Testimony

• Dr. Michel F. Levesque
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  Testimony

  Dr. Michel F. Levesque

  My name is Michel Lévesque, and I am a physician, neuroscientist and neurosurgeon based at Cedars-Sinai Medical Center in Los Angeles. I am Associate Clinical Professor of Neurosurgery at the UCLA School of Medicine and member of the UCLA Brain Research Institute. I am also the founder of NeuroGeneration, a biotechnology company pioneering autologous neural stem cell therapies, and Chairman of the Foundation for Neural Repair, a not-for-profit foundation, sponsoring translational research to accelerate human trials using neural stem cells. Mr. Chairman and members of the Subcommittee, I want to thank you for the opportunity to testify today on our current experience with the use of stem cells in humans, and more specifically, adult neural stem cell-derived neurons, for neurodegenerative disorders like Parkinson’s disease. Although non-partisan, my testimony attempts to provide a realistic perspective on the promises and limitations of cell therapy for neurological disorders, either from embryonic- or adult-derived stem cells. As a scientist and physician treating patients with irreversible neurological disorders, it is of utmost importance to understand both the fact and fiction of cell therapy and the hopes it generates in our patients and their families. WHAT IS STEM CELL THERAPY? Stem cell research and therapy are some of several new tools, like vaccines, genes or small molecules, targeting diseases not treated by traditional medication therapies. Stem cell research looks at basic mechanisms of the cell cycle, at sequential expression of different genes during the formation of the embryo, and at cellular specialization and differentiation into different tissues. Stem cell research can also explore the causes of diseases, cell degeneration and cell death. Stem cell therapy attempts to replace the cell loss and induce repair mechanisms in models of disease. Clinical research and therapeutic trials, on the other hand, study the safety and efficacy of stem cell therapy in patients with certain disorders. Neural repair and neural transplantation using cell therapy aim at introducing cellular products, or biological modifiers, to replace the deficient cells and/or induce local neural repair in the central nervous system. WHAT ARE HUMAN ADULT NEURAL STEM CELLS? In nature, neural stem cells are formed after a cascade of sequential events activates genes within embryonic cells during development. They are derived from a specific layer of the embryo and can only become, under normal conditions, precursors of cells found only in the central nervous system. Since 1996, our laboratories have been involved with the isolation and characterization of human adult-derived neural stem cells, obtained from patients undergoing neurosurgical procedures. In the adult brain, these cells cannot on their own trigger repair responses. However, if placed in experimental laboratory conditions stimulating certain genes, these neural stem cells can be “awakened” and begin to divide and replicate events of normal development. These newly created neural stem cells can grow for several months in laboratory conditions reaching several millions in number, a process called cell expansion. Their ability to self-replicate and form all types of cells found in the central nervous system can be verified in vitro under controlled conditions. They can be placed in storage or maintained in sterile incubators until ready for use. Prior to transplantation, neural stem cells are then exposed to a modified environment triggering differentiation, stopping the replication process to produce mature neurons of different types, including dopamine-secreting neurons, which are deficient in Parkinson’s disease. In the laboratory, differentiated neurons can be characterized with specific markers, and their function demonstrated by the increased production of dopamine. These cells have survived transplantation and corrected motor deficits in a rat model of Parkinson’s disease. Our animal studies showed that human adult neural stem cells do not divide once differentiated, do not form aberrant tissue or tumors after chronic transplantation, and have normal karyotypes (number of chromosomes). Sterility is documented throughout the expansion phases. These newly formed cells are unadulterated, having not been exposed to years of chronic oxidative stress and other predisposing factors leading to neurodegeneration. Autologous adult neural stem cells represent a new source of cell replacement with identical genetic material to the patient, and mitigate the risks of immune rejections and transmittable diseases generally associated with tissue transplants from a source external to the patient such as HIV, Encephalitis, Hepatitis and Creutzfeld-Jacobs Disease. CAN STEM CELL THERAPY HELP NEURODEGENERATIVE DISEASES SUCH AS PARKINSON’S DISEASE? Parkinson’s disease is associated with a progressive cell loss of midbrain dopamine-secreting neurons. Dopamine is an essential brain chemical for proper modulation and execution of motor function. Because of the limited spatial involvement and biochemical specificity, this disease may seem relatively easy to repair. Dopamine neurons delivered by fetal transplantation previously were shown to help certain patients with Parkinson’s disease, but had significant risk factors, complications, and ethical issues. The causes of Parkinson’s disease remain unknown. Like Alzheimer’s disease, there is evidence showing that a combination of environmental factors and genetic predisposition are precursors to the disease. Current animal models, derived from toxic exposure or transgenic manipulation, do no replicate all changes found in the human brain. In fact, Parkinson’s disease is much more complex in human patients because of secondary physiological and chemical changes throughout the rest of the brain, superimposed on long-term medical therapy. Indeed one of the major complications of dopamine drug therapy is the paradoxical creation of dyskinesia, another movement disorder involving uncontrollable thrashing movements. This complication was also found in some patients receiving fetal transplantation, suggesting that an uncontrolled delivery of excessive dopamine may not be beneficial. Stem cell-derived products have the advantages of being produced under controlled environment and characterized both in their types and function prior to transplantation. Embryonic stem cells have the potential to generate any type of cells and presumably can be guided in their differentiation to generate an unlimited number of dopamine neurons. One of the problems is to understand the proper steps to guide the gene expression along the formation of neural stem cells and then to achieve proper differentiation. In addition there remain risks of unstable phenotypic expression, possible transdifferentiation into other types of tissue causing tumors, immune reactions in the host brain and questionable functional benefits. Several additional studies are needed in order to answer these questions and objectively compare these “off the shelf” cell lines to our customized approach using autologous adult neural stem cells. While the use of somatic nuclear cell transfer (SNCT) technology could decrease risks of immune reactions, this area of research minimizes the importance of “imprinting”, or influences of the extra-nuclear material on normal cellular development. Currently available embryonic cell lines are not appropriate to answer these scientific questions. Embryonic cell therapy has yet to be scientifically proven as safe, if even effective, in human patients. MATURE NEURONS DERIVED FROM THE PATIENT’S OWN BRAIN CAN BE TRANSPLANTED BACK SAFELY AND IMPROVE SYMPTOMS. We recently presented the clinical outcome of our autologous method at the International Congress of Parkinson’s disease and Movement Disorders in Rome. In accordance with our institutional review board, we transplanted a patient with advanced Parkinson’s disease with differentiated neurons derived from an initial needle biopsy. At three years post-operatively, the overall Unified Parkinson’s Disease Rating Scale (UPDRS) improved by 81% while “on” medication and 83% while “off” medication. We demonstrated here the long-term clinical remission of Parkinson’s disease symptoms in a single patient. Because of their biocompatibility, safety and potential integration into the host striatum, autologous adult neural stem cells and stem cell-derived neurons represent an effective alternative to current cell therapy aimed at the restoration of dopamine neuronal loss in Parkinson’s disease. Under the guidance and supervision of the Food and Drug Administration (FDA) office of Cellular, Tissues and Gene Therapies and the Center for Biologics Evaluation and Treatment (CBER) we are about to begin Phase II trials using this promising cell therapy. CONCLUSION Degenerative and traumatic disorders of the brain represent an enormous burden to the patient, their family and health care providers. The current debate between the embryonic stem cell proponents and those who are opposed to their use distracts from other avenues with promising outcome, such as adult stem cell therapy. It also overlooks other important issues of resource allocation between basic and clinical research, health insurance, and patient care. Scientific knowledge has rapidly progressed in the last five years and stem cell research and therapy remains a very promising field for treatment of neurological disorders. In a recent biotechnology industry meeting, a presentation had the approximate title: “Businesses are from Mars, Academics are from Venus”. What was forgotten there is that patients are from planet Earth and this is what should guide our efforts. Adult human neural stem cells derived from a patient’s own tissue can become a source of replacement neurons, useful for grafting in the treatment of neurodegenerative disorders. With time and adequate support this approach has the potential of making neural stem cell therapy acceptable and available to a large number of patients. Dear members of the committee, I appreciate the opportunity to present our results with the use of human adult neural stem cell-derived neurons and to contribute to an honest and objective debate on these important issues.

• Dr. Jean D. Peduzzi-Nelson, Ph.D.
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  Testimony

  Dr. Jean D. Peduzzi-Nelson, Ph.D.

