Debating the Ethics of Stem Cell Research

Ethics of Stem Cell Research

Stem Cell Research Ethics

The Ethics of Stem Cell Research: A Nursing Perspective

The Ethics of Stem Cell Research: A Nursing Perspective

When the world-famous cloned sheep, Dolly, was euthanized at the relatively young age of 6-1/2 years she was suffering from advanced aging and lung disease (Meek, 2003). In human years, Dolly was only about 40-years old and had been suffering from arthritis for many years. This outcome is consistent with the claims of some scientists that current cloning technology does not accurately replicate natural sexual reproduction and disproportionately generates debilitating and sometimes lethal genetic defects. Dolly was the product of somatic cell nuclear transfer (SCNT), which involved removing the DNA from a sheep somatic (adult) cell, inserting it into an egg, and then transferring the egg to a receptive womb. This technology is very similar to what is currently being developed by stem cell researchers, especially the induced pluripotent stem cells (iPSCs) derived from adult human tissue. What Dolly's demise reveals, however, is that this technology is far from perfected.

On the other hand, adult stem cells have been successfully harvested and used clinically for decades (O'Meara et al., 2014). Bone marrow transplants are the obvious example, but the clinical use of stem cell technology continues to expand in many directions. Sarah Hancox, age 27 and a senior nurse at the Queen's Medical Centre and City Hospital in Nottingham, plans to donate the umbilical cord blood (UCB) harvested during the birth of her child. Two recently opened cord blood banks at the hospital where she works makes this a convenient process and she is excited about the opportunity to help relieve the suffering of very ill patients she encounters as a nurse. The stem cells isolated from her cord blood could be used to reconstitute bone marrow in a leukemia patient, for example, after the patient has undergone chemotherapy or radiation treatment to destroy the endogenous hematopoietic stem cells (O'Meara et al., 2014). This technique has become so successful that the number of procedures conducted at the Basel University Hospital in Switzerland, over the past four decades, has increased from 109 during the first decade to 939 during the past decade. In addition, the mortality rate from allogeneic hematopoietic stem cell transplantation has declined from 43 to 22% over the same period, while the risk of treatment failure has been cut in half. These improvements have occurred despite the eventual inclusion of older patients, patients with more advanced disease, and the increasing use of mismatched donor/host transplantations.

The above two examples highlight the sometimes vast divide between what is occurring in stem cell research laboratories and in medical clinics, but the magnitude of this difference will shrink over time as science advances. Scientists, however, cannot and should not provide answers to the often contentious ethical issues raised by stem cell technology. The ethical issue of human cloning was catapulted into the world's imagination by the birth of Dolly and subsequent unsubstantiated claims of successful human cloning (e.g., Borger, 2002), but a more immediate concern, for example, is the use of discarded in vitro fertilization embryos as a source of pluripotent stem cells for research and medicine. Nurse Hancox is excited about donating her cord blood to help cancer patients and therefore has no ethical problems with this technology, but would she be just as excited about donating eggs for stem cell research or would she have strong ethical reservations? In the past, both cord blood and excess in vitro fertilized embryos were discarded, so what is the difference ethically between these two sources of stem cells?

This research paper will attempt to provide guidance for nursing professionals who are facing or will face the ethical issues created by stem cell research and the many potential clinical applications. In order to accomplish this task, the history of stem cells in science and medicine, the different types and sources of stem cells that have been discovered, and the many ethical issues this technology has created, will be reviewed and discussed. The overall goal is to provide enough information for nursing professionals so that they can make up their own minds what stem cell technologies and research goals are ethically acceptable.

History of Stem Cell Research

The interest in pluripotent cells has been around for quite some time, but in 1954 this interest transformed into experimentation (Solter, 2006). During that year researchers were able to isolate teratocarcinomas from the 129 mouse strain. Culturing these cells in vitro produced a wide variety of differentiated cell types within the same culture dish, such as nervous tissue, organs, skin, hair, and heart. The term teratocarcinoma was derived from the Greek word 'teratos,' which means monster. What is significant about this type of tumor is that a single cell derived from the tumor was shown to be capable of generating multiple cellular phenotypes normally arising from the three germ layers: mesoderm, endoderm, and ectoderm. This ability is called 'pluripotency', which is one of the criteria used to define stem cells. The pluripotent capacity of these cells suggests that they represent a very early developmental stage of embryogenesis.

