Organizational Principles to Guide and Define the Child Health Care System and/or Improve the Health of all Children

POLICY STATEMENT Human Embryonic Stem Cell (hESC) and Human Embryo Research

COMMITTEE FOR PEDIATRIC RESEARCH and COMMITTEE ON abstract BIOETHICS Human embryonic stem cell research has emerged as an important KEY WORDS platform for the understanding and treatment of pediatric diseases. human embryonic stem cell, stem cell research, embryo, ethics From its inception, however, it has raised ethical concerns based ABBREVIATIONS hESC—human embryonic stem cell not on the use of stem cells themselves but on objections to the source iPSC—inducible pluripotent stem cell of the cells—specifically, the destruction of preimplantation human IVF—in vitro fertilization embryos. Despite differences in public opinion on this issue, a large This document is copyrighted and is property of the American majority of the public supports continued research using embryonic Academy of Pediatrics and its Board of Directors. All authors fi fl stem cells. Given the possible substantial benefit of stem cell research have led con ict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through on child health and development, the American Academy of Pediatrics a process approved by the Board of Directors. The American believes that funding and oversight for human embryo and embryonic Academy of Pediatrics has neither solicited nor accepted any stem cell research should continue. Pediatrics 2012;130:972–977 commercial involvement in the development of the content of this publication. All policy statements from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, INTRODUCTION revised, or retired at or before that time. In the past 10 years, significant progress has been made in basic and translational research using human embryonic stem cells (hESCs), with specific implications for pediatric diseases such as hypoxic- ischemic encephalopathy,1 bone marrow failure syndromes,2 leuke- mia,3 and congenital heart disease.4 Although the fundamental principle of stem cell research remains the same (ie, the development of un- differentiated cells into committed cell lineages for the purpose of tissue renewal and repair), the science has evolved to encompass many new applications, including cell-based therapies5 and drug screening.6,7 Although these new applications are intriguing, they remain in the early www.pediatrics.org/cgi/doi/10.1542/peds.2012-2482 stages of development, and additional research is needed to make the doi:10.1542/peds.2012-2482 transition from bench to therapeutics. It is anticipated that continued PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). advances will have a substantial impact on the understanding and Copyright © 2012 by the American Academy of Pediatrics treatment of pediatric diseases. hESCS Three unique properties of hESCs are as follows: (1) they are un- specialized or undifferentiated; (2) they can differentiate into more specialized cell types, such as brain, bone marrow, or heart, depending on the developmental signals they receive (referred to as pluripotency); and (3) they can continue to divide and renew themselves for longer periods than differentiated cells.8 Current sources of hESCs include excess embryos that would have been discarded after a successful in vitro fertilization (IVF) process, from previously frozen embryos created as part of an earlier IVF

972 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 29, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS process, and from de novo synthesis. the laboratory to generate an ongoing stem cells is now the standard of care In addition, hESCs may be generated source of cells, referred to as a cell for pediatric high-risk leukemia as from embryos with arrested9 or oth- line. Because of the unique self- well as for certain solid tumors, im- erwise abnormal growth that would renewing capacity of stem cells, the mune deficiencies, and metabolic render them unsuitable for implanta- lines can often be maintained in- disorders. Stem cells have also been tion. In these cases, the removal of the definitely. Because of constraints on identified in the brain, cardiac muscle, cells to form the stem cell line results the use of federal funds for research connective tissue, and bone. Most ev- in the destruction of the embryo. that results in the destruction of idence suggests that these cells are There is some recent evidence that a human embryo, federal research not pluripotent, as are hESCs, but hESC lines can be generated from 1 to grants involving hESCs entail the ex- could be induced to accelerate their 2 cells obtained by a biopsy procedure perimental manipulation of existing repair mechanism in cell-based re- that does not require destruction of hESC lines and do not directly