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

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