Overview of selected bioethical issues raised by stem cell science and its applications


Few issues in biomedical science have been as complex and contentious and have generated as much heated argument amongst all segments of society as the use of stem cells for the repair or replacement of damaged tissues (see Caulfield et al, 2015).

While the majority of the public favors stem cell research - some say the figure is as high as 60% - there are many who are strongly opposed. (See Supplement 1 - Legal and Political History of Stem Cell Science) The ever changing landscape of stem cell research and the complexity of its underlying science suggest that public opinion is likely to continue to evolve as the public becomes more informed. If a medical breakthrough or treatment is achieved using stem cells, public approval is very likely to rise.

The headlines from 2001 have hardly changed – they could be from 2015:
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At the same time, few subjects in biomedical science have so captured the imagination of the scientific community and the public.
Beyond tissue repair, cultured stem cells might also be applied to the analysis of disease mechanisms and normal development, as assays for screening new drugs or as vehicles for gene transfer (i.e., gene therapy).

Currently there are several FDA approved clinical trials using stem cells to treat: spinal cord injuries, amyotrophic lateral sclerosis (ALS), heart disease, muscular dystrophy, multiple sclerosis, and macular degeneration.In addition to assessing whether there are any therapeutic benefits, these clinical trials are designed to determine the best method to deliver the stem cells to the target organ and whether injections of stem cell block capillaries, damage brain tissue, give rise to tumors or differentiate into the wrong kind of cells.


To date, we still wait for the promise to become a reality. Each potential use of stem cells promises revolutionary advances. It is important to contain the hype. So, keep in mind – as of spring of 2015, using embryonic stem cells, iPS cells, or adult-derived stem cells we still have:
  • Realized NO cures
  • Uncovered NO new disease mechanisms
  • And developed NO new drugs.

Fortunately, there is one avenue where clinical improvements have been made and that is in using hematopoietic stem cells. We will discuss this in detail in Module 6 - Human Hematopoietic System.
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Issues generated by stem cell research


What is the value of this clump of cells? Another human, or a new hope for the diseased and the dying?

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Issues generated by stem cell research are among the most profound and contentious ever encountered in Bioethics. Debates center on the moral status of these pre-implanted embryos that are now stored in in vitro fertilization (IVF) clinics. While many believe that life begins at conception as the sperm fertilizes the ovum, compelling issues related to the potential of human life, such as when does human life actually begin, have emerged at the forefront of the debate. Profound questions like this have no definitive answers but have created significant tension within our society. It is important for us all to consider these questions carefully. Our answers are likely to lie in our religious and cultural persuasion.

Deriving stem cells from embryos raises many other difficult philosophical, ethical, legal, and social questions which should be considered:[insert links that describe the various religious viewpoints]
  • What is personhood and when does it begin?
  • What is the moral status of a blastocyst?
  • What is the moral status of the more than 400,000 100–200 cell embryos stored frozen in liquid nitrogen tanks in many infertility clinics?
  • Should embryos be protected under the same laws that govern research on human subjects?
  • Should federal funds in the US be devoted to support research in this area or should there be an outright ban on all such research?
  • Should private labs experimenting with human embryonic stem cells be subject to government oversight?

The recent development of iPS technology which involves the generation of pluripotent stem cells without the use of pre-implanted embryos or destruction of a blastocyst elicits another set of ethical concerns. These concerns raise new questions including:
  • If iPS or other types of pluripotent cells eventually could be manipulated to create the equivalent of a human germ cell or embryo, what, if any, would be the difference between a natural and created human embryo?
  • Will iPS and other “engineered” stem cell types behave in the same capacity as embryonic stem cells?
  • On a broader level, given the myriad of important issues raised: does society have the right or obligation to limit or restrict the development of technology?

And now, assume for the moment that some type of potential stem cell treatment has become available but is yet to be tested and approved by the FDA:
  • Should a desperate patient be given this unproven therapy?
  • What animals, e.g., mice or non-human primates, should be used to determine the safety and efficacy of this potential stem cell therapy?