  Thank you Senator Brownback and distinguished senators of the subcommittee for the invitation to present to you today. First of all, I would like to commend your subcommittee for bringing to light some of the remarkable advances in adult stem cell research. I have long admired the work of Dr. Michel Levesque in Parkinson’s disease and I am glad that the subcommittee had the opportunity to see the remarkable improvement of his patient with Parkinson’s disease who had received a treatment derived from the adult stem cells in his own brain. I am thrilled to hear Dr. Levesque’s plan to expand the clinical trials at Cedars Sinai Hospital in California. I know that actually seeing and hearing patients that improved is the strongest evidence of the potential of adult stem cells. This evidence provides strong refutation to claims about the limited usefulness of adult stem cells and other sources of cells such as umbilical cord cells. Hearing from patients that actually improved using adult stem cells is more interesting than scientific data and discussions about the stem cell/cloning controversy, but I need your indulgence to present the truth about stem cells and cloning. 1. Some people naively think that the stem cell controversy is just related to the abortion issue, political party alignment, religious beliefs, or scientific freedom. However, none of these are the driving force in the effort to promote Federal funding of human embryonic stem cells or human cloning. The most profitable, not the best, treatment for people is being promoted. The main reason for the current emphasis on human embryonic stem cells and cloning is money. The old statement of ‘follow the money’ explains many of the statements made regarding this controversy. It is a superior business plan to have a mass-produced product such as embryonic/fetal/cloned stem cells that can be sold nationwide and have patentable intellectual property . Cloned stem cells derived from embryos with genetic defects represent the possibility of millions in patentable stem cell lines. Adult stem cell therapies are much better for people with diseases or injuries but generate an inferior business plan. In the case of adult stem cells where, in most cases, a person’s own cells can be used, one can only develop a procedure that is generally not patentable according to new patent laws. However, the embryonic/fetal/cloned stem cells can lead to tremendous profits in the short run. Proof of this is the millions of dollars furnished by venture capitalists to help pass a measure that would provide $3 billion for stem cell research in California. 2. Checks and balances in the form of public policy are needed in society to control greed, especially in those cases where the greater good of the people will be served. Embryonic/fetal stem cells have the problems of overgrowth, rejection, possible disease transmission, and ethical issues. Tumors have been found in experimental animals , and disastrous results have been reported in 2 separate clinical trials , using embryonic/fetal tissue/cells. The government should not finance an area of research that is not only dangerous, but also viewed by many people as unethical. Many Americans are against the deliberate destruction of human life. The ban on Federal funding of human stem cells (except for the 67 human stem cell lines) provides a small hope that the financially unprofitable adult stem cells (that are better for people with diseases or injuries) might go forward. 3. The myth of the availability of countless frozen embryos in fertility clinics is just not true. To use even one of these embryos would require legal release from the parents that in most states is not easily accomplished. In many cases, it is not that easy to locate the parents especially in the cases of divorce or separation. It is generally assumed that it would not be hard to get parents to agree. However, when it comes to make the final decision, many parents are unsure that they want these potential lives destroyed. Many of the frozen embryos are also not viable. Despite the impressive results with in vitro fertilization, recent studies suggest that these children have a higher rate of congenital anomalies and human overgrowth syndrome , . 4. The best way to honor the memory and work of President Reagan is to not provide Federal funding for something that President Reagan, if alive today, would vehemently oppose. There is no doubt that President Reagan would not favor Federal support of research using human embryos. This is very clear from an address given by President Reagan : "I, Ronald Reagan, President of the United States of America, by virtue of the authority vested in me by the Constitution and the laws of the United States, do hereby proclaim and declare the unalienable personhood of every American, from the moment of conception until natural death, and I do proclaim, ordain, and declare that I will take care that the Constitution and laws of the United States are faithfully executed for the protection of America's unborn children." 5. The often stated advantage that embryonic stem cells can make every cell in body is not an advantage for people with diseases or injuries. This is only important in terms of a business plan. Science has not worked out all the requirements needed to direct them properly on their path and make sure that they do not develop improperly or become tumors. There are many sources of stem cells in the adult body. Whether each type of adult stem cells can make every different cell type in the body is a mute issue. For example, neurons (nerve cells) can be derived from cells in the adult brain , , bone marrow , muscle or skin cells . Also there is evidence from Dr. Verfaillie and colleagues at University of Minnesota that stem cells from adults are able to form any cell type in the body . 6. Several clinical disasters have occurred using embryonic cells/tissue that contain stem cells. The clinical trials in Parkinson’s disease had dramatic differences in their findings depending on the original source of the cells: fetuses or the person’s own cells. You’ve already heard and seen the spectacular results of Dr. Levesque. However, you may not have heard about the clinical trial disasters using embryonic/fetal tissue. When a transplant consists of embryonic/fetal tissue, the stem/progenitor cells are the only cells that survive. A clinical trial was done by Dr. Freed and colleagues in which 19 patients received cells derived from 4 different fetuses from abortions at 7-8 weeks after conception. The patients that were under 60 years showed about a 28% improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS). However, about 15% of these patients showed devastating deterioration at 1 year after treatment that was believed to result from cellular overgrowth. In another clinical trial for Parkinson’s disease using embryonic tissue (kept in cold media until transplant), similar results were obtained but the rapid deterioration in some patients was believed to be from rejection of the foreign cells/tissue derived from embryo or fetus . 7. Terrible catastrophes using embryonic/fetal stem cells are also observed in animal experiments. In an animal model of Parkinson’s disease, rats injected with embryonic stem cells showed a slight benefit in about 50% of the rats, but one-fifth (20%) of the rats died of brain tumors caused by the embryonic stem cells . This was confirmed in another similar study conducted by a different group of researchers who also found tumor formation in about 20% of the rats . In yet another study it was reported that keeping embryonic or fetal stem cells in culture for long periods of time cause genetic mutations and tumor formation when these cells are transplanted. 8. Cloned human stem cells will not be useful as long as the cloned human embryos are incapable of forming a person. It often stated that there is no chance of human reproductive cloning because 99.2% of cloned embryos can not survive. However, these same faulty cloned embryos are being praised as being a source of valuable stem cells that will advance the cure of genetic disorders. If these cloned human embryos are so abnormal that they almost never can survive in the womb then stem cells derived from them would also abnormal and not useful for research. The big push for cloned stem cells is the possibility of patenting stem cell lines derived from these cloned embryos. 9. If human cloning is funded to produce cloned stem cells, reproductive cloning could not be prohibited. Eventually if scientists continue to produce cloned human embryos, it will be possible to form cloned human embryos without defects that will readily give develop to a fully mature person. Although it is often stated that no one would risk the million dollar penalty, the amount invested that resulted in a cloned cat in Texas was 3.7 million dollars. A lot of Americans have less of a moral dilemma with the birth of an individual derived from a clone than creating human life then destroying it for some vague scientific purpose . To my knowledge, there have been no genetic diseases in animals cured with stem cells from clones even though there is no current bans regarding cloning. However, patents of these human stem cells from cloned embryos are likely to bring millions to biotech companies. 10. Adult stem cells have been shown to make insulin. Although there are many claims to the contrary, recent studies have shown that stem cells from adults can make insulin. At the University of Florida in Gainsville, Dr. Tang and associates were successful in getting insulin-producing cells from adult bone marrow stem cells. These cell secreted insulin in a controlled manner and reversed diabetes in mice . Also a cell type isolated from bone marrow called MIAMI cells were shown to produce insulin. Insulin producing cells are also produced from embryonic stem cells . However, the stem cells from embryos were inferior to the stem cells from adults because the insulin producing cells from the embryos were not responsive to changing levels of glucose . 11. Research is not being slowed by the current ban on Federal funding of human embryonic/fetal stem cells. Every clinical trial, new drug, new treatment is based on animal studies. There is no ban on animal embryonic or fetal stem cells or animal cloned cells. There is only a ban on Federal funding of human embryonic stem cells from the destruction of new embryos. As a matter of fact, this ban will bring balance so that adult stem cell research will be further explored even though it is less profitable. There is no ban on using embryonic or fetal stem from animals or private funding of research using human stem cells. 12. Many alternative treatments besides stem cells are showing progress for treating diseases and injuries. Before I talk about the progress in adult stem, I would like to mention that in terms of injuries or diseases such as Alzheimer’s disease, spinal cord injury, head injury, diabetes, ALS (Lou Gehrig’s disease), liver or heart damage and Parkinson’s disease, there are many other alternatives therapies being scientifically or clinically explored. A prominent stem cell researcher named Dr. Ron McKay said recently that it was a fairy tale to think that stem cells could help Alzheimer’s disease . In the case of diabetes, there is an exciting new drug called liraglutide that seems promising in type 2 diabetes . In a recent study using a mouse model of Parkinson’s disease, therapeutic immunization using immune cells prevented nerve cells from dying. Progress is also being made in diabetes across the country using islet cell transplants. Recently at my university, University of Alabama at Birmingham, Professor Devin Eckhoff performed an islet cell transplant into a young woman who was totally dependent on insulin shots since age 2. The transplanted cells were obtained from a pancreas of a patient who died in an accident. These transplanted cells immediately began to function and it is hoped that this patient will never have to take insulin shots again. . 