There are many ways in which human stem cells can be used in research and the clinic. Studies of human embryonic stem cells will yield information about the complex events that occur during human development. A primary goal of this work is to identify how undifferentiated stem cells become the differentiated cells that form the tissues and organs. Scientists know that turning genes on and off is central to this process. Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. A more complete understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy. Predictably controlling cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. While recent developments with iPS cells suggest some of the specific factors that may be involved, techniques must be devised to introduce these factors safely into the cells and control the processes that are induced by these factors.

Human stem cells could also be used to test new drugs. For example, new medications could be tested for safety on differentiated cells generated from human pluripotent cell lines. Other kinds of cell lines are already used in this way. Cancer cell lines, for example, are used to screen potential anti-tumor drugs. The availability of pluripotent stem cells would allow drug testing in a wider range of cell types. However, to screen drugs effectively, the conditions must be identical when comparing different drugs. Therefore, scientists will have to be able to precisely control the differentiation of stem cells into the specific cell type on which drugs will be tested. Current knowledge of the signals controlling differentiation falls short of being able to mimic these conditions precisely to generate pure populations of differentiated cells for each drug being tested.

Human ES cells could be employed to screen potential toxins. The reasons for using human ES cells to screen potential toxins closely resemble those for using human ES-derived cells to test drugs (above). Toxins often have different effects on different animal species, which makes it critical to have the best possible in vitro models for evaluating their effects on human cells.

Perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for regenerative therapies. Today, donated organs and tissues are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including Alzheimer’s diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

For example, it may become possible to generate healthy heart muscle cells in the laboratory and then transplant those cells into patients with chronic heart disease. Preliminary research in mice and other animals indicates that bone marrow stromal cells, transplanted into a damaged heart, can have beneficial effects. Whether these cells can generate heart muscle cells or stimulate the growth of new blood vessels that repopulate the heart tissue, or help via some other mechanism is actively under investigation. For example, injected cells may accomplish repair by secreting growth factors, rather than actually incorporating into the heart. Promising results from animal studies have served as the basis for a small number of exploratory studies in humans. Other recent studies in cell culture systems indicate that it may be possible to direct the differentiation of embryonic stem cells or adult bone marrow cells into heart muscle cells.

In people who suffer from type 1 diabetes, the cells of the pancreas that normally produce insulin are destroyed by the patient’s own immune system. New studies indicate that it may be possible to direct the differentiation of human embryonic stem cells in cell culture to form insulin-producing cells that eventually could be used in transplantation therapy for persons with diabetes.

Finally, human ES cells could be used to develop new methods for genetic engineering. Currently, the genetic complement of mouse ES cells in vitro can be modified easily by techniques such as homologous recombination. This is a method for replacing or adding genes, which requires that a DNA molecule be artificially introduced into the genome and then expressed. Using this method, genes to direct differentiation to a specific cell type or genes that express a desired protein product might be introduced into the ES cell line. Ultimately, if such techniques could be developed using human ES cells, it may be possible to devise better methods for gene therapy.

To realize the promise of novel cell-based therapies for such pervasive and debilitating diseases, scientists must be able to manipulate stem cells so that they possess the necessary characteristics for successful differentiation, transplantation, and engraftment. The following is a list of steps in successful cell-based treatments that scientists will have to learn to control to bring such treatments to the clinic. To be useful for transplant purposes, stem cells must be reproducibly made to:

* Proliferate extensively and generate sufficient quantities of tissue.
* Differentiate into the desired cell type(s).
* Survive in the recipient after transplant.
* Integrate into the surrounding tissue after transplant.
* Function appropriately for the duration of the recipient’s life.
* Avoid harming the recipient in any way.

• Understand and control the mechanism of turning undifferentiated cells into specialized cells. This involves identifying the complex signals needed to turn the genes on and off that initiate and govern the differentiation of cells.
• Identify, isolate and purify different adult stem cell types. Purified and/or expanded stem cells will be required for safe, efficacious treatments.
• Control the differentiation of stem cells to target cell types needed to treat disease such that sufficient quantities of the correct stem cell or differentiated cell can be generated for treatment.
• Learn to make stem cell transplants patient-compatible to avoid rejection by the immune system.
• Demonstrate clinical improvement and normal cell development and function once stem cells have been transplanted into the patient s body. Stem cells must become integrated with the patient s own tissues and learn to function as one of the patient s natural body cells.

Also, to avoid the problem of immune rejection, scientists are experimenting with different research strategies to generate tissues that will not be rejected.

To summarize, stem cells offer exciting promise for future therapies, but significant technical hurdles remain that will only be overcome through years of intensive research.