fund the generative therapy, such as the use of the embryo, but this procedure has acquisition of stem cells from the native neural stem cells to repair not obviated the need to continue to embryo. To maximize collaboration and spinal cord injury.11,12 Traditionally, derive stem cells in the traditional access to hESC lines available nation- this technology has been limited by manner, which results in the de- ally and internationally, the National the fact that adult stem cells are more fi struction of an embryo.10 Traditionally Institutes of Health Of ce of Extramural differentiated, are harder to isolate created embryonic stem cell lines are Research maintains a publicly acces- from tissue, exist in relatively small needed to serve as a comparison with sible registry that investigators may numbers, and are more difficult to the newly developed lines to establish access to apply for funds pertaining to maintain in long-term culture when whether they are indeed equivalent to a particular cell line. State and private compared with hESCs. funding of stem cell research may not traditionally developed lines. More- The generation of iPSCs from adult be similarly constrained. over, although a single cell biopsy may cells represents a major advancement be performed in IVF cases to test for in the understanding of the molecular genetic diseases, it is unclear whether ADULT STEM CELLS AND mechanisms of cell differentiation. In it would be appropriate to transfer to INDUCIBLE PLURIPOTENT STEM 2007, iPSCs were successfully gener- a uterus an embryo that underwent CELLS ated from human fibroblasts by en- such biopsy for the creation of stem In an attempt to find alternative gineering them to express genes cell lines. It is not known whether the sources for stem cells, several addi- implicated in dedifferentiation and the biopsy makes the embryo less likely tional methods have been developed maintenance of “stemness.”13 These to implant. Women undergoing IVF over the past 15 years. These include cells were capable of differentiating typically choose to transfer to their the isolation and genetic reprogram- into all 3 embryonic germ layers (en- uterus embryos with the highest ming of specific adult cells (usually doderm, mesoderm, and ectoderm). likelihood of implantation and, even- skin fibroblasts) into inducible plu- It is anticipated that, as the tech- tually, healthy birth. If embryos that ripotent stem cells (iPSCs). The de- nology evolves, iPSCs will have im- have undergone a biopsy for purposes velopment of these methods has portant implications for pediatric unrelated to health are not going to not replaced the use of hESCs but diseases, including the study of tumor be chosen for implantation and will be has offered additional insight into differentiation,14,15 hematopoiesis,16,17 eventually discarded, then the single the biology of cell differentiation, neurodegenerative disorders,18 and biopsy procedure does not result in dedifferentiation, and aging in new damaged tissue regeneration.19,20 “sparing” embryos (although it may biological models. Opponents of funding for hESC re- result in a delay in destruction). Re- Most mature tissues have small pop- search believe that advances in the search is ongoing to identify novel and ulations of stem cells that facilitate use of iPSCs obviate the need for cells fi more ef cient methods of obtaining continued tissue growth and repair. derived directly from the human em- stem cells from human embryos, and These were first recognized in bone bryo. Although the use of iPSCs it is anticipated that this area will marrow, and advances in their iso- appears to hold great promise, there is continue to evolve. lation and expansion have revolution- evidence that, when compared with Once small numbers of embryonic ized the treatment of hematologic and embryonic cells, iPSCs tend to retain stem cells have been isolated from other malignancies. Bone marrow their “molecular identity” and may, human embryos, they are cultured in transplantation with hematopoietic therefore, be less stable and efficient

PEDIATRICS Volume 130, Number 5, November 2012 973 Downloaded from www.aappublications.org/news by guest on September 29, 2021 when programmed to develop into tant, optimizing gas exchange, and those embryos but see the 2 acts as a particular cell line.21 Their cellular protecting against pathogen invasion. separate. People who do object argue growth parameters may also be al- Continued developments in this area that the use of such stem cells is tered and have an increased suscep- could enhance the treatment of neo- morally complicit.30 In some ways, this tibility to unregulated growth similar natal lung disease, a leading cause of concern may be time-limited (eventu- to a neoplastic process, raising can- morbidity and