13. There has been tremendous progress in adult stem cell research in the last few years. In another study, adult stem cells transplanted into mice with liver injuries helped restore liver function within two to seven days. Transplantation of stem cells from adult human brain causes myelination to occur in a focally demyelinated spinal cord of the rat . Demyelination is common in spinal cord injury and disease states such as Multiple Sclerosis, and interferes with signal conduction between the neurons. Human cells from adult have been used to treat animal models of disease states. For example, human cells led to functional improvement in animal models of Parkinson’s disease using human bone cells or neural stem cells . Human brain adult stem cells can even be obtained after death, so if a person’s own stem cells are not used, there are other less objectionable alternatives. Another alternative to the use of embryonic stem cells is human umbilical cord blood. Human umbilical cord blood has the potential to form neurons , as well as other cell types . Human umbilical cord blood injected intravenously caused a functional improvement when injected into experimental animals with traumatic brain injury or stroke , . Bone marrow stromal cells from adult rats promote functional recovery after spinal cord injury in rats when given 1 week after injury , even when the cells are injected intravenously . Bone marrow stromal cells also will migrate to site of a head injury when given intravenously and caused a functional improvement. 14. There has been progress in treating genetic disorders using adult stem cells or viruses in animal studies but no progress using cloned stem cells to treat genetic disorders in animals. In the case of genetic defects, there are several other alternatives to cloning. One is gene therapy that has been successfully used in mice and humans. More recently stem cells have been used as vehicles to deliver genes to the brain , , , . Another valuable source of research into genetic disorders is adult stem cells that can obtained from patients with genetic defects or a strong genetic predisposition to develop particular diseases. 15. Tremendous progress has been made using adult stem cells in clinical trials in treating diseases and injuries. You have already heard about the wonderful results of Dr. Levesque at Cedars-Sinai in treating Parkinson’s disease using a person’s own stem cells. I would now like to describe the use of olfactory mucosa in the treatment of spinal cord injury. Olfactory Mucosa The olfactory mucosa lines the upper nasal cavity. The story begins with a brilliant neurologist from Portugal named Dr. Carlos Lima. He is also a pathologist that has published on the olfactory system and studied a collection of hundreds of olfactory mucosas from cadavers. In 1991 (the year before stem cells were first discovered in the brain), he decided to explore the potential of olfactory mucosa in the treatment of spinal cord injury because the olfactory system was the only system in the adult nervous system that regenerates. With very limited facilities, Dr. Lima began a study using fourteen guinea pigs in which the spinal cord was completely cut (transected). A week later, he implanted a piece of olfactory mucosa from the nose of that animal. He noticed that the guinea pigs that received the transplant were able to walk much better than the guinea pigs without the transplant. When he examined the spinal cords, the guinea pigs that improved showed tissue bridging between the two cut ends. We now know that there are several advantages to using the olfactory mucosa. The major advantage of the olfactory mucosa is its lifelong continual regenerative capacity, including the production of nerve cells. It is also accessible with minimally invasive techniques. The olfactory mucosa contains two cells types that we know help repair the nervous system: stem cells and olfactory ensheathing cells. The olfactory ensheathing cells encourage the growth of nerve cell processes (axons) and promote the myelination (covering on nerve cell processes that speed up the signal between neurons). Removal of part of the mucosa causes no permanent damage to olfaction (smelling). Problems of rejection, overgrowth, disease transmission, and ethical issues can be avoided because a person’s own olfactory mucosa can be used. When Dr. Lima visited my lab, he showed me and my collaborator, Dr. Jay Meythaler, his procedure. I began a rat study that was supported by the Foundation for Neural Repair. In this study, we compared a wide variety of treatments in rats with chronic, severe spinal cord injury. The person doing the functional testing was unaware of the treatment that the rat received. The average functional scores of the 6 weeks prior to the treatment period were compared to the average functional scores of weeks 5-10 after treatment. The improvement was greatest in the rats with the olfactory mucosa transplants. Improvement was also found in the rats that received bone stromal cells IV injections. This improvement with the olfactory mucosa cells is the greatest improvement that I have found in the twelve years of evaluating treatments for severe spinal cord injury. Below is the graph of the results: Excellent graft integration and reduction in lesion size were observed in the spinal cords of rats receiving the olfactory mucosa transplants. Clinical Trials by Dr. Carlos Lima and Colleagues in Portugal Based on the animal results, Dr. Lima proposed a clinic trial in Portugal. A team of physicians was formed that was headed by the neurologist and pathologist, Dr. Carlos Lima and included the Neurosurgeon, Dr. José Pratas-Vital, an Otolaryngologist, Dr. Pedro Escada; and a Neurosurgeon, Dr. Armando Hasse-Ferreira. As a first step in this procedure, the team of doctors did numerous sham operations on cadavers to master the technique. The whole procedure was reviewed and approved by the Ethical Committee and Administration of the Hospital Egas Moniz- Lisbon. Dr. Lima and his team of doctors have requested that I present the results of the study. All of the people were treated in Portugal between six months and six years after their injury. The normal improvement, if any, that occurs after spinal cord injury takes place in the six months to a year after injury so these patients were treated at a time when no further improvements are expected. In this procedure, the area of the spinal cord damage is exposed surgically in patients with severe spinal cord injuries. Then a small piece of olfactory mucosa in the upper part of nose is removed from that same patient. The olfactory mucosa is then rinsed, cut in small pieces and placed in the spinal cord. Below are the MRIs of one of the patients from Portugal named Ana: The area that the arrow is pointing at on the left is the MRI before the treatment. There is a cystic cavity that appears white. On the right is the MRI after the treatment, the arrow points to the same area that is almost completely filled. It appeared that as in the animal studies, there was bridging of the injury. It is impossible to tell if there was tissue in a living individual but it is probable. All of the patients recovered well from the surgery. Olfaction returned to normal by three months after the surgery. All of the patients showed improvements. One of the patients regained bladder control at fifteen months after the surgery. Regaining bladder control is extremely important to patients with spinal cord injury. All but one of the patients gained feeling in some areas of their body where they previously had no feeling. All of the patients gained the ability to move certain muscles that they could not move before the olfactory mucosa treatment. In order to quantify the changes as a result of the treatment, an evaluation called the ASIA neurological exam is used. As you can see from this diagram below, points are given for each part of the body that has sensation or movement. A normal person has 112 on the sensory scale and 100 on the motor scale. The results of his first seven Portuguese patients that were treated from six months to six years after injury are presented using the ASIA neurological exam. The beginning score (Pre-Op) is the score before receiving the olfactory mucosa treatment and is shown on the far left. The results after the olfactory mucosa treatment by Dr. Carlos Lima and colleagues are recorded every six months after surgery. The patients were operated on at different times, so some of the patients only have a few scores so far. An increase in score means that there is an increase in sensory or motor function. In summary, all of Dr. Lima’s patients that were treated with the olfactory mucosa showed some improvement. However, most of the patients did not have access to the best rehab facilities. This was very frustrating because it appeared that the patients would improve further if only better rehab facilities were available. In hopes of the patients being able to have access to better rehab facilities, several American patients that had requested the treatment were enrolled in the clinical trial. Some of these patients were carefully evaluated by physicians in the US before and after the olfactory mucosa treatment in Portugal. Two of these brave young women are here today to tell about their experiences. Results in Two Americans after Olfactory Mucosa Treatment by Dr. Lima Laura Dominguez had her accident on July 3, 2001. Afterwards she had no movement of her legs or hips and no feeling below her collarbone. Laura was 18 years old, tetraplegic with a lesion at the 6th cervical level that was 2 cm. long. The lesion was mixed glial and connective tissue produced by a contusion and laceration. She went to a variety of excellent rehabilitation centers including Dr. John McDonald’s in St. Louis and Project Walk in California. These centers helped her improve her upper body strength but she still could not move her hips, legs or feet and she had no feeling in these areas. In the U.S., Dr. Steve Hinderer and The Rehabilitation Institute of Michigan (currently headed by Dr. Jay Meythaler, associated with Detroit Medical Center and Wayne State University) began to look into the potential of Dr. Lima’s procedures at the encouragement of Fred Nader whose daughter had a spinal cord injury. Almost two years after her accident, Laura and her family decided to go to Portugal to have the olfactory mucosa surgery performed by Dr. Lima and his team of doctors in March of last year. After her surgery, she regained some sensation and motor control of certain muscles. She is now able to point her toes. With braces, she is able to walk some distance. Although she has made remarkable improvements, a rehabilitation program that is actually tailored to these types of patients needs to be developed. Laura has received some help in developing a vigorous rehabilitation program from a talented karate instructor named Ivan Ujeta. Aquatherapy (water therapy) has proven to be particularly helpful. However, Laura and her family feel that rehabilitation programs need to be better developed. Susan Fajt was in a car accident on Nov. 17, 2001. The spinal cord lesion was at thoracic level 7 and 8 and was about 3 cms long. Susan was an ASIA A (complete). She had no voluntary movement or sensory sensation below her level of injury. Susan had no sensory or motor activity on S4-S5 segments. About 21/2 years after her injury, Susan went to Portugal to have the surgery performed by Dr. Lima and his team in June of last year (2003). She started to experience real gains around six months after the olfactory mucosa treatment with increased bladder control, sensory recovery and first movements of her thigh muscles. Susan and her father looked for the best rehab program; however, it seemed that the optimal rehabilitation program has yet to be designed. Her father John Fajt began, with Susan’s help, to develop and patent devices such as a cross-trainer, standing wheel-chair (Venus craft), and camel wheel-chair (lowers or raises to facilitate going into and out of the pool) that would help her progress. She gained voluntary movements of her thigh muscles. In May, at Dr. Albert Bohbot in France, Susan got more strength in these muscles and began walking on a walker with braces on legs. The graph below shows the changes in her ASIA scores. The story of these two courageous young women dramatically shows the progress of adult stem cells and tissue and the need for further research into the less profitable, but more beneficial, direction of adult stem cells. Further work is needed to improve this technique, with the addition of other treatments including a rehabilitation program that will maximize the functional improvement. My statements represent my scientific viewpoint and not the opinion of The University of Alabama at Birmingham which has no official opinion on this topic. A special note of thanks to Dr. Joseph Horton at The University of Alabama at Birmingham who arranged for the digitization of some of the MRIs on very short notice.