Further experimentation revealed that not all cells derived from a teratoma are as pluripotent as others (Solter, 2006). This finding was viewed by some researchers as evidence of the existence of tumor stem cells, not only by functional assays, but also by appearance. These tumor stem cells eventually became known as 'embryonal carcinoma cells' and appeared as small, tight colonies in vitro with prominent nucleoli and a thin dark cytoplasm. Injecting these cells into a mouse host would trigger the development of tumors with a wide variety of phenotypes, thereby validating the existence of tumor stem cells. Further experimentation with teratomas resulted in the identification and development of antibodies capable of specific recognition of embryonal carcinoma cells in tumor biopsies from both mice and humans. The stage-specific embryonic antigen 1 (SSEA1) could identify mouse embryonal carcinoma cells, while SSEA3 and SSEA4 could identify human counterparts.

Unfortunately, embryonal carcinoma cells are difficult to control and more than a few contributed to tumor formation after transfer into mouse blastocysts; however, many of the same molecular tools used to identify and isolate embryonal carcinoma cells proved to be valuable when isolating normal stem cells from mice and humans (Solter, 2006). Once this transition had been made, scientific interest in teratomas faded. The crucial discoveries that ushered in the modern era of stem cell research were (1) the discovery of stem cells resident in normal tissues, (2) the ability to maintain viability of these stem cells in vitro with a feeder layer, such as a single layer of mouse fibroblast cells adhered to the bottom of the culture dish, and (3) the prevention of differentiation using leukemia-inhibiting factor (LIF) and the subsequent in vitro expansion of a stem cell line.

The current definition of a stem cell depends on the number of different cellular phenotypes it can generate (Solter, 2006). A totipotent stem cell can generate all the cellular phenotypes that will ever appear in an organism, while a pluripotent stem cell is capable of generating multiple cellular phenotypes from all three germ layers. Multipotent stem cells, however, are much more limited and the cellular phenotypes it can generate are generally restricted to a subset of phenotypes associated with one or two germ layers. For example, researchers were able to show that totipotent stem cells from mice were capable of contributing to the formation of germ cells, in addition to most if not all somatic cells in a mouse body, and could thus be passed on from generation to generation; however, researchers have been unable to prove the existence of totipotent human stems cells.

In the absence of totipotent human embryonic stem (ES) cells many researchers turned toward investigating the possibility that somatic cells could be reverted to pluripotency (Easley, Latov, Simerly, & Schatten, 2014). This considerable body of research has produced human induced pluripotent stem cells (hiPSCs), which can give rise to a limited number of different phenotypes. These cells cannot generate phenotypes from all three germ layers and are therefore not a true pluripotent stem cell, but researchers have revealed that these cells are multipotent and capable of generating multiple cellular phenotypes closely related to the tissue of origin. Current efforts are directed towards isolating, reverting, and controlling the differentiation pathways, thereby creating a possible therapeutic strategy to repair damaged or diseased tissue. The development of pluripotent progenitors from somatic cells also avoids the many moral and ethical objections concerning the harvesting of stem cells from fertilized human embryos. The other advantage of generating hiPSCs is that the patient can be both donor and recipient, which essentially eliminates the risk of graft vs. host disease (GvHD).

Types of Stem Cells

There are two general classes of human-derived stem cells: embryonic and adult (Ding, Shyu, & Lin, 2011). Of these two general classes, only stem cells derived from fetal tissue have raised significant ethical and legal objections. What follows is a brief description of the primary types of human stem cells that have captured the interest of scientists, clinicians, ethicists, policymakers, and religious organizations.

