The Ethical Challenges of the Revolution

The Ethical Challenges of the Stem Cell Revolution

By Audrey R. Chapman

The Ethical Challenges of the Stem Cell Revolution

By Audrey R. Chapman

This book first published 2020

Cambridge Scholars Publishing

Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK

British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library

Copyright © 2020 by Audrey R. Chapman

All rights for this book reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the copyright owner.

ISBN (10): 1-5275-5587-9 ISBN (13): 978-1-5275-5587-7

To my husband Karim

TABLE OF CONTENTS

Acknowledgements ...... viii

Chapter One ...... 1 Introduction and Overview

Chapter Two ...... 24 The Ethics of Stem Cell Choice

Chapter Three ...... 47 Regulations, Guidelines, and Oversight Mechanisms

Chapter Four ...... 77 Challenges in the Translation of Pluripotent Stem Cell Research into Therapies

Chapter Five ...... 100 The California Institute of Regenerative Medicine (CIRM)

Chapter Six ...... 125 Clinical Trials with Therapies Derived from Pluripotent Stem Cells

Chapter Seven ...... 149 Developing Gametes from Pluripotent Stem Cell Lines: A New Path to Reproduction?

Chapter Eight ...... 170 Justice Issues in Stem and Access to its Benefits

ACKNOWLEDGEMENTS

This book results from my 20 years of involvement with and reflections on pluripotent stem cell research and its translation into therapies. It began when I was a Program Director at the American Association for the Advancement of Science (AAAS) and served as the co-director of one of the first projects to assess the ethical, religious, and scientific issues involved in research with human embryonic stem cells. It continued when I moved to the University of Connecticut where I have an appointment as the Healey Professor of at the Medical School. I was initially a member of the UConn university-wide oversight committee for stem cell research and then became the chair ten years ago. I have also served on State of Connecticut policy making bodies and as an ethics reviewer for the State of Maryland Stem Cell Funding Program, the latter for the past ten years. As I wrote this book, I had assistance from a number of people that I would like to acknowledge. Akshayaa Chitibabu did background research on the state stem cell programs when she was an undergraduate at UConn before she went on to do graduate work at Oxford University. Several members of the UConn Stem Cell Research Oversight Committee read early versions of the first few chapters. I would particularly like to thank Miller Brown, a faculty member at Trinity College, for his valuable comments on several of the chapters he reviewed. Jason Cory Brunson, then a post- doctoral fellow in the Center for Quantitative Medicine at UConn Health and now a faculty member of the Department of Medicine at the University of Florida, proofread the manuscript, offered feedback, validated and update references, and helped to format the final draft. David Jensen, the editor of the California Stem Cell Report, provided documents and reviewed several of the chapters. Ellen Malaspina and Lisa Cook, administrative assistances in the Department of Public Health Sciences at UConn Health, formatted the manuscript. I also appreciate the small grant I received from the Connecticut University Foundation that supported Cory Brunson’s work. I would also like to thank my husband Karim for his advice, patience and support. Finally, I would like to acknowledge the companionship of my Cavalier King Charles spaniel Jamie who kept me company much of the time while I was drafting the manuscript.

CHAPTER ONE

INTRODUCTION AND OVERVIEW

In October 1998, I was attending a meeting at the American Association for the Advancement of Science (AAAS) when I learned that an announcement would soon be made of a major scientific breakthrough in the field of human stem cell research. At that time, scientists had identified a few types of adult stem cells, the specialized cells involved in regenerating tissues for renewal and damage repair. By the late 1960s, physicians had also begun to use one type of , hematopoietic stem cells harvested from bone marrow, to try to treat patients with diseases like leukemia. However, scientists generally found adult stem cells difficult to isolate, replicate, and maintain in culture, and, because adult stem cells are differentiated cells, assumed that each kind of adult stem cells could only give rise to cell types in its own lineage (Cohen 2007, 14–17). Although scientists had identified primordial stem cells in mice 18 years before that were more plastic and could differentiate into a wide variety of cells, finding equivalent cells in had so far eluded them (Chapman, Frankel, and Garfinkel 1999, 2). A few weeks later, on November 5, an article appeared in Science magazine reporting that a team led by James Thomson, a researcher at the University of Wisconsin, had for the first time successfully isolated and cultured human embryonic stem cells (Thomson et al. 1998, 1145–7).1 Why was this accomplishment so significant? In contrast with adult stem cells, embryonic stem cells are pluripotent. This means that they are, in theory, able to give rise to all cell types and tissues of the body. Embryonic stem cells can also self-renew without losing their genetic structure, multiply rapidly, and persist in culture indefinitely. As such, cell scientists and many others in the scientific and medical communities quickly realized that human research would hold enormous potential for contributing to our understanding of the fundamentals of human biology. Additionally, they recognized that research with embryonic stem cells

