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Embryonic Stem Cells: Relevance to Pharmacy Practice and Formulation of Health Care Policies
J. Douglas Coffin, Ph.D.
Department of Biomedical & Pharmaceutical Sciences, Skaggs School of Pharmacy, College of Health Professions & Biomedical Sciences, The University of Montana, Missoula, MT 59812. Email: douglas.coffin@umontana.edu. Ph: 406-243-4723.
Why should a pharmacist care about stem cells?
Health care news and science columns across the world have been buzzing with the latest news about stem cell biology including political implications, scientific breakthroughs and the overriding ethical considerations about this “new” and promising technology. So what is all the fuss about and why should a practicing pharmacist care? There are two essential reasons why a pharmacist should spend their valuable time and effort to learn the basics about stem cell biology. First, in practical terms a pharmacist is likely to be dealing with patients undergoing stem cell transplants now or in the very near future. Like all other medical treatments involving drug therapies, the pharmacist should have a basic, background knowledge regarding the procedure involved and the pharmacological ramifications of the medication(s) they are dispensing. Second, the stem cell debate has political and ethical considerations that health care professionals should be fully informed of when they are asked to formulate policies in professional and public organizations, offer opinions or provide commentary. In both cases it is essential to know the facts regarding stem cell biology and therapeutics. The caveat here, as with any controversial issue, is that the essential “facts” can be subject to change.
What are stem cells?
To understand stem cells, first recall the basics of mitosis or cell proliferation when the “parent” or progenitor cell produces two “daughter” cells (Figure 1). Second, 
envision cell “differentiation” where a cell can change its phenotype to become another type of cell. A good example of cell differentiation occurs in hematopoeisis where a nucleated red blood cell progenitor in bone marrow changes or differentiates thereby losing its nucleus and its ability to ever divide again. It also loses its ability to become another cell type and, therefore, it is “terminally differentiated”. By definition stem cells have the capability to produce mitotic progeny that can do two things at once. First, they renew their own population by replacing the progenitor cell with one of the daughter cells. This maintains a continuous supply of progenitor cells or “blasts”. Second, the daughter cells can differentiate into a new, required cell with a specialized function (Figure 1). In our red cell example, as the “erythroblast” progenitor divides in bone marrow one daughter cell stays in the bone marrow to maintain the erythroblast progenitor population while the other daughter cell differentiates into a “-cyte” losing it nucleus and entering the circulation as an erythrocyte to transport oxygen.
Consideration of this dual capability leads to the essence of stem cell function: Development of, and replacement or repair of tissues in the human body. Only by replenishing the stem cell or progenitor population in bone marrow can our body repopulate the 200 billion red blood cells that we normally lose every day. It then follows that dysfunction of a stem cell compartment leads to pathologies: Depletion of the erythroblast stem cell compartment in bone marrow can lead to aplastic anemia. Conversely, loss of control in a stem cell compartment can lead to overpopulation of a given cell type with abnormal differentiation. That pathology is known commonly called cancer; and it follows that cancer cells often originate from stem cells.
The epidermal layer of skin serves as an example of a self-renewing tissue, with homeostatic tissue repair in the event of injury and basal cell carcinoma when the epidermal stem cells become neoplastic. The multilayered epidermis one of the most rapidly dividing tissues in the body. The upper layer that experiences the most abrasion is composed of dead keratinocytes. The lowest, or basal layer is composed of epidermal stem cells that differentiate as they rise to the surface of the skin to replenish the keratinocytes as they die. Note that since it is a stem cell layer, some basal cells must remain in that layer or the epidermis would lose its ability to make more keratinocytes. Did you ever wonder why, when you scratch your skin, that it does just wear out? It heals because the basal (stem) cell layer replenishes the keratinocytes on a continuous basis over many years. But when the basal stem cells are mutated by too much UV light from the sun they can become cancerous, grow out of control and fail to properly differentiate into keratinocytes. Basal cell carcincoma is one of the more treatable forms of cancer(1). So, if the stem cells of blood become cancerous (leukemia) or if the tissue is destroyed as happens to the pancreatic islet cells in diabetes, how can stem cell biology be exploited to therapeutically regenerate the damaged tissues?
Current stem cell therapies
Damage to the stem cell compartment of a self-renewing tissue can result in organ failure; from cancer if the organ is overtaken by malignant cells, or from aplasia (that is a lack of functioning cells) when the tissue loses its capability for self-renewal or repair. Is it possible to replace the stem cells of a given tissue thereby therapeutically regenerating the stem cell population? The answer is obviously “yes” but currently that is only available for a limited number of diseases (Figure 2). Leukemia’s, or cancer of the blood forming elements have been successfully treated for many years by using irradiation and chemotherapy to destroy ALL of the hematopoietic cells (cancerous and healthy), followed by a bone marrow transplant to regenerate normal hematopoietic stem cells(2). Metastatic breast cancer has also been treated by these means (Figure 2)(3). However, scientists and clinicians see this as only a small portion of the therapeutic potential for stem cell therapy. The key to expanding stem cell therapeutics is gaining the ability to control differentiation of the earliest most pluripotent forms of stem cells that can repopulate all tissues; the embryonic stem cells (Figure 3).