Fetal stem cells. The most controversial stem cells are those derived from human embryos, but in contrast to adult stem cells, these are truly pluripotent and therefore have captured the attention of biologists and medical scientists interested in understanding human development and how these cells could be used to treat and possibly cure disease (Blow, 2008). ES cells have been derived from discarded embryos generated during in vitro fertilization (IVF) treatments (National Institutes of Health, 2002). Typically, multiple oocytes are fertilized during IVF procedures and only a select few are transferred to the womb. The remaining fertilized embryos have been discarded in the past, but a few scientists have requested and been given permission by parents to harvest the cells from the inner cell mass (Shand, Berg, Bogue, Committee for Pediatric Research, & Committee on Bioethics, 2012). The cells derived from the inner cell mass of fertilized blastocysts are theoretically totipotent, which implies that this technology could be used to clone human beings. Accordingly, many ethicists, policymakers, and religious organizations view this technology as morally objectionable. In addition to having the potential to differentiate into any number of cellular phenotypes, human ES cells can continue to divide in vitro for much longer than adult stem cells harvested from other tissues.

Umbilical cord blood. Human umbilical cord blood has been banked in multiple locations for over a decade and has been the source of hematopoietic stem cells for children requiring bone marrow transplants (National Institutes of Health, 2002). In some cases the cord blood has come from the same children needing treatment, so there is little chance that the transplant will be rejected. More recent research has revealed that umbilical cord blood contains cells that can be reverted in vitro to resemble the pluripotency commonly associated with ES cells, thereby increasing the potential uses of this source of stem cells (Salk Institute, 2009). Stem cells isolated from cord blood are also immunologically immature, which makes host rejection less likely even when there is a mismatch between the donor and recipient.

Placenta-derived stem cells. The placenta is typically discarded during delivery of the newborn, but recently it has been recognized to be a rich source of multipotent stem cells (Caruso, Evangelista, & Parolini, 2012). In comparison to umbilical cord blood, however, cells isolated from the placenta tend to be more differentiated and less like ES cells in phenotype. The restriction in potency has not discouraged researchers from investigating and testing the efficacy of placental-derived stem cells in regenerative medicine and the results have been encouraging. Distinct locations within the placenta seem to be enriched in cells with stem cell-like properties and can give rise to multiple phenotypes for a given lineage, such as skin and muscle.

Adult stem cells. Researchers over the past two decades have come to realize that adult tissues contain a small number of stem cells (Shand et al., 2012). These stem cells can be found in the bone marrow, skin, heart, connective tissue, and brain and have been successfully isolated for research and clinical purposes. In fact, the use of bone marrow transplants to reconstitute the hematopoietic cell types in pediatric leukemia patients is considered best practice for this patient population. The use of stem cells from other tissues has mainly focused on tissue regeneration, since these cells tend to be more differentiated and therefore more restricted (multipotent) in what cellular phenotypes they can give rise to. In addition, it has been difficult to expand these types of cells to numbers sufficient for multiple uses or clinical applications; however, the risk of tumor formation after transplantation is very low.

Induced pluripotent stem cells (iPSCs). As mentioned in the introduction, somatic cells from adults have been successfully reverted to a less differentiated phenotype (Easley et al., 2014). Although the term 'iPSCs' suggests these cells are pluripotent, researchers have so far been unable to revert adult somatic cells to a true pluripotent state. Some researchers would argue, however, that reversion to a pluripotent state may not be desirable since a more differentiated state tends to be more stable and less likely to contribute to tumor formation. This is one of the primary concerns of generating pluripotent stem cells from adult somatic cells, in addition to concerns about accumulated genetic mutations and other abnormalities. By comparison, stem cells derived from fertilized embryos or umbilical cord blood would be genetically more intact and free of other abnormalities. Researchers are making progress in this area and the first clinical trial was begun last year in Japan for the treatment of macular degeneration (NIH, 2012).

Harvesting Stem Cells

The harvesting of human ES cells from fertilized embryos typically involves the destruction of the blastocysts and the isolation of the cells that make up the inner cell mass (Shand et al., 2012). Although there have been laboratory attempts to isolate one or two cells from an intact embryo, thereby sparing the embryo from destructions, researchers have not determined whether this technique reduces the viability of the embryo. One of the main reasons for developing a harvesting technique that spares the embryo is to avoid the ethical dilemma of destroying a potential human life.

