Stem cells: new frontiers of ethics, law, and policy

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✓ After the successful isolation of human embryonic stem cells in 1998, ethics and policy debates centered on the moral status of the embryo—whether the 2- to 4-day-old blastocyst is a person, and whether we should protect it at all costs. As the research has moved quickly forward, however, new questions have emerged for the study of stem cell ethics, law, and policy. Powerful new lines made without eggs or embryos have recently been reported, the intellectual property and regulatory environment is uncertain, and clinical trials using adult stem cells and cells derived from embryonic stem cells are about to commence. The new landscape of ethics, law, and policy is discussed in the context of these developments, with an emphasis on the evaluation of risks and benefits for first-in-human clinical studies.

Abbreviations used in this paper: ESC = embryonic stem cell; FDA = US Food and Drug Administration; hESC = human ESC; iPSC = induced pluripotent stem cell; IVF = in vitro fertilization; NSC = neural stem cell; USPTO = US Patent and Trademark Office.

✓ After the successful isolation of human embryonic stem cells in 1998, ethics and policy debates centered on the moral status of the embryo—whether the 2- to 4-day-old blastocyst is a person, and whether we should protect it at all costs. As the research has moved quickly forward, however, new questions have emerged for the study of stem cell ethics, law, and policy. Powerful new lines made without eggs or embryos have recently been reported, the intellectual property and regulatory environment is uncertain, and clinical trials using adult stem cells and cells derived from embryonic stem cells are about to commence. The new landscape of ethics, law, and policy is discussed in the context of these developments, with an emphasis on the evaluation of risks and benefits for first-in-human clinical studies.

Last November's discoveries of iSPC lines made without embryos provoked much publicity and renewed the debate about whether these cells will eliminate the need to use pluripotent stem cells made from leftover human embryos. These questions will be answered with time and more research, and the new cells may join adult and ESC lines already in the laboratory and on the road to the clinic. As the debate about the human embryo continues to simmer, the science has moved ahead. So too has the study of the ethical, legal, and policy dimensions of stem cell research.

The Globalization of Embryonic Stem Cell Research

It has been a decade since James Thomson's isolation of hESCs. Yet restrictions on hESC research raise questions about how individual nations will fare in an increasingly fractured legal and political landscape. Studies conducted at Stanford University and the University of Michigan reveal an “innovation gap,” whereby the peer-reviewed literature publication rate for research using hESC lines is increasing in offshore laboratories, but is decreasing in US laboratories.17 Tracking which lines go where yields important clues about the globalization of new biomedical technologies. From just 2 major US suppliers of hESCs—Harvard and WiCell—nearly 2,500 lines have been shipped since 1998, many of them to offshore laboratories. Among other things, we find that South Korea and Germany are importing lines with increasing frequency (McCormick, Scott and Owen-Smith, unpublished data). Each country has different moral and regulatory frameworks—one permissive, one restrictive. Yet the source of demand for hESC lines is somewhat different: although South Korea's stem cell fraud gained international attention, the nation remains home to many cloning laboratories. In Germany, destroying an IVF embryo obtained through local clinics can bring criminal penalties, but German researchers can import cell lines from other countries.22 The UK funds hESC research without restriction and has a national bank designed to distribute lines to scientists working in the UK and beyond, although the bank is proceeding carefully from ethical and quality control standpoints. Perhaps as a result of this and other factors, the UK remains the world's biggest importer of US lines. These patterns of distribution and use have important policy consequences for ethics, cross-border collaboration, and international commerce.

The fact that so many hESC lines are in so many hands puts November's discoveries in perspective. We find that a handful of National Institutes of Health–approved lines (also called the “presidential lines”) are requested more often than others. This is probably because they are better characterized and that fact gives a certain comfort to researchers when they are planning experiments. According to one iPSC report, a cell line can be directly reprogrammed in as little as 25 days using common retroviral methods.25 Since that paper was published, new lines, including disease-based cultures used in animal models, have been reported.7,15 Researchers will begin to compare iPSC and hESC lines, asking such questions as “can egg function be reduced to 3 genes?” Just as it took years to validate and characterize the first hESC lines, it will take time to properly characterize the new iPSC lines.