1 This book does not use the common abbreviations for human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) but spells out the full name. 2 Chapter One offered the possibility of developing therapies for diseases and disorders for which there are no current treatments, such as diabetes, spinal cord injury, macular degeneration, Parkinson’s disease, and myocardial infarction. It soon became apparent that these pluripotent stem cells might eventually provide a basis for replacing, engineering, or regenerating human cells, tissues, and possibly even developing organs to restore or establish normal functioning. A leading scientific journal, Science magazine later heralded the successful derivation of the human embryonic stem cell and the landmark papers written on the “remarkable abilities of these stem cells” as the scientific breakthrough of the year (Vogel 1999, 2238–9). During the past twenty years, scientists have continued to make significant discoveries in the stem cell field. Most notably, in 2007 scientific researchers in Japan and the United States determined how to regress differentiated human adult stem cells into an earlier stage of development having many of the characteristics of embryonic stem cells. Prior to this remarkable scientific feat, almost magical in its execution, scientists had considered the fates of differentiated cells to be permanently determined. Like embryonic stem cells, these human induced pluripotent stem cells, as they were named, are pluripotent and capable of differentiating into most, perhaps all, cell types in the human body. And like human embryonic stem cells, human induced pluripotent stem cells may potentially serve as the basis for developing therapies for a range of disorders. As in the genetics field a few decades earlier, developments in the stem cell field soon attracted intense media scrutiny. And as with discoveries in the genomic field, there was a great deal of excitement about the clinical potential of these pluripotent stem cells. The overly optimistic claims of some stem cell scientists and sponsors of this research that therapies for hitherto untreatable diseases and disorders would shortly be available likely encouraged this coverage; conversely, the media interest may have encouraged these claims. As the International Society for Stem Cell Research (ISSCR) observed, both popular coverage and even some reporting in the scientific and medical literature about pluripotent stem cells frequently have been problematic: “Potential benefits are sometimes exaggerated and the challenges to clinical application and risks are often understated” (International Society for Stem Cell Research 2016, 28). Public fascination with pluripotent stem cells often has come without an understanding of the complexities and time involved in translating basic scientific research in a new field into medical therapies, or of the ethical issues involved. The publicity surrounding developments in the field has led many patients and patient support groups to view prospective pluripotent stem cell–based therapies as potential miracle cures Introduction and Overview 3 and to clamor for their development on the assumption that they could be available relatively quickly. People have forgotten or did not know that it took nearly thirty years from the time the first gene therapies began clinical trials for even one to be approved for clinical use. While at the time of writing no new therapies derived from pluripotent stem cells have been approved for clinical use by a major national regulatory body, except conditionally in Japan, some thirty to forty are in various stages of clinical trials. So why does it take so many years to develop therapies from new fields of science? Much of this book will try to answer this question. To provide a brief overview, it has taken many years for researchers to better understand basic pluripotent stem cell biology, particularly how to control human induced pluripotent stem cells. Scientists had to learn how to derive relevant specialized cells and then test their use and potential both in the laboratory and in various types of animals. The three stages of required clinical trials to test candidate therapies in patients can easily take ten years and are often risky, especially first-in-human trials, as in the case of pluripotent stem cell–derived therapies, when researchers do not know the balance of risks and benefits. All of this takes significant financial resources, and the funds are often not forthcoming. To provide an example, Semma Therapeutics, a firm based on the work of a Harvard University cell scientist working on a cure for type 1 diabetes, had raised $44 million from investors and thought that money would fund its work through human clinical trials. However, despite having raised more than $100 million more, it has only been able to test its technology on primates and pigs (Garde 2019). Moreover, despite the investment of time, resources, and effort, most of the candidate therapies that begin clinical trials do not ultimately receive approval. It is thought that only 10 to 14 percent of all types of therapies that begin trials ultimately are approved for clinical use, and the figure may be even lower for cell-based therapies. Problematically, when therapies have not been forthcoming from major scientific centers and biotech companies, some patients have sought other, riskier options in clinics offering unapproved stem cell treatments, often with deleterious consequences. These unapproved and sometimes untested stem cell therapies have a considerable risk of adverse events. In some cases, patients receiving transplants of these cells have developed tumors, including in their spinal cords and brains. Clinics offering unapproved stem cell applications exist in many countries and include hundreds in the United States. Another issue that has held back developments in the field is the ethical, religious, and political debate surrounding the use of human 4 Chapter One embryonic stem cells, the cells which many in the field consider to hold the most therapeutic promise. Human embryonic stem cells are derived from a three- to five-day old (technically a ), and the process of extracting the inner cell mass of these stem cells to create embryonic stem cell lines results in the destruction of the embryo. Some people worry that embryo destruction will diminish respect for human life. Other people, particularly those who accord the embryo a high moral status, consider its destruction to be unethical. There is profound and substantial disagreement based on deeply held theological, ethical, and philosophical beliefs about the status of the embryo prior to implantation. This has given rise to debate about the ethical and religious appropriateness of conducting human embryonic stem cell research. However, it is important to remember that in the stem cell debate the disagreement is over the status of an early preimplantation embryo, a cluster of unorganized cells about the size of a pinhead located outside a mother’s body, and not of a developing fetus implanted in the mother’s uterus. Although this debate often centers on theological issues too abstruse for many members of the public, it has had a major impact on the stem cell field. The preoccupation with the embryo status issue and the debate about the appropriateness of proceeding with human embryonic stem cell research have often resulted in inadequate attention to other important ethical and regulatory issues related to pluripotent stem cell research and applications. In a January 2017 interview with , , a recipient of the 2012 Nobel Prize for Medicine for his discovery of induced pluripotent stem cells, commented that one of his biggest concerns about the future of the stem cell field is that the science has moved too far ahead of the consideration of ethical issues (Ravven 2017). I agree with this worry. There has been insufficient consideration given to the development of guidelines for the conduct of the research, the determination of priorities for investment in this research, the identification of appropriate and inappropriate applications for pluripotent stem cells, and, importantly, ways to assure that, once therapies are developed, they are affordable and widely accessible. As Cynthia Cohen has noted, “Stem cell research brings to the fore unique and fundamental ethical issues not only about whether to engage in research using early human but also about a host of other issues that revolve around how we ought to use the regenerative powers that this research offers” (Cohen 2007, 196). She goes on to note that, when an innovative area of scientific activity emerges that promises to provide significant insights about human development and new forms of medical therapy, but also has unique ethical challenges, it becomes more than a private endeavor of a small number of scientific researchers. It Introduction and Overview 5 becomes in addition a public societal activity (Cohen 2007, 197). I would add that, in such circumstances, it also becomes a social responsibility to provide adequate oversight for this research and to encourage the development of therapies with potential for public benefit. This book focuses on these neglected issues. The goal of this book will be to tell the story of the development of the pluripotent stem cell field, focusing on the ethical and regulatory issues involved in the translation of pluripotent stem cell research into medical therapies. Translation refers to “the process of applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of human disease, sometimes abbreviated as ‘from bench to bedside’” (Fang and Casadevall 2010). The book will explore the scientific, ethical, and regulatory challenges inherent in the process of translating stem cells, particularly pluripotent stem cells, into therapies and propose ways to address them. I would like to note that the book builds on my own involvement in the stem cell field. When I first learned of the development of embryonic stem cells, I did not anticipate that ethical issues related to their research, development, and translation would become as central to my professional life as they have. At that time, I was a senior staff member at AAAS directing two programs, one of which was a Program of Dialogue on Science, Ethics, and Religion. Within a few months, I found myself codirecting a project at AAAS examining the ethical and religious issues arising from embryonic stem cell research that sought to identify a way of resolving disagreements between supporters and opponents, something we were unable to do. A few years later, I left AAAS to become a professor at UConn Medical School where I served on and then became chair of the UConn Embryonic Stem Cell Oversight Committee, something I continue to do. While it existed, I also was a member of a stem cell committee developing public policy for the State of Connecticut. In addition, I have been a member of a proposal review committee for the State of Maryland’s stem cell research funding program for the past nine years. These responsibilities, the many stem cell related meetings I have attended, and myriad discussions I have had about the field have helped to shape the views expressed in this book.

