead to the following:

  1. If these stem cells can produce nerve cells in the laboratory, they could be transplanted into the striatum to replace the lost nerve cells, or;
  2. If the adult stem cells already present in the patient’s brain could be stimulated to produce more neurons, they might be able to “self-repair” the striatum.

Either way, further stem cell research could yield new treatments to HD given enough time, research, and luck.

What is fetal neural transplantation? What does this have to do with HD and stem cells?^

Fetal neural transplantation is a surgical technique that involves removing nerve cells from an aborted fetus and transplanting them into a human patient. Clinical trials have attempted to use this technique as a treatment for HD by removing striatal nerve cells (those mainly affected by HD) from a human fetus and grafting them into the brain of an adult patient. The therapeutic value of fetal transplantation has been promising so far. Notable improvements include increases in brain activity and motor and cognitive functions. Although the initial results have been encouraging, the clinical usefulness of fetal neural transplantation for HD treatment remains unclear.

The use of human fetal tissue creates a major roadblock to the development of this technique for two reasons. Technically, fetal tissue is difficult to obtain and prepare. Ethically, the use of fetal tissue raises serious concerns. Therefore, the development of an alternative source of nerve cells for neural grafting will be crucial for the continuation of neural transplantation research. Stem cells currently hold great potential as an alternative source. Theoretically, neural stem cells could be developed in the laboratory and then grafted into the patient’s brain. Ultimately, the future of fetal neural transplantation as a clinically effective HD therapy relies heavily on the future of stem cell research.

Will stem cell research provide the cure for HD?^

Researchers generally do not believe that stem cell research will be the “magic cure” for HD. Rather, it is likely to be part of the fight against the neurodegeneration seen in HD. Ultimately, the medical and scientific community will need to improve early diagnosis, reduce the severity of cell loss, combat inflammation, provide new neurons (which is where stem cells factor in), and utilize progressive rehabilitation techniques to allow complete regeneration. While stem cells may not cure HD, they could serve as a crucial component to effective treatment.

For further reading^

  1. Allison, Wes. “Preliminary success of fetal brain-cell transplantation in Huntington’s Disease.” The Lancet.
    A short, but fairly technical article.
  2. Begley, Sharon. “Cellular Divide.” Newsweek, 9 July 2001: 22-27.
    An easy-to-read explanation of stem cells and an update on progress as of July 2001.
  3. Bjorklund, Anders and Ollie Lindvall. “Cell replacement therapies for central nervous system disorders.” Nature Neuroscience, June 2000, 3 (6): 537-544.
    A technical paper discussing the progress of fetal neural transplantation in treating Parkinson’s and Huntington’s Disease.
  4. Freeman, Thomas, et.al. “Tranplanted fetal striatum in Huntington’s disease: Phenotypic development and lack of pathology.” Proceedings of the National Academy of Sciences of the United States of America, 5 December 2000, 97 (25): 13877-13882.
    A highly technical paper discussing the potential of fetal neural tissue to treat HD.
  5. Gibbs, W. Wayt. “Biological Alchemy.” Scientific American, February 2001: 16-17.
    A less technical article depicting the discovery of neural adult stem cells and discussing the possible plasticity of adult stem cells.
  6. Mitchell, Steve. “Rare stem cells produces many cell types.” United Press International, 21 June 2002.
    A short, easy-to-read article about adult stem cell plasticity.
  7. “Stem Cells: A Primer.” National Institutes of Health, May 2000.
    A comprehensive, easy-to-read explanation of stem cells and their potential applications. Great online resource.
  8. “Stem Cells: Potential for Good?” The Economist, 18 August 2001: 59-61.
    A thorough explanation of stem cells and the controversy surrounding their development and use.
  9. “Stem Cells: Scientific Progress and Future Research Directions.” Department of Health and Human Services, June 2001.
    An extensive, fairly technical summary of everything you would want to know about stem cells.
  10. Weiss, Samuel. “Stem Cells and Huntington Disease.” Horizon, Huntington Society of Canada Newsletter, Summer 2001, No. 101: 1-2.
    An easy-to-read explanation of stem cells and their potential to treat HD.

-J. Czaja, 3-07-03