The Mystique of Stem Cells

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There is a great deal of discussion these days regarding the use of stem cells. As with any scientific discussion that enters the public domain, mass misinformation and exaggeration of facts is occurring. In this article we will seek to dispel much of the misinformation being propagated by various sources, and in the process educate the reader on what stem cells are, areas where they are being used clinically, and where the industry is headed in the coming years.

What are Stem Cells?

Our first task is to take a look at the science of stem cells. At the most basic level, a stem cell is a cell whose purpose is to generate new cells while having the ability to make copies of itself. Everyone has stem cells inside of them and while those stem cells serve a variety of purposes their main purpose is to repair the body. The potency and number of stem cells found in a person are in direct relation to their age. Thus, stem cells in a young person are found in higher numbers and have greater reparative capabilities than stem cells found in an older person. And herein lies one of the great debates about stem cells; potency vs. utility.

If it is true that the age of the stem cell has a direct impact on its potency then it must be the case that embryonic stem cells are more potent and thus have more therapeutic value (utility) than adult stem cells. There is little doubt that embryonic stem cells are more potent than adult stem cells. After all, what other cell in the body is capable of going from a single cell and transforming into a living, breathing human in 9 months? However, as is so often the case in life, one’s greatest strength is also their greatest weakness, and in the case of embryonic stem cells their potency is fraught with issues. That said, we now turn our attention to embryonic stem cells.

Embryonic Stem Cells

An embryonic stem cell is a cell that is derived from the inner cell mass of an embryo. The excitement so often talked about with embryonic stem cells is the fact that they are pluripotent, meaning they can become any of the 200 cell types found in the body. This gives way to many applications, perhaps the largest of which is the ability to generate organs. Science has clearly demonstrated their able to take an embryonic stem cell and create various stem lines from it (i.e. heart, liver, kidney).


And while it may be possible to create livers from an embryonic stem cell, the next question one must ask is could the livers be placed in humans without the majority of livers being rejected by the host? Further, due to the extreme potency of embryonic stem cells and the immature nature of the cell, can the energy be harnessed in such a way so as not to cause cancer? The evidence to date would indicate not, and we’ll make this clear through examining 3 fundamental scientific points that show:

  1. By virtue of their immaturity and heightened potency, embryonic stem cells cause cancer.
  2. While embryonic stem cells can create stem cell lines (i.e. liver, heart cells), that does not mean the lines contain the same characteristics and attributes of actual human tissue.
  3. Embryonic stem cell lines are not commercially viable because the lines can’t be genetically matched to the recipient and thus its highly likely they won’t be compatible with the recipients immune system.

1. Embryonic stem cells cause cancer.

The actual definition of an embryonic stem cell is based on its ability to cause the teratoma type of cancer in the mouse. Now what exactly is a teratoma? The word “teratoma” comes from Greek, and means “monstrous tumor .” This type of cancer occurs rarely in humans and is fatal if not surgically removed before spreading. Defendants of embryonic stem cells tell us that teratomas will not occur when embryonic stem cells are used in medicine, since it is not embryonic stem cells that are given to people, but embryonic stem cells made into specific tissues that the patient needs.


The problem with this argument is that biology is not perfect. Even if conceptually in 10 years it is possible to make functioning liver cells from embryonic stem cells, how will it be possible to purify 100% of the newly generated liver cells and have no left over cancer cells? It only takes one single cancer cell to cause a tumor to form. To this point, the defenders of embryonic stem cells will say that even if a tumor cell is left over, it will be rejected by the immune system.


Unfortunately teratomas possess mechanisms to “hide” from the immune system, whereas normal tissue does not. An example of this is a mouse study in which teratomas developed and were not rejected, while the few embryonic stem cells that did differentiate into heart tissue were rejected by the animal .

2. It is not possible to generate the equivalent of human adult tissues from embryonic stem cells.

The embryonic stem cell represents the fertilized egg. It has the same immaturity as the fertilized egg. During normal development it takes numerous biological processes to occur for a cell to “grow up” from the immature state of the fertilized egg to the maturity of a heart cell in a 63 year old person with heart disease. Since embryonic stem cells are so immature, it is naïve to think that by exposing the cells to certain chemicals we can “accelerate” their maturation from processes that take decades and make them occur in a much shorter period of time.