• Dr. Irving Weissman, M.D.
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  Dr. Irving Weissman, M.D.

  My name is Irv Weissman. I received my MD degree in 1965 from Stanford, where I am now the Karel and Avice Beekhuis Professor of Cancer Biology, Director of the Institute of Cancer and Stem Cell Biology and Medicine, and Professor in the Departments of Pathology, Developmental Biology, and by courtesy, Biology; I attach my full CV for your information. I was also Chairman of the National Academies (NAS, NAE, IOM, NRC) Panel on the Scientific and Medical Aspects of Human Reproductive Cloning, which also dealt with the issue of human pluripotent and human embryonic stem cell research. My field of research is adult tissue stem cell biology. We were first to isolate any adult (or tissue) stem cell—the mouse hematopoietic (blood-forming) stem cell (HSC), followed by the human HSC, the human CNS (brain cell forming) stem cell, and most or all blood system committed progenitors in mouse and man. I am cofounder of the following adult or tissue stem cell companies—Stem Cells, Inc ( mainly human CNS stem cells) and SyStemix, Inc (human HSC). SyStemix released the stem cell service transplant functions to Celtrans, now Cellerant, Inc, to deliver human HSC and blood system progenitors to patient populations. I own stock in Stem Cells, Inc, and Cellerant, Inc and am a Director of both companies. These relationships have been disclosed to Stanford, and subjected to extensive review to assure avoidance of conflicts of interest, including the establishment of oversight committees, when indicated . I have no commercial or advising relationship with any for profit entity in the fields of human embryonic stem cells or nuclear transfer (NT) to produce human pluripotent stem cells . As a scientist in adult/tissue stem cell research I have played a role in helping define the field, and in that role pointing out errors or misstatements or less than rigorous research. Stem cells are defined as cells that can divide to give rise to new stem cells, by a process we call self-renewal; and also progenitors and mature tissue cells, in a process called differentiation. The clonal progeny of a single HSC include HSC and all blood cells . The progeny of brain stem cells include more brain stem cells, as well as the differentiated brain cell types. Any use of the term stem cell must have the characterization of the cell (at the single cell level), include a proof of the capacity for self-renewal and differentiation. These are generally accepted definitions of the field by the leaders in the field of stem cell biology. However, much of the testimony you have heard in the past and will continue to hear have fallen short of this standard. All those who have testified, are testifying and will testify should be held to that standard. So far, isolated tissue stem cells upon transplantation to appropriate hosts results in robust regeneration of all the kinds of cells in the tissue from which the stem cells were isolated, almost always requiring only small cell numbers. Many clinically important avenues have been opened by this type of adult tissue stem cell research. For example, human HSC (blood-forming stem cells) have been isolated from patients with widespread cancers, in which the cancer cells and the HSC are intermixed in blood and bone marrow; the isolated blood-forming stem cells are no longer contaminated with cancer cells. In 3 early phase clinical trials it was shown that these pure HSC’s regenerate the blood forming system of patients treated with massive doses of chemotherapy; the chemotherapy is used to kill as many cancer cells in the body as possible, and the HSC transplants (that are not cancer cell contaminated) restore blood formation as efficiently as any bone marrow transplant, but without giving back cancer cells to the patient. In mouse models of human disease we have been able to replace the disease-causing blood forming system with a blood-forming system that resists that disease; an example is mouse type 1 (juvenile) diabetes, where a timely transplant permanently stops the autoimmune attack on the insulin-producing pancreatic cells. Other such blood diseases include sickle cell anemia, thalassemia, severe-combined immunodeficiency (the so-called bubble boy disease), and the mouse model of lupus, among many others. In addition, the replacement of the blood forming system of mouse strain A with HSC from mouse strain B has allowed the permanent transplantation of heart, or skin, or insulin-producing islet cells from B donors to A hosts without any subsequent immunosuppression. Nuclear accidents and exposure to other blood-destroying agents can only be treated with HSC or blood progenitors. We are now exploring in mouse models the utility of brain-forming stem cells in various neurodegenerative disorders, including spinal cord injury, inborn errors such as Batten’s Disease, Niemann-Pick, etc, as well as Alzheimer’s, Lou Gehrig’s, Parkinson’s, and Huntington’s Diseases, and even cerebral palsy. All of this research is at an early stage, and we cannot predict which, if any indications will be ameliorated or cured. You might think that I am biased. But science is a field that demands independent replication, so any bias I have will be tested empirically. For all of these reasons, you should know that I am the strongest possible advocate for tissue (adult) stem cell research and therapies, but I am also the strongest critic of inappropriate extrapolations and inadequate claims from ‘stem cell’ therapies that are unproven. We have only found adult tissue stem cells so far for a few tissues, and much discovery research will be needed to find others, if they exist. A central issue in this hearing is whether adult or tissue stem cells of one type, can change their fate to that of another tissue, for example blood-forming stem cells to brain, or heart, or skeletal muscle, by transdifferentiation. When the first reports of HSC transdifferentiation to regenerating heart cells, or brain cells, or liver cells, or skeletal muscle cells were reported I was excited that the HSC we had isolated might have much broader clinical uses than we had initially envisioned. So we embarked on experiments to repeat the original findings., hoping to make them better understood and easier and more efficient by improving the processes involved. But we found that we could not confirm blood-forming stem cells giving rise to brain, or heart, or liver, or skeletal muscle in a robust fashion. I attach several of our papers that represent attempts to reveal normal tissue regeneration using stem cells from distinct tissues. In brief, we could not substantiate the claims; only rare (less than 0.1%) of any damaged and repairing tissues (heart, leg muscles, brain) had donor cell markers in regenerating host tissues. All of these rare cases of donor markers in host cells turned out to be due to a very rare event that can occur in tissue damage—the fusion of donor blood cells used in mopping up damaged areas with resident tissue cells that survived the damage, not the transdifferentiation of blood-forming stem cells to brain, or heart, or muscle, or liver. These findings, like many in biomedical sciences, turned out to be due to different interpretations of similar findings, or due to some consistent misleading methods to reveal the underlying phenomena. All of us in the life sciences have experienced the disappointment that what we thought was a major finding turned out to be due to something other than we suspected at the time. Luckily, the practice of studying particular subjects in several independent labs provides a continually self-correcting aspect to our field. Moreover these cell fusions were rare and not robust events leading to massive tissue regeneration. While with added experiments these rare cell fusion events may turn out to be of some biological interest, none of us should expect that such cells provide a means to regenerate different tissues and organs. On the other hand, adult tissue stem cells (as described above) can lead to robust regeneration, but only of the tissue from which they came. These findings (and others) have led us to posit several requirements, all of which should be met before one begins clinical trials in stem cell research, and of course before the press should pronounce preliminary results as conclusions and before legislative bodies should base their decisions on these findings as facts. These are: 1) The original research finding must be published in a peer-reviewed journal….but that is not enough. 2) The experiments as reported must be replicated in several independent laboratories..,,but that is not enough. 3) Any way you investigate the phenomenon you should be able to come to the original conclusions…but that is not enough. 4) Preclinical (i.e. animal) experiments should show that the injected cells can robustly regenerate the damaged tissues in a timely fashion before they should be considered for human clinical trials. About 3 years ago I was asked by the Presidents of the National Academies (National Academy of Sciences, National Academy of Engineering, National Research Council, Institute of Medicine of the National Academies) to lead a panel to gather information and provide a thorough, objective report on two related issues, the scientific and medical aspects of human reproductive cloning, and the use of nuclear transfer technology to produce human pluripotent stem cell lines. They chose the panel to provide experts in the related fields of life sciences, medicine; and medical ethics as it applies to human participants in medical research trials or experiments. We all agreed that we had not made up our minds on these subjects beforehand; that we would gather as much data as could be obtained; that we would have a public meeting of experts and would-be practitioners of both fields; and that we would keep our deliberations and thoughts confidential until we had heard and read all of the relevant data and had discussed them thoroughly, and prepared our consensus report for public disclosure. I have appended the executive summary of that report. In brief, we found from very extensive animal studies that a clonal embryoid blastocyst (I call it embryoid because it was not generated by sperm-egg fertilization, but by transfer of a body cell nucleus into an egg whose own nucleus had been removed) implanted into the uterus of a hormonally prepared female of the same species only results in a live birth in 0.8% of the cases, and even in those cases most died soon after birth. More ominously, unlike a miscarriage that is over in the first trimester without measurable morbidity or mortality, these reproductive clones aberrantly died throughout pregnancy, often taking the mother with them. This would clearly be an unacceptable risk for humans, as codified in the medical ethics literature, e.g., the Nuremburg code. Accordingly,we concluded, unanimously, that there should be a legally enforceable ban on human reproductive cloning, defining human reproductive cloning as placement in a uterus of a human blastocyst derived by nuclear transplantation. As you know, Congress has not chosen to separate the issues and provide for such a ban by itself. From a scientific, medical, and medical ethical perspective, there was not considered to be a similar justification for a ban on nuclear transfer (NT) to produce human pluripotent stem cells. In order to judge the potential scientific and medical value of such research, we considered all experiments published in animal systems, and unanimously recommended that biomedical research using nuclear transfer to produce stem cells be permitted, and called for a broad national dialogue on the societal, religious, and ethical issues on this matter. I am here today to bring you up to date on these issues so that you can enlarge the debate on societal grounds. Let me remind you of the process of producing such lines in mice, which presumably would be the blueprint for the production of human pluripotent cells. A somatic cell (from skin, or other adult tissues) is placed into an enucleated egg, the cell resulting from that NT is stimulated to divide, resulting in an embryoid ‘blastocyst’. That ‘blastocyst’ contains about 40 pluripotent (many potentialities) cells inside a hollow sphere of so-called trophoblastic cells. The trophoblast cells are necessary for the blastocyst to implant in the uterus, the trophoblast cells contributing to the placenta. The blastocyst cannot proceed to even the next stage of development unless it implants and receives signals and nutrition from the uterus. A blastocyst lacking the trophoblast cells cannot implant. The pluripotent cells of the preimplantation embryoid blastocyst can then be removed and cultured to produce the pluripotent stem cell line. These pluripotent cells lack the capacity to make reproductive clones, and only make all tissue types in a disorganized fashion. Neither these nor true embryonic stem cells can make embryos, or fetuses, and therefore it would be a misnomer to claim they can be used to generate’ embryo farms’. It has been shown in mice that the genome of the donor body cell is what is retained in the pluripotent stem cell line. Nuclei taken from mice with severe combined immunodeficiency (the so-called