Testimony

• Dr. Pablo Rubinstein, M..D.

• Dr. David C. Hess, M.D.
  Read statement

  Testimony

  Dr. David C. Hess, M.D.

  Senate Testimony I am David C. Hess M.D. Professor and Chairman of the Department of Neurology at the Medical College of Georgia. I am a physician and neurologist, a specialist that cares for people with neurological diseases. Many neurological diseases such as stroke, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease) are formidable foes, resistant to treatment and take an enormous toll in suffering. A week will not pass when I do not receive an email or a call from a suffering patient asking for a stem cell injection to help them recover their ability to walk or speak.. Some patients are so desperate that they offer up themselves to be the first patient to try the stem cells. I can’t blame them; there are few effective treatment for their diseases and they are looking for any ray of hope. They have also been influenced by exaggerations in the media. Yet there is some foundation to their hope. The field of “regenerative medicine” is taking off and there are new “Regenerative Medicine” and “Stem Cell” institutes and centers being established all over the country. Many scientific dogma have been slain in the past 5 years. One dogma was that new neurons are not born in the brains of humans-in other words, you just steadily lose what you have as you age. However, in a set of clever experiments by Drs Ericksson and Gage in1998 it was shown that humans even in their 60s can make new nerve cells in their hippocampus, a comforting fact for all of us. Moreover, mice make more new neurons if they are kept in an “enriched” environment and exercise (Kempermann, 2002). If we can extrapolate these findings to humans, it suggests that by keeping our minds active we are less likely to lose them. We also now know that new neurons can be made in response to a brain injury in other parts of the rodent brain, not just the hippocampus. For example, after a stroke, new neurons are born and travel to the damaged tissue and appear to aid in its repair (Arvidsson, 2002). Now we have to learn how to enhance and stimulate these natural repair mechanisms. Adult stem cells can be obtained from a variety of organs ranging from the brain (so called neural stem cells) to the skin. However, the best studied and most accessible adult stem cells are in the bone marrow. Bone marrow is a rich source of stem and progenitor cells. I will briefly review the potential of adult or non-embryonic stem cells to treat human disease. I will focus on bone marrow stem cells. As a physician my perspective is on the clinical potential of these advances and my motivation is to see some of these cells used to treat these devastating neurological diseases that I see every day. As a physician-researcher, I am trying to make some small contributions to the stroke recovery field thanks to past support from the American Heart Association and currently the NIH. Bone marrow contains two major types of stem or progenitor cells and maybe many more. The two major types are the hematopoietic stem cells and the mesenchymal stem cells or marrow stromal cells. Hematopoieitc stem cells have been used for years in bone marrow transplants and have cured thousands of patients with leukemias and other forms of cancer. These hematopoietic stem cells and their progeny- the white blood cells, red blood cells and platelets- have the ability to circulate throughout the bloodstream and reach every organ in the body. Their plasticity, that is, the ability of these cells to “turn “into other cell types such as nerve cells, liver cells and pancreas cells that produce insulin, is still hotly debated. However, there is evidence that these cells can rarely differentiate into Purkinje cells in the brain, a very sophisticated type of neuron. The phenomenon is not restricted to rodents; there is now autopsy evidence from humans that bone marrow cells are involved in the formation of neurons at a low level (Mezey, 2003) Some recent evidence had suggested that cell fusion was responsible for some of the plasticity that had been described for bone marrow stem cells (Terada, 2002; Wang, 2003; Vassilopoulos, 2003). In cell fusion, the bone marrow cells would not actually “turn into” another cell type-they would just fuse with the mature cell giving it twice the number of chromosomes and thereby making it potentially unstable. However, while cell fusion may indeed account for some of the “ plasticity” of bone marrow cells, particularly in the liver, it does not seem to account for all of it. In recent work, bone marrow cells have been shown to become functional insulin-secreting cells in the pancreas of mice without any evidence of cell fusion.(Ianus, 2003). There may also be bone marrow-derived cells that circulate in the peripheral blood with “stem cell” or “progenitor cell” qualities. Recently the progeny of the hematopoietic stem cell, a subpopulation of circulating blood monocytes, have been shown to be able to differentiate into nerve cells and blood vessel cells called endothelial cells (Zhao, 2003). This is potentially of great clinical relevance as monocytes are easy to isolate from human blood and could be a rich source of replacement cells. There are also bone marrow cells that do not normally circulate in the bloodstream but instead reside in the bone marrow and serve as supporting cells for the hematopoietic stem cells. These cells are called mesenchymal stem cells or marrow stromal cells. It is these cells that are the source of much excitement in the field of regenerative medicine. Some of the most exciting research, in terms of an eventual human clinical application, are the Multipotent adult progenitor cells (MAPC) isolated by Catherine Verfailie and described comprehensively in the July 2002 issue of Nature ( Jiang, 2002). These cells can be isolated from rodent and human bone marrow. They are able to differentiate into cells of all three germ layers (endoderm, mesoderm and ectoderm ) that is they can from endothelial cells or blood vessel lining cells, hepatocytes (liver cells), and nerve cells. They not only do this in the petri dish, they also do it in the live animal. Moreover, they do not senesce or die prematurely and importantly they do not form teratomas or tumors like embryonic stem cells tend to do. Dr Walter Low a collaborater of Dr Verfaillie has shown that these MAPCS can aid in brain repair after stroke in a rodent (Zhao, 2002). The obvious advantages of these cells for regenerative medicine is their easy isolation from human bone marrow and the potential for a patient to be their own donor without fear of rejection. A closely related cell type is the marrow stromal cell. Marrow stromal cells have been shown to be involved in brain repair after stroke and traumatic brain injury by Dr Chopp at Henry Ford Hospital and to repair the injured spinal by Dr Darwin Prockop’s group at Tulane. Like many other adult stem cells, these cells can be delivered intravenously and then “home” like a guided missile to the injured tissue. There are chemical signals released by injured tissue that attract these cells. Marrow stromal cells are easy to culture, easy to expand, and since they are autologous they would not be rejected. How exactly these cells repair injured tissue is not clear. While in some cases this is actual replacement of damaged cells, it seems more likely that these cells serve as growth factor “factories” and aid the tissue to repair itself by reactivating latent developmental programs. There is also another type of circulating bone marrow-derived cell, the endothelial progenitor cell (EPC) that has also attracted much recent interest. Endothelial cells are cells that line all the blood vessels of the body. Besides being mere conduits for blood, we now know that they play an active and necessary role in the development and sustenance of the body’s organs. Bone marrow cells that can circulate in the bloodstream and form new endothelial cells and blood vessels were first described and characterized in 1997 (Asahara). We now know that these EPCS contribute to vessel and organ repair after ischemia to the heart, limbs and brain (Rafii, 2003). This is critically important as cardiovascular disease and stroke are two of the three biggest killers in the U.S. We have learned that by giving animials extra doses of these EPCS, we can improve their outcome from heart attack and salvage their limbs that are starved for blood.. Also, these EPCs can be mobllized from the bone marrow and into the peripheral blood with drugs and different growth factors . Some of these growths such G-CSF are already approved by the FDA for other indications The field is moving fast. Bone marrow-derived stem cells are already being tested in small numbers of patients with heart attacks. In the TOPCARE trial, bone marrow cells harvested from