Stem Cells

Background: Issue in Brief

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Stem cell research is one of the hot fields in biomedical science, both in terms of research potential and public controversy. Since the first isolation of usable stem cells, tremendous scientific interest has flourished over the potential of stem cell research to improve our understanding of human development and disease and potentially for cell-based therapies to cure a wide range of diseases. However, since the gold standard stem cells, embryonic stem cells, require the destruction of a human embryo, great controversy has arisen regarding the ethics of stem cell research. Around the world, researchers and politicians have struggled to develop guidelines that will allow for ethical and socially responsible stem cell research. In 2006, the landscape of stem cell research changed when the creation of induced pluripotent stem cells (iPSCs) were first announced. Induced pluripotent stem cells are created using adult cells, which are returned to a pluripotent state.

Overview: What's a Stem Cell Line?
Human embryonic stem cells were first isolated in 1998 at the University of Wisconsin. In basic terms, they are undifferentiated cells – essentially “blank slates” – that can develop into the over 200 cell types found in the body.  Embryonic stem cells are typically derived from embryos that are four to five days old.  Pre-implantation embryos at this stage of development are called blastocysts, hollow microscopic balls of cells.  Blastocysts are comprised of three different structures: the trophoblast, which is the outer layer of cells; the blastocoel, which is the hollow cavity inside the trophoblast; and the inner cell mass, a group of approximately 30 cells found at one end of the blastocoel.
 
The inner cell mass is extracted from the embryo and cultured in a nutrient rich environment in a Petri dish in order to create stem cell lines.  The term “embryonic stem cell line” refers to embryonic stem cells that:

•  Have proliferated for six months in a cell culture, creating millions of cells that have not developed into a specific cell type
•  Are pluripotent, meaning they have the capability to differentiate into all of the cell types in the human body
•  Appear without genetic defects that would affect normal development[i]

Embryonic stem cells have the unique ability to self-replicate indefinitely before creating specialized cells, which is one of the advantages of performing research on them. However, to be used for therapies, embryonic stem cells must be differentiated into specialized cells because undifferentiated stem cells are known to cause tumors.[ii]

In recent years, researchers have been exploring the potential of Induced Pluripotent Stem Cells (iPS cells) as possible substitutes or supplements to embryonic stem cells. iPS cells are produced by “reprogramming” the genetic code of adult cells. This is done by selectively inserting and forcing the expression of certain genetic factors that cause a cell to return to a state of pluripotency. At this time researchers are still uncertain of what clinical differences may exist between iPS cells and embryonic stem cells, meaning that, at this time, further research on both kinds of stem cells is necessary to fully understand the medical potential of these new discoveries.

The Promise of Stem Cell Research



One potential application of embryonic stem cells is the creation of new methods for testing drugs.  The use of differentiated cells from human pluripotent cell lines would allow scientists to test new medications on a wider range of cell types.  Scientists would be able to compare drugs more accurately if they can grow many identical cells on which to test them, though scientists will need to greatly expand their understanding of stem cell differentiation to be able to reliably generate pure populations of differentiated stem cells. [iii]

Likely the most publicly hailed potential of embryonic stem cells is in cell-based therapies.  Cell-based therapies are those in which stem cells are induced to differentiate into specific cell types for the purpose of repairing adult cell populations or tissues.[iv]  Given that embryonic stem cells replicate almost indefinitely, they would be a renewable source of replacement cells and tissues.[v]  These replacements could treat diseases such as Parkinson and Alzheimer disease, spinal cord injury, burns, heart disease, diabetes, and rheumatoid arthritis.[vi]  The creation of cell-based therapies would require easy and reproducible manipulation of stem cells; this can only be achieved through continued intensive research.[vii]

Studying human embryonic stem cells could provide information on the complex process of human development.  An important part of this research would be the identification of how and why undifferentiated cells become differentiated.[viii]  Some serious conditions, such as cancer and birth defects, are caused by abnormal cell division and differentiation.  If scientists could better understand the genetic and molecular control of these processes, they may better understand how these problems occur and be able to develop more efficient strategies for therapy. [ix]
 
There are many potential scientific applications for stem cell research.  From basic research on human development and the biological and genetic makeup of stem cells to their potential therapeutic uses, stem cells are thought to have an amazing amount of potential.  To develop this potential requires the continuation – and possible expansion – of stem cell research.