Since umbilical cord blood has historically been considered a waste product in Western societies the ethical concerns surrounding the harvesting of ES cells from fertilized human embryos are avoided. For this reason, considerable effort is being invested in improving the harvesting techniques for stem cells from cord blood (Danby & Rocha, 2014). The main limitations of its use for clinical applications are the small number of stem cells that can be recovered from a single donation. During delivery the cord is clamped and the blood removed using a syringe containing heparin (Demerdash et al., 2013). For bone marrow transplantation the nucleated cells are recovered using centrifugation and injected into the femur of patients who have undergone chemotherapy or radiation treatment (Danby & Rocha, 2014). Since the number of hematopoietic stem cells is so small, this technique is limited to children or small adults, although double cord blood transplants have been used successfully. For research purposes, nucleated cells isolated from cord blood by centrifugation can be cultured for 10 days and the stem cells will form colonies of adherent cells (Demerdash et al., 2013). These can then be recovered, expanded, and then differentiated into a defined phenotype before clinical application.

While the isolation of stem cells from umbilical cord blood may seem technically challenging, the isolation of adult stem cells from tissues is much more difficult and painful for the donor (De Sa Silva et al., 2012). Bone marrow donations are obtained by boring a hole into the center of a large bone and withdrawing the marrow. The bone marrow is not only a source of hematopoietic stem cells, but also mesenchymal stem cells that can give rise to a number of cellular phenotypes, including bone, connective tissue, muscle, adipose tissue, and stroma (Murphy & Atala, 2013).

By comparison, the harvesting of somatic cells for generating hiPSCs can be relatively simple and pain-free (Verma & Verma, 2011). Among the first cell types harvested were skin fibroblasts, which can be isolated from a skin biopsy and expanded ex-vivo. Pluripotency is then induced using a cocktail of transcription factors, which some researchers have reported as ridiculously easy and reproducible.

Stem Cells in Medicine

Currently, the use of ES and hiPSCs for tissue regeneration is limited to laboratory research because these cells tend to produce teratomas and other tumors when transplanted into a host (Verma & Verma, 2011). Should this hurdle be overcome, then the applications are theoretically limitless, from the repair of damaged or diseased tissue, including brain and heart tissue, to growing a new organ in a culture dish in preparation for transplantation. The main advantage that hiPSCs have when compared to ES cells is that they could be harvested from and used to treat the same patient. This would eliminate or reduce the need for immunosuppressive drugs to prevent host rejection of the transplanted tissue.

Currently, all stem cell clinical applications are based on the use of adult stem cells. The tissue sources of stem cells in common use are bone marrow, cord blood, and peripheral blood (O'Meara et al., 2014). Each source has its own unique advantages and disadvantages. UCB, for example, contains only a small number of hematopoietic stem cells, which restricts its use to reconstituting the hematopoietic system in children and small adults (Danby & Rocha, 2014). The primary limitation of adult stem cells, including umbilical cord blood, is therefore the ability to transfer a large number of cells into the patient. Researchers are working on this problem and at least one study reported expanding a mesenchymal stem cell population derived from cord blood sufficiently to meet most clinical applications (Luo et al., 2010). The mesenchymal stem cells could be used for wound repair, including reconstituting a healthy epidermis in burn patients.

Nursing Ethics: Stem Cell Research and Clinical Applications

The Icelandic legislature has recently updated its laws concerning stem cell research and clinical applications (Arnason, 2010) and seems to represent one of the more progressive approaches to stem cell research ethics. Advances in stem cell research, along with a changing ethical landscape, have necessitated these changes to keep up with the times. In the past, the use of in vitro generated human embryos was limited to IVF procedures and research efforts designed to improve IVF techniques. The recent changes recognized that ES cells derived from human embryos can make significant contributions to science and medicine; therefore, embryos created during in vitro fertilization procedures, but not for research purposes, can be used for research and the generation of stem cell lines. The rationale for this change was a cost-benefit analysis comparing the ethical benefits of destroying these embryos vs. The medical advances that could be made. This is decidedly a utilitarian ethical perspective, because it seeks the solution that would provide the greatest benefit for the most people.