The Embryonic Stem Cell Ethical Controversy

The controversy over human embryonic stem cell research has involved two principal areas of disagreement. The first is whether it is ever morally appropriate to destroy an embryo, even an embryo left over from fertility treatments or an embryo of insufficient quality for implantation, as the 6 Chapter One source of most of the human embryonic stem cell lines have been, and whether the potential benefits of the research provide a justification for doing so. At issue here is whether the human embryo possesses significant moral status as a potential human being and therefore must be protected from harm. Among those who answer this question in the affirmative a second question arises. This is whether researchers who have played no role in the destruction of an embryo may ethically utilize the embryonic stem cells so produced (Chapman, Frankel, and Garfinkel 1999, 12). As the number of human embryonic stem cell lines has increased enabling researchers to use established lines, this latter issue has become more relevant. Significant numbers of Catholics, members of the Eastern Orthodox tradition, and conservative Protestants hold what could be termed an “embryo protection position” based on a belief that the embryo is a full human being from the moment of conception. According to Richard Doerflinger, the Associate Director of the Secretariat of Pro-Life Activities of the United States Conference of Catholic Bishops, “The human embryo, even in the first week of development before implantation, is a human being – a living, developing individual of the human species” (Doerflinger 2010, 212). Because “the embryo is part of the continuum of human development that stretches from that first formation of a unique organism to the natural end of life” (Doerflinger 2010, 212), he reasons that the embryo, like all humans, has inherent and inalienable human rights, including an equal right to life (Doerflinger 2010, 212). Some individuals and communities who share this perspective locate the beginnings of human personhood and the related claims of moral status and dignity on the human genetic constitution of the conceptus. Others stress that the early embryo, like all human beings, reflects the image of the Divine. The potential of preimplantation embryos to become full-fledged human beings and a belief that it is always morally wrong to destroy this potential have constituted another source of opposition to embryonic stem cell research. Those who accord the embryo a high moral status as an actual or potential person oppose the destruction of the embryo for research purposes as well as any form of involvement in human embryonic stem cell research. (Vatican Congregation for the Doctrine of the Faith 1987; Farley 2001; Doerflinger 1999; Meilaender 2001). Many people holding an embryo protectionist position also oppose public policies that would fund embryonic stem cell research, arguing that it would force taxpayers to subsidize this research against their beliefs (“Giving Artificial Priority to Embryonic over Adult Stem Cell Research in State Funding: Hearings on S.B. 59, Before the Senate Finance Committee” 2007). The question of the ethical appropriateness of federal funding has been a Introduction and Overview 7 recurring issue in the political debate in the United States about human embryonic stem cell research. The second question noted above was whether it is ethically permissible in the embryo protection framework for a researcher who had no role in the destruction of the embryo to utilize the embryonic stem cells so produced. Although there is some diversity of views on the subject, the official Catholic doctrinal position is that it is not. According to the Pontifical Academy for Life of the Vatican, those who use human embryonic stem cells derived by others who destroyed a human embryo in order to extract the cells materially cooperate in the destruction. Or to put it another way, to benefit from the destruction of human embryos is to be complicit in that destruction (cited in Cohen 2007, 175). Other embryo protection advocates are concerned that researchers using embryonic stem cells may create an additional demand for human embryonic stem cells, and that this will increase the likelihood that others will destroy embryos to produce such cells (Devolder and Harris 2005). In contrast, some Catholic ethicists have argued that researchers opposed to the destruction of human embryos could legitimately participate in research on cultured embryonic stem cells (Prieur et al. 2006). Not all religious communities have concurred with this view of the moral significance of the early embryo. This is not a religion-versus-science issue. Even some in the Roman Catholic tradition maintain now that the embryo does not become a distinct individual in its earliest stages, before development of the around 14 days after conception and/or its implantation, and therefore believe its use for certain kinds of research can be justified (Farley 2001, 115–16). This orientation with its “developmental” view of personhood grants that human life begins at conception, but that human personhood serves as the basis of claims of full moral status and dignity. Personhood, according to this perspective, develops gradually, culminating at birth. The implication of this perspective is that because the early embryo and fetus only gradually become a human person, they are not entitled to the same moral protections as will be accorded to them later as they mature (Geron Ethics Advisory Board (Karen Lebacqz, Michael M. Mendiola, Ted Peters, Ernlé Young, and Laurie Zoloth-Dorfman) 1999, 32). Some of these advocates share the widely held philosophical and moral view that status as a person or as an entity with interests requires, at a minimum, a nervous system capable of sentience and possibly of cognition and consciousness, which the early embryo does not have (Robertson 2001, 75). For others, holding the developmental position viability outside the womb constitutes an important prerequisite for moral status and dignity. Many of those who are members of progressive 8 Chapter One

