NIH Statement Before the Senate Appropriations Subcommittee, April 26, 2000

Mr. Chairman and Members of the Subcommittee, we are pleased to appear before you to discuss the promise of human pluripotent stem cell research. Recent published reports on the isolation and successful culturing of the first human pluripotent stem cell lines have generated great excitement among scientists, patients and their families. Research using human pluripotent stem cells holds enormous promise for advances in the prevention, treatment, and diagnosis of a vast array of diseases. Virtually every realm of medicine might be touched by this innovation. Because of this enormous promise, NIH believes that this research must proceed, as long as it is conducted ethically and legally.

What are stem cells?

Stem cells are self-renewing and can give rise to the more specialized cells of the human body, such as muscle cells, blood cells and brain cells. They are best described in the context of normal human development. When a sperm fertilizes an egg, the product is a single cell that has the potential to form an entire organism. This fertilized egg is a totipotent stem cell, which has the potential to develop into a complete organism. In the first hours and days after fertilization, this cell begins to divide into identical totipotent stem cells. Then, approximately four days after fertilization, these totipotent stem cells begin to specialize, forming a hollow sphere of cells called a blastocyst. One part of the blastocyst is a cluster of cells called the inner cell mass, which are the stem cells that will go on to form most of the cells and tissues of the human body. These are pluripotent stem cells, which are different than totipotent stem cells—pluripotent stem cells do not develop into a complete organism.

Recently, human pluripotent stem cells have been isolated from two sources: the inner cell mass of human embryos at the blastocyst stage and from fetal tissue obtained from terminated pregnancies. Because these cells are capable of limitless division and self-renewal, they can be maintained indefinitely in tissue culture, making them a vital resource for research.

Why are human pluripotent stem cells important?

There are several reasons why the isolation of human pluripotent stem cells might lead to better treatment, even cures, of many diseases. At the most fundamental level, pluripotent stem cells could help us to understand the complex events that occur during normal human development. By identifying the mechanisms underlying routine cell differentiation we hope to understand how disease-causing aberrations occur. Another goal of this research would be the identification of the factors involved in the cellular decision-making process that results in cell specialization—why do some cells become heart cells, for example, while other cells become liver cells? We know that turning genes on and off is central to this process, but we do not know much about these "decision-making" genes or what turns them on or off. Some of our most serious medical conditions, such as cancer and birth defects, are due to abnormal cell differentiation and cell division. A better understanding of normal cell processes will allow us to further delineate the fundamental errors that cause these often deadly illnesses.

Human pluripotent stem cell research could also dramatically change the way we develop drugs and test them for safety. While a limited number of cultivated cell lines are currently available and provide invaluable tools for drug development and testing, pluripotent stem cells would allow expansion of this testing to more varied cell types. For example, drugs could be tested first on particular cell lines to determine toxicity, before they are tested in either animals or humans. Although this would not replace testing in animals and in human beings, it would streamline the process of drug development, and reduce potential for harm in humans and animals. Only the drugs that are both safe and appear to have a beneficial effect in cell line testing would graduate to further testing in laboratory animals and human subjects.

Perhaps the most far-reaching potential application of human pluripotent stem cells is the generation of cells and tissue that could be used for "cell transplantation therapies," which are aimed at diseases and disorders resulting from the destruction or dysfunction of specific cells and tissue. Although donated organs and tissues can sometimes be used to replace diseased or destroyed tissue, the number of people suffering from such disorders far outstrips the number of organs and tissues available for transplantation. Pluripotent stem cells, stimulated to develop into specialized cells and tissue, offer real hope for the possibility of a renewable source of replacement cells and tissue to treat a myriad of diseases, conditions, and disabilities for which replacement tissue is in short supply. Examples of these include neurological disorders, burns, heart disease, osteoarthritis and rheumatoid arthritis.

Human Pluripotent Stem Cells and Diabetes Research

One of the best examples of the promise of this line of research is in the treatment of Type 1 diabetes. Research on islet cell transplantation and stem-cell biology offers compelling opportunities for the development of new, innovative approaches for treating and ultimately curing this disease.