Using the new lines for basic research is one thing, but moving them into treatments is another. Commenting on the new discoveries, the chief executive officer of Geron, a Northern California ESC company remarked that developing cell therapies of any type would take time and money.1 Geron has invested many millions of dollars and over a decade in hESC research and development, most recently providing FDA safety data in anticipation of a Phase I trial for the treatment of spinal cord injury announced in 2008. Although oligodendrocytes derived from embryonic lines have their own set of ethical and technical concerns (such as a rogue embryonic cell producing a tumor or identifying and obtaining consent from the right patient population for the clinical trials), stem cell companies must develop proprietary lines and pass regulatory approvals. If this calculus is applied to individually matched therapies using reprogrammed cells or cells made by nuclear transfer, the current economics for broad-based use of personal therapies simply do not add up. The debate about which type of stem cell will be more useful, and how long the treatments are from the clinic, overshadows the fact that treatments for some diseases will come from conventional therapies first.

Technical and Moral Challenges to Stem Cell Patents

Last March the USPTO issued a preliminary invalidation of 3 hESC patents owned by the Wisconsin Alumni Research Foundation (WARF). The patents came under fire for being too broad, and the owners were criticized for using heavy-handed negotiating tactics. On the heels of these concerns, a California taxpayer group, backed by several prominent scientists, requested a reexamination of the patents. One of the thresholds for patentability is that inventions be novel and nonobvious. In the ruling, the USPTO found the claims of the inventor, James Thomson, to be obvious to a person with ordinary skill in the art. For its part, WARF will engage in a lengthy appeal process. Our analysis of the challenge and the invalidation finds that time, the US legal system, and history favor the owners of patents under challenge. Historically, only 12% of reexaminations succeed in overturning the patent. In fact, patent holders themselves request half of reexaminations for the purpose of strengthening their claims. The end result is that WARF—and its exclusive licensee, Geron—may emerge in a stronger position if the patents prevail.18

NeuralStem, a biotech company developing treatments for central nervous system disease, has asked the USPTO to reexamine a patent on fetal-derived NSCs owned by Stem Cells, Inc. The strength of core embryonic and adult stem cell patents is that they claim a right to the lines themselves (in legalese, the “composition of matter”). The practical consequence is that not only can the owners charge for the lines they own, but anywhere the patent is in force it can prohibit anyone who wishes to make, use, or sell the line without first negotiating a fee-based, royalty-bearing license. The NSC claims were rejected by the USPTO last September, including rights to own the lines. Patent scholars and the biotech community will closely watch both reexaminations to see if the critical composition of matter claims stand or fall.

In the European Union, Thomson's discoveries are under attack on moral grounds. Under a 1998 directive prohibiting the patenting of inventions that are contrary to “public order” or morality, the European Patent Office (EPO) evoked an ESC patent developed in a murine model based on a broad interpretation that it could apply to human lines. But EPO rulings carry only so much weight at the national level. European Union member states are free to interpret moral exclusions in ways that are consistent with local cultural norms. The United Kingdom and Sweden have allowed patenting of hESC lines; others, like Germany, have annulled them on moral grounds. The German case is especially troubling because the denial was based on a hypothetical use of human embryos to derive an NSC line.

The situation in Europe thus has far-reaching consequences for research and business. Not only can patents on human ESCs be denied, but patents on the downstream derivatives, including adult stem cells and terminally differentiated types, can be similarly affected. Even patents on cell culture techniques could be captured by moral exclusions. Depending on the jurisdiction, an entire sector of cell technologies, including those discovered using animal models, may be deemed unpatentable.18

The New Ethics of Stem Cell Research

New concerns for bioethics focus on research oversight, both at the bench and in the clinic. At Stanford and in other California institutions engaged in stem cell research, stem cell research oversight (SCRO) committees use separate but overlapping sets of guidelines and regulations from 3 sources: the National Academy of Sciences, the California Institute of Regenerative Medicine, and California law. These regulations join out-of-state and international legislation that must be evaluated in light of harmonization with local law.8,23

In California, any bench research using stem cells—adult or embryonic—must first undergo SCRO committee approval. The composition of SCRO committees includes basic scientists, embryologists, IVF physicians, ethicists, legal experts, patient advocates, and community members. One of the most active academic committees, an SCRO committee tackles issues raised in an area of biology that can change faster than ethicists can deliberate. One question centers on whether human cognition or other traits might emerge from preclinical studies transplanting human ESCs or NSCs into the brains of animals. California law and California Institute for Regenerative Medicine regulations require review of human cells defined as “pluripotent.” This means that the new iPSC lines are caught by the legislation, prompting questions related to the consent of cell donors. When somatic cells are directly reprogrammed into an immortal line, the donors' genetic information could live indefinitely in culture—or in transplant patients. California law now mandates SCRO committee review of in vitro adult stem cell research using cancer stem cells or stem cells isolated from mobilized blood. (The SCRO committee members also consider which cells—such as progenitor, oligopotent, and unipotent cells—are subject to oversight.)