For example, embryonic stem cells treated with specific chemicals can mature into what resemble heart cells. The cells even beat in the test-tube! However, these cells are not true heart cells since many of the properties or characteristics of an adult heart cell are not possessed by these “accelerated maturity” cells. Accordingly, to date, no real tissue equivalent has been generated by embryonic stem cells.

3. Embryonic Stem Cells are not compatible with the Recipient.

Let us imagine that the problem of cancer, and the problem of lack of maturity, has been resolved. A very significant obstacle that few people talk about is the fact that the tissues generated from embryonic stem cells are not compatible with the general population. Humans are very unique from each other immunologically. This is why recipients of organ transplants are required to take drugs that suppress the immune system.


Even if people take immune suppressing drugs, the transplant surgeon will not perform the transplant unless the tissues are immunologically matched. The likelihood of finding immunologically matched organs is between 1in 100,000 to 1 in 10,000,000. At present there are approximately 100 embryonic stem cell lines, which are derived from approximately 100 individuals.


Therefore even through using immune suppressive drugs (which are toxic and have many side effects), the ability of embryonic stem cells to be used on a widespread basis is impossible. http://en.wikipedia.org/wiki/Teratoma Nussbaum et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J. 2007 May;21(7):1345-57

Adult Stem Cells

By most definitions, an adult stem cell is any other type of stem cell that is not embryonic. Another way to think of an adult stem cell is to classify them as any stem cell that is “post” birth. Those cells that are available “post” birth are thought to be mature, and that which is mature is called an “adult”. Stem cells that fall into the category of adult include stem cells derived from the bone marrow, cord blood, placenta, fat, and amnion.

“In Principle” Adult Stem Cell Therapy has Been Used for Decades

While embryonic stem cells have numerous drawbacks that limits their ability to be used clinically, adult stem cell therapy has been used for decades. We are referring here to the procedure of bone marrow transplantation, which essentially is transplantation of bone marrow stem cells. The bone marrow contains a type of stem cell called the “hematopoietic” cell, which means “hema” = blood, “poietic” = forming.


The concept of bone marrow transplantation is to completely eradicate the malignant stem cells circulating in the patients bone marrow and replace these stem cells with stem cells from a healthy donor. The elimination of the malignant cells is performed through administration of high dose chemotherapy and radiation. The healthy donor cells are then transplanted in the patient, effectively taking over the blood making and immune response process.

Despite the potential complications of bone marrow stem cell transplantation, this procedure has literally saved tens, if not hundreds of thousands of lives. After patients recover from the lag time between destruction of their own hematopoietic compartment and reconstitution of hematopoiesis by the donor stem cells (2 weeks to a month), and after they exit the “danger period” for GVHD (6 months to a year), many patients are essentially “cured” of their disease; patients whose prognosis otherwise would have been certain death.

GVHD is also known as Graft vs. Host Disease. GVHD is a common side effect of bone marrow transplants involving bone marrow from a different donor. This disease is characterized by the donated bone marrow attacking the host’s immune system and can affect many areas of the body; most notably the skin, eyes, stomach and intestines. The disease can range from mild to life threatening.

Mesenchymal Stem Cells- Leading the Path to Clinical Usage

One of the most advanced adult stem cells in clinical trials is the mesenchymal stem cell. Osiris therapeutics has patent rights on this cell type which classically is known for its ability to differentiate into non-hematopoietic cells. In contrast to the cells used for bone marrow transplantation, mesenchymal stem cells are known for their ability to differentiate into bone, cartilage, muscle (including cardiac), and neurons.


One of the main advantages of using mesenchymal stem cells is that according to various groups, including Osiris, these cells can be administered into a patient while coming from a “different source”, without having to worry about immune rejection and GVHD. This offers the possibility of developing these cells as an “off the shelf” therapy that can be acquired from the local pharmacy. Currently bone marrow derived mesenchymal stem cells are in Phase III clinical trials for Crohn’s Disease and GVHD, and Phase I cardiac trials using these cells have demonstrated very promising results.

