Senate Commerce Subcommittee on Science, Technology, and Space – Testimony by Jean D. Peduzzi-Nelson, Ph.D.

Date: 07/14/2004

July 14, 2004

Jean D. Peduzzi-Nelson, Ph.D.

Department of Physiological Optics, University of Alabama at Birmingham

“The Truth is not Being Presented”

Summary

Money is the driving force in the effort to promote Federal funding of human embryonic stem cells or human cloning. 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 has patentable intellectual property. 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. 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 two 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 embryonic 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.

Many myths, untruths, and half-truths surround this controversy. The myth of the availability of countless frozen embryos in fertility clinics is just not true. In addition, 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. Although there are claims that most federal funding goes to adult stem cells, these figures include funding for adult stem cells for cancer and immune deficiency that have been used successfully for about twenty years. Much of the funding in new areas of stem cell research (spinal cord injury, diabetes, ALS, Alzheimer’s disease, etc.) is going to projects using embryonic/fetal stem cells.

Tremendous progress has recently been made using adult stem cells in clinical trials in treating diseases and injuries. Dr. Levesque at Cedars-Sinai showed an 80% improvement in treating Parkinson’s disease using a person’s own stem cells. Dr. Carlos Lima of Portugal has treated a number of spinal cord injured patients, including the American patients testifying today, with their own olfactory mucosa, and all of the patients have shown improvements. Adult stem cell clinical trials are proceeding slowly because of lack of funding, but show the most success.


Testimony

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.1 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
  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,3,4 and disastrous results have been reported in 2 separate clinical trials,5,6 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.7,8
  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 Reagan9: .
  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,10,11 bone marrow,12 muscle13 or skin cells.14 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.15
  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 colleagues16 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.17
  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.18 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.19 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.20
  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.21 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.22 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.23
  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.24 In the case of diabetes, there is an exciting new drug called liraglutide that seems promising in type 2 diabetes.25 In a recent study using a mouse model of Parkinson’s disease, therapeutic immunization using immune cells prevented nerve cells from dying.26 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.27
  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.28 Transplantation of stem cells from adult human brain causes myelination to occur in a focally demyelinated spinal cord of the rat.29 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 cells30 or neural stem cells.31 Human brain adult stem cells can even be obtained after death,32 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,33,34 as well as other cell types.35 Human umbilical cord blood injected intravenously caused a functional improvement when injected into experimental animals with traumatic brain injury or stroke.36,37 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 intravenously39 and caused a functional improvement.40
  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 mice41 and humans. More recently stem cells have been used as vehicles to deliver genes to the brain.42,43,44,45 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.

Before Treatment. After Olfactory Mucosa Transplant.
 

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.

References

1 Marshall, E.(2000) The Business of Stem Cells, Science, 287:1419-1421.

2 The Ledger.com, Lakeland, FL, Published Thursday, May 20, 2004, “Venture capital money backs California stem cell measure”, PAUL ELIAS.

3 L.M. Bjorklund et al.; “Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model,” Proc. Natl. Acad. Sci. USA 99, 2344-2349; 19 Feb 2002.

4 F Nishimura et al.; “Potential use of embryonic stem cells for the treatment of mouse Parkinsonian models: improved behavior by transplantation of in vitro differentiated dopaminergic neurons from embryonic stem cells”; Stem Cells 21, 171-180; March 2003.

5 Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. New Engl. J. Med. 344:710-9.

6 Olanow CW. Goetz CG. Kordower JH. Stoessl AJ. Sossi V. Brin MF. Shannon KM. Nauert GM. Perl DP. Godbold J. Freeman TB. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. [Clinical Trial. Journal Article. Randomized Controlled Trial] Annals of Neurology. 54(3):403-14, 2003.

7 Sutcliffe, A.G, D’Souza SW, Cadman J, Richards, B, McKinlay IA, Liberman B (1995) Minor congenital anomalies, major congenital malformation and development in children conceived from cryopreserved embryos. Hum Reprol. 10: 3332-3337.