Protestant religious denominations concur with this developmental framework. The policymaking bodies of two such religious denominations, the United Church of Christ and the Presbyterian Church (USA), have explicitly endorsed conducting embryonic stem cell research as long as it is directed toward compelling goals, such as helping persons whose pain and suffering might be alleviated (Cohen 2007, 103–4). Nevertheless, many of those holding a developmental view, both members of the religious community and others such as humanists, also affirm that the early embryo must be treated with respect consistent with showing or symbolizing our respect for human life generally and its potential to develop into full personhood. Karen Lebacqz contends that it is possible to specify a meaning for respect for the embryo that will be the subject of research if the embryo is valued, harm to it is minimized, and there are moral limits on its use (Lebacqz 2001). A distinction John Robertson makes also helps illuminate what respect for the embryo can potentially mean. According to Robertson, “The goal of treating disease and saving life justifies the symbolic loss that arises from destroying embryos in the process. By contrast, selling human embryos or using them in cosmetic-toxicology testing seems to be disrespectful…because those uses fulfil no life-affirming, or other important, purpose” (Robertson 2001, 77). This is my position as well. The teachings of most major religious traditions – Jewish, Islamic, Buddhist, and Hindu – do not specifically address the moral significance of the early embryo. However, religious scholars have sought to interpret passages from these scriptures in ways that provide indirect answers. Jewish scholars often cite the statement in the Babylonian Talmud that until the fortieth day after conception embryos are “as if they were simply water” and affirm that genetic material outside the uterus has no legal or moral status in Jewish law (Cohen 2007, 104–5). The Jewish religious tradition also places a strong emphasis on the task of healing, and the general thrust of Jewish responses to medical advances has been positive, even optimistic (Zoloth 2001). The majority of Sunni and some Shiite Muslim scholars hold that the human embryo is ensouled and becomes an individual human at 120 days after conception (Cohen 2007, 106), well after the early stages of embryo life. There are differing views on this matter within Hinduism. Because rebirth is central to Hindu thought, many traditionalists claim there is no time when the human embryo is not ensouled. Some alternative Hindu traditions that have influenced contemporary Hindu beliefs put the beginnings of personhood later, at three to five months of gestation (Cohen 2007, 107–8). No one body or person can speak for the many strands within Buddhism and there is some debate among Buddhist scholars about whether Introduction and Overview 9 the human embryo is owed protection from the time of fertilization. When representatives of this tradition were contacted by the Singapore Advisory Committee to solicit their view on human embryonic stem cell research, the Secretary General of the Singapore Buddhist Federation responded, affirming the moral permissibility of the research if the intention is to help and benefit humankind by finding human therapeutics (Walters 2004, 22). It is therefore likely that some, perhaps many, persons within these traditions would accept the use of preimplantation human embryos for reasonable, beneficial purposes like human embryonic stem cell research that have the promise of developing therapies for serious diseases. While it is difficult to make generalizations about those whose thinking is shaped by more secular considerations – including many scientists, ethicists, and members of the public – beneficence, the potential benefits of embryonic stem cell research for developing therapies for diseases such as Parkinson disease, diabetes, and cardiac myopathy – plays an important role for many of them. At one end of the spectrum, there are scientists who argue that the early embryo at five to six days after fertilization merely amounts to a group of cells clustered together that are not entitled to any special moral consideration (Cohen 2007, 78). Other secular thinkers believe that the early human embryo is owed special respect as a symbol of human life and therefore should be created and discarded in research only if this would aid in the development of useful knowledge (Cohen 2007, 71). Likewise, many are likely to subscribe to the importance of the fourteen-day threshold as the time at which embryos should receive some form of respect and therefore should not be treated arbitrarily or frivolously. Many are likely to be advocates of what Ted Peters refers to as the medical benefits framework and to frame the ethics of the stem cell debate in terms of our responsibility for ameliorating the present suffering of patients (Peters 2007, 61–63). Two such ethicists have sought to highlight what is at stake in this argument: “If ethicists or the public would restrict the uses of embryonic stem cells, then they must bear responsibility for those patients they have chosen not to try to save by this means” (Eric Juengst and Michael Fossil quoted in Peters 2007, 73). The knowledge that many hundreds of thousands of embryos leftover from the assisted reproduction industry are stored in tanks of liquid nitrogen, and that most of them will never be used for reproductive purposes, constitutes another incentive to advocate for their utilization for embryonic stem cell research so that they can contribute to the development of medical therapies. Some of these frozen embryos are not of sufficient quality for them to be transferred to a woman’s uterus for gestation. Many of the frozen embryos remain in storage indefinitely because couples no 10 Chapter One longer need them but are reluctant to destroy them and have not been approached to donate the embryos for research. A 2002 survey found about 400,000 frozen embryos in the United States, another survey in 2011 estimated 612,000 embryos in storage, and currently many reproductive endocrinologists think the total may be as high as one million (Lewin 2015). There are also frozen embryos in storage in other countries.