The Icelandic legislature upheld its earlier ban on human cloning, but opened a small door that permitted the use of human SCNT, the same technique that permitted the creation of Dolly the sheep (Arnason, 2010). The reason for this change was to expand the potential sources of stem cells that can be used for research and medical purposes, but with the caveat that SCNT should be resorted to only if embryonic and adult stem cells cannot meet the needs of scientists and clinicians. The law makes the distinction between a fertilized embryo and a blastocyst generated by SCNT, because the former has two parents and the latter only one. Under Icelandic law, it is illegal to transfer the latter into a receptive womb. The ethical framework used to make this exception was also utilitarian, based on the relative value of generating stem cells from an individual, which can then be used to repair or replace damaged or diseased tissue in the same individual.

Icelandic government healthcare agencies and professional medical associations engaged in a joint discussion that eventually led to these changes (Arnason, 2010). Reports that have been published since this legislation was enacted reveal substantial public support for the current version of this law. Public criticism of the changes was essentially absent, including any serious criticism by religious organizations. These changes appear to reflect a growing recognition that the potential benefits realized through stem cell research are not trivial. These changes were possible in part because the general public in Iceland was supportive of advancing stem cell research as long as cloning restrictions and bans were kept in place. Iceland provides a good example of the ethical lines that have been drawn by more progressive Western governments concerning stem cell research and human cloning.

In the United States, the American Nurses Association (ANA) issued a position statement in 2007 concerning human stem cell research. This position is analogous to that taken by the Icelandic legislature and supports the use and development of stem cells derived from excess IVF human embryos with parental consent. In addition, the ANA supports the use of SCNT research for therapeutic cloning and strongly rejects the use of any stem cell technology for the purpose of human cloning. A more recent press release from the ANA (2009) applauded President Obama's decision to lift the ban against federal funding of the generation of ES stem cell lines, because these lines are viewed by the ANA as essential for developing safe and effective medical interventions. Like the Icelandic legislators, the ANA's ethical position is utilitarian in orientation.

The Center for Bioethics and Human Dignity (CBHD) at Trinity International University has published their position on the issues of stem cell research (Bevington & CBHD Research Staff, 2009). Generally speaking, adult stem cells derived from infants, adults, umbilical cords, placentas, and cadavers raise no serious ethical concerns because human life is not being sacrificed for research or medicine. In addition, if stem cell are isolated from natural miscarriages or stillborn fetuses, or if stem cells can be isolated from fetuses during gestation without harming the fetus, then this is ethically acceptable. Should any technique be developed that results in the harm or killing of a human being, including an unborn fetus, then this is considered immoral. Therapeutic cloning or SCNT would fall into the latter category of being immoral because the resulting embryo would be killed in order to harvest the stem cells. The CBHD does not distinguish between natural embryos that have two parents and embryos created using SCNT that have only one parent. Several bible passages are cited to support their position.

The CBHD then examines the prevailing utilitarian perspective of the relative value of harvesting a few embryos in order to treat and cure diseases afflicting millions (Bevington & CBHD Research Staff, 2009). From their prospective, one immoral act cannot be condoned even if it promises to save the lives of millions. The CBDH alludes to the horrific experiments that have been carried out in the name of science and the greater good throughout human history as justification for their position. Romans (3:8) is cited to support this position, which states that to "… do evil that good may result & #8230;" goes against the teachings of God. It does not take much imagination to equate this position with the timeless ethical principle in medicine of 'first, do no harm.'

The opinions of a few academic religious bioethicists seem to cast the ethical position taken by the CBHD as an extreme view. At a bioethics forum held at Santa Clara University in 2001, a report issued by the California Advisory Committee on Human Cloning (CACHC, 2001) conveyed the views of a Protestant expert as supportive of a ban on human cloning based primarily on safety concerns. If the safety concerns can be addressed, however, benevolence was cited as one potentially permissible motivation for allowing reproductive cloning for an infertile couple unable to have children by any other means. The motivation for reproductive cloning was the determining criteria for deciding whether reproductive cloning was moral or immoral.