8 DeBaun, E.L Niemitz and A. P. Feinberg (2003) Association of In Vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am. J. Hum. Genet. 72: 156-160.

9 PERSONHOOD PROCLAMATION, National Sanctity of Human Life Day,1988,
By the President Reagan, A Proclamation:.

10 Vescovi AL. Parati EA. Gritti A. Poulin P. Ferrario M. Wanke E. Frolichsthal-Schoeller P. Cova L. Arcellana-Panlilio M. Colombo A. Galli R. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Experimental Neurology. 156(1):71-83, 1999.

11 Song HJ. Stevens CF. Gage FH. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nature Neuroscience. 5(5):438-45, 2002.

12 Keene CD. Ortiz-Gonzalez XR. Jiang Y. Largaespada DA. Verfaillie CM. Low WC. Neural differentiation and incorporation of bone marrow-derived multipotent adult progenitor cells after single cell transplantation into blastocyst stage mouse embryos. [Journal Article] Cell Transplantation. 12(3):201-13, 2003.

13 Romero-Ramos M. Vourc’h P. Young HE. Lucas PA. Wu Y. Chivatakarn O. Zaman R. Dunkelman N. el-Kalay MA. Chesselet MF. Neuronal differentiation of stem cells isolated from adult muscle. Journal of Neuroscience Research. 69(6):894-907, 2002.

14 Toma JG. Akhavan M. Fernandes KJ. Barnabe-Heider F. Sadikot A. Kaplan DR. Miller FD. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nature Cell Biology. 3(9):778-84, 2001.

15 Jiang Y. Henderson D. Blackstad M. Chen A. Miller RF. Verfaillie CM. Neuroectodermal differentiation from mouse multipotent adult progenitor cells. Proceedings of the National Academy of Sciences of the United States of America. 100 Suppl 1:11854-60, 2003.

16 Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. New Engl. J. Med. 344:710-9.

17 Olanow, C.W., Goetz, C.G., Kordower, J.H., Stoessl, A.J., Sossi, V., Brin, M.F., Shannon, K.M., Nauert, G.M., Perl, D.P., Godbold, J., et al. 2003. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Annals of Neurology 54:403-414.

18 L.M. Bjorklund et al.; “Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model,” Proc. Natl. Acad. Sci. USA 99, 2344-2349; 2002.

19 F Nishimura et al.; “Potential use of embryonic stem cells for the treatment of mouse Parkinsonian models: improved behavior by transplantation of in vitro differentiated dopaminergic neurons from embryonic stem cells”; Stem Cells 21, 171-180; March 2003.

20 Morshead, C.M., P. Benveniste, N.N. Iscove and D. van der Kooy (2002) Hemapoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nature Medicine 8:268-273.

21 Tang, D-Q, L-Z Cao, B.R. Burkhardt, C-Q Xia, S.A. Litherland, M.A. Atkinson, and L-J Yang (2004) In Vivo and In Vitro Characterization of Insulin-Producing Cells Obtained From Murine Bone Marrow. Diabetes 53:1721-1732.

22 D’Ippolito G. Diabira S. Howard GA. Menei P. Roos BA. Schiller PC. Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. Journal of Cell Science. 117(Pt 14):2971-81, 2004.

23 Soria B. Roche E. Berna G. Leon-Quinto T. Reig JA. Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. [Journal Article] Diabetes. 49(2):157-62, 2000.

24 Stem Cells An Unlikely Therapy for Alzheimer’s Reagan-Inspired Zeal For Study Continues By Rick Weiss, Washington Post, June 10, 2004; Page A03.

25 www.glucagon.com/liraglutide.htm.

26 Benner, E.J., R. L. Mosley, C.J. Destache, T.B. Lewis, V. Jackson-Lewis, S. Gorantla, C. Nemachek, S. R. Green, S. Przedborski, and H.E. Gendelman Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. PNAS, 2004.