Embryologists have long known the paradigms for cellular growth and differentiation as an embryo develops from a single cell to a neonate with 1015 (one zillion) cells. Of those one zillion cells, there are over two hundred different types in the neonate or human adult. The magnitude of that statement requires some pause for consideration of what an embryo is relative to the human adult.
Compare a single or small number of cells that are mostly one type in the embryo to an adult with over 200 cell types totaling 1015. Then try and consider the process for that transformation with very little error. That process requires about 215 cell divisions commensurate with the daughter cells “differentiating” or changing their cell type in a coordinated manner so that the resulting organism has all the required cell types and tissues for normal metabolic function and tissue repair/replacement (homeostasis).
Obviously, not all cells are equal in the human organism. Some of the approximately 200 cell types are “terminally differentiated” i.e. they have arrived at their final destination and cannot return. Others still have some potential to assume a new cell type or continue their differentiation. It follows that the earlier the stem cells are found, with fewer cell divisions and less differentiation, the more “potential” or pluripotency they have to differentiate into a broader range of cell types.
Consider Parkinson’s disease as an example of the inverse relationship between the extent of stem cell differentiation versus its potential to become other cell types. Surgeons have made many attempts to implant new neurons into the substantia nigra (the part of the brain destroyed by Parkinson’s disease)(4). They soon discovered that embryonic tissue provides a better source for transplants than adult tissue. Then, the earlier in development that the neurons are harvested from an aborted fetus, the better the results of the transplant. This phenomenon results from the earlier stem cells being less differentiated and, therefore, more pliable or pluripotent to adapt to the host environment; and they are less likely to generate tissue rejection. The same results have been found for attempts to graft tissue into the endocrine pancreas to treat diabetes and for grafts of cardiac muscle following a heart attack.
Results from lab experiments using mice have shown tremendous potential for use of embryonic stem cells, the ultimate pluripotent cell, for such transplants(5). Scientists hope that ES cell differentiation can be controlled to the point where human stem cells can be used to repopulate many different tissues to treat the most dread diseases such as cancer, diabetes, heart disease, Parkinson’s or Alzheimer’s (Figure 3).
Pluripotency has been found in other stem cell populations such as those derived from umbilical cord blood or bone marrow(3). But those tissues have not shown the same pluripotency or potential to form various cell types that has been demonstrated by embryonic stem cells. Although, many of the comparative experiments have not been completed. The current technical barriers lie in designing stable cell culture systems for in vitro stem cell differentiation and in obtaining and characterizing human embryonic stem cells. Murine hematopoietic stem cells were characterized by identifying cell surface makers(6) and this is the approach used to characterize most other stem cells; including human embryonic stem cells. However, current research on human embryonic stem cells has barely reached the characterization stage because of limited access. Thus, we have a conundrum with uncertainty as whether human embryonic stem cells are really necessary because stem cells from other sources (e.g. umbilical blood) may function just as well; but that question cannot be answered because of the lack of availability to human embryonic stem cells to conduct the experiments.
Ethical considerations
The need to access human embryonic stem cells is apparent to most scientists, but they do not function in a vacuum and they depend on public money through government grants to fund their research. Given that some people believe that life begins at conception and given that it is generally necessary to destroy an embryo or at least put an embryo at risk to obtain human embryonic stem cells a public policy stalemate exists. Should unused embryos from in vitro fertilization clinics be used to harvest human embryonic stem cells? Or, does that represent unethical destruction of a human life? Similar to the abortion rights issue that question centers on: When does life begin? Should taxpayer’s money be used to fund that research? Do the potential benefits of human stem cell therapy out-weight the concerns for using an embryo?
Since many of the benefits of human embryonic stem cell therapy are still “potential” because they have not been proven experimentally we arrive back at the conundrum: If we can’t do the experiments then how can we determine whether the benefit is worth the ethical risk? Most of these ethical questions are not resolved by experimentation and, therefore, cannot be resolved at the laboratory bench. Instead, they are matters of public policy, subject to public opinion and policies or laws determined by the elected officials in our Republic. Hopefully, a greater understanding of the scientific facts by health care professionals and the public at large regarding embryonic stem cell research will allow formulation of public policy that best serves both the health care needs and the social morays of our nation.
Literature Cited
- Bath-Hextall, F., Bong, J., Perkins, W. and Williams, H. (2004). Interventions for basal cell carcinoma of the skin: systematic review. BMJ 329:705.
- Passegue, E., Jamieson, C.H., Ailles, L.E. and Weissman, I.L. (2003). Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A 100 Suppl 1:11842-11849.
- Lennard, A.L. and Jackson, G.H. (2000). Stem cell transplantation. BMJ 321:433-437.
- Lindvall, O. and Bjorklund, A. (2004). Cell replacement therapy: helping the brain to repair itself. NeuroRx 1:379-381.
- Chen, C.C., Grimbaldeston, M.A., Tsai, M., Weissman, I.L. and Galli, S.J. (2005). Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci U S A 102:11408-11413.
- Spangrude, G.J., Heimfeld, S. and Weissman, I.L. (1988). Purification and characterization of mouse hematopoietic stem cells. Science 241:58-62.