Type 1 diabetes, often referred to as Juvenile Diabetes, is characterized by the inability of the body to produce insulin, a hormone necessary for glucose metabolism. This form of diabetes occurs when the body's immune system attacks and destroys its own insulin-producing beta cells in the islets of the pancreas. As a result of inadequate insulin production, glucose does not enter cells as readily as when insulin levels are normal. The standard treatment is to try to control the glucose level with insulin injections. Insulin treatment can sustain the patient's life, but not necessarily prevent the devastating complications of type I diabetes, which include kidney failure, blindness, amputation, heart attack and stroke. Clinical trials have shown that these complications can be prevented or significantly delayed by maintaining blood glucose levels as close to normal as possible. However, precise blood glucose control is difficult to achieve and requires multiple daily injections of insulin or use of an insulin pump. These regimens are extremely challenging to follow, especially for children and teenagers. In addition, one risk of such precise blood glucose control is the development of dangerously low blood sugars which could cause loss of consciousness, seizures or other complications.

To address these problems, researchers are investigating alternative approaches to restoring insulin-producing capacity, including attempts to develop an artificial pancreas, whole pancreas transplantation, and islet cell transplantation. Formidable bioengineering problems attend development of an artificial pancreas, and while researchers are working diligently to overcome them, a time frame for success cannot be predicted. Whole pancreas transplantation, while successful in some patients, is an extremely difficult surgical procedure and it requires lifelong treatment with immunosuppressive drugs that can have toxic side effects. This surgery is typically performed only in adults, often in conjunction with a needed kidney transplant for which immunosuppressive drugs would already be required. But, the success rate for the survival of the transplanted pancreas is much lower than the survival rate for the transplanted kidney.

Islet cell transplantation is a much simpler procedure than whole pancreatic transplantation and has several potential advantages. Until very recently, serious technical problems have been a major impediment to rapid progress in islet transplantation research. These key challenges have been: (1) to keep the body's immune defense system from rejecting the transplanted islets; and (2) to ensure that there is a sufficient supply of islet cells for transplantation. To date, only about five percent of people with diabetes who have received transplanted islets along with immunosuppressive drugs have been able to stay off insulin longer than one year. Stem cell research offers the potential to overcome these obstacles.

The renewed promise of islet cell transplantation derives from two complementary research opportunities. The first is the development of new methods for adjusting the immune system to keep the body from rejecting transplanted islet cells. The second is the prospect that stem cell research could ensure the needed supply of islet cells for transplantation. Human pluripotent stem cells offer the greatest promise of providing a limitless source of islet cells for treating and curing type 1 diabetes. Together, these opportunities offer unprecedented hope for curing type 1 diabetes, especially for children and young adults whose disease has not yet progressed to the point of debilitating complications.

Human Pluripotent Stem Cell Research and the Nervous System

As significant as the promise of stem cells is for the treatment of diabetes, the potential of stem cells for treating diseases of the nervous system is equally impressive. It is startling to consider the range of neurological disorders for which scientists are actively investigating stem cell therapies in animal models. A partial list would include classic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS); acute insults of stroke, brain trauma and spinal cord injury; multiple sclerosis and other demyelinating disorders; and inherited disorders such as Tay-Sachs disease and Duchenne muscular dystrophy. It might be possible to use stem cells to treat epilepsy and brain tumors. We have only begun to understand the extraordinary range of possibilities that stem cells present for treatment of these maladies.

The most obvious and exciting use of stem cells in neurological disorders is to replace lost nerve cells. Many diseases destroy particular types of nerve cells, and mature nerve cells cannot produce new cells to replace those that are lost. Animal experiments have demonstrated that the potential exists for coaxing stem cells to specialize and replace the dopamine cells that are lost in the brain in Parkinson's disease. A similar approach might apply to several other neurological disorders. Stem cells, given appropriate control signals, might specialize to replace the lost acetylcholine producing nerve cells in Alzheimer's disease, to restore lost motor neurons in ALS, or to produce inhibitory cells to help restrain electrical activity in epilepsy.