mortality in preterm ally, an alternative mechanism for cer concerns. In addition, some iPSCs infants. Insulin-secreting populations deriving cell lines that does not result may be susceptible to silencing of of pancreatic islet cells have been in the destruction of an embryo may genes required for fetal development developed.26 Additional research is be discovered). But, as pointed out and differentiation.22 This concept of needed to stimulate these cells to earlier, even as new mechanisms are lineage bias will continue to be an produce enough insulin to be physio- developed, traditionally derived stem active area of research requiring on- logically functional. If achieved, this cells must be used to set the standard going comparison of the pluripotency could serve as a powerful therapy for against which to compare the newly of iPSCs and hESCs. For example, the children facing lifelong insulin re- derived lines.24 gene involved in fragile X syndrome, placement and morbidity associated The moral status* of preimplantation the most common inherited form of with type I diabetes mellitus. A new ex utero human embryos may never mental retardation in children, pro- technique for culturing hESCs has be truly settled, and debates about duces a protein vital to normal brain allowed for their differentiation into the ethics of stem cell research are development in normal patients but skin cells that expand rapidly and may ongoing. Despite differences in public acquires a silencing mutation in those serve as a replacement for autologous opinion on this issue, a majority of the with the disease. Researchers have skin grafts27 and their long-term cos- public supports continued research shown that this gene functions nor- metic sequelae. A direct comparison using embryonic stem cells.31 Those mally in human embryonic cells and of the tumor-killing capacity of natural people who disagree may argue becomes silenced as the cells differ- killer cells derived from hESCs versus that preimplantation ex utero human entiate. In iPSCs, however, the gene is umbilical cord blood stem cells found embryos should be accorded equal already silenced before the cells begin hESCs to be more efficient at killing moral status to fully developed to differentiate.23 The use of iPSCs in leukemias and solid tumors as well as humans, but others counter that they human trials is problematic, given the protecting against metastasis and have lesser moral status. Those in the high level of manipulation of these recurrence in an in vivo model.28 latter category may argue that pre- cells and the resulting concerns about Further work in this area will be implantation ex utero embryos have how they will function in vivo. Whether particularly beneficial to children, in no moral status (because they lack iPSCs will prove a useful substitute for whom the late effects of cancer che- relevant characteristics, such as sen- hESCs has yet to be determined. At motherapy have been of increasing tience or ability to feel pain), or in- this time, comparative studies using concern. stead they may attempt to place iPSCs will require an ongoing source embryos along a moral status hier- of hESCs, which are still considered ETHICAL ISSUES archy with other biologically alive the scientific gold standard for em- entities, such as nonhuman animals. bryonic cell lines.24 There are few ethical concerns raised Even those who believe these embryos about the use of isolated hESCs. hESC RESEARCH AND PEDIATRIC have little or no moral status may still Rather, concerns focus on the sources DISEASE believe they should be treated with of the cells and, particularly, on the respect or that there are certain The American Academy of Pediatrics need to destroy a human embryo limits to what may be done with supports hESC research because to derive the cell lines.29 If the a human embryo. Alternatively, those current research reveals it may posi- destruction of a human embryo is who believe that the preimplantation tively affect the treatment of pediatric a morally wrong act, then the use of diseases. In the past decade, several stem cells derived from the de- *Moral status refers to the determination that an promising advances have been made struction of the embryo may also be entity “counts” or that its interests must be taken with specific applications in pediatrics. morally problematic. Some people into account, from a moral (as opposed to legal) hESCs have been programmed to dif- who object to the destruction of em- point of view. Not all entities with moral status will have legal status (eg, nonhuman animals). Not all ferentiate into type II alveolar lung bryos do not similarly object to entities with legal status will have moral status cells25 capable of producing surfac- the use of stem cells derived from (eg, corporations).