These questions and others will be discussed in Supplement 2 on Animal Rights and Welfare and in Module 8 that discuss Applications of Stem Cell Science.

Thought question

  • In a pluralistic country such as ours, how should the government regulate stem cell science when there are so many diverse cultural and religious perspectives?









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Stem cells and the church

Questions like the ones we have raised pit enthusiastic researchers and optimistic patient groups seeking to advance knowledge and develop lifesaving therapies against ardent religious and conservative activists who believe it is unethical to experiment on any human embryonic and fetal tissues. For these groups, whenever the derivation of stem cells results in the destruction of the embryo, the groups consider these experiments illegal, immoral, and unnecessary, even if they might produce significant medical benefits to people in need.


Pope: Yes to adult stem cells, no to embryonic

(AP) VATICAN CITY — Pope Benedict XVI has reaffirmed his opposition to embryonic stem cell research, saying it's morally wrong to destroy an embryo no matter how beneficial the resulting treatment is.
Benedict made the comments Saturday to participants of a Vatican conference on adult stem cells convened under an unusual new partnership between the Vatican's culture office and a small U.S. biotech firm, NeoStem Inc.
Church teaching holds that life begins at conception. As a result, the Vatican opposes embryonic stem cell research because embryos are destroyed in the process. It supports research using adult stem cells.
Benedict said: "The destruction of even one human life can never be justified in terms of the benefit that it might conceivably bring to another."

(Published November 12, 2011)











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Where do stem cells come from?

Embryonic stem cells are derived from several sources. Most are derived from embryos that are no longer needed that are stored in fertility clinics. There are currently more than 400,000 embryos stored in freezers that are in excess of clinical need.

Options for IVF embryos
Parents of IVF embryos may be given a choice of what to do with their pre-implanted embryos in excess of clinical need. If the embryos have been kept in the freezer for one year or longer, parents may choose to:
  • Continue to store the embryos in the freezer which may cost about $1,200/year.
  • Give the embryos up for adoption (not many embryos are given up for adoption).
  • Dispose of the embryos in a dignified manner.
  • Donate the embryos for research purposes.

Thought question


Should parents of donated embryos be compensated for the donation and for any subsequent patenting of technology derived from their donated embryos?









A second source of stem cells can be obtained from aborted fetuses, where the germ cells (ovaries and testes) are of particular interest.

A third source of stem cells, known as multipotent stem cells, can be found in many types of adult tissue such as bone marrow, adipose tissue (fat), and umbilical cord blood. Adult stem cells are needed every day to replenish a variety of cell types in our body that normally wear out and die in large numbers. Examples of cells that need to be constantly replaced are blood, skin cells, and the lining of our intestinal tract. Areas of the body not previously thought to contain stem cells, such as the brain, have in recent years been discovered to contain these self-renewing cells.

Given advancing research, including induced pluripotent stem, where somatic (skin) cells are programmed to revert back to stem cells, the need to destroy human embryos to harvest (derive) pluripotent stem cells is removed.

Given advancing research, including creation of induced pluripotent stem (iPS) cells, many ask -- Why not just pursue research with adult stem cells to eliminate any ethical concerns?

Several reasons are given why adult stem cells are difficult to use.
  • They are not found in great numbers.
  • They are difficult to isolate and maintain in culture.
  • They proliferate at a slower rate.
  • They are less diverse and less likely to change into another type of cell.
  • Also worrisome is that adult stem cells may contain more DNA abnormalities that are caused by exposure to environmental contaminants.
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Somatic cell nuclear transfer (SCNT) and cloning


Due to the rapid advances in stem cell research – and given impetus due to political restrictions on federal funding using embryos (Loike and Fischbach 2009), several new sources have been developed to obtain human embryonic stem cells (ESC), or ESC-like cells. The fourth source for acquiring human embryonic stem cells is through a technology referred to as somatic cell nuclear transfer (SCNT), sometimes referred to as cloning (research or therapeutic cloning; reproductive cloning). Due to the rapid advances in stem cell research – and given impetus due to political restrictions on federal funding using embryos (Loike and Fischbach 2009) - this is one of several new sources THAT have been developed in the laboratory to obtain human embryonic stem cells (ESC), or ESC-like cells.