the same patient’s bone marrow or their blood were delivered via a catheter in the coronary artery to injured heart tissue (Assmus, 2002). The procedure was safe and initial results were encouraging. There is also a trial using bone marrow cells in patients with congestive heart failure (Perin, 2003). Another type of bone marrow or blood stem cell is the human umbilical cord stem cell. These are derived form umbilical cords that are normally discarded after a delivery. Umbilical cord blood is a rich source of stem cells. These have already been exploited as a source of bone marrow transplants in the cancer field. These umbilical cord stem cells also have great potential as a treatment for neurological diseases. When delivered intravenously to a rodent with a stroke, they help improve the recovery from the stroke (Chen, 2001). Despite these hopeful signs, much work needs to be done. Before we are able to treat humans safely and effectively, we need to define the optimal dosing of these cells, the optimal type of bone marrow populations to use, the timing of when to administer, and the best route of administration (inject directly into the organ, intravenously, intra-arterially). We also need to learn more about how they these bone marrow cells and other adult stem cells home to damaged tissue so we can exploit this therapeutically. The major advantages of bone marrow derived stem cells are: 1.) they are autologous (except for umbilical cord stem cells) and will not be rejected; 2) they can be easily isolated from bone marrow aspirates: and 3) they avoid the ethical concerns that many have with embryonic stem cells. However, we also have to keep in mind that repairing the nervous system is a daunting task. Neurons make tens of thousands of connections with other neurons. Some send their projections (axons) for meters and then connect to another cell. In most of the experiments so far we have little evidence that stem cells delivered into an adult will be able to make all these connections and become fully functional. It is likely that most of the cell transplants in the brain work by stimulating the brain to repair itself. We need to learn more about enhancing these endogenous (self) repair processes. In this growing field of “Cell Therapy”, we will need to target diseases with specific cell types and approaches-one size will not fit all. We may need to treat some of these diseases with a combination of both “cells” and growth factors. The treatments we develop for Parkinson’s disease will be different from those we develop for stroke. There are no magic bullets-only painstaking research will allow us to advance. References Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002 Sep;8(9):963-70. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM.Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997 Feb 14;275(5302):964-7. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM; Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction.Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002 Dec 10;106(24):3009-17. Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 2003 Apr 4;92(6):692-9 Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J, Chopp M.Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 2001 Nov;32(11):2682-8. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998 Nov;4(11):1313-7 Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L.Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2199-204. Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Inest 2003 March 111(6): 843-50 Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow.. Nature 2002 Jul 4;418(6893):41-9 Kempermann G, Gast D, Gage FH.Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol. 2002 Aug;52(2):135-43. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. 2002 Aug 27;59(4):514-23 Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B. Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1364-9 Perin EC, Geng YJ, Willerson JT. Adult stem cell therapy in perspective. Circulation. 2003 Feb 25;107(7):935-8. Rafii S, Lyden D.Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003 Jun;9(6):702-12. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002 Apr 4;416(6880):542-5 Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003 Apr 24;422(6934):901-4 Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003 Apr 24;422(6934):897-901 Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002 Mar;174(1):11-20. Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2426-31 Senate Testimony I am David C. Hess M.D. Professor and Chairman of the Department of Neurology at the Medical College of Georgia. I am a physician and neurologist, a specialist that cares for people with neurological diseases. Many neurological diseases such as stroke, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease) are formidable foes, resistant to treatment and take an enormous toll in suffering. A week will not pass when I do not receive an email or a call from a suffering patient asking for a stem cell injection to help them recover their ability to walk or speak.. Some patients are so desperate that they offer up themselves to be the first patient to try the stem cells. I can’t blame them; there are few effective treatment for their diseases and they are looking for any ray of hope. They have also been influenced by exaggerations in the media. Yet there is some foundation to their hope. The field of “regenerative medicine” is taking off and there are new “Regenerative Medicine” and “Stem Cell” institutes and centers being established all over the country. Many scientific dogma have been slain in the past 5 years. One dogma was that new neurons are not born in the brains of humans-in other words, you just steadily lose what you have as you age. However, in a set of clever experiments by Drs Ericksson and Gage in1998 it was shown that humans even in their 60s can make new nerve cells in their hippocampus, a comforting fact for all of us. Moreover, mice make more new neurons if they are kept in an “enriched” environment and exercise (Kempermann, 2002). If we can extrapolate these findings to humans, it suggests that by keeping our minds active we are less likely to lose them. We also now know that new neurons can be made in response to a brain injury in other parts of the rodent brain, not just the hippocampus. For example, after a stroke, new neurons are born and travel to the damaged tissue and appear to aid in its repair (Arvidsson, 2002). Now we have to learn how to enhance and stimulate these natural repair mechanisms. Adult stem cells can be obtained from a variety of organs ranging from the brain (so called neural stem cells) to the skin. However, the best studied and most accessible adult stem cells are in the bone marrow. Bone marrow is a rich source of stem and progenitor cells. I will briefly review the potential of adult or non-embryonic stem cells to treat human disease. I will focus on bone marrow stem cells. As a physician my perspective is on the clinical potential of these advances and my motivation is to see some of these cells used to treat these devastating neurological diseases that I see every day. As a physician-researcher, I am trying to make some small contributions to the stroke recovery field thanks to past support from the American Heart Association and currently the NIH. Bone marrow contains two major types of stem or progenitor cells and maybe many more. The two major types are the hematopoietic stem cells and the mesenchymal stem cells or marrow stromal cells. Hematopoieitc stem cells have been used for years in bone marrow transplants and have cured thousands of patients with leukemias and other forms of cancer. These hematopoietic stem cells and their progeny- the white blood cells, red blood cells and platelets- have the ability to circulate throughout the bloodstream and reach every organ in the body. Their plasticity, that is, the ability of these cells to “turn “into other cell types such as nerve cells, liver cells and pancreas cells that produce insulin, is still hotly debated. However, there is evidence that these cells can rarely differentiate into Purkinje cells in the brain, a very sophisticated type of neuron. The phenomenon is not restricted to rodents; there is now autopsy evidence from humans that bone marrow cells are involved in the formation of neurons at a low level (Mezey, 2003) Some recent evidence had suggested that cell fusion was responsible for some of the plasticity that had been described for bone marrow stem cells (Terada, 2002; Wang, 2003; Vassilopoulos, 2003). In cell fusion, the bone marrow cells would not actually “turn into” another cell type-they would just fuse with the mature cell giving it twice the number of chromosomes and thereby making it potentially unstable. However, while cell fusion may indeed account for some of the “ plasticity” of bone marrow cells, particularly in the liver, it does not seem to account for all of it. In recent work, bone marrow cells have been shown to become functional insulin-secreting cells in the pancreas of mice without any evidence of cell fusion.