Complex questions will face SCRO committee and institutional review board review of first-in-human clinical trials. Stem cell research involves balancing the interests of 2 groups: 1) the cell, gamete, and embryo donors and 2) the volunteers participating in clinical trials. The ethics of cell and embryo donation has been discussed elsewhere.14,28,12 Among other things, donors must be fully informed of the potential consequences of the research so they can document their preferences. Concerns about privacy emerge, too. Many years may pass from the time cells are donated before therapies are fully realized, so future recipients may be at risk from previously unknown diseases transmitted through donor cell lines. To ensure safety, researchers may need to recontact donors and inquire about their health at the time trials commence and again as therapies enter into broader use.11

It is difficult to evaluate risk before proceeding to first-in-human studies, but stem cells raise new questions for clinical oversight. Proliferative potential, behaviors of cells outside the local environs of the niche, and the evaluation of preclinical data are 3 among many facets of risk evaluation.4 A substantial back-and-forth within and between SCRO and institutional review board committees and ad hoc experts will be necessary on a range of issues, such as cell plasticity and the homeostatic mechanisms regulating cell numbers and cell fates.27 Protocols with preclinical roadmaps will help committees evaluate risk in early studies and gauge benefit later in clinical development. These could include methods to control proliferation or misdifferentiation (such as apoptotic switches or gene regulation); fate mapping studies as evidence that cells target, function, and if necessary, graft and persist; and functional assays and evidence of efficacy in animal models mimicking the human disease.10 In certain cases, approvals may require proof of efficacy in primate models.

Risk assessment may change with cell type and route of administration. Investigators will need to clearly explain strategies and reasons for using stem cells rather than the downstream derivatives. For complex neuronal diseases where migratory potential and engraftment are uncertain, stem or progenitor cells may be better suited for neuroprotection than for replacement. Although it is not necessary to understand the precise mechanism of repair or renewal, information about the pathogenetic mechanisms of the disease, the probable behaviors of the administered cell type, and the effects of the transplants on the host environment (and vice versa) will be useful. For allogenic transplants, immune suppression will be required, which could decrease therapeutic effectiveness. Immune rejection could also destroy the cells, cause an inflammatory response, and harm the patient. Interestingly, hESC-derived neural lines may provoke a lower degree of immune response than other nonmatched cell types.6,16,19

During review, the predictive power of animal models will be intensely deliberated. Species-specific interactions among cells, tissues, and organs will confound analysis—even with FDA requirements of results in at least 2 animal models. However, preclinical work with certain neural cell types is encouraging. Human NSC transplanted into spinal cord–injured mice survived, migrated, differentiated, and restored locomotion, with no evidence of scarring or tumors.3 Oligodendrocytes derived from hESCs restore function in spinal cord–injured rats.9 Although fetal and adult stem cell isolates are not usually tumorigenic, lines derived from hESCs or other pluripotent cell types carry tumor risk. Although teratoma formation rarely occurs in hESC-derived neural xenografts in mice, in one study tumors developed in 70% of mice receiving murine neural precursors from ESCs.5 In another study, derived hematopoietic precursors from monkey ESCs were transplanted into fetal mice, sheep, and monkeys. The xenografts did not produce tumors, but the primate-to-primate allografts did.20 Moreover, irrespective of cell type, xenograft models of disease or injury may not accurately predict the same response in humans because of the immune-compromised state of the animals.

Jesse Gelsinger was the first person to die during a gene transfer trial in 1999. His case is firmly cemented in the annals of clinical ethics and gains relevance in the context of stem cell clinical trials. In 2002, insertional mutagenesis plagued an ex vivo stem cell trial involving 10 newborns suffering from X-linked severe combined immunodeficiency disease (X-linked SCID). The trial, using retroviral gene delivery, was halted after T-cell leukemia developed in 3 infants. Following these results, the FDA put its gene transfer studies on hold. These cases have heightened ethical awareness of first-in-human trials using stem cells, particularly when gene transfer is involved. As a result, ethical oversight of future ex vivo trials using transduced stem cells for amyotrophic lateral sclerosis and Parkinson disease2,21 will receive close scrutiny. In the future, advances in chromosomal targeting may decrease the problems associated with random gene integration. Precise gene editing using zinc finger nucleases has been used in cultures of umbilical cord blood stem cells and hESCs.13