Replacing lost nerve cells is only the beginning of the list of possible therapeutic applications for stem cells. For some disorders, such as multiple sclerosis, stem cells might replace supporting cells—such as the glial cells, which provide the insulation necessary to allow some nerves to conduct electrical impulses rapidly. Stem cell strategies might be useful for correcting inherited defects. For example, in disorders that devastate children's brains we might rely on the ability of stem cells to migrate widely in the brain and supply the vital missing enzyme that leads to early and tragic death from Tay-Sach's disease. In addition, stem cells might regenerate the many different kinds of complex brain tissue that are damaged as a result of brain trauma or stroke. Transplanted tem cells might also supply natural growth and survival chemicals to pave the way for regeneration of remaining healthy neural tissue following spinal cord injury. Recent findings suggest that stem cells might be harnessed to seek out and destroy brain tumor cells that evade surgery or radiotherapy. The list of possible applications of stem cells continues to grow as we learn more about these cells.

Future Challenges

There is much to be done before these discoveries can be incorporated into clinical practice. First, we must do the basic research to understand the process by which human cells become specialized, so that we can direct pluripotent stem cells to become the type(s) of tissue needed for transplantation. For example, applying basic knowledge obtained from research in developmental and stem cell biology will enable the production of progenitor stem cells and the rational design of cellular therapies for human diseases such as diabetes. It is essential to underscore that studies of stem cells and the genes that regulate their development could be important for the development of ways to intervene in type 1 diabetes, and various neurological conditions, even beyond their use in transplantation.

Second, before these cells can be used for transplantation, the well-known problem of immune rejection must be overcome. Because human pluripotent stem cells derived from embryos or fetal tissue would be genetically different from the recipient, future research would need to focus on modifying human pluripotent stem cells to minimize tissue incompatibility or to create tissue banks with the most common tissue-type profiles. In addition, just delivering cells to the appropriate sites within the human body is an extremely difficult task. All of these factors argue for intensified efforts to understand the basic biology of pluripotent stem cells and, with due caution, to apply what is learned towards the treatment of disease.

What are the limitations of adult stem cells?

Recent findings have shown that even the adult human brain harbors neural stem cells, and that these adult stem cells can respond to a wide range of external and internal influences, such as learning, stress, exercise, seizures, and trauma. In addition, if pancreatic stem cells are ever isolated from adult tissue, it might be possible to direct these cells to differentiate into islet cells. The identification of adult pancreatic stem cells would open up entirely new prospects, beyond transplantation strategies, for encouraging the body's own stem cells to help repair damage.

It is important to note that scientists who are leading the way in studying adult stem cells present compelling arguments why we must pursue research on both pluripotent and adult stem cells. While some stem cells are present in adults, there may not be an adult stem cell for every type of cell in the body, and they may be present in only minute numbers. In addition, they may be very difficult to isolate; for example, in the case of adult neural stem cells, they may be confined to certain regions of the brain that are not easily accessible. More importantly, pluripotent and adult stem cells are not qualitatively alike. Pluripotent stem cells have truly amazing abilities to self-renew and to form many different cell types, even complex tissues, but in contrast the full potential of adult stem cells is uncertain, and, in fact, there is evidence to suggest they may be more limited. Unlike pluripotent stem cells, the adult stem cells may be able to divide only a limited number of times, which would limit their usefulness in the production of adequate numbers of well characterized cells for reliable therapies. Another issue is the question of how robust transplanted adult cells may be or how vulnerable to disease processes. In light of these limitations, it is important that we pursue research on both pluripotent and adult stem cells simultaneously.

NIH Guidelines

Given the enormous promise of human pluripotent stem cells to the development of new therapies for the most devastating diseases, it is important that both privately and federally funded researchers have the opportunity to pursue this promise. To this end, on December 2, 1999, NIH published draft Guidelines in the Federal Register. NIH is currently in the process of analyzing public comments and will publish final Guidelines in the Federal Register. NIH will not fund human pluripotent stem cell research until final Guidelines have been published and an oversight process is in place.

Conclusion

Mr. Chairman, we appreciate the opportunity to discuss this promising and extraordinary science and are pleased to respond to any questions you may have.