(Ianus, 2003). There may also be bone marrow-derived cells that circulate in the peripheral blood with “stem cell” or “progenitor cell” qualities. Recently the progeny of the hematopoietic stem cell, a subpopulation of circulating blood monocytes, have been shown to be able to differentiate into nerve cells and blood vessel cells called endothelial cells (Zhao, 2003). This is potentially of great clinical relevance as monocytes are easy to isolate from human blood and could be a rich source of replacement cells. There are also bone marrow cells that do not normally circulate in the bloodstream but instead reside in the bone marrow and serve as supporting cells for the hematopoietic stem cells. These cells are called mesenchymal stem cells or marrow stromal cells. It is these cells that are the source of much excitement in the field of regenerative medicine. Some of the most exciting research, in terms of an eventual human clinical application, are the Multipotent adult progenitor cells (MAPC) isolated by Catherine Verfailie and described comprehensively in the July 2002 issue of Nature ( Jiang, 2002). These cells can be isolated from rodent and human bone marrow. They are able to differentiate into cells of all three germ layers (endoderm, mesoderm and ectoderm ) that is they can from endothelial cells or blood vessel lining cells, hepatocytes (liver cells), and nerve cells. They not only do this in the petri dish, they also do it in the live animal. Moreover, they do not senesce or die prematurely and importantly they do not form teratomas or tumors like embryonic stem cells tend to do. Dr Walter Low a collaborater of Dr Verfaillie has shown that these MAPCS can aid in brain repair after stroke in a rodent (Zhao, 2002). The obvious advantages of these cells for regenerative medicine is their easy isolation from human bone marrow and the potential for a patient to be their own donor without fear of rejection. A closely related cell type is the marrow stromal cell. Marrow stromal cells have been shown to be involved in brain repair after stroke and traumatic brain injury by Dr Chopp at Henry Ford Hospital and to repair the injured spinal by Dr Darwin Prockop’s group at Tulane. Like many other adult stem cells, these cells can be delivered intravenously and then “home” like a guided missile to the injured tissue. There are chemical signals released by injured tissue that attract these cells. Marrow stromal cells are easy to culture, easy to expand, and since they are autologous they would not be rejected. How exactly these cells repair injured tissue is not clear. While in some cases this is actual replacement of damaged cells, it seems more likely that these cells serve as growth factor “factories” and aid the tissue to repair itself by reactivating latent developmental programs. There is also another type of circulating bone marrow-derived cell, the endothelial progenitor cell (EPC) that has also attracted much recent interest. Endothelial cells are cells that line all the blood vessels of the body. Besides being mere conduits for blood, we now know that they play an active and necessary role in the development and sustenance of the body’s organs. Bone marrow cells that can circulate in the bloodstream and form new endothelial cells and blood vessels were first described and characterized in 1997 (Asahara). We now know that these EPCS contribute to vessel and organ repair after ischemia to the heart, limbs and brain (Rafii, 2003). This is critically important as cardiovascular disease and stroke are two of the three biggest killers in the U.S. We have learned that by giving animials extra doses of these EPCS, we can improve their outcome from heart attack and salvage their limbs that are starved for blood.. Also, these EPCs can be mobllized from the bone marrow and into the peripheral blood with drugs and different growth factors . Some of these growths such G-CSF are already approved by the FDA for other indications The field is moving fast. Bone marrow-derived stem cells are already being tested in small numbers of patients with heart attacks. In the TOPCARE trial, bone marrow cells harvested from the same patient’s bone marrow or their blood were delivered via a catheter in the coronary artery to injured heart tissue (Assmus, 2002). The procedure was safe and initial results were encouraging. There is also a trial using bone marrow cells in patients with congestive heart failure (Perin, 2003). Another type of bone marrow or blood stem cell is the human umbilical cord stem cell. These are derived form umbilical cords that are normally discarded after a delivery. Umbilical cord blood is a rich source of stem cells. These have already been exploited as a source of bone marrow transplants in the cancer field. These umbilical cord stem cells also have great potential as a treatment for neurological diseases. When delivered intravenously to a rodent with a stroke, they help improve the recovery from the stroke (Chen, 2001). Despite these hopeful signs, much work needs to be done. Before we are able to treat humans safely and effectively, we need to define the optimal dosing of these cells, the optimal type of bone marrow populations to use, the timing of when to administer, and the best route of administration (inject directly into the organ, intravenously, intra-arterially). We also need to learn more about how they these bone marrow cells and other adult stem cells home to damaged tissue so we can exploit this therapeutically. The major advantages of bone marrow derived stem cells are: 1.) they are autologous (except for umbilical cord stem cells) and will not be rejected; 2) they can be easily isolated from bone marrow aspirates: and 3) they avoid the ethical concerns that many have with embryonic stem cells. However, we also have to keep in mind that repairing the nervous system is a daunting task. Neurons make tens of thousands of connections with other neurons. Some send their projections (axons) for meters and then connect to another cell. In most of the experiments so far we have little evidence that stem cells delivered into an adult will be able to make all these connections and become fully functional. It is likely that most of the cell transplants in the brain work by stimulating the brain to repair itself. We need to learn more about enhancing these endogenous (self) repair processes. In this growing field of “Cell Therapy”, we will need to target diseases with specific cell types and approaches-one size will not fit all. We may need to treat some of these diseases with a combination of both “cells” and growth factors. The treatments we develop for Parkinson’s disease will be different from those we develop for stroke. There are no magic bullets-only painstaking research will allow us to advance. References Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002 Sep;8(9):963-70. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM.Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997 Feb 14;275(5302):964-7. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM; Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction.Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002 Dec 10;106(24):3009-17. Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 2003 Apr 4;92(6):692-9 Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J, Chopp M.Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 2001 Nov;32(11):2682-8. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998 Nov;4(11):1313-7 Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L.Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2199-204. Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Inest 2003 March 111(6): 843-50 Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow.. Nature 2002 Jul 4;418(6893):41-9 Kempermann G, Gast D, Gage FH.Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol. 2002 Aug;52(2):135-43. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. 2002 Aug 27;59(4):514-23 Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B. Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1364-9 Perin EC, Geng YJ, Willerson JT. Adult stem cell therapy in perspective. Circulation. 2003 Feb 25;107(7):935-8. Rafii S, Lyden D.Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003 Jun;9(6):702-12. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002 Apr 4;416(6880):542-5 Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003 Apr 24;422(6934):901-4 Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003 Apr 24;422(6934):897-901 Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002 Mar;174(1):11-20. Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2426-31