Ethical Perspectives on Embryonic Stem Cells Outside the United States

Several countries have grappled with the question of the ethical appropriateness of engaging in embryonic stem cell research. There are often differences in perspective among their populations and regulators, but the debate has nowhere been more contentious or more ongoing than in the United States, possibly because religious norms play less of a role in public policy debates. Some predominantly Catholic countries, like Italy, Austria, Ireland, and Germany, have placed strict constraints on embryonic stem cell research, although in the case of Germany it has more to do with the history of the horrific Nazi experiments carried out ostensibly for eugenic purposes than with religious beliefs. For many Germans, to sanction the destruction of human life at any stage of development is to repeat the sins of the past. Germany bans the creation of human embryonic stem cells for research, but it allows stem cell investigators to import human embryonic stem cells derived in other countries for research within Germany (Cohen 2007, 147). In contrast, the United Kingdom has had a permissive attitude toward human embryonic stem cell research but also a more comprehensive regulatory apparatus than most other countries. In 1994, prior to the discovery of embryonic stem cells, the U.K had constituted the Warnock Committee of Inquiry into Human Fertilization and Embryology to consider the social, ethical, and legal implications of methods of assisted reproduction and embryo research and to recommend policies for their use. The Warnock Committee determined that the stage of development of the embryo makes an important difference to the degree of protection that it should be afforded. It also affirmed that, while the human embryo is entitled to some measure of respect beyond that of nonhuman subjects, that respect is not absolute and may be evaluated against the benefits arising from research. Consistent with this view, the Warnock Committee concluded that it was permissible to use the spare embryos remaining after IVF treatment for research if the couples for whom those embryos had been created consented to research use of them (Cohen 2007, 141–42). The government adopted the basic recommendations of the Warnock Committee and Introduction and Overview 11 established the Human Fertilisation and Embryology Authority (HFEA), a centralized agency that licenses all IVF procedures in the country (Cohen 2007, 143). In 2001, Parliament amended the Human Fertilisation and Embryology Act to bring stem research within its regulatory scope (Cohen 2007, 144). The broad coalition of government, scientific, patient advocacy, Church of England, and biotechnology groups that had supported the 1990 HFEA Act also endorsed this extension of the law. In the interim between the passage of these two laws, antiabortion and religious groups that had opposed the earlier law were weakened by infighting and lack of public support (Cohen 2007, 146). Thus, no one can derive pluripotent stem cells from donated embryos for stem cell research or conduct stem cell research in the U.K. without a license from the HFEA (Cohen 2007, 143–44). Japan has also been receptive to stem cell research, and the government has provided significant public funding for the development of new stem cell lines derived from spare embryos leftover from reproductive purposes and from embryos created for research. According to Cynthia Cohen, the Japanese do not conceptualize human embryos in ways that are akin to western bioethics, nor do they have debates about the status of embryos. Japanese tradition does not believe that it is always wrong to destroy the embryo/fetus but instead thinks about the embryo in fluid terms. (Cohen 2007, 155–58). Nevertheless, Japan has established careful oversight measures for embryonic stem cell research that require donor consent, prior review, and approval by an institutional review board (Cohen 2007, 160). A 2005 public opinion survey of attitudes toward embryonic stem cell research based on representative samples in Europe and North America found that the majority of people in Europe, Canada, and the United States supported stem cell research, provided it was carefully regulated: the figures were 62 percent of Europeans, 73 percent of Americans, and 81 percent of Canadians. Attitudes were more strongly associated with religious convictions in the United States than in Canada or Europe, although many strongly religious persons in all three regions approved of embryonic stem cell research (Allum et al. 2017).