27 Black, H. UAB’s first islet-cell transplant a success, UAB Reporter, vol. 28(27), April 26, 2004.

28 Y.-Y. Jang, M.I. Collector, S.B. Baylin, A.M. Diehl, S.J. Sharkis, Hematopoietic stem cells convert into liver cells within days without fusion. Nature Cell Biology: 6, 532-539, 2004.

29 Akiyama Y; Honmou O; Kato T; Uede T; Hashi K; Kocsis JD: Transplantation of clonal neural precursor cells derived from adult human brain establishes functional peripheral myelin in the rat spinal cord. Exp Neurol 167:27-39, 2001.

30 Hou LL. Zheng M. Wang DM. Yuan HF. Li HM. Chen L. Bai CX. Zhang Y. Pei XT.[Migration and differentiation of human bone marrow mesenchymal stem cells in the rat brain].Sheng Li Hsueh Pao – Acta Physiologica Sinica. 55(2):153-9, 2003.

31 Liker MA. Petzinger GM. Nixon K. McNeill T. Jakowec MW.Human neural stem cell transplantation in the MPTP-lesioned mouse. Brain Research. 971(2):168-77, 2003.

32 Palmer TD. Schwartz PH. Taupin P. Kaspar B. Stein SA. Gage FH. Cell culture. Progenitor cells from human brain after death. Nature. 411(6833):42-3, 2001.

33 Sanchez-Ramos JR. Song S. Kamath SG. Zigova T. Willing A. Cardozo-Pelaez F. Stedeford T. Chopp M. Sanberg PR. Expression of neural markers in human umbilical cord blood. Experimental Neurology. 171(1):109-15, 2001.

34 BuzaAska L. Stachowiak E. Stachowiak M. DomaAska-Janik K.Neural stem cell line derived from human umbilical cord blood – morphological and functional properties. Journal of Neurochemistry. 85 Suppl 2:33, 2003.

35 Goodwin HS. Bicknese AR. Chien SN. Bogucki BD. Quinn CO. Wall DA. Multilineage differentiation activity by cells isolated from umbilical cord blood: expression of bone, fat, and neural markers. Biology of Blood & Marrow Transplantation. 7(11):581-8, 2001.

36 Lu D. Sanberg PR. Mahmood A. Li Y. Wang L. Sanchez-Ramos J. Chopp M. Intravenous administration of human umbilical cord blood reduces neurological deficit in the rat after traumatic brain injury. Cell Transplantation. 11(3):275-81, 2002.

37 Sanberg PR. Chopp M. Willing AE. Zigova T. Saporta S. Song S. Bickford P. Garbuzova-Davis S. Newman M. Cameron DF. Sanchez-Ramos J.Potential of umbilical cord blood cells for brain repair. Journal of Neurochemistry. 81 Suppl 1:83, 2002.

38 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. Proceedings of the National Academy of Sciences of the United States of America. 99(4):2199-204, 2002.

39 Akiyama Y. Radtke C. Honmou O. Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. [Journal Article] GLIA. 39(3):229-36, 2002.

40 Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M.(2001) Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 12:559-63.

41 Shen JS. Watabe K. Ohashi T. Eto Y. Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements. Gene Therapy. 8(14):1081-7, 2001.

42 Schwarz EJ. Reger RL. Alexander GM. Class R. Azizi SA. Prockop DJ. Rat marrow stromal cells rapidly transduced with a self-inactivating retrovirus synthesize L-DOPA in vitro. Gene Therapy. 8(16):1214-23, 2001.

43 Nakano K. Migita M. Mochizuki H. Shimada T. Differentiation of transplanted bone marrow cells in the adult mouse brain. Transplantation. 71(12):1735-40, 2001.

44 Park KW. Eglitis MA. Mouradian MM. Protection of nigral neurons by GDNF-engineered marrow cell transplantation. Neuroscience Research. 40(4):315-23, 2001.

45 Ehtesham M. Kabos P. Gutierrez MA. Chung NH. Griffith TS. Black KL. Yu JS. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Research. 62(24):7170-4, 200.

{
Adult/73
|
Embryonic/0
}