Ethics and Stem Cell Research

Embryonic stem cells are particularly controversial mainly due to their origins and acquisition methods.  Because the derivation of an embryonic stem cell line requires the destruction of the embryo, opponents have asserted that stem cell research kills embryos and unnecessarily destroys human life.  Embryonic stem cells can be obtained from unused embryos generated at IVF clinics and through somatic cell nuclear transfer, as described below. Embryonic germ cells, another type of pluripotent cell, can be derived from aborted fetuses, which draws objections from those opposed to abortion.



IVF

Embryonic stem cells can be derived from blastocysts created via in vitro fertilization (IVF).  The most common source, and many would argue the most ethical source, of embryonic stem cells is from embryos leftover from an IVF treatment.  Normally these extra blastocysts are either frozen for potential use later or disposed.  Most of the embryos frozen for future attempts at pregnancy are not used.  

Almost half a million embryos have been frozen and stored in the United States since the late 1970s; however, only a very small percentage of them (2.8% or approximately 11,000) have been designated for research by patients. However, recent research found that the majority (60%) of people with cryopreserved embryos no longer needed for reproductive purposes, would rather have those embryos used for stem cell research than be destroyed.  Excess embryos that are not being saved for future family planning purposes or embryos of poor quality that have been obtained with the informed consent of the donor are viewed by experts as the most ethical source of embryonic stem cells.[x] A poll taken by Research!America in 2005 showed that 62% of Americans favor research using donated eggs from fertility clinics.[xi]

IVF clinics could also produce blastocysts specifically for research that could allow scientists to study the origins of genetic diseases; however, opponents find this research to be unethical because it involves the creation of a blastocyst that will never develop into a human being.[xii]

Somatic Cell Nuclear Transfer (SCNT)



Another method of obtaining embryonic stem cells is called somatic cell nuclear transfer (SCNT), also known as therapeutic cloning.  This method involves removing the nucleus of an unfertilized egg cell (ovum), replacing it with the nucleus of a somatic, or non-sex, cell (e.g., a skin cell), and stimulating this cell to begin dividing.[xiii]  This process can create a stem cell line that is genetically matched to the patient, making it far less likely that the patient’s body will reject the new cells, which is one of the greatest obstacles to using cultured cells for therapies. This technology has not yet been successful in the production of human embryonic stem cells.[xiv] In addition, this technology has been somewhat eclipsed by induced pluripotent stem cells, which can also be patient-specific.

Recently, a new technique has been developed using inserted genes to reprogram a somatic cell into a pluripotent, stem cell-like, cell; these cells are called induced pluripotent (iPS) cells. Originally, inactive retroviruses were used to insert these genes leading to some concerns about its safety. New techniques have been developed as alternatives to the retroviral technique and in order to prevent some of the possible side effects. However, the original retroviral approach remains the most efficient method for producing iPS cells. Further ethical concerns arise from evidence that some iPS cells may trigger an immune response from the body the body of the original source, and iPS cells in general are not capable of producing as many adult cell variants as embryonic cells. Regardless of these concerns, iPS research appears to remain a fruitful object of research and a cause for excitement.

The difference between therapeutic cloning and reproductive cloning is significant.  Therapeutic cloning deals with regenerative research – its goal is not to create an entire organism.  Reproductive cloning, on the other hand, has the goal of generating an organism that has the same nuclear DNA as another currently or previously existing organism. However, both therapeutic and reproductive cloning are accomplished through the same technology:  somatic cell nuclear transfer.  Some people are concerned that this technique could be misused or taken too far:  that is, if therapeutic cloning is allowed, it would be medically and technologically possible to clone an entire being as well.  Much of the public mistrust surrounding this topic stems from alarm over the term ‘cloning,’ which has led to a misunderstanding that the intention of SCNT research is to clone human beings.
 