Recommendations of Early U.S. Embryonic Stem Cell Ethics Review Panels

Realizing that the derivation of embryonic stem cells from early human embryos raised ethical, legal, religious, and policy questions, the American Association for the Advancement of Science (AAAS), with support from the Institute for Civil Society, decided to undertake a study shortly after the 12 Chapter One announcement of Thomson’s derivation of embryonic stem cells. I was then Director of the AAAS Program of Dialogue between Science and Religion and served as the codirector of the study. We assembled a working group with multi-disciplinary expertise and diverse ethical views to advise us and to assist with preparing a report. Prior to the study, I had naively believed it would be possible to identify a compromise position. In November 1998, the very month of the announcement of the derivation of embryonic stem cells, another team of scientists had published a paper detailing that they had derived primordial germ cells from the gonadal ridge of human tissue obtained from aborted fetuses (Shamblott et al. 1998). I thought that a recommendation to use germ cells extracted from naturally aborted (miscarried) fetuses might be broadly acceptable. However, primordial germ cells turned out to have less scientific potential than embryonic stem cells and to be problematic to collect (Chapman, Frankel, and Garfinkel 1999, 4). Moreover, the members of the working group ethically opposed to considered the option of extracting stem cells from naturally aborted fetuses suspect. The AAAS report was issued in August 1999 with the recommendation to proceed with embryonic stem cell research despite the opposition of some of the members of the working group (Chapman, Frankel, and Garfinkel 1999). In November 1998, shortly after the announcement of the derivation of embryonic stem cells, then-President asked the National Bioethics Advisory Commission (NBAC) to provide a thorough review of all issues relating to human stem cell research, balancing scientific and ethical considerations. Ten months later NBAC issued its report. The Commission adopted what it termed an intermediate position, “that the embryo deserves respect as a form of life, but not the same level of respect accorded persons” (National Bioethics Advisory Commission 1999, 50). It explained its position as follows: “research that involves the destruction of embryos remaining after infertility treatment is permissible when there is good reason to believe that this destruction is necessary to develop cures for life-threatening or severely debilitating diseases and when appropriate protections and oversight are in place in order to prevent abuses” (National Bioethics Advisory Commission 1999, 52). The NBAC report affirmed the ethical acceptability of federal funding for the derivation and use of embryonic stem cell research provided they were embryos remaining after infertility treatments. NBAC stated that federal agencies should not fund research involving the derivation or use of human embryonic stem cells from embryos made solely for research purposes using IVF or from embryos made using somatic cell nuclear transfer (cloning). In order to be able to fund the derivation of embryonic stem cells, it recommended that an exception be made to the statutory ban on federal Introduction and Overview 13 funding of embryo research in which a human embryo is destroyed or harmed (the Dickey–Wicker Amendment). However, the President announced his opposition to funding the derivation of embryonic stem cells before the report was issued. NBAC additionally identified requirements for donation to stem cell research of embryos remaining after infertility treatment, so that prospective donors would receive the timely, relevant, and appropriate information required to make informed and voluntary choices about the disposition of their embryos. Yet another issue the NBAC report addressed was the need for national as well as local oversight and review of human stem cell research. It pointed out that a national mechanism would enable the development of uniformly applicable guidelines and standards across the country while a local mechanism, such as an IRB, could review and approve protocols. In anticipation of such funding for already derived human embryonic stem cell lines, Donna Shalala, the Secretary of the Department of Health and Human Services, asked the General Counsel of the department, Harriet Raab, to advise on the legality of such funding. Raab’s opinion was that embryonic stem cells were not embryos within the meaning of the Dickey–Wicker amendment and thus not covered by the federal ban on funding research with embryos (Raab 1999). This legal opinion proved to be decisive both for initially determining the eligibility of embryonic stem cell research for federal funding and for protecting the funding in a subsequent legal challenge, Sherley v. Sebelius, that claimed embryonic stem cell research violated the Dickey–Wicker Amendment.