• Dr. Jean D. Peduzzi-Nelson, Ph.D.
  Read statement

  Testimony

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

  Thank you Senator Brownback and Senator McCain and distinguished senators of the subcommittee for the invitation to present to you today. Stem cells are a major medical breakthrough with tremendous potential but we are now at a ‘Y in the road’ as far as the future of medicine. In deciding our course, the way is clouded by opposing ethical views, vested interests of certain scientists & the biotech community, political allegiances and celebrities. I would like the members of the subcommittee and the audience to set aside all those factors for just a few minutes. I ask you now to think about a very basic question: If your loved one was suffering from a terrible injury or disease, what type of stem cell treatment do you think would work the best: 1) their own cells or 2) cells derived from embryos, fetuses or cloned embryonic cells? I don’t think you need to be a scientist to answer that question. It also turns out that if you look at the scientific evidence, not speculation about the future by prominent scientists on either side of the issues, but just the facts of where we are today based on clinical and preclinical trials, the logical choice in medical treatment is also the best medical treatment. Stem Cells Disease transmission Slower rate of growth Uncontrolled growth More restricted development Ethical objections Less funding opportunities Possible rejection More difficult commercialization Embryonic or Fetal Stem Cells Cloning Cloned Stem Cells Person’s Own Stem Cells Treatments for Wide Variety of Diseases and Injuries I would now like to review the scientific data that prove that an intuitively obvious concept is also supported by the results of recent clinical trials and preclinical trials (experimental animal studies). First, I would like to review the clinical trials using stem cells and their derivatives in spinal cord injury and Parkinson’s disease. Two clinical trials using fetal tissue have been done in the US and one on-going clinical trial in Portugal using a person’s own tissue. All of these spinal cord injury trials are important to the question of stem cell research because the cells that survive after the tissue transplant are the stem cells and their early derivatives. The mature cells in the tissue except for some support cells would die off. The first study using fetal tissue was done at the University of Florida, beginning in 1997, in the treatment of syringomelia - a condition in which a large cavity forms in the spinal cord. Minced spinal cords (SC) from 4-8 different human fetuses taken from elective abortions were grafted into the cavity in the spinal cord. At 18-month follow-up of the first 2 patients, the condition of the patients was not very different . Another study was performed more recently using pig fetal tissue at Washington University and SUNY/Albany. There have been no further announcements regarding this study although the first patient was done in April 2001 . The study in Portugal has had impressive results using a person’s own olfactory mucosa . The olfactory mucosa lines the upper nasal cavity and contains stem cells and cells that encourage growth of nerve cell processes called olfactory ensheathing cells. Patients with severe (complete) spinal cord injuries were operated at 6 months following the injury. Other patients in this study (not reported below) were up to 7 years post-injury with similar or better results. On the next page are the charts comparing the results from the first 2 patients from each of the 2 different trials. In comparing the results of using embryonic tissues or using one’s own tissue: 1) There was little change in the condition of the patients using the embryonic tissue. There appeared to be no massive rejection even though 4-8 different embryos were used for each patient in the University of Florida trial and no reports of rejection in the trial using pig cells used in Washington University and SUNY/Albany. 2) In the Portuguese study, there were increases in motor and/or sensory scores by 1 month in almost all the patients receiving their own olfactory mucosa suggesting that a person’s own tissue is more effective. The first patient done regained bladder control at 16 months after the treatment and no longer uses catheters. The second patient that had less improvement was the patient that had the largest lesion (6 cm) of all of the patients done so far. The changes observed might have been greater for the patients treated in Portugal if rehabilitative therapy was available there. 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. In both cases, the cells were matured in culture before being transplanted into the patient. A clinical trial was done by Dr. Freed and colleagues in which 19 patients received cells derived from 4 different fetuses with 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). About 15% of these patients showed severe decline in function at 1 year after treatment. In another Parkinson’s study done by Dr. Michel Levesque, the patient who was 57 years old at the time of treatment, received cells derived from his own brain stem cells . This patient showed an 83% improvement in the UPDRS. Below is a chart that summarizes the percentage improvement in the 2 clinical trials. The greater improvement and lack of harmful late effects using a person’s own cells is primarily due to the fact that the cells were derived from an adult as opposed to fetuses. Of lesser contribution to the overall improvement probably was that the cells were genetically identical and not rejected. There was no evidence of massive rejection in any of the studies using fetal cells/tissues, even when pig cells were used without long-term immune-suppressing drugs to prevent rejection. However, better results were obtained using person’s own adult cells. The study by Freed and colleagues also suggests that the primary problem with the fetal cells is not rejection. Using cells derived from fetuses, the severe functional deterioration seen in several patients was due to overgrowth of the cells derived from fetuses, not a lack of cell survival. It is rather ironical that the qualities cited for the superiority of embryonic or fetal stem cells are actually responsible for causing problems. Rapid growth is not always a desirable quality as clearly seen with weeds in a garden or cancer in the body. In the Parkinson’s study, cells derived from the embryo and the adult were both allowed to mature in culture, but the end result was quite different. As the graph demonstrates, the patient’s own cells markedly improved and no debilitating side effects were observed. A possible explanation for these findings is that adult stem cells are the natural components of the adult body and endogenous mechanisms exist to control their growth and maturation to replace damaged neurons . The cells from the adult may have certain molecules on their surface (ligands or receptors) that