SCNT and Egg Donation

Not all ethical dilemmas in stem cell research involve the status of the embryo; specifically, the ethics of egg donation is an emerging issue.  SCNT requires a large number of eggs provided by a donor through an invasive procedure that poses health risks.  Experts have worked to formulate guidelines to protect women who donate eggs, sperm, and embryos for research and guarantee that they understand the risks they are undertaking.  Some criteria, in particular the "Guidelines for Human Embryonic Stem Cell Research" by the National Academy of Science, prohibit compensation for egg donors to prevent the creation of a commercial market for eggs that they fear would cause some women to overlook the risks of donation and could lead to the exploitation of women.  

Other bioethicists believe that egg donors should be compensated for the burdens and risk involved in donation.[xv]  In 2009, New York issued a policy permitting reimbursement for women who donate eggs to research, as long as such reimbursements remain within the standards for compensation already established for eggs donated for reproductive purposes. Agreement on guidelines outlining ethical egg and sperm donation practices is an important, if overlooked, aspect of ensuring stem cell research is conducted in an ethical manner.

Adult Stem Cells



Many opponents of embryonic stem cell research point out that adult stem cells also possess the ability to develop into various cell types and should therefore be used for research instead of embryonic stem cells.  Adult stem cells are undifferentiated cells, like embryonic stem cells, that are found in several organs and tissues in the human body.  Extraction and study of these stem cells would allow for informed patient consent and avoid the ethical issues dealing with the use of embryos.  However, adult stem cells are not pluripotent, like embryonic stem cells, rather, they are multipotent since they can efficiently differentiate into several different cell types, but only in their tissue of origin.  

Several experiments have intimated that certain adult stem cell types are actually pluripotent:they are able to form specialized cell types of other tissues, but only at very low frequencies. This capability is known as transdifferentiation or plasticity.[xvi] While plasticity would expand the types of tissues into which adult stem cells can differentiate, not enough is known about plasticity and not all adult stem cells have demonstrated transdifferentiation capabilities.  In addition, adult stem cells have a limited life span and have not been found in every organ.  This means that research on only adult stem cells would exclude research on certain organs and tissues.

Umbilical Cord Blood Stem Cells



Another potential source for stem cells is the umbilical cord.  Umbilical cord blood stem cells, preliminary research shows, have a higher differentiation potential than adult stem cells, although it is not yet certain whether they are truly pluripotent.[xvii] Another positive aspect of umbilical cord blood stem cells is that they can be saved, stored and multiplied without any of the ethical dilemmas associated with obtaining embryonic stem cells.  The growing number of cord blood banks around the world illustrates the increasing belief in the potential of cord blood stem cells.

In early 2007, researchers announced that they had isolated stem cells from amniotic fluid without harming the mother or fetus.  These amnio stem cells show great pluripotentiality, but scientists are not sure if they have the ability to form as many cell types as embryonic stem cells. However, amnio stem cells are genetically matched to the fetus, and scientists may be able to use them to treat birth defects or freeze them to treat sicknesses later in life without fear of immune rejection. While these cells show great promise, scientists emphasize that they will not make embryonic stem cells irrelevant.  In particular, embryonic stem cell research is much more advanced than amnio stem cell research, and embryonic stem cells are important to the study of early human development.

Ethical Overview

The human embryonic stem cell debate delves into some important ethical questions:  What is the moral status of the human embryo?  Is their use for embryonic stem cell research compatible with the respect due to an organism with full or partial moral status?  Is it immoral to impede stem cell research when it has such a strong potential to save and improve lives?  The responses to these and other such ethical questions strongly depend on whether one believes that embryos have moral status equivalent to born human beings.

Given the polarizing nature of these questions, it is unlikely that a consensus will be reached.  However, as addressed by the American Association for the Advancement of Science in their stem cell report, public policy does not aim to incorporate all viewpoints and ethical priorities, but to promote the “basic values essential to civic order and the pursuit of widely different individual conceptions of the good.”[xviii]
 
Key legislation/events


Embryonic stem cell research is legal in the US and is eligible for federal funding, through the NIH and other granting bodies; however, it has been a tumultuous decade for stem cell researchers as policy has evolved and made its way through the courts.