Like normal reproduction, somatic cell nuclear transfer (SCNT) starts with an egg or oocyte. But here the nucleus of the egg is removed. Then the nucleus from a somatic (skin) cell is transferred into the enucleated egg which would be analogous to the sperm entering the oocyte. As this develops into a blastocyst, cells from the inner cell mass can be isolated and purified to serve as a source for pluripotent stem cells. See Module 4 - Somatic Cell Nuclear Transfer for a more detailed discussion on SCNT.


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Hochedlinger and Jaenisch (2003) New England Journal of Medicine

Cloning distinctions

It is essential to know the difference between reproductive cloning and therapeutic cloning. As you can see from the figure above, the process is the same with one important difference.

With reproductive cloning (the middle diagram) where the intent is to create a baby, the embryo would be taken from the Petri dish and placed into a uterus and would be allowed to gestate through a normal pregnancy. The born child would be viewed biologically as an identical twin of the donor of the somatic cell.

Thought questions


  • What would be the psychological challenges faced by the parents who used SCNT and IVF to create an identical twin of an older sibling?
  • What might be the expectations of the younger twin in aspiring to achieve the same educational and athletic milestones of the older sibling?









The purpose of therapeutic cloning is to provide stem cells for medical purposes. It is preferable to avoid the term therapeutic and refer to this form of cloning as “research” cloning because to date, we are far from having reached any therapeutic use. Additionally, because it may be years until we do see some therapeutic results, it is best to refer to this process as somatic cell nuclear transfer (SCNT).

Reproductive cloning at the present time is considered unethical. Therefore, of absolute importance, in somatic cell nuclear transfer (SCNT) (research/therapeutic cloning), the embryo is allowed to develop only until the 14th day. The 14-day embryo would never be placed into a uterus.

Induced pluripotent stem cells (iPS) are a fifth process for obtaining stem cells. In this process, the insertion of specific transcription factors into differentiated cells converts them to pluripotent stem cells without the use of an ovum. We present iPS technologies in much more detail in Module 5.

Is this where the promise lies? If these stem cells can be coaxed to become whatever the need is for the donor, be it nerve, cardiac muscle, or pancreatic islet cells, the derived cells could be given to the donor without any risk of rejection as the DNA would be identical and there would be no immune response.
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Ethical considerations

Given what we now know about embryonic stem cell research and somatic cell nuclear transfer procedures, we need to understand the ethical implications. As stated earlier, basically, there are two opposing arguments.

For those believing that human life begins at conception, stem cell research and therapeutic cloning are unacceptable:
  • It is unseemly to create human life in any form only to destroy it.
  • There is a slippery slope argument that this will lead to scavenging of organs from adults.

The opposing perspective posits that if medical research can increase chances of survival, this research could help many in need and actually enhance respect for human life.

Unfortunately, there is no common ground between these two arguments.

When does a fetus gain moral status?

Questions like this are related to one's religious or theological perspective. The question of when does a developing embryo or fetus have moral status varies among religious groups.

  • For some, ensoulment occurs at conception.
  • For others, until day 14, there is no identity. After day 14, twins can no longer form. Most researchers respect this date and will not proceed with embryo research after day 14.
  • In Orthodox Jewish tradition, personhood requires implantation and a 40 day gestation.
  • In several Islamic traditions, ensoulment occurs at the 120th day.

Is it right to seek human eggs for science?

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Reproduction requires a supply of eggs or oocytes (ova), fertilized normally or through IVF. As well, eggs are needed for research such as in somatic cell nuclear transfer (SCNT). Where are these eggs going to come from?