bubble boy disease) give rise to pluripotent stem cells that also have that disease, seen most graphically if the tissue HSC from these lines are transplanted into suitable radiated mice. The pluripotent cells can contribute to every other tissue, but can’t make immune lymphocytes. Correction of the defective gene in the cell line corrects the disease even when transplanted into appropriate hosts. This suggests that one might be able to develop similar cell lines derived from humans with genetically determined diseases such as immunodeficiency, or adult or juvenile diabetes, or immune disorders such as lupus, rheumatoid arthritis, or multiple sclerosis, or neurodegenerative diseases like Lou Gehrig’s, some Parkinson’s, some Alzheimer’s, Huntington’s Disease, and all lysosmal storage diseases—just to name a few such diseases-- to try to elucidate how certain genes lead to the disease, whether studied in test tubes or in immunodeficient mice. And this is only a short list of human genetically determined disorders. There are now several experiments in mice that show at least some cancers can be used in NT to produce pluripotent cells, so not all of the mutations that lead to these cancers prohibit them from being reprogrammed to make pluripotent cells. At least one of these,malignant melanoma, has been shown by Rudi Jaenisch to redevelop melanomas if put into appropriate mice. One could also begin to figure out how to develop tissue stem cells from a particular person that might be transplanted back into that person—perhaps after fixing the defective disease genes—a process called therapeutic cloning in the popular press. (This is the only NT application that is appropriately called therapeutic cloning). So you might think we would be encouraged at the potential medical advances in adult stem cell research, in embryonic stem cell research, and in NT stem cell research to expand our efforts for new discoveries and new therapies in these exciting areas. However, the bills put forward by Senator Brownback and Representative Weldon call for banning NT research, with criminal penalties at every stage of research as well as therapies derived from that research. Before one enacts the first (that I know) ban on biomedical research in US history based on ideology, not safety, we should realize what will be lost, and think deeply about the political, medical, societal, commercial, and moral consequences of such a ban. To do so we need to know what experiments and therapies today, cannot be accomplished with adult tissue stem cells or the allowed human embryonic stem cell lines. These can be summarized in 4 areas: 1) Genetic diversity of embryonic and pluripotent stem cell lines. The genetic diversity of the usable 9-64 lines currently available is that of the population that in the US undergoes in vitro fertilization; they are largely white, well to do, and always infertile. There is no doubt that the wide variety of racial and ethnic populations that characterize America are not represented in these cell lines, and of course, it would be extremely unlikely if any had the genetically determined diseases such as sickle cell anemia, thalassemia, and adult onset diabetes, to name a few, prevalent in black, Mediterranean, and native American populations resident in the US. There are probably tens to hundreds of genetic disorders, and none will be represented in this limited number of cell lines. NT is a method to make sure they are represented. 2) Genetically determined human diseases. The NT technology might give us cell lines important to understand how simple (one gene defect) or multigenic disorders are caused, and how they might be approached and treated. For example, Lou Gehrig’s Disease (LGD) is multigenic, resulting in a loss of motor neurons with tragic consequences for reasons we don’t understand. If one could have a pluripotent LGD cell line, one might be able to repair one gene at a time, and determine if in test tubes, or in immunodeficient mice ( systems wherein mouse embryonic stem celL –derived tissue stem cells can give rise to motor neurons and the muscle cells they serve)whether the disease development is halted. Knowing those genes as validated targets should be useful for medical scientists, gene therapists, stem cell transplanters, and even small molecule pharmaceutical companies. 3) Cancer cells. All cancers differ from other cells in the body in that they have suffered several, if not many genetic mutations or alterations that play a role in their progress from a normal cell to a cancer cell that can spread and kill a person. There are, to date, no exceptions. It is therefore likely that NT research could make available pluripotent cell lines made from real patients’cancers capable of evolving the particular cancer, and these lines should be susceptible to the same kinds of research to define the dangerous genes, and how to attack them. For both reasons 2) and 3) shown above it should be clear that we are hoping for a chance to learn about how these terrible life-shortening diseases develop, how we can intervene, and eventually, how we might cure them. No other methods that I know of and that are presently available allow these kinds of approaches. It is hard for me as an MD and medical researcher to ignore such promising lines of inquiry. 4) Therapeutic cloning. The possibility that we will someday be able to make NT stem cells from us for us could open the way for a broad scale development regenerative medicine. While it is undetermined whether these approaches will replace the few known adult tissue stem cell therapies, it would be foolish to bet the health of the American people that they will not; and in addition, there are many, many tissues that we do not have replacement stem or progenitor cells yet. And even the approved human embryonic stem cell lines will likely not be useful or allowed for direct transplantation therapies, as they are compatible with few or no persons, and they are all grown in a way that they could be contaminated with leukemia viruses from the mouse feeder layers they are grown on. At the same time one should not be susceptible to the hype that tomorrow, or even 5 years from now we will have transplantable cells from NT lines for therapies, as these cells are developed from early stage cells, and will need to undergo the changes all of our stem cells naturally undergo to give rise to mature tissue stem cells. We should remember that high quality research takes time, and we must not overestimate how quickly the work will go. But if we don’t start, we’ll never get there. This last point deserves some comment. Congress has been wise enough to understand that the support of basic medical research eventually leads to medical breakthroughs and medical therapies. No line of fundamental biomedical research at the beginning results in short-term therapies. One hears often that embryonic stem cell research or pluripotent stem cell research must be lacking in possibilities as no cures have yet been found. Using that logic, funding NIH and NSF should be abandoned. Human embryonic stem cells were first reported in 1998, first distributed beyond the founder lab a couple of years later, and first allowed for NIH funding in 2002, following the President’s executive order. Any clinical trial with cells takes at least 1-2 years to get the cells properly established to be safe and nontoxic, and of course several years of preclinical animal experiments to show there is an indication for a trial. It is frankly impossibly premature to conclude they will not work. And NT pluripotent stem cell lines have only been reported once, this year, in a preliminary report from South Korea. Twice in the 20th century governments approached biomedical genetics research with the intent to regulate or ban it (albeit not criminalize it). In the late 1970’s, and early 1980’s the Cambridge Mass city council and the Berkeley CA city council considered prohibiting recombinant DNA research in their jurisdictions, and the issue of safety was raised in the US congress. Recombinant DNA is spliced together DNA segments, and the issue at that time was putting human genes like insulin into bacteria to produce human insulin for diabetics. Many thought such genetic manipulations could be dangerous, and others wished it banned because it offended them, or because they reserved to God the right to “create life”. But instead of banning the research, the NIH regulated such research. Even today to carry out a recombinant DNA experiment with new methods or possibly dangerous genes it is required to seek and obtain approval from these regulatory bodies. What was the result? Only the birth of biotechnology, the expansion of these research techniques to every branch of biomedical research, and the annual saving or making better of >100,000 lives per year. Had this recombinant DNA research been banned those lives would be saddled with disease or lost. The lost or impaired lives of those people would, in my view, be the moral responsibility of those who advocated or helped enact the ban. In addition biotech firms were started in the US, and US citizens were first to get the treatment benefits, By now US biotechnology companies rival classical Pharma companies for value and world leadership. The US is the world leader in these advances, advances that were slow in coming, but undoubtedly have changed the lives of diseased patients for the better. The second example occurred in the 1920s’ and 1930’s in Russia. At that time Russia and the US lead the world in genetics research. But in Russia a maverick geneticist named Trofim Lysenko became a science advisor to Joseph Stalin, and persuaded Stalin that Darwin and Mendel’s views on natural selection were wrong. By Darwinism, for example, spontaneous variants could occur rarely, and might affect, for example, resistance to cold or dark in only about 1 in 1 million seeds. Another view, proposed by Lamarck, stated that gradual changes in light and temperature over the growing season would cause all plants to undergo adaptations, and that all germ cells would transfer such changes. In that view one could change the response to cold in a single plant, only requiring that winner adaptations would be inherited in seeds; such a result would have shaken up American genetics. Unfortunately for Russia Stalin chose Lysenko’s proposed methods and potential results, a choice that proved to be wrong. The tried and true method of painstaking determination of the rare cold-resistant “mutants” and their selection for next generation’s produce was left high and dry. So Lysenko was revered and Darwinists reviled. The Russian crops failed, and the next generation of Russian scientists were untrained in genetics. Several important Russian geneticists were blackballed and some jailed. Others, migrated to the US, or if already in the US, stayed, where they helped lead the US to unquestioned leadership in the field. As a result for the next 50 years Russia produced no great geneticists and no great genetics. The biomedical revolution bypassed the Russians, as did medical treatments and the economic benefits that would have accrued. I urge you to think hard whether you wish to overrule good science and medicine and ban some kinds of biomedical research and therapies for the first time in American history. In my own personal moral view, those in a position of advice or authority who participate in the banning or enforced delays of biomedical research that could lead to the saving of lives and the amelioration of suffering are directly and morally responsible for the lives made worse or lost due the ban, or even of a moratorium that would deny such treatments in that short window of time when it could help or save them. I recognize that for some there are strong religious and/or other moral bases for beliefs that the NT ‘blastocyst’ has the same rights as born friends and family. In our pluralistic society they have the sovereign right to act on their beliefs for their own conduct.. But my reading of the oath I took upon receiving my MD that the health of the patients are my first priority. This supersedes any personal moral, political, ethnic, and religious beliefs that would block the treatment of current or future patients; and that oath has guided my career. If you have real concerns about our economy, or our ability to recruit and train the best and brightest for biomedicine, or our ability to develop and prescribe the best therapies for our patients, I believe you will choose the American way of sensible actions, and when appropriate, regulation, not abolition. In summary, adult tissue stem cells, embryonic stem cells, and NT stem cells each have important and unique properties to allow the biomedical and clinical community the opportunity to pursue the understanding of human development, the regeneration of damaged tissues, the development of human genetic diseases, and the broadest possible approaches of translating those discoveries to the treatment of patients with grievous diseases. In my view it is irresponsible to fail to pursue all such avenues in parallel to stop or ameliorate the tragedies our families endure because of these diseases. And of course, in my view it is worse than irresponsible to ban these pursuits. Thank you for your attention. Irv Weissman, MD.