Other facets are unique to ethical review of stem cell clinical protocols. Volunteers could have moral reasons to decline a cellular transplant derived from a destroyed embryo. But, they might agree to cells made from nuclear transfer or direct reprogramming. In some trials, healthy subjects are unlikely to be recruited for Phase I studies. Last-recourse treatments for fatal, rapidly progressive disease have a different ethical calculus from those designed to treat chronic disease. Greater risk might be justified if death or continued decline is imminent. For disabled individuals with prospects of a longer life, cellular immortality is a double-edged sword: a beneficial or harmful outcome can last as long as the patient does.

As for other early-phase trials, consent should be considered in the context of a person's disability. Patients' assessments of serious injuries and disease are often different from those of the public.26 Newly disabled persons (and the surrogates and families who care for them) may overestimate the long-term emotional impact of a recent injury. As a result, participants might be more likely to agree to a trial now than they would after time passes and their expectations change. For those living with a debilitating or deadly disease, a person's hope for an incremental benefit from a safety trial—however remote—might outweigh any considerations of risk. Restoration of bowel function for a patient with a spinal injury represents a significant improvement in quality of life. On the other hand, an inoperable tumor caused by the transplant may mean a lifetime of peripheral pain.

Because of the hype and expectation surrounding stem cell therapies, sponsors, clinical researchers and review committees must ensure that volunteers and surrogates fully understand what the treatment offered in any given study is intended to accomplish—what is hoped for—as well as the possible risks. New guidelines for the conduct of clinical trials of treatments for spinal cord injury emphasize both the evaluation of risk and the aim of safety in first-phase studies.24 Just as California law requires a test of comprehension for cell, gamete, and embryo donors, a similar test as part of clinical informed consent will determine whether patients and surrogates have a realistic understanding of the study's aims.

Summary

Science is moving rapidly forward, and new questions have emerged in the areas of stem cell ethics, law, and policy. As the family of stem cell lines grows, which will emerge as the most useful for research and treatment, and how will they be distributed to those who need them? How can we effectively collaborate across borders, either among states or among countries? Which nations will develop the first treatments and cures? Will medical tourism, fueled by the hope for stem cell cures, begin to rise?

The answers to these questions are just beginning to emerge. First-in-human trials are high-reward, high-risk endeavors and are full of uncertainty. Investigators and sponsors should present review committees with a clear and thoughtful research plan that will satisfy requirements to “do no harm.” Ethicists and nonspecialists should take time to familiarize themselves with the basics of stem cell biology and the predictive power of animal models. Although gene transfer and stem cell therapy share a place at the leading edge of medicine, we need to be clear where they differ in terms of biology, mechanisms of action, and curative potential. More than ever before, the world will be watching these experiments to see if the field can live up to its bold promise.

Acknowledgments

I thank Theo Palmer and Clive Svendsen for their helpful discussions prior to preparing the manuscript.

References

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    • Search Google Scholar
    • Export Citation
  • 2

    Capowski EESchneider BLEbert ADSeehus CRSzulc JZufferey R: Lentiviral vector-mediated modification of human neural progenitor cells for ex vivo gene therapy. J Neurosci Methods 163:3383492007

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  • 3

    Cummings BJUchida NTamaki SJAnderson AJ: Human neural stem cell differentiation: association with recovery of locomotor function. Neur Res 28:4744812006

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    • Export Citation
  • 4

    Dawson LBateman-House ASMueller Agnew DBok HBrock DWChakravarti A: Safety issues in cell-based intervention trials. Fertil Steril 80:107710852003

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  • 5

    Dihné MBernreuther CHagel CWesche KOSchachner M: Embryonic stem cell-derived neuronally committed precursor cells with reduced teratoma formation after transplantation into the lesioned adult mouse brain. Stem Cells 24:145814662006

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    • Export Citation
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    Drukker MKatchman HKatz GEven-Tov Friedman SShezen EHornstein E: Human embryonic stem cells and their differentiated derivatives are less susceptible to immune rejection than adult cells. Stem Cells 24:2212292006

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    • Export Citation
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    Hanna JWernig MMarkoulaki SSun CWMeissner ACassady JP: Treatment of sickle cell anemia mouse model with iPS cells generated from autologous akin. Science 318:192019232007