974 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 29, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS ex utero embryo has some moral a number of other ethical issues that to commodify children or even dem- status may determine that the inter- arise in this context. For example, onstrate disrespect for the embryo ests of those who could benefitfrom there are ethical concerns regarding (although payment of money can also future developed treatments weigh in acquisition of embryos from different be viewed as a way of demonstrating favor of their use. In particular, they sources. The most common source is respect). Because of the varying may find benefit in the use of embryos excess embryos from the IVF process. positions on this issue and the ab- that are already destined for disposal. But embryos may also be created sence of a need to pay donors for any For the purposes of this policy state- specifically for stem cell research. For time, effort, or risk involved in creating ment, it is important to recognize that those who believe that embryos have the excess embryos, the American the moral status of preimplantation ex some moral status (whether it is Academy of Pediatrics finds financial utero embryos is a point of debate equivalent to that of fully developed incentives to be inappropriate in this and that any policy or regulatory humans), the creation of embryos for context. Payment for the time, effort, oversight system should be sensitive research purposes may be more eth- and risks involved in gamete donation to differing moral positions. ically problematic than the use of ex- raises different issues and is beyond The American Academy of Pediatrics cess embryos that would otherwise be the scope of this statement. recognizes the ethical considerations destroyed. Even those who believe the If embryos are created by using ge- inherent in hESC research but also embryo has no moral status may be netic material from multiple individu- recognizes the potential benefitto uneasy about creating them for purely als, it may be unclear who should children of future discoveries, partic- research uses. Because there are provide the consent for research. Most ularly children for whom successful fewer objections to the use of embryos IVF clinics do not look to gamete treatment of their diseases is cur- already created, research in this area donors specifically, but rather to the rently limited. At this time, research may be limited to cells derived from individuals (or individual) who are with hESCs offers a promising line excess IVF embryos. This would be planning to use the embryos for re- of inquiry for many of these diseases. congruent with the view that embryos productive purpose to make decisions Because of the continued ethical have some moral status as well as the about disposition, including research. debates in this context, a regulatory view that embryos have little or no Consent forms for gamete donation oversight framework should strive to moral status but should nonetheless should make clear that the recipients find as much common ground as be treated with respect. will have this dispositional authority. Similarly, agreements between parties possible, although widespread agree- The use of excess IVF embryos creates who are creating embryos should set ment on all issues may be impossible. other ethical issues. Couples un- forth terms of disposition at the outset In a pluralistic society, minority views dergoing IVF may be both emotionally of the process, including what to do in should be respected but should not and financially vulnerable. Care must cases of disagreement, separation/ necessarily determine policy. The de- be taken to ensure that the informed divorce, or death. hESCs should only velopment of stem cell lines through consent process for research donation be derived from embryos donated for the destruction of preimplantation ex has adequate protections. Under no research under either a previous utero embryos and research on stem circumstances should couples feel agreement or current consent from cell lines should be permitted. Public obligated to donate, and they should parties with dispositional authority. funding for such work should also be be fully informed about the relevant permitted. Although some may argue issues, including other choices they that their taxes should not be used to can make regarding their excess em- CONCLUSIONS fund research to which they object, bryos. Moreover, couples should not In a pluralistic society, substantive this is no different than the use of feel that their IVF care is in any way disagreements may be addressed taxes to support other activities some dependent on their decision to donate. through the legislative or regulatory taxpayers object to, such as military Finally, it would be improper to offer process. The National Institutes of spending. Minority views can be financial incentives to couples in ex- Health has issued guidelines on human respected, in part, by the promotion of change for donating their embryos for stem cell research that identify eligi- research into ways to obtain hESCs the creation of stem cells because bility for federal funding (setting without destroying embryos. such incentives raise concerns about standards for donation, consent, and In addition to the debate about de- undue inducement. In addition, for the use of cells derived before the struction of embryos, there are some, payment for embryos may seem guidelines took effect). The guidelines