A serious ethical question that we need to consider is whether it is ethical to ask women to donate their eggs for research purposes. A number of issues are of concern with egg donation that range from minor to profound, not the least of which are the number of discomforts as well as the physical and psychological risks associated with ovarian stimulation and egg retrieval (harvesting). These risks range from common minor discomforts and symptoms to the risk of death which fortunately is low but still must be considered. Questions about compensating donors and commodification also need to be addressed.

These questions and the donation process will be discussed fully in Supplement 4: Ethical Considerations of Egg Donation.

Further ethical and social implications of stem cell science


Clearly, stem cell science is fraught with myriad ethical and social dilemmas and conundrums. We have designed this distance-learning on-line course to discuss, in detail, many of the most contentious bioethical issues. You will find these discussions embedded in the Modules and Supplements. So, look forward to learning about:

  • The dilemmas associated with procuring eggs for research purposes raising issues of coercion and commodification of the body.
  • An infamous case of scientific fraud that compromised stem cell lab workers and cast a cloud over stem cell research.
  • The ethics of animal rights and animal welfare in stem cell research; what does it mean to create a chimera where human neural cells are implanted into a mouse brain?
  • Stem cell tourism where desperate people travel to all parts of the globe to gain access to unproven stem cell products and therapies.
  • Why informed consent for clinical stem cell trials may be inadequate.
  • The issues raised with our (lack of) regulations for patenting stem cell technology, and the lack of oversight of research supported by non-federal funding.
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Case Studies

Case studies will also appear throughout the on-line course. They are designed to challenge the reader to consider the implications of stem cell science, medicine and bioethical conundrums from diverse perspectives.

Case Study #1 Background: Pre-implantation genetic diagnosis (PGD)


Soon after fertilization, the haploid nuclei of egg and sperm merge to form a single nucleus with the diploid number of chromosomes. This one-cell zygote divides as it moves along in the fallopian tube; divisions keep occurring. Up until the 8-cell stage, each cell is totipotent, having the ability to form the placenta as a defining feature.

The 8-cell stage of the embryo is a landmark as this is when pre-implantation genetic diagnosis (PGD) can take place. This PGD procedure is a remarkable melding of genetics with embryology where bioethical oversight has a role.

Those who have provided their ova and sperm to create an embryo may have specific concerns related to heritable diseases due to their family’s medical history. PGD has become an increasingly used technology to prevent embryos carrying specific genetic mutations from being implanted into the woman’s uterus.

Taking advantage of the IVF process, many eggs are harvested, fertilized, and allowed to develop to the 8-cell stage. At this point, using a technique developed by Dr. Mark Hughes, one cell of the 8-cell embryo is gently suctioned out of the bolus of cells.

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Pre-implanted embryos found to have genes for genetic disorders such as Huntington’s disease, cystic fibrosis, Down's syndrome, muscular dystrophy, Tay Sachs disease, and many others are likely to be discarded. One or two of the embryos that are free of screened genetic mutations will be implanted into the uterus to gestate. The remaining pre-implanted embryos that are free of the mutation may be stored for future use in the fertility clinic (Damewood 2001; Verlinsky, Rechitsky et al. 2001).

Ethical Issues
Needless to say, while PGD is a much welcomed advance, significant issues are generated. Many in the disability community are concerned that embryos are screened out that could develop into productive and much loved individuals.

Individuals could argue that parents and doctors choosing to not implant embryos with certain grave genetic conditions may in fact ultimately be preventing the creation of a hypothetical individual who might have a very difficult if not prematurely terminated life. Furthermore, there are financial and emotional costs to society that should be considered. These are very sensitive and emotional issues, yet implicit in many parents' thinking about embryo termination is preventing suffering, lifelong struggle, and cost. Society is increasingly concerned about how to pay for all manner of costly interventions and schooling.