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    Hanna K: Ball of confusion: how stem cells have stymied review boards. Research Practitioner 8:1281362007

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    Keirstead HSNistor GBernal GTotoiu MCloutier FSharp K: Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25:469447052005

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    • Export Citation
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    Lindvall OKokaia Z: Stem cells for the treatment of neurological disorders. Nature 441:109410962006

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    Lo BZettler PCedars MIGates EKriegstein AROberman M: A new era in the ethics of human embryonic stem cell research. Stem Cells 23:145414592005

    • Search Google Scholar
    • Export Citation
  • 12

    Lomax GPHall ZWLo B: Responsible oversight of human stem cell research: the California Institute for Regenerative Medicine's medical and ethical standards. PLoS Med 4:e1142007

    • Search Google Scholar
    • Export Citation
  • 13

    Lombardo AGenovese PBeausejour CMColleoni SLee YLKim KA: Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat Biotechnol 25:129813062007

    • Search Google Scholar
    • Export Citation
  • 14

    Magnus DCho M: Ethics. Issues in oocyte donation for stem cell research. Science 308:174717482006

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    Nakagawa MKoyanagi MTanabe KTakahashi KIchisaka TAoi T: Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26:1011062008

    • Search Google Scholar
    • Export Citation
  • 16

    Okamura RMLebkowski JAu MPriest CADenham JMajumdar AS: Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192:1341442007

    • Search Google Scholar
    • Export Citation
  • 17

    Owens-Smith JMcCormick J: An innovation gap in ES cell research. Nat Biotechnol 24:3913922006

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    Plomer ATaymor KTScott CT: Challenges to embryonic stem cell patents. Cell Stem Cell 2:13172008

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    Revazova ESTurovets NAKochetkova ODAgapova LSSebastian JLPryzhkova MV: HLA homozygous stem cell lines derived from human parthenogenetic blastocysts. Cloning Stem Cells [epub ahead of print]2007

    • Search Google Scholar
    • Export Citation
  • 20

    Shibata HAgeyama NTanaka YKishi YSasaki KNakamura S: Improved safety of hematopoietic transplantation with monkey embryonic stem cells in the allogeneic setting. Stem Cells 24:145014572006

    • Search Google Scholar
    • Export Citation
  • 21

    Silani VCova LCorbo MCiammola APolli E: Stem-cell therapy for amyotrophic lateral sclerosis. Lancet 364:2002022004

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    Starck C: Embryonic stem cell research according to German and European law. German Law J 7:6256562006

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    Stayn S: A guide to state laws on hESC research: a call for interstate dialogue. BNA Med Law Pol Rep 5:7187252006

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    Steeves JDLammertse DCurt AFawcett JWTuszynski MHDitunno JF: Guidelines for the conduct of clinical trials for spinal cord injury (SCI, as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 45:2062212007

    • Search Google Scholar
    • Export Citation
  • 25

    Takahashi KTanabe KOhnuki MNarita MIchisaka TTomoda K: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:8618722007

    • Search Google Scholar
    • Export Citation
  • 26

    Ubel PLoewenstein GJepson C: Whose quality of life? A commentary exploring discrepancies between health state evaluations and the general public. Quality Life Res 12:5996072003

    • Search Google Scholar
    • Export Citation
  • 27

    Weissman I: Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287:144214462000

  • 28

    Zettler PWolf LELo B: Establishing procedures for institutional oversight of stem cell research. Acad Med 82:6102007

Article Information

Address correspondence to: Christopher Thomas Scott, 701 Welch Road, Suite A1105, Palo Alto, California, 94305. email: cscott@stanford.edu.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Associated Press: Biotech firms react coolly to new stem cell findings. November212007. (http://www.komotv.com/news/tech/11697266.html) [Accessed 21 January 2008]

    • Search Google Scholar
    • Export Citation
  • 2

    Capowski EESchneider BLEbert ADSeehus CRSzulc JZufferey R: Lentiviral vector-mediated modification of human neural progenitor cells for ex vivo gene therapy. J Neurosci Methods 163:3383492007

    • Search Google Scholar
    • Export Citation
  • 3

    Cummings BJUchida NTamaki SJAnderson AJ: Human neural stem cell differentiation: association with recovery of locomotor function. Neur Res 28:4744812006

    • Search Google Scholar
    • Export Citation
  • 4

    Dawson LBateman-House ASMueller Agnew DBok HBrock DWChakravarti A: Safety issues in cell-based intervention trials. Fertil Steril 80:107710852003