In addition to their ability to become bone, cartilage, muscle, and neurons, mesenchymal stem cells have also demonstrated themselves to have a tremendous ability in silencing the body’s autoimmune response. In a phase II Crohn’s trial using mesenchymal stem cells, 33% of the patient population underwent clinical remission of the disease. Having demonstrated their ability to shut off certain pathological responses in the immune system while preserving the body’s ability to fight disease, using mesenchymal stem cells in the treatment of autoimmune diseases would appear to be an almost certainty.

Adult Stem Cell Issues

The only problem with adult stem cells is that these cells are usually not found at high enough concentrations in the areas where they are needed. If we consider people who have had a heart attack or stroke, they contain much higher concentrations of stem cells in their peripheral blood than healthy people. The reason for this is because the body enlists stem cells to migrate to the injured tissue in order to heal it. The problem is that in many cases there are not enough stem cells available to promote full healing.


Thus, if one could increase the number of stem cells in the body then theoretically, one could enhance the ability of the body to heal itself. And indeed, this appears to be possible, as numerous studies have shown that augmenting the body’s natural process through administration of adult stem cells is highly beneficial to patients. Examples of studies yielding positive data after adult stem cell administration include heart failure , peripheral artery disease , and Crohn’s Disease.

FDA clinical trials are broken into three phases; I, II, III. When a drug candidate successfully passes all three phases given FDA guidelines, the product is released to market as an approved therapy.


Abdel-Latif et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007 May 28;167(10):989-97 Hernandez et al. Autologous bone-marrow mononuclear cell implantation in patients with severe lower limb ischaemia: A comparison of using blood cell separator and Ficoll density gradient centrifugation. Atherosclerosis. 2006 Sep 15;

www.osiris.com

Current Clinical Usage of Stem Cells

While there are a few embryonic stem cell clinics operating across the world, the majority of practitioners are focused on the use of adult stem cells as this is the only stem cell type which has ample clinical data supporting both safety and efficacy in a variety of indications. Currently there are 20+ countries in the world where stem cell therapy is permissible and clinics are using adult stem cells for a wide variety of diseases, ranging from neurological, to autoimmune, to heart and peripheral vascular disease.


A sampling of the diseases being treated includes Stroke, Type II Diabetes, Rheumatoid Arthritis, Parkinson’s, MS, Autism, and Heart Disease. While the clinical data available for different indications varies in depth and breadth, there is a basis for clinical implementation based on the available published data. We will now look at three examples; Type II Diabetes, Heart Disease, and MS.

Type II Diabetes

Type II Diabetics are unable to control blood sugar levels, initially as a result of tissue desensitization to insulin, and afterwards as a result of pancreatic dysfunction. Although various oral and injectable medications exist to improve glycemic control, none of these methods reverses damage to the insulin producing cells in the pancreas.

Stem cell therapy has been demonstrated in numerous animal models to induce regeneration of damaged pancreatic beta cells; the cells that produce insulin. Work from Tulane University demonstrated that administration of mesenchymal stem cells was able to reduce insulin requirements in animals whose insulin producing cells were damaged by experimental toxic agents. Additionally, human studies from Argentina have reported positive responses in 85% of Type II Diabetics treated with bone marrow stem cells.

In addition to having the potential to regenerate pancreatic cells, adult stem cells are known to positively influence secondary complications of diabetes. For example, neuropathic pain caused by peripheral nerve damage has been demonstrated in animal studies to be reduced after stem cell administration. Additionally, stem cells provide new endothelial cells which conceptually increase vascular health and the ability to generate new blood vessels in tissues lacking oxygen.