keeps the cells from uncontrolled growth. Both studies allowed the stem cell to mature before implantation. If maturation of stem cell is a necessary safety step, then the fact that embryonic cells are so immature is a disadvantage. It would be possible and simpler to have large-scale commercialization of cells derived from embryos or fetuses but the end product would be grossly inferior for the recipients. There are many types of adult human stem cells that are readily available that lack the problems of overgrowth, rejection, and disease transmission. Most people do not need a total body replacement. Even if costly and complicated procedures of cloning are done to produce the human stem cells (not technically possible yet), the cells will not be genetically identical because of the mitochondrial DNA and improper imprinting. There is evidence that the debate is raging in the scientific community. A recent scientific article describing a clinical trial included an opinion that the authors, although using a patient’s own blood stem cells, in no way support a ban on using human embryonic stem cells . Preclinical Trials: Preclinical trials (experimental animal studies) not only provide the basis for future clinical trials described above, but also support the same conclusion that is reached in reviewing the clinical trials. There is abundant evidence that adult stem cells can be used as a therapy and are readily available in people. The conclusion from the preclinical studies is that adult stem cells work just as well, if not better, than embryonic stem cells and are probably safer . There is no need for embryonic stem cells especially cloned ones. Ten years ago, it was discovered that stem cells exist in the adult brain and spinal cord and can be readily isolated , . Many initial ideas about adult stem cells in the brain were wrong. For example, the cells were first thought to only be present in rodents, but later found in people . It was once thought that only embryonic stem cells have the capacity to become many different cell types. More recently, it has been found that neural stem cells from adults have this potential . Stem cells and their cellular derivatives may be useful in many ways. In the nervous system, they can be replacement neurons, source of growth factors, or a substrate of growth. Another misconception was that adult stem cells might not be functional in their ability to transmit a signal to another neuron. There is recent evidence that adult stem cells can mature and form functional connections with other neurons in culture , . A surprising finding was that many cells in the adult (not just the cells in the brain and spinal cord) have the potential to be neurons. Sources of adult human stem cells that are capable of forming neurons include the brain , , olfactory mucosa in the upper nose , , cornea , choroid and sclera of the eye, teeth , bone marrow , , and skin . Further evidence that bone marrow can be a source of neurons for the brain is supported by findings in the patients’ brains who have received bone marrow transplants . There is no reason to use embryonic/fetal tissue or to clone people to obtain genetically similar embryonic stem cells when there is a ready supply of stem cells in adult humans. There are several studies that support the usefulness of adult stem cells. Stem cells obtained from adult spinal cord have been shown to survive and mature into neurons when transplanted into the brain . 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 using 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 IV caused a functional improvement when injected into experimental animals with traumatic brain injury or stroke , . 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 vehicle to deliver genes to the brain , , , . 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 IV and caused a functional improvement Below is a brief summary (in italics) of recent findings using other treatments besides stem cell for injuries and diseases of the nervous system. This summary is meant to make 2 major points: 1) Other treatments used alone or in combination with adult stem cells may hold the greatest promise in treating spinal cord injury and other damage to the nervous system. 2) While there is no ban on animal cloning, a review of recent literature revealed more than 40 articles of promising treatments other than stem cells for spinal cord injury but only 1 or just a few articles showing any therapeutic benefit of therapeutic cloning. The one article that received significant press coverage attempted to show a benefit of cloning in an animal study also revealed some of the difficulties with this procedure . Other cell types: Other cell types that do not form neurons also help in recovery. After selective demyelination in rat spinal cord, olfactory ensheathing cells myelinated axons and led to greater motor and somatosensory evoked potentials and a better functional outcome . Olfactory ensheathing cells promote locomotor recovery in the transected cord after delayed transplantation . These cells were also found to stimulate growth of motor axons . Olfactory ensheathing cells when used with methylprednisolone promoted functional recovery and axonal regeneration after lesioning of the corticospinal tract . Growth Factors: With the discovery of new growth factors such as neurotrophic factors and cytokines that influence the survival and growth of neurons, it was hoped that spinal cord injury could soon be treated. Brain-derived neurotrophic factor (BDNF) reduces the necrotic zone and supports neuronal survival after spinal cord hemisection in adult rats and suppresses apoptosis of oligodendrocytes . Also neurotrophin-3 (NT-3) enhances sprouting of corticospinal tract after adult spinal cord lesion even in chronic SCI . Basic fibroblast growth factor (bFGF) reduced the pathology observed in spinal cord injured rats receiving bFGF via the CSF following a spinal cord injury . Acidic fibroblast growth factor (aFGF) promote axonal growth between spinal cord slices and when combined with peripheral nerve segments led to improved locomotor function after spinal transection . Insulin growth factor 1 (IGF-1) stimulates myelin formation in the nervous system and also stimulates the production of neurons and synapse formation . In our own lab studies using cells derived from adult stem cells to treat rats with severe, chronic spinal cord injuries, significant functional improvement was observed when the factors (diff media) used for stem cells maturation are used alone. Further improvements are found when adult stem cell (SC) or IGF-1 is added to the treatment suggesting the benefit of combination treatments. Another cytokine, transforming growth factor-beta (TGF-beta) caused a decrease in the lesion size following SCI . Yet another cytokine, glial cell line-derived neurotrophic factor (GDNF) when incorporated in a fibrin glue promotes dorsal root regeneration into spinal cord . Metabolites such as inosine also appear to encourage growth