Witness Panel 2

• Ms. Laura Dominguez
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  Witness Panel 2

  Ms. Laura Dominguez

  My name is Laura Dominguez. I am 19 years old and live in San Antonio, TX. Three years ago, while on the way home from summer school, my brother and I were involved in a car accident that left me paralyzed from the neck down. The accident was caused by an oil spill on the highway. An oil spill that we had nothing to do with, but by chance was on the roadway in our lane. I suffered a C6 vertebrae burst fracture and my spinal cord was severely damaged. At that time doctors gave me absolutely no chance of ever walking again. I refused to accept their prognosis and began searching for other options. After being hospitalized (in several hospitals) for almost a year, my mother and I relocated to San Diego, CA so that I could undergo extensive physical therapy. While in California, we met a family whose daughter was suffering from a similar spinal cord injury. They were also looking for other alternatives to deal with spinal cord injuries. After extensive research and consultations with medical experts in the field of spinal cord injuries, we decided the best procedure, that exists today, was being performed in Portugal. We teamed up with the Nader family, a group of Doctors from the Detroit Medical Center, and flew to Portugal to undergo this new surgical procedure. The surgery involved the removal of tissue from my olfactory sinus area and transplanting it into my spinal cord at the injury site. Both procedures, the harvesting of the tissue and the transplant were done at the same time. I was the tenth person in the world and the second American to have this procedure done. After the surgery, I returned to California to continue physical therapy. I stayed there until July of 2003 and then returned back to San Antonio, TX. At that time an MRI was taken and it revealed my spinal cord had begun to heal. Approximately 70% of the lesion now looked like normal spinal cord tissue. I was also starting to regain feeling in my upper body and within six months I had regained feeling down to my abdomen. Improvements in my sensory feelings have continued until the present time. I can now feel down to my hip level and have started to regain feeling and some movement down to my legs. My upper body has gained more strength and balance. Another one of the most evident improvements has been my ability to stand and remain standing, using a walker, and with minimal assistance. When I stand I can contract my quadriceps and hamstring muscles. I can also stand on my toes when I am on my feet. And more importantly, while lying down in a prone position, I am able to move my feet. My training has continued to this day and I am able to better use the muscles in my hip area. I am able, with assistance and the use of braces, to walk a distance of over 1400 feet. It takes approximately thirty minutes to walk this distance and it is extremely tiring, but it can be done. I will continue to challenge myself until I can fully walk again with little or no assistance from braces or the help of a therapist. I hope…no, I know…this will be possible by my 21st birthday. It is my understanding that the nervous system is one of the most difficult and complex to repair after an injury or trauma. But in my case, the procedure that was performed in Portugal is working as I have regained more feeling and movement. Some of the movements that I am able to make are functions that are controlled by the very tip of my spinal cord. Although the intensive physical training that I had enhanced my ability to regain strength and movement, prior to surgery I did not have the type of function and feeling that I have now. It only stands to reason that if adult stem cells can repair the complex functions of the spinal cord, they can repair and help other injured internal organs or other parts of the body, whether an injury is caused by trauma or disease. The way I see it, scientists have been given the knowledge and tools to develop and make use of adult stem cells, whether they are derived from tissue removed from the olfactory mucosa or otherwise. This knowledge should be taken full advantage of to help people overcome injuries that can be helped by stem cells or people that suffer from some terminal or debilitating diseases. At the very least, some people can benefit from the possibility of a better quality of life. My life changed from one minute to the next. A catastrophic injury can happen to any person under any circumstance, whether it be a car accident such as mine or some other innocent event or occurrence. The U.S. has been the world leader in science and health and its citizens should not be forced to go to other countries to look for help or cures. The tools to help Americans should be made available in this country.