On August 9, 2001 President Bush announced that federal funding would be available for research on all stem cell lines already in existence.  In these cases, according to President Bush, the “life and death decision has already been made” and the embryos would have been destroyed anyway [xxi]  During this same speech Bush announced the creation of the President’s Council on Bioethics to monitor stem cell research, to recommend guidelines and regulations, and to consider the medical and ethical ramifications of all biomedical innovation.  The National Institutes of Health (NIH) has since created a stem cell registry and a stem cell bank, allowing researchers and other scientists to verify which stem cell lines can receive funding and to order from these pre-approved lines.  

Neither side was content with the President’s decision.  Opponents of embryonic stem cell research would have preferred a complete ban on federal funding and argued that the President’s ban did nothing to prevent privately funded research, which they viewed as the killing of more embryos.  Meanwhile, supporters claimed that the quality of some of the stem cell lines was questionable and that more stem cell lines were needed – in short, that potentially life-saving medical research was being unduly restricted. 

As it turned out, not all of the 60 stem cell lines approved for federal funding are viable for research.  Most of these stem cell lines have been deemed unsuitable for research: some of the lines failed to expand into undifferentiated cell cultures[xxii] and most of the lines were cultured with mouse feeder cells, making them inappropriate for human transplantation.[xxiii]  There are currently no more than 22 viable stem cell lines eligible for federal funding.[xxiv]

In 2006, Congress approved the Stem Cell Research Enhancement Act, which would have lifted Bush’s ban on federal funding of stem cell lines created after August 9, 2001.   Instead, federal funding would have been available for research on stem cell lines derived from discarded human embryos created for fertility treatment purposes.  However, on July 19, 2006 President Bush vetoed the legislation.  While this Act passed in both the House and the Senate, it lacked the 2/3 majority needed to overturn the President’s veto.

In 2009, following his inauguration, President Obama passed Executive Order 13505, which revoked the previous restrictions on federal funding for stem cell research, and ordered the issuance of new NIH guidelines on such research. Subsequently, after the release of draft guidelines and comments from scientists, religious institutions, and private citizens, the NIH issued these new guidelines governing federal funding for stem cell research. While the federal government is still not permitted to fund research that creates embryos in order to produce new stem cells, federal funds are now available for research on all existing stem cell lines. Following these new regulations, the first clinical trial of embryonic stem cells commenced in October 2011.


State Initiatives

State legislatures have also established their own policies regarding embryonic stem cells.  New Jersey was the first state to appropriate funding for human embryonic stem cell research in 2004.  Later that year California followed suit, approving Proposition 71 which allocated $3 billion over ten years for stem cell research.  For this purpose, Proposition 71 established the California Institute for Regenerative Medicine (CIRM), a state agency that makes grants and provides loans for stem cell research and research facilities.  

However, any research done on non-federally funded stem cell lines cannot be conducted in federally-funded research facilities or with federally-funded equipment.  This has meant that much of the money allocated to stem cell research has gone towards the large overhead costs of constructing new research facilities and buying new equipment.  Connecticut, Maryland, Ohio, Illinois , New York, and New Jersey have also created stem cell funding initiatives.

Up to date information on world-wide stem cell legislation can be found at http://www.hinxtongroup.org/wp.html. 



International Initiatives



Other governments have taken different approaches to the stem cell research issue.  The European Union has taken steps to increase funding for stem cell research, committing €11.9 million to 13 stem cell research centers in eight countries over four years (2002-2006).  Under the seventh research framework program (FP7), which took effect in 2007, the EU has continued to fund embryonic stem cell research regardless of the date that the stem cells were procured from embryos.  While EU policy is relatively open to stem cell research, individual member states of the EU have vastly differing policies.  Britain, for example, has permissive research laws, while countries such as Germany and Italy have very restrictive laws governing embryonic stem cell research.

 One of the most open countries for stem cell research is Singapore.  