of spared axons and possibly injured axons following spinal cord injury . The spinal cord distal to the injury consists of cells that are shrunken and appear unhealthy. One possibility is that this natural metabolite especially when used as part of a combination treatment may stimulate the growth of these cells. Many recent studies have used a combination of growth factors. The combination of EGF and bFGF showed better functional recovery than vehicle or either factor alone . Insulin-like growth factor (IGF) and epidermal growth factor (EGF) rescued motor neurons better than each individually even when delivered after 4-week delay . Although significant stimulation of axonal growth is observed with growth factors, problems in delivery, penetration, and down-regulation or truncation of receptors have perhaps kept their full potential from being realized. Gene therapies: To overcome the problem of the growth factors actually reaching the affected neurons, two strategies have been taken. First, certain cell types have been modified to produce growth factors then grafted into the injury site. Second, endogenous cells have been genetically modified primarily using virus vectors. Fibroblasts genetically modified to produce BDNF or NGF support regrowth of chronically injured axons. The in vivo transfer of GDNF cDNA can promote axonal regeneration and enhance locomotion functional recovery . Neurotrophin-secreting Schwann cell implants improved urinary bladder structure after spinal cord contusion . NT-3 gene in an adenoviral vector was delivered to the spinal motoneurons by retrograde transport through the sciatic nerve, causing induced growth of axons from the intact corticospinal tract across the midline to the denervated side . Another approach is to actually stimulate one of the intracellular pathways that play a role in neurite outgrowth. Viral delivery of vectors carrying the mutated form of MEK1 that activates of the extracellular-signal-regulated kinases (ERKs) induces axonal regeneration across the transection site of the spinal cord in young rats . Newer approaches that direct transient production of growth factors specifically in motor neurons also hold great promise . Substrate or Matrix: There have been several studies that provide a substrate for growth is useful. Self-assembling peptide scaffolds support differentiation as well as extensive neurite outgrowth in culture . When a collagen tube is implanted into hemisected adult rat spinal cord, there is growth of the rostral spinal axons into the caudal ventral roots . Growth factor-treated nitrocellulose implants that bridge a complete transection lesion of adult rat spinal cord caused regrowth of ascending sensory axons across the traumatic spinal cord injury site . Implants using poly-beta-hydroxybutyrate (PHB) as carrier scaffold and containing alginate hydrogel, fibronectin, and Schwann cells can support neuronal survival and regeneration after spinal cord injury . Using a polymer scaffold seeded with stem cells led to better functional recovery in hemisected SC and appeared to encourage the growth of corticospinal axons . When a hydrogel is implanted into the injury site of a rat with chronic, severe SCI, there was improved function and evidence of blood vessels, and axonal growth . Modifying the Immune System: The immune system plays an important role in spinal cord injury. Many cytokines and other factors released by immune cells also influence neural cells. Several studies suggest a benefit of activated macrophages or specific T cells in reducing the amount of secondary injury and stimulating growth after spinal cord injury in rats . Recent clinical trials using activated macrophages are being conducted in Israel . However, others have found that activation of macrophages in a normal cord can actually cause axonal injury and demyelination and suggests inherent danger of activating the immune system after SCI . IL-10 is neuroprotective after a spinal cord injury . Another study found that IL-10 and MPS reduce the amount of damaged tissue but do not change functional outcome . Inhibitors and Scar: For many years, Schwab and colleagues explored the potential of the IN-1 antibody to block myelin associated inhibitory molecule, Nogo, after SCI. IN-1 caused improvement in function if given shortly after injury . Other myelin-associated inhibitors such as MAG have been described. Blockers of Nogo and MAG appear to cause functional improvement . Many suggest that the scar inhibits and have tried various inhibitors such as iron chelators . Beta-aminopropionitrile treatment that inhibits the formation of glial scar accelerates recovery of mice after spinal cord injury . Other efforts involve implantation of a collagen tube to interfere with scar formation . The semaphorins may be important contributor to the inhibitory effects of the scar . Rehabilitation: There has been tremendous progress in the field of rehabilitation with use of weight-supported treadmills , functional electrical stimulation and biofeedback. In our own lab, we found a statistically significant improvement in rats with a moderate degree of spinal cord injury that are placed in an enriched environment compared to standard caging . An enriched environment consists of a social environment where there is free access to novel items that include exercise equipment. My primary reason for being here today is that I don’t want victims of injuries and diseases to again become victims. The best chance of cellular treatment for them is using their own stem cells. Victims of injuries and diseases are again being used to justify a treatment that is not in their best interest. Both the clinical trials and pre-clinical trials suggest that adult stem cells and/or using one’s own stem cells is a more effective treatment for diseases and injuries. The data just keep accumulating that this is the direction to go despite the fact that most of the research is being done using embryonic stem cells in experimental animals or human cell lines . The least funded area is still ‘bench to bedside’ research using one’s own stem cells or using adult stem cells. Despite the fact that there are much fewer experimental studies using adult stem cells, amazing progress has been made as evidenced by the clinical trials. The idea that we should look to cloning for a treatment for diseases or injuries is way in the future. Despite all the claims of its promise there has been only 1 or 2 experimental animal study to suggest that this is a promising direction . We have at least 200 experimental animal studies in the field of spinal cord injury alone that show that a particular cellular, growth factor, or other treatment causes a functional or anatomical improvement and only 1 or 2 in the field of cloning despite the fact that there is no ban on performing animal cloning. With only a limited amount of funding available, more focus is needed in directing research funds to areas that can help people in the next 5-10 years and not several lifetimes away.