Heart Disease

Heart diseases are typically characterized by tissue death, weakening of the heart muscles, and decreased blood supply to the heart. Current medical treatments provide symptomatic relief and in some cases slow down progression, however short of transplantation, none of the current approaches address the root cause or offer the possibility of regeneration. Recent studies have demonstrated that the failing heart secretes various chemical mediators that “call in” stem cells in an attempt to regenerate injured/malfunctioning tissue. Additionally, clinical studies have demonstrated that administration of stem cells can benefit patients with heart failure.www.stemcellsargentina.com


In a study conducted at Hanover Medical School in Germany , they found that the control group had increased LVEF of .7% whereas those given bone-marrow stem cells achieved an average of 6.7% increase in LVEF. In another study conducted at Navy General Hospital in Beijing, China fourteen patients underwent cell grafting. Those patients treated had symptomatic relief of heart failure within 3 days. Left ventricular ejection fraction increased by 9.2% and 10.5% at 1 week and 3 months after the procedure, respectively, versus baseline (p < 0.01 for the 2 comparisons). In addition, left ventricular end-systolic volume decreased by 30.7% after 3 months (p < 0.01).


The studies conducted have shown that stem cells have the ability to generate new blood vessels in heart tissue that is lacking oxygen. In situations such as heart failure, where the cardiac muscles are damaged or dysfunctional, stem cells have also demonstrated the ability to not only home into the damaged areas but also to initiate a cascade of biological events which culminate in healing of the muscle; thereby increasing the heart’s ability to pump blood throughout the body.

Multiple Sclerosis

Multiple Sclerosis (MS) is caused by an immune mediated attack targeting components of the myelin sheath. The myelin sheath is known to act as an “insulator” for neurons so that they can communicate properly with one another. Current approaches, such as interferon, copaxone, and immune suppressants all act in a non-specific manner blocking immune responses against the myelin sheath, but also block immune responses against pathogens such as bacteria and viruses.


While these approaches are useful for reducing the severity of disease, they do not repair damage to nervous system tissue that has already occurred or protect the patient from other potentially dangerous viruses or bacteria.

Adult stem cells have demonstrated in clinical trials that they have the ability to reprogram the immune system to stop attacking tissue, while at the same time promoting healing of the damaged tissue. Mesenchymal stem cells reprogram the immune system through production of a specialized type of T cell called the T regulatory cell. The biological role of these cells is to protect the body against auto-reactive immune responses, such as those seen in MS.


Patients with MS are known to have lower numbers of these protective cells and numerous studies have demonstrated that mesenchymal stem cells increase the number of these protective T regulatory cells, as well as their activity.Wollert, K.C., Meyer, G.P., Lotz, J., Ringes-Lichtenberg, S., Lippolt, P., Breidenbach, C., Fichtner, S., Korte, T., Hornig, B., Messinger, D., et al. 2004. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141-148.

Gao, L.R., Wang, Z.G., Zhu, Z.M., Fei, Y.X., He, S., Tian, H.T., Zhang, N.K., Chen, Y., Xu, H.T., and Yang, Y. 2006. Effect of intracoronary transplantation of autologous bone marrow-derived mononuclear cells on outcomes of patients with refractory chronic heart failure secondary to ischemic cardiomyopathy. Am J Cardiol 98:597-602.

The Future of Stem Cells

With reams of published data supporting the use of adult stem cells in the treatment of disease, adult stem cell therapy is a clinical reality now. Whether embryonic stem cells are validated through clinical trials and are then brought forth at a clinical level remains to be seen and is likely years away. With work underway in every corner of the globe there is little doubt that the industry will continue to evolve until one day the word stem cell is a commonplace term in the world of medicine.

The United States is years away from having all the data necessary to allow for widespread use of stem cells in the treatment of disease, leaving people with only one option; to travel outside the U.S. to countries where stem cell therapy is permissible. With 20+ countries accepting stem cell therapy as a viable medical protocol in the treatment of disease, adult stem cells are quickly gaining acceptance from the global medical community.

Bio:


One organization leading the way in the clinical application of adult stem cells is Cellmedicine. Cellmedicine is comprised of a series of clinics found in Costa Rica, Mexico, and Panama, and is looking to establish roots in India and Europe in the near to intermediate future. Cellmedicine differentiates itself from other clinics in that its vertically integrated, having the capacity to do every form of adult stem cell therapy available (i.e. fat derived, bone marrow, mesenchymal, cd34+) in addition to doing all laboratory and cell culturing work needed. To learn more about stem cell therapy, please visit
www.cellmedicine.com or go to www.clinicaltrials.gov to learn more about the clinical investigations currently underway.