• Dr. Dennis Turner
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  Witness Panel 2

  Dr. Dennis Turner

  Thank you, Chairman Brownback, for your interest in Parkinson’s Disease, in my treatment by Dr. Levesque, and in my hopes and concerns for the future. For fourteen years I’ve had Parkinson’s Disease. This irreversible disease involves the slow destruction of specialized cells in the brain, called Dopamine Neurons. By early 1991 I suffered extreme shaking of the right side of my body, stiffness in my gait and movements. After some years of medication, I developed fluctuation and poor response to Sinemet. This made daily activities needing the coordinated use of both hands hard or impossible, such as putting in contact lenses. My disability prevented me from using my right arm. Other than my Parkinson’s symptoms I was physically very active and fit. Because of this Dr. Levesque felt that I’d be a good candidate for an experimental treatment. He explained that he would take a very small tissue sample from my brain, removing its adult neural stem cells. He would then multiply and mature these cells into Dopamine Neurons, then inject these cells back into the left side of my brain. He proposed treating only the left side because it controls the right side of the body, the side with the most severe Parkinson’s symptoms. Dr Levesque did not tell me that this treatment would permanently cure my condition. Science has yet to learn what causes Parkinson’s Disease, much less how to remove it. However, since this cell-replacement approach had never been tried in a human patient we hoped for the best. And since my only other realistic alternative was to continue growing worse until I eventually died, I decided to have the surgical procedures in 1999, one to remove the tissue and another to inject the cells. I was awake for both procedures, under local anesthesia. Soon after having the cells injected my Parkinson’s symptoms began to improve. My trembling grew less and less, until to all appearances it was gone, only slightly reappearing if I became upset. Dr. Levesque had me tested by a Neurologist, who said he wouldn’t have known I had Parkinson’s if he had met me on the street. I was once again able to use my right hand and arm normally, enjoying activities that I given up hope of ever doing. Since being diagnosed with Parkinson’s Disease my condition had slowly, but continuously worsened. I can’t say with certainty what my condition would have become if Dr. Levesque had not used my own adult stem cells to treat me. But I have no doubt that because of this treatment I’ve enjoyed five years of quality life that I feared had passed me by. Last year, after four years of being virtually symptom free, my Parkinson’s symptoms began reappearing in my body’s left side. Today I have various degrees of trembling in both hands, although I feel that the left is slightly worse. Nevertheless, I wouldn’t hesitate for a second to have Dr. Levesque use my adult stem cells to treat me a second time, since in my case they were safe, effective, and involved no risk of rejection. Because of my improvements through Dr. Levesque’s treatment I’ve been able to indulge in my passion for big game photography these past five years. While on safari in 2001 I scrambled up a tree to avoid being run over by a Rhino. I swam in the South Atlantic with Great White Sharks. Two weeks ago I returned from Africa after photographing Cheetahs and Leopards in the wild. Here are a few examples of the pictures I took. They represent memories and experiences I feel I have Dr. Levesque to thank for. I came here to offer him my sincere gratitude, and to offer others with Parkinson’s a concrete reason for hope. This summarizes my history with Parkinson’s and the positive effects I experienced through a treatment that used my own adult stem cells. I’m very happy with its results and would dearly love to have a second treatment.

• Ms. Susan Fajt
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  Witness Panel 2

  Ms. Susan Fajt

  Before the U.S. Senate Commerce Subcommittee on Science, Technology, and Space Senator Sam Brownback, Chairman July 14, 2004 My name is Susan Fajt, and I want to thank Chairman Brownback and members of this Committee for this opportunity to tell you of the adult stem cell treatment I received for spinal cord injury in Portugal by Dr. Carlos Lima, and its results to date. But first, allow me to share with you some basic facts about spinal cord injury to explain why I chose Dr. Lima's procedure. On November 17, 2001, I suffered a spinal cord injury and became paralyzed in an auto accident. My life has changed in ways unfathomable. Emotions run strong and decisions must be made to end needless suffering. I chose to live and fight for a cure. Perhaps paralysis has robbed me of my freedom, but it can never take away my belief that a cure is attainable through research. There are currently no effective treatments available for spinal cord injury in the United States. When I was injured I was twenty-four years old, and I loved life more than you can imagine! Today, I have been given a great honor to tell you the story of my quest for a cure for this catastrophic condition. Once realizing that my injury was no longer a nightmare but a devastating reality, I set out to find the best possible treatment in hopes I would be cured, and recover everything I had lost. After tears of pain and years of searching, I found, through my own research, Dr. Carlos Lima in Portugal. My treatment with Dr. Lima took place on June 17th, 2003. I was the 11th patient in the world, and the third from the United States, to receive this treatment. Dr. Lima used an adult stem cell treatment that uses an Olfactory Muscosa graft to promote growth of axons to bridge the site of contusion, in my hopes that functional recovery would help me to once again walk, run, dance, and do everything I would love, not to mention normal daily activities which are so easily taken for granted, such as bowel and bladder control. Only part of my dreams has been attained. But I have come farther than my American doctors ever thought. My most recent MRI took place 5 days ago. The doctors were in disbelief at the improvement they saw where my spinal cord had been injured. I have recovered some functional improvement through Dr. Lima's procedure, such as the ability to hold my bladder and at times even void on my own. Sensation has been restored, though it is not completely normal. When concentrating I am now able to contract my thighs slightly; once again, this was also impossible before my surgery in Portugal. But most important on my way to recovery is that I can now walk with the aid of braces. I am now preparing to shed the shell of this wheelchair, which has confined me for over two years, to more often use my braces and walker for mobility. This is something my doctors here in America told me would never be possible with my level of injury and to accept my fate. With Dr. Lima's adult stem cell based therapy, I have accomplished much more than my U.S. doctors said was possible. But this is only the first step to a complete cure. The next step is to find combination treatments as well as an excellent rehabilitation program that will compliment the results of Dr. Lima's surgery so that a complete recovery can be obtained from a spinal cord injury. I have literally gone all over the world in the quest for a program that will allow me to benefit as much as possible. Unfortunately, no such program exists to date. Through love and faith, my father and I have taken upon an endeavor of creating new devices that assist me in working two to three hours each day to reach my maximum potential. In the near future, I hope to open a rehabilitation program so that others can benefit from our innovative equipment. Spinal cord injury is one of the cruelest injuries to affect the human condition. It causes extreme neurological pain, and excruciating psychological trauma amongst other things. Fortunately, I am not built to accept failure, so I plead with you to hear my cry for funding and other support for therapies, such as the one I received, that will free me and millions of others who also suffer in this primitive wheelchair. A cure for spinal cord injury will not be an easy task. However, where there is a will there is a way! In addition to increasing funding to record levels, increasing public awareness about spinal cord injury and about treatments such as Dr. Lima’s, which are showing real results, is imperative and desperately needed. The U.S taxpayer pays over $30 million per day on care for spinal cord injury and only $68 million per year in a search for a cure. Common sense tells me that by taking away two days of our care and in its place use this money for a cure, time will inevitably be on our side. Medical research in the United States is more advanced and far more superior to any other country in the world. Yet citizens, such as myself, risk their lives and are forced to seek treatment in foreign countries. Researchers need to be held accountable by the U.S. government to design and implement research that results in human clinical trials. No more research for the sake of research. Furthermore, funding needs to be invested in staggering amounts for rehabilitation programs, as we have nothing of substance to help us recover after sustaining a spinal cord injury. I ask you for just one moment to imagine if I where your daughter, wife or loved one. Would you help me with my quest and take the opportunity you have before you to promote and publicize this research, which has already helped me, so that I may one day dance the dance of life again, or would you allow me to suffer needlessly? The matter of funding medical research is of great national importance, and I plead with you to do what your heart tells you. Please re-direct the research in this country so that more resources and public awareness is given to treatments like the one I received in Portugal. Free us from paralysis, and in return at the end of your life you will know you have left this world a better place than what you have found it. In closing, I will echo the words that the Honorable President Ronald Reagan spoke to Gorbachev, “if you seek peace… tear down this wall!” Members of the committee, if you seek cures for the millions of Americans currently suffering from spinal cord injuries and diseases, tear down these walls and free us from our wheelchairs! Thank You, Susan Rebecca Fajt

• Dr. Robert A. Goldstein, M.D., Ph.D.
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  Witness Panel 2

  Dr. Robert A. Goldstein, M.D., Ph.D.