• Dr. Joanne Kurtzberg, M.D.

• Dr. John W. McDonald, M.D., Ph.D.
  Read statement

  Testimony

  Dr. John W. McDonald, M.D., Ph.D.

  Good afternoon Mr. Chairman and members of the Committee. I am Dr. John W. McDonald and I am an Assistant Professor in the Departments of Neurology, Neurological Surgery, Anatomy and Neurobiology and Director of the Spinal Cord Injury Program at Washington University School of Medicine in St. Louis. I am also a staff physician at Barnes-Jewish Hospital, the Rehabilitation Institute of St. Louis and St. Louis Children’s Hospital. I am here today on behalf of the Coalition for the Advancement of Medical Research*, a coalition of over 75 patient, scientific and university organizations dedicated to ensuring that all forms of stem cell research be allowed to be explored here in the United States. The Coalition started two years ago to ensure that stem cell research receives the same sorts of funding that all other research receives from the federal government. The group also is dedicated to ensuring that critical, cutting-edge research is not criminalized. As the director of the Spinal Cord Injury Program, I see thousands of children and adults with devastating spinal cord injuries. These patients have no real hope for recovering functions most of us take for granted, from bowel and bladder control to simply feeling a loved one’s embrace. And only some of the 11,000 people who get injured each year recover with traditional rehabilitation, which assumes that recovery is only possible after six months to 2 years. I am currently working on a variety of ways to treat patients with spinal cord injury or disease. For example, I’ve seen significant improvements in a very small group of patients using activity-based therapy, which relies on electrical stimulation to help patients exercise their paralyzed limbs. While significant, even those successes are minimal and extremely preliminary — it’s still unclear whether these techniques can help most spinal cord injuries, and to what extent they alone can restore function. We need to examine other promising approaches, and I believe that embryonic stem cells have the most potential. While adult stem cells also have potential for significantly improving clinical treatment of a wide range of diseases, I believe it is critical that we also explore the use of embryonic stem cells. If you compare stem cells to a tree, adult stem cells have already developed and specialized down a particular path, or limb. On the other hand, embryonic stem cells are still at the base of the trunk, ready to be guided down any of a number of limbs. It’s therefore much more feasible to try to encourage embryonic stem cells to develop into whichever type of cell is needed. As you can see from the video, we have already found encouraging support for the use of embryonic stem cells to cure or treat some of the most debilitating diseases. The two rats you see have the same injury, but the rat that received transplanted embryonic stem cells has recovered significantly more use of its hind legs and tail. My hope is that one day the patients I see in the Spinal Cord Injury Program will also be able to regain movement, just like the rat in this video. As a scientist, I cannot guarantee that embryonic stem cells will lead to cures and treatments. I can tell you, however, that they hold great promise. Science is a process in which we knock on 20 doors: Nineteen open with nothing behind them; One opens to reveal a pot of gold. We cannot predict which door will be that magic door. The field of stem cell research, whether it be embryonic, adult or cord blood stem cells, is still extremely new. It is entirely too early to rule out any one of these areas of research in favor of any other. My wheelchair bound patients should not have to wait for us to explore each possibility one at a time. In the years that have been spent debating the issue here in Washington, research that could one day lead to cures and treatments for so many diseases has been held back. Some senior researchers have either left the United States to work elsewhere or have decided to work in other areas of biomedical research. And many of the next generation of researchers has decided to stay away for these areas because of the uncertain political environment. Mr. Chairman, please allow all forms of stem cell research to move forward, adult, cord-blood and embryonic, so that we can continue to look for medicine’s pot of gold. * The Coalition is comprised of nationally-recognized patient organizations, universities, scientific societies, foundations, and individuals with life-threatening illnesses and disorders, advocating for the advancement of breakthrough research and technologies in regenerative medicine – including stem cell research and somatic cell nuclear transfer – in order to cure disease and alleviate suffering.

Witness Panel 2

• Mr. Stephen R. Sprague
  Read statement

  Witness Panel 2

  Mr. Stephen R. Sprague

  My name is Stephen Sprague and I am personally fortunate to have the opportunity of speaking with you today. In a life before leukemia, I've appeared before lots of committees, but never about matters affecting life or death. Today, I'm here wearing a proud new hat...that of a long-term adult cord blood transplant survivor, and my remarks are much more critical...for those like me in the cancer community, and I hope, for you who have an opportunity to help us now...not with more research, but by supporting proven patient applications. While you probably can't tell, I'm an aging baby boomer and was already a medical veteran before I got my leukemia diagnosis 7 years ago at age 47. I'm a diabetic and had survived a heart attack and quadruple bypass surgery in 1993. In spite of that, I was totally unprepared for a battle with cancer. This was November 1995. In those days, and even today with new experimental wonder drugs for cancer, chemotherapy only stalled what was inevitable for long-term survival...the traditional bone marrow transplant. "The Cure That Can Kill" as some of us have learned to call it. Since CML is usually a slowly-progressing, manageable cancer, I continued to seek a decent quality-of-life while mentally preparing for transplant...the only option. For whatever reason, in May 1997, only 18 months after my initial diagnosis, I found myself in blast crisis, the end-stage of this disease. After a rigorous few months in the hospital, my oncologist, Dr. Andrew Pecora, got me into my first remission while we began what would quickly become a frustrating marrow donor search. I soon discovered that less than a third of those seeking transplant have a matching sibling, the best and most obvious donor source. Since I was an only child, I needed to find an unrelated matching donor if a transplant were to even be an option for me. To make a very long and complicated story short, I was not one of the lucky ones to find an acceptable match in any of the marrow donor registries. "Enjoy your remission for as long as you can and get your affairs in order" I was told, "while we keep looking and try to figure something else out." This sad predicament is still an all-too-familiar one for many adult leukemians. Even now, far too many patients referred for a primary marrow donor search are unable to actually proceed to transplant due to the complexity of antigen matching, as well as the problems inherent in tracking down and eventually collecting the matching marrow from a hopefully still-willing and still-available donor. Fortunately for me, there soon came a series of events that, to this day, I find difficult to understand or describe. Just as I was beginning to lose my remission, my doctor, who directs Hackensack (NJ) University Medical Center's prestigious Stem Cell Transplant Program, was planning to begin one of the very first clinical trials for end-stage adult CMLers using neonatal stem cells obtained from umbilical cord blood. And equally astonishing, a perfect cord blood match was found for me within days, from the New York Blood Center's world-renowned Placental Blood Program, as it was known at the time. And in life-or-death struggles like these, days matter. Incredibly, some still-anonymous New York City mother had decided to do what few new mothers were doing back in those days...donating their newborn's cord blood to a public cord blood bank. It was that donation from a newborn baby girl that happened to be my one and only match. I entered the hospital on October 30th, 1997. Magic and miracles happened, including a pioneering treatment using cord blood. And by the grace of God, I was discharged 40 treacherous days later, December 8th, 1997, with a new, working immune system and no trace of leukemia. And no hair. Fast-forward a bit and here I am today...5 years, 7 months and 12 days later...with 100% donor cells, all-female chromosomes just like my donor, completely cancer-free and in relatively good health. And still not much hair. In my post-transplant activities as a patient advocate volunteer, I have come to learn a lot of things...about myself, about life and death, and about perspectives, appreciations and priorities. And most importantly, about hope. My point is simply this. Part of that hope for desperate patients seeking transplant...patients like I was...involves options. Heading down the transplant trail is a risky endeavor, even in the best of circumstances. But that critical first step can't ever be taken without first finding the right stem cell match. As you will come to appreciate, umbilical cord blood remains a largely untapped, non-controversial and readily available alternative source of non-embryonic, neonatal stem cells. That's the good news. That most of it continues to be trashed as medical waste instead of finding its way into a public cord blood bank remains the problem. A solvable problem. Registering the good intentions of prospective volunteer marrow donors has been one solution to providing stem cells to patients in need. Collecting and preserving the actual cord blood thanks to new parents willing and eager to donate at the time of delivery may be a better one. Or at least another viable option. As cord blood finds its way into the medical mainstream, it is my personal hope, shared by my cancer companions...the lucky ones as well as the less fortunate ones who have died searching for their elusive marrow match...that an infrastructure to assist patients nationwide can be created, regulated and funded to take better advantage of this natural and precious "gift of life." If more of those estimated 4 million new parents each year have a better opportunity to donate their newborn's cord blood, an important new donor bank can be created quickly, conveniently, without pain, and without controversy. And it remains my privilege to serve as living proof of the promise of cord blood for the adult leukemia community. Although we think of it as a children's disease, 90% of all leukemia cases are diagnosed in middle-aged adults. But regardless of age, cord blood is a proven alternative for saving lives that needs your support to become more readily available. Thank you for the opportunity to share my concerns with you and I would be happy to answer questions at the appropriate time. Stephen R. Sprague, Cord Blood Crusader PO Box 140676 Staten Island, NY 10314-0676 (718)556-5325 spraguecml@AOL.COM