    • Search Google Scholar
    • Export Citation
  • 5

    Dihné MBernreuther CHagel CWesche KOSchachner M: Embryonic stem cell-derived neuronally committed precursor cells with reduced teratoma formation after transplantation into the lesioned adult mouse brain. Stem Cells 24:145814662006

    • Search Google Scholar
    • Export Citation
  • 6

    Drukker MKatchman HKatz GEven-Tov Friedman SShezen EHornstein E: Human embryonic stem cells and their differentiated derivatives are less susceptible to immune rejection than adult cells. Stem Cells 24:2212292006

    • Search Google Scholar
    • Export Citation
  • 7

    Hanna JWernig MMarkoulaki SSun CWMeissner ACassady JP: Treatment of sickle cell anemia mouse model with iPS cells generated from autologous akin. Science 318:192019232007

    • Search Google Scholar
    • Export Citation
  • 8

    Hanna K: Ball of confusion: how stem cells have stymied review boards. Research Practitioner 8:1281362007

  • 9

    Keirstead HSNistor GBernal GTotoiu MCloutier FSharp K: Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25:469447052005

    • Search Google Scholar
    • Export Citation
  • 10

    Lindvall OKokaia Z: Stem cells for the treatment of neurological disorders. Nature 441:109410962006

  • 11

    Lo BZettler PCedars MIGates EKriegstein AROberman M: A new era in the ethics of human embryonic stem cell research. Stem Cells 23:145414592005

    • Search Google Scholar
    • Export Citation
  • 12

    Lomax GPHall ZWLo B: Responsible oversight of human stem cell research: the California Institute for Regenerative Medicine's medical and ethical standards. PLoS Med 4:e1142007

    • Search Google Scholar
    • Export Citation
  • 13

    Lombardo AGenovese PBeausejour CMColleoni SLee YLKim KA: Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat Biotechnol 25:129813062007

    • Search Google Scholar
    • Export Citation
  • 14

    Magnus DCho M: Ethics. Issues in oocyte donation for stem cell research. Science 308:174717482006

  • 15

    Nakagawa MKoyanagi MTanabe KTakahashi KIchisaka TAoi T: Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26:1011062008

    • Search Google Scholar
    • Export Citation
  • 16

    Okamura RMLebkowski JAu MPriest CADenham JMajumdar AS: Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192:1341442007

    • Search Google Scholar
    • Export Citation
  • 17

    Owens-Smith JMcCormick J: An innovation gap in ES cell research. Nat Biotechnol 24:3913922006

  • 18

    Plomer ATaymor KTScott CT: Challenges to embryonic stem cell patents. Cell Stem Cell 2:13172008

  • 19

    Revazova ESTurovets NAKochetkova ODAgapova LSSebastian JLPryzhkova MV: HLA homozygous stem cell lines derived from human parthenogenetic blastocysts. Cloning Stem Cells [epub ahead of print]2007

    • Search Google Scholar
    • Export Citation
  • 20

    Shibata HAgeyama NTanaka YKishi YSasaki KNakamura S: Improved safety of hematopoietic transplantation with monkey embryonic stem cells in the allogeneic setting. Stem Cells 24:145014572006

    • Search Google Scholar
    • Export Citation
  • 21

    Silani VCova LCorbo MCiammola APolli E: Stem-cell therapy for amyotrophic lateral sclerosis. Lancet 364:2002022004

  • 22

    Starck C: Embryonic stem cell research according to German and European law. German Law J 7:6256562006

  • 23

    Stayn S: A guide to state laws on hESC research: a call for interstate dialogue. BNA Med Law Pol Rep 5:7187252006

  • 24

    Steeves JDLammertse DCurt AFawcett JWTuszynski MHDitunno JF: Guidelines for the conduct of clinical trials for spinal cord injury (SCI, as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 45:2062212007

    • Search Google Scholar
    • Export Citation
  • 25

    Takahashi KTanabe KOhnuki MNarita MIchisaka TTomoda K: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:8618722007

    • Search Google Scholar
    • Export Citation
  • 26

    Ubel PLoewenstein GJepson C: Whose quality of life? A commentary exploring discrepancies between health state evaluations and the general public. Quality Life Res 12:5996072003

    • Search Google Scholar
    • Export Citation
  • 27

    Weissman I: Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287:144214462000

  • 28

    Zettler PWolf LELo B: Establishing procedures for institutional oversight of stem cell research. Acad Med 82:6102007

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