  Chairman Brownback and members of this Subcommittee, thank you for the opportunity to appear before you today to participate in this important hearing on adult stem cell research. I am Robert Goldstein, Chief Scientific Officer of the Juvenile Diabetes Research Foundation (JDRF). I am joined today by the Langbein family who represent the millions of families who struggle with the daily challenges and fears of caring for a loved one with juvenile diabetes. Jamie was diagnosed at the age of one, and she has been on an insulin pump since the age of four. Jamie’s diabetes affects her life every day, all day. Her parents must test her blood sugar eight times a day, and every time she eats, exercises, or goes to a birthday party, Jamie must account for what she eats or how much exercise she does and adjust her dose of insulin accordingly so she doesn’t end up in the hospital or in a coma. Her mom gave up her career as an attorney so that she could always be nearby if Jamie had problems with her pump or blood sugar while at school, and her parents get up frequently during the night to check her blood sugar level. Jamie worries about being different from her friends in school, and her parents worry about the long-term complications of diabetes and their daughter’s future and whether their other children will be diagnosed with the disease. This is just one child of the nearly two million people who battle juvenile diabetes each and every day. JDRF is the leading charitable funder of juvenile diabetes research worldwide. Established more than 30 years ago by parents of children with juvenile diabetes, our mission is to find a cure for juvenile diabetes and its complications. Over the years, JDRF has provided some $800 million in grants for diabetes research at most of the world’s leading universities, laboratories, and hospitals. To fund that science, JDRF volunteers do their part every day to raise money in our communities across the country – through walks, galas, and other events -- and we are proud of the strong partnership for funding research that we have developed with the federal government. JDRF, as the world’s leading charitable funder of diabetes research, aggressively pursues all avenues of promising research and makes its funding decisions based upon vigorous scientific review based, in many ways, upon the NIH model. In the area of stem cell science, JDRF funds scientists exploring the opportunities created by both adult and embryonic stem cell research. In Fiscal year 2004, JDRF commitments in the area of stem cell research total $8.2 million. Of this amount, $6.3 million is spent in the area of embryonic stem cell research and less than $2 million is spent on other areas of stem cell research, including adult stem cells. We focus on both areas – as well as dozens of other avenues of scientific investigation – because no one can predict what area of research will produce new therapies or a cure for juvenile diabetes. Adult stem cell research has been pursued for more than 35 years, and as you know, embryonic stem cells were just discovered in 1998. JDRF will continue to support both adult and embryonic stem cell research so that we can pursue a cure as strongly as possible. However, the research community believes that embryonic stem cells offer more promise in the area of diabetes. Let me explain why, using pancreatic islet cell transplantation as an example. Islet transplantation has been a spectacular breakthrough in diabetes research. In islet transplantation, the beta – or insulin-producing – cells are isolated from a cadaver pancreas and then infused into a person with juvenile diabetes through a catheter inserted into the portal vein of their liver. Once transplanted, these new islets recognize blood sugar levels and begin to produce and release insulin into the patient’s body. Islet transplantation had been attempted since the 1970s with limited success. However, in the year 2000, researchers made a breakthrough in the procedure, and since that time nearly 300 people have received islet transplants and the majority of them lead significantly better and healthier lives. In most of these individuals, therapeutic control of their diabetes has improved remarkably, and in many instances they do not even have to take insulin injections. Furthermore, many of the patients have reported a reversal in some of their complications, especially hypoglycemia unawareness but also improvement in vision and less pain from neuropathy. These results are very exciting, but there are significant hurdles in moving this from an experimental procedure to a standard therapy that could benefit the millions of people with diabetes – many of them children. One such hurdle is the severe shortage of donated pancreases. In 2001, approximately 400 pancreata were available for islet transplantation and research, compared to the almost two million Americans with juvenile diabetes. Here, then, is one reason why we are so excited about recent advances in embryonic stem cell research. Recent studies have demonstrated the ability to coax embryonic stem cells into insulin-producing cells in the lab. We have good reason to believe that embryonic stem cells will one day be able to grow large amounts of insulin-producing beta cells for transplant, but more work needs to be done. Unfortunately, adult stem cells have not shown the same promise when it comes to diabetes. Last month, Harvard University researcher Douglas Melton published a paper in Nature pointing out that in mice, new beta cells in the pancreas are formed through the replication of existing beta cells rather than through the differentiation of adult stem cells. This finding indicates that adult stem cells in the pancreas do not contribute to beta cell formation, and that embryonic stem cells may prove to be the only stem cells that will be useful to generate beta cells for the treatment of Type 1 diabetes. Other studies indicate that mouse embryonic stem cells can be differentiated into insulin-producing cells, and several studies suggest that this can be done using human embryonic stem cells. JDRF funds research to develop beta cells from adult stem cells, or to regenerate beta cells from existing precursor cells. Researchers have reported that human adult duct tissue might have the potential to develop into beta cells. Other groups have results that indicate that transplanted bone marrow cells may be able to show insulin production. Some have used these findings to argue that adult stem cells may be the answer for curing juvenile diabetes. JDRF takes the position that research using both embryonic and adult stem cells, perhaps even in side-by-side comparisons, will get us to our goal fastest. Mr. Chairman, adult stem cells may one day prove to be the answer to alleviating the pain and suffering caused by certain diseases – I certainly hope that is the case. We have heard some remarkable stories from some of the witnesses today. But we have no idea of knowing which diseases those may be, and unfortunately we are not certain of the widespread application of these treatments. We do know that to date, adult stem cells have not been shown to hold as much promise for juvenile diabetes as embryonic stem cells. Given this reality, how can we turn our backs on other exciting research opportunities, such as embryonic stem cell research, thereby potentially delaying life-saving therapies and cures for millions of people? And how can we adequately compare the effectiveness of adult and embryonic stem cell research unless both avenues are pursued simultaneously and with equal rigor? We are in an extraordinary time of opportunity in the area of medical research, and this country is leading the way. Scientists around the world agree that stem cell research holds tremendous promise for hundreds of millions of people. I applaud you for continuing to monitor advances in the area of adult stem cell research, and I encourage you to do the same for embryonic stem cell research. For certain diseases such as juvenile diabetes, embryonic stem cells hold the most promise, and we can’t afford to lose any more time. While we have made great strides towards our goal of a cure, more needs to be done, and we don’t have time to wait. Insulin is not a cure for juvenile diabetes, nor does it prevent the onset of complications such as kidney failure, blindness, heart disease and amputations. Diabetic retinopathy is the leading cause of adult blindness in the United States; ninety percent of patients have evidence of retinopathy after fifteen years of diabetes with approximately 25,000 new cases of blindness per year. Diabetes is also the leading cause of renal failure in the United States, accounting for forty percent of new cases per year. Greater than half of all patients with diabetes develop neuropathy, making diabetic neuropathy the most common cause of non-traumatic amputations and autonomic failure. In his or her lifetime, a diabetic patient with neuropathy has a fifteen percent chance to undergo one or more amputations. Mr. Chairman, in the battle against diabetes, we are in a race against time. Not a day goes by that JDRF doesn’t receive calls or letters or email messages from mothers or fathers of children with type 1 diabetes asking “When will my child be cured?” On the one hand, it is extremely difficult to explain the pace of science, particularly to a mother whose five-year-old has to prick his finger six or seven times a day to test his blood sugar, who needs three or four injections of insulin every day, who is afraid to go to sleepovers or summer camp for fear of falling into a coma, and who is at constant risk of developing a host of complications that could cut short his life. But on the other hand, it is downright tragic to have to explain how the pace of science could be slowed even further by focusing on one area of research and excluding another. To put the urgency of finding a cure into perspective, I’d like to share some words from Mary Tyler Moore, JDRF’s International Chairman, that she shared with Members of the House. Mary states that “in the nearly six years since human embryonic stem cells were first successfully cultured in a lab,…diabetes has contributed to the deaths of as many as 3 million people and cost our nation over $750 billion. It has caused nearly 500,000 amputations, rendered over 100,000 people blind, and forced a quarter million people to require kidney transplants or dialysis. And 120,000 moms have been told that their child has Type 1 diabetes – a disease which during that time period would require each of these children to have 8,700 injections of insulin and 17,500 pricks of their fingers to check blood sugar levels – just for that child to survive.” Thank you again for the opportunity to appear before you today. I am happy to answer any questions you may have.