• Mr. Keone Penn
  Read statement

  Witness Panel 2

  Mr. Keone Penn

  My name is Keone Penn. Two days ago, I turned 17 years old. Five years ago, they said I wouldn’t live to be 17. They said I’d be dead within 5 years. I was born with sickle cell anemia. Sickle cell is a very bad disease. I had a stroke when I was 5 years old. Things got even worse after that. My life has been full of pain crises, blood transfusions every two weeks, and more times in the hospital than I can count. The year before I had my stem cell transplant, I was in the hospital 13 times. I never was able to have a normal life. My stem cell transplant was not easy, but I thank God that I’m still here. I will graduate from high school this year. I want to become a chef because I love to cook. I think I’m pretty good at it. Sickle cell is now a part of my past. One year after my transplant, I was pronounced cured. Stem cells saved my life. Thank you.

• Mr. Steven L. Barsh
  Read statement

  Witness Panel 2

  Mr. Steven L. Barsh

  Good afternoon. Thank you for the opportunity to testify today on the very important topic of cord blood and why a National Cord Blood Stem Cell Bank Network should be provided for to save the lives of some of this great nation’s most severely ill children and adults. We first learned a little over 2 years ago that our one year old son Spencer had ALD or Adrenoleukodystrophy. 50% of ALD children have a deadly cerebral onset of this rare neurodegenerative disease leading to loss of function and death by age 10. The remaining 50% have a severe to deadly form as adults. A parent’s worst nightmare, this is the disease behind the film Lorenzo’s Oil. Spencer started to have repeated MRI brain studies and in February of last year, MRI studies showed changes had started in his brain indicating a deadly cerebral onset had begun. Cord blood and bone marrow transplants are the only “accepted” therapies when a cerebral onset of ALD has begun and is caught in time. Via the National Marrow Donor Program (NMDP) we had already been searching for a perfect 6/6 bone marrow match and couldn’t find one. Plus, we were looking at nearly 6 months before we could even get to transplant while Spencer would be deteriorating. Even if you find someone on the NMDP donor list, it doesn’t mean you can get to them quickly. It’s a heartbreaking and gut-wrenching process of calling in potential donors, having them screened, confirming they will go through surgery, etc. You loose precious time, waiting. Worse yet, more then 50% of people are turned away told there is no suitable donor for them. ALD, like many metabolic diseases, can move very quickly along its destructive path and deficit changes can sometimes be seen daily. This is particularly true for rare metabolic diseases such as Hurler’s, MLD, Tay-Sachs, and others – all diseases that can now be treated by a cord blood transplant. In metabolic diseases, lessening the time to transplant equals less deficits and a better transplant outcome. Time is enemy #1. In cord blood, the unit has already been typed, checked, prepped, and is waiting in a freezer right now. Spencer’s pre-transplant work-up testing started just 4 weeks after his bad MRI (only 5 days after my wife and I made the decision that he should be transplanted). There was no 6 months of waiting. We held on tightly to our 2 1/2 year old son Spencer while he was in a pediatric isolation and intensive care unit for nearly 40 days. There he received his cord blood stem cell transplant preceded by highly toxic medications including massive chemotherapy. He was lucky. He had what was considered an “easy course of transplant.” At the same time, we saw kids who didn’t make it as the procedure proved too toxic. While cord blood stem cells work for most of their very fortunate recipients, more research needs to be done. More and higher quality cord blood units need to be available not only for transplantation, but for research purposes; and stem cell research in general needs to be carefully and properly further explored to harness all of its life saving potential. His cord blood transplant was just 13 months ago, but who’s counting? He is doing extremely well. We see improvements and deficit reversal on a weekly basis. At only 6 months post transplant, physicians began to see improvements in Spencer’s MRIs as well as clinical presentation. It appears that Spencer is actually re-myelinating as the early progenitor stems cells from the cord blood are differentiating into other cells types in his brain. The MRI and clinical observations have been confirmed both at Duke and by a diverse team at the Children’s Hospital of Philadelphia (CHOP). I believe that the non-technical word they have used was “amazing” going on to say “They’ve never seen anything like this. We usually don’t see MRIs improve.” Cord blood works. With only 1/10th of the funding provided to the NMDP today, cord blood from a National Cord Blood Stem Cell Bank Network is a solution for the more then 50% of people who the NMDP turns away. These treatment options must be available to the children and adults who have these devastating diseases including malignant diseases. In closing: It’s important to remember that you can get to transplant with cord blood extremely quickly which is very, very critical with many diseases. The early progenitor stem cells in Spencer now appear to be differentiating into other cell types that are repairing problems in his brain. “Just amazing” is the term we hear time and again. At only 1/10th of the funding provided to the NMDP, A National Cord Blood Stem Cell Bank Network can be provided for so that this life saving technology, that works today, can be available to everyone in need. We now have a normal 3 year old son. His name is Spencer Barsh. Cord blood, saved his life. Thank you for your time and thoughtful consideration.