The Development of U.S. Federal Policies on Funding Stem Cells

The dialectic between the scientific promise and the ethical contentiousness of embryonic stem cell research has shaped the development of the pluripotent stem cell field. Importantly, by limiting funding and discouraging researchers from engaging in human embryonic stem cell research, the controversy has slowed scientific developments. The ethical controversy has also deterred sufficient attention from being paid to the ethical analysis of research itself and to the study of the complex translational issue involved in transforming the basic research into therapies. In the United States, the controversy has constrained the role of the federal government and both opponents and supporters have refrained from developing guidelines and providing oversight of the field. The opposition has also limited federal funding for research in this field, particularly for human embryonic stem cell research, and discouraged the 14 Chapter One government from establishing oversight bodies needed for the responsible development of the field. The main federal public policy battles have been about the appropriateness of federal funding and not about prohibiting or restricting the research. This is a significant issue because public investment has often been essential for the development of early-stage scientific research like embryonic stem cell science (Robertson 2010, 194). The federal shortfall has meant that other actors, primarily state funding programs and small biotechnology start-ups, have played major roles in the development of the field. To provide a brief overview of the role of the U.S. federal government: in 1999 then-President Clinton accepted the NBAC recommendation to proceed with federal funding of embryonic stem cell research but rejected its proposed federal funding for the derivation of embryonic stem cells. To enable the federal government to provide funding, the National Institutes of Health (NIH) developed guidelines for funding embryonic stem cell research and called for the submission of proposals. However, NIH had not yet issued its first grants when President George W. Bush took office in 2001 and halted the process. President Bush had represented himself as a right-to-life supporter and during the campaign had pledged to oppose federal funding for research that involved the destruction of human embryos. Nevertheless, a year after taking office, he opted for a compromise position to permit federal funding for embryonic stem cell research but to restrict eligibility for federal support to research with already existing embryonic stem cell lines. The rationale was that, by so doing, the federal government would not use taxpayer money to sanction or encourage further destruction of human embryos. He also affirmed that the federal government would continue to support research on other types of stem cells, such as adult stem cell research. This policy evoked criticism from both sides in the stem cell debate. Some opponents of the research argued that a government agency that funds such research is complicit in the destruction of embryonic human life even if private funds are subsidizing the act of destruction. Criticisms from supporters of the research centered on concerns that the number and quality of stem cell lines eligible for federal funding would be inadequate (Cohen 2007, 171–77). There turned out to be many fewer stem cell lines available than President Bush had assumed at the time he announced his policy – 21 rather than 65 – and some of these lines were difficult to access or had other problems (National Institutes of Health, n.d.). The constraint on federal funding led several states to initiate programs to fund embryonic stem cell research in their states, with researchers able to use stem cell lines developed after 2001. The California Introduction and Overview 15

Institute for Regenerative Medicine (CIRM) has been the most important of these state programs, dwarfing the investments in Connecticut, New York, and Maryland, the three next largest state programs. Proposition 71, adopted in a state-wide referendum in 2004, created CIRM with authorization to borrow and spend $3 billion on research over ten years. In 2009, shortly after he came into office, President ordered the lifting of the moratorium on federal funding for embryonic stem cell research with lines created after 2001, but his administration retained many of the other restrictions on federal funding that were in place. The 2009 NIH guidelines still confine eligibility for federal funding to surplus embryos created for reproductive purposes through in-vitro fertilization, require strict informed consent rules for donation, and rule out any form of incentive in cash or in kind for the donation (National Institutes of Health 2009). Despite President Obama’s apparent recognition of the need for proper guidelines and strict oversight to pursue the research ethically (Obama 2009 quoted in Robertson 2010, 196), his administration did not rectify the absence of federal guidelines for conducting pluripotent stem cell research or establish a federal oversight mechanism. Nor did his administration provide generous funding for the field. The funding figures for FY 2016, the final year of the Obama presidency, show that, of the $31 billion National Institutes of Health budget, only $206,000,000 went to human embryonic stem cell research. In comparison, $457,000,000 was devoted to human adult stem cell research, $652,000,000 to non-human adult stem cell research, and $374,000,000 to human induced pluripotent stem cell research (National Center for Health Statistics 2019, 8).

The Discovery of Induced Pluripotent Stem Cells

The embryonic stem cell controversy, combined with limited and potentially unstable federal government funding for human embryonic stem cell research, encouraged scientists to search for alternative sources of pluripotent stem cells. Legal challenges regarding federal funding of stem cell research meant that federal funding might be ended. The most important legal challenge occurred when two adult stem cell researchers sued the head of the Department of Health and Human Services in 2010, claiming that its funding for human embryonic stem cells research violated the Dickey– Wicker Amendment, a law that prohibits federal funding for research that involves harm to or the destruction of human embryos. Ruling for the plaintiffs, a federal district court judge issued an injunction that suspended all NIH funding for human embryonic stem cell research (Katsnelson 2010). The suspension only lasted for only 17 days, and the Court of Appeals ruled 16 Chapter One against the plaintiffs on the basis that NIH had reasonably interpreted the restrictions in the Dickey–Wicker Amendment when it decided to fund human embryonic stem cell research. Nevertheless, the case instilled enough uncertainty to deter some researchers from entering the field (Wadman 2013). Early proposals for alternative sources of pluripotent cells included extracting embryonic stem cells from embryos created through parthenogenesis or from defective, dead, or nonviable embryos. It was also suggested that scientists an embryo, something that at that time had never occurred, and extract pluripotent cells from the clone. Another proposal, paralleling what is done in pre-implantation genetic diagnosis, was to remove a single cell from an eight or 16 cell blastocyst which had been created through in vitro fertilization and culturing the cell to develop an embryonic stem cell line (Robertson 2005, 19). Advanced Cell Technology, a small biotechnology company, later used this method to create embryonic stem cell lines when developing a therapy, but the process was difficult, and it seemed unlikely that many parents would subject their potential child to the risks of having this type of blastocyst biopsy done for unrelated research purposes. Then in 2006, a Japanese scientist, Shinya Yamanaka, and his colleagues discovered a way to reprogram specialized adult cells to turn them into earlier-stage stem cells with many of the characteristics of embryonic stem cells. The reprogramming involved inserting four genes encoding for transcription factors using retroviral vectors. Yamanaka named these regressed cells induced pluripotent stem cells. The next year two teams of scientists, one led by Shinya Yamanaka and the other by James Thomson, published papers showing they were able to apply this methodology to reprogram adult human dermal fibroblasts into an earlier stage of cell development comparable in many regards to human embryonic stem cells (Takahashi et al. 2007). Like embryonic stem cells, induced pluripotent stem cells are pluripotent and capable of differentiating into all cell types, but they do so less efficiently than embryonic stem cells and have some problematic features that will be discussed in Chapter Two. In 2012, Shinya Yamanaka received the Nobel Prize in Physiology or Medicine for his revolutionary work. Stem cell scientists and opponents of human embryonic stem cell research have welcomed this discovery because induced pluripotent stem cells provide a way to avoid the destruction of embryos. It is also simpler to develop new stem cell lines using the Yamanaka methodology than to derive new embryonic stem cell lines. Like embryonic stem cells, induced pluripotent stem cells have the potential to become a multipurpose research Introduction and Overview 17 tool to understand and model diseases and for drug discovery and testing. By enabling scientists to regress cells from patients suffering from specific diseases, induced pluripotent stem cells offer a way to study diseases from their earliest stages. However, embryonic stem cells continue to be the gold standard against which researchers compare induced pluripotent stem cells (Cyranoski 2018). Moreover, induced pluripotent stem cells have some significant limitations, particularly for the development of medical therapies. The reasons for this will be discussed in the next chapter. Even some advocates of induced pluripotent stem cell technology acknowledge that many technical and basic scientific issues remain before it will be appropriate to use induced pluripotent stem cells as the basis for medical therapies. The question is whether these problems can be resolved or they are inherent in the reprogramming process.