Additionally, PGD paves the way to create “designer” babies, promotes gender selection, and creates opportunities to produce a child with particular genetic features that will be used to cure or treat relative.
The discarded embryos found to contain particular mutations, for example, can serve as valuable in vitro models by researchers who are studying the source of genetic disorders and how the genes affect development.

Thought question


Is it ethical to use the pre-implanted embryo containing the genetic mutation for cystic fibrosis to generate stem cell lines able to be used to study the disease in vitro?









Case Study #2: Embryo selection to provide stem cells for an ill sibling


Mr. and Mrs. Doe are both carriers for the recessive disorder Fanconi Anemia. Mrs. Doe gave birth to their first child, Molly, who has this serious disorder that includes fused joints, missing thumbs, and an incomplete gut. The long-term prognosis is grim as those with this disorder develop leukemias and cancers and have a shortened life expectancy. Given this, the Does were desperate to identify a donor who could provide a matching hematopoietic stem cell (HSC) transplant that would be an HLA match to Molly’s tissue. Not able to locate such a match, they ultimately resorted to utilizing pre-implantation genetic diagnosis (PGD) technology. Here, an embryo, among several that were created using IVF technology, that was a genetic match to Molly and was free of the gene causing Fanconi Anemia, was implanted into Mrs. Doe’s uterus. Mrs. Doe subsequently gave birth to Adam, whose umbilical cord blood stem-cells were removed and used for a stem cell transplant to cure Molly of the disorder.

(Case adapted from: What are the medical and ethical considerations of this actual case? Sankoorikal 2001; Verlinsky, Rechitsky et al. 2001)

Thought questions

  • What are the ethical implications of conceiving a child for the sole purpose of treating another sibling?
  • Is Adam being exploited?
  • Is Adam just a means to an end?
  • If more stem cells are needed for Molly when Adam is 14 years old, can he refuse to undergo a bone marrow procedure to that would provide stem cells for his sister?









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Conclusion


As great as the promise of stem cell research is, the concomitant bioethical issues that this research raises are equally daunting and must be confronted. Still, even if confronted, not all of these bioethical issues can be resolved. Other approaches based on scientific discovery, historical precedents, and philosophical approaches can be utilized to manage or diffuse these bioethical concerns.

Please note that the bioethical issues presented in this on-line course are not exhaustive. We have selected representative examples to enable the reader to gain insights into the leading bioethical issues and to understand the balance between scientific discovery and societal concerns. We also present varied strategies that can be used to approach these contentious bioethical challenges.

Stem cell technologies are advancing and are increasingly available. It is critical for us to use them responsibly and wisely. As an integral part of stem cell science, there is an overriding consideration, indeed an ethical imperative. This imperative will be stated repeatedly within this on-line course. We hope it will guide you.

In research and medicine, our actions should be guided not by what we can do, but rather what we should do.


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References


  • Caulfield, Timothy, et al. (2015) "Research ethics and stem cells." EMBO reports 16.1: 2-6.
  • Damewood, M. D. (2001). "Ethical implications of a new application of preimplantation diagnosis." JAMA 285(24): 3143-3144.
  • Loike, J. D. and R. L. Fischbach (2009). "Benefits of the stem cell ban." The Scientist (June 8th 2009.).
  • NAS (2005). Guidelines for Human Embryonic Stem Cell Research, National Academy of Sciences.
  • Payne, A. (2011). Pope: Yes to Adult Stem Cells, No Embryonic. The Associated Press. November 12, 2011 at 8:57 AM ET
  • Sankoorikal, T. A. V. (2001). "Using Scientific Advances to Conceive the Perfect Donor: The Pandora's Box of Creating Child Donors for the Purpose of Saving Ailing Family Members." Seton Hall L. Rev. 32: 583.
  • Verlinsky, Y., S. Rechitsky, et al. (2001). "Preimplantation diagnosis for Fanconi anemia combined with HLA matching." JAMA 285(24): 3130-3133



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