PEDIATRICS Volume 130, Number 5, November 2012 975 Downloaded from www.aappublications.org/news by guest on September 29, 2021 serve as an important roadmap for protection of human subjects. In LIAISONS using hESCs in research and attempt to particular, the American Academy Clifford Bogue, MD – Society for Pediatric Re- search strike an acceptable balance between of Pediatrics supports the following – fi fi Christopher A. DeGraw, MD, MPH Maternal the potential scienti c bene ts, the restrictions on hESC research: and Child Health Bureau ethical issues and concerns surround- a. hESCs should be derived from Denise Dougherty, PhD – Agency for Healthcare ing this research, and the need for embryos that were created by Research and Quality proper protection of human subjects. In Glenn Flores, MD – Academic Pediatrics Asso- using IVF for reproductive pur- ciation addition to guidelines developed at the poses and are no longer needed Gary L. Freed, MD, MPH – American Pediatric national or state level, it may be useful for this purpose. Society to create institutional stem cell over- Elizabeth Goodman, MD – Society for Adolescent b. The individuals who sought re- sight bodies which could ensure the Health and Medicine productive treatment must give Alan E. Guttmacher, MD – National Institute of application of legal restrictions and voluntary written informed con- Child Health and Human Development evaluate ethical issues that may arise in – sent for the human embryos to A. Craig Hillemeier, MD Association of Medical specific research proposals. School Pediatrics Department Chairs be used for research purposes. Paul P. Wang, MD – Society for Developmental RECOMMENDATIONS c. No payments, cash or in kind, and Behavioral Pediatrics should be offered for donated 1. Given the substantial potential bene- STAFF fit on child health and development, embryos used for hESC deriva- William Cull, PhD the American Academy of Pediatrics tion. believes that public funding and d. There is a clear separation be- COMMITTEE ON BIOETHICS, 2011–2012 oversight for human embryo and tween the prospective embryo Mary E. Fallat, MD embryonic stem cell research should donor(s)’s decision to create Aviva L. Katz, MD continue. Funding for research that human embryos for reproduc- Mark R. Mercurio, MD seeks to identify mechanisms to de- tive purposes and the prospec- Margaret R. Moon, MD tive embryo donor(s)’s decision Alexander L. Okun, MD rive embryonic stem cells without Sally A. Webb, MD resulting in the destruction of an to donate human embryos for Kathryn L. Weise, MD embryo is also appropriate. research purposes. 2. The American Academy of Pediat- PAST CONTRIBUTING COMMITTEE LEAD AUTHORS MEMBERS rics endorses the National Institutes Jessica Shand, MD Armand H. Matheny Antommaria, MD, PhD of Health Guidelines on Human Stem Jessica Berg, JD, MPH Ian R. Holzman, MD Cell Research (http://stemcells.nih.gov/ Clifford Bogue, MD policy/2009guidelines.html), which LIAISONS COMMITTEE FOR PEDIATRIC identify eligibility for federal fund- Douglas S. Diekema, MD, MPH – American RESEARCH, 2011–2012 ing (setting standards for donation, Board of Pediatrics consent, and the use of cells de- Scott C. Denne, MD, Chairperson Kevin W. Coughlin, MD – Canadian Pediatric Andrew J. Bauer, MD rived before the guidelines took ef- Society Michael D. Cabana, MD, MPH Steven J. Ralston, MD – American College of fect). The guidelines serve as an Tina L. Cheng, MD Obstetricians and Gynecologists important roadmap for using hESCs Daniel A. Notterman, MD in research and strike an accept- Ben Scheindlin, MD Jeffrey J. Bergman, DO CONSULTANT able balance between the potential Jessica Berg, JD, MPH scientific benefits, the ethical issues PAST CONTRIBUTING COMMITTEE and concerns surrounding this re- MEMBER STAFF search, and the need for proper Jessica Shand, MD Alison Baker, MS

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PEDIATRICS Volume 130, Number 5, November 2012 977 Downloaded from www.aappublications.org/news by guest on September 29, 2021 Human Embryonic Stem Cell (hESC) and Human Embryo Research COMMITTEE FOR PEDIATRIC RESEARCH and COMMITTEE ON BIOETHICS Pediatrics 2012;130;972 DOI: 10.1542/peds.2012-2482 originally published online October 29, 2012;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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