In October 2003 Singapore opened Biopolis, a “purpose-built biomedical research hub where researchers from the public and private sectors are co-located.”[xxv] Phase I of the center is comprised of seven buildings, two of which house private sector biomedical researchers.  The other five house the biomedical research institutes of Singapore’s lead R&D agency.  Researchers from all over the world have come to live and work in Biopolis, with approximately 2,000 researchers, scientists and technicians living in Phase I.  In late 2005 the Singapore Stem Cell Consortium committed US$45 million for research in the field over the next three years.  Singapore’s overall R&D budget reached $6.5 billion (2% of GDP) in 2010, with much of that money going to research such as that of the Genome Institute of Singapore’s (GIS’s) Stem Cell Group, which worked to map the genes regulating stem cell function.
 
In 2004, members of the Stem Cell Policy and Ethics Program and The Johns Hopkins Berman Institute of Bioethics brought together approximately 60 esteemed international researchers to form the ‘Hinxton Group’ to explore the ethical and policy challenges of international collaboration on stem cell research, given the variations on national guidelines governing this contentious field of study.  The Hinxton Group has convened and released a consensus statement on stem cells, ethics, and law, with the latest of these statements released in 2010.  The Hinxton Group will continue its work on international ethical and legal stem cell research issues, creating a database of stem cell research guidelines and laws and a public discussion board on science, ethics, and policy.[xxvi]
As the international community overtakes the United States in stem cell research, many wonder what will happen when stem cell cures are discovered overseas. What implications will be seen from the shifting of economic capital overseas at a time when the United States is struggling to stay on top in scientific and technological innovation? 



Conclusion



Human embryonic stem cells show incredible promise in medical advancement, but pose unresolved ethical dilemmas.  Human embryonic stem cells have shown the most medical promise in understanding human development and future therapeutic uses.  However, the source of these cells – human blastocysts – has ignited a controversy over the definition of personhood and the moral status and rights that should be accorded to embryos.

-- Written by Stephanie Levy & Savannah Thomas. Thanks to Debra Mathews from the Berman Institute of Bioethics at Johns Hopkins University for reviewing this issue brief.

 

Key legislation/events

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Works Cited:

[i] Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2006. [accessed December 12 2006]

[iii] Ibid.

[iv] Ibid.

[v] Maienschein, p. 267.

[vi] Stem Cell Basics” [accessed December 12 2006]

[vii] Ibid.

[viii]Stem Cell Basics: What are the potential uses of human stem cells and the obstacles that must be overcome before these potential uses will be realized?” In Stem Cell Information, Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2006. [accessed December 12 2006]

[ix] Ibid.

[x] Stem Cell Research and Applications Monitoring the Frontiers of Biomedical Research.  American Association for the Advancement of Science, November 1999. Accessed December 18, 2006.

[xi]Americans Speak Out on Stem Cell Research, A Public Opinion Study for Research! America, Summer 2005.

[xiv] Maienschein, p. 272.

[xv] Egg Donation and Human Embryonic Stem Cell Research, New England Journal of Medicine, January 26, 2006 Volume 354: 324-326 [accessed December 18, 2006]

[xvi]Stem Cell Basics: What are adult stem cells?” in Stem Cell Information, National Institutes of Health

[xvii] Cord Blood yields ‘ethical embryonic stem cells, August 18, 2005, New Scientist Magazine.  

[xviii] Stem Cell Research and Applications Monitoring the Frontiers of Biomedical Research.  American Association for the Advancement of Science, November 1999. Accessed December 18, 2006.

[xix]Americans Speak Out on Stem Cell Research, A Public Opinion Study for Research! America, Summer 2005.

[xx] Stem Cell Research and Applications Monitoring the Frontiers of Biomedical Research.  American Association for the Advancement of Science, November 1999. Accessed December 18, 2006.

[xxi] President Discusses Stem Cell Research, August 9, 2001.

[xxii]Information on Eligibility Criteria for Federal Funding of Research on Human Embryonic Stem Cells” In Stem Cell Information. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2006. [accessed December 12 2006]

[xxiii] Thompson, Nicholas. “Science Friction: the growing--and dangerous--divide between scientists and the GOP. The Washington Monthly, July/August 2003. [accessed December 12 2006]