Ethical and Regulatory Issues Related to the Translation of Stem Cells into Therapies

As noted above, the preoccupation with the ethical appropriateness of deriving embryonic stem cells from early stage preimplantation embryos and the political controversy over the U.S. federal government funding embryonic stem cell research have discouraged sufficient consideration of ethical and regulatory issues related to pluripotent stem cell research and the translation of pluripotent stem cells into clinical therapies. Now that clinical trials have begun and therapies are on the horizon, it becomes even more important to consider these issues. This book will address the following subjects related to these questions in subsequent chapters. The choice of the stem cell type – embryonic stem cells, induced pluripotent stem cells, or multipotent adult stem cells – for research and the development of therapies has significant ethical as well as scientific implications that will be explored in Chapter Two. To date, ethical consideration of the type of stem cell to use has primarily focused on the moral status of the preimplantation embryos used to create embryonic stem cell lines. Ethicists and scientists have generally perceived induced pluripotent stem cells as less ethically problematic and some consider them equally suitable for research and applications. However, there are questions as to whether researchers working with already derived embryonic stem cells are complicit in embryo destruction. Nor are all types of pluripotent or multipotent cells equally appropriate and promising for clinical applications, and the selection of a type of stem cell best able to give rise to safe medical therapies is a profoundly ethical issue. 18 Chapter One

Responsible conduct of research and its translation into therapies require ethical guidance and oversight mechanisms, especially for an innovative and controversial field of research with a host of unique and fundamental ethical questions. Guidelines are needed both to inform research conduct and to reassure the public that the research is being conducted ethically. Chapter Three will review how pluripotent stem cell research is being regulated and monitored in the United States and in a few other countries where pluripotent stem cell research is being conducted. The United Kingdom, Canada, Japan, and Germany have national stem cell bodies review and authorize stem cell research. In contrast, the U.S. federal government has not developed guidelines for research, for pluripotent stem cell applications, or for the conduct of clinical trials with pluripotent stem cells. Nor has it established a national oversight body. This has left a vacuum in the country that has the largest and most significant stem cell research program. Research agencies, some state governments, and professional societies have sought to compensate at least in part by proposing guidelines, some unofficial and voluntary, that this chapter will review. The situation has also meant that, in the United States, institutionally based stem cell review boards have played a key role in reviewing the ethical and scientific appropriateness of individual protocols. This chapter will also examine the functioning of these institutionally based stem cell review committees and the implications of delegating oversight to local boards operating without the benefit of national guidelines. The development of new stem cell–based therapies confronts many challenges. One issue is raising sufficient funds initially for the research, secondly for conducting clinical trials – which can be quite expensive – and then for manufacturing the therapies. A second major challenge is the manufacturing process itself. It is far more complex to manufacture stem cell–based therapies than to produce small-molecule chemically based drugs. As Insoo Hyun points out, “Unlike pills, which are stable, uniform, and easily reproducible in mass quantities, stem cells and their derivatives are dynamic, living, biological entities that are difficult to scale up to huge numbers of specialized cells of uniform quality” (Hyun 2013, 50). To do so it is necessary to identify the means to produce cell based therapeutic products that are safe, effective, and standardized, and that comply with good manufacturing practices. A third major challenge for the field is the growing number of stem cell clinics promoting unauthorized and often risky stem cell products that are affecting the reputation of the field and harming patients. Chapter Four will provide an overview of these scientific, technical, manufacturing, and financial challenges and their ethical implications. Introduction and Overview 19

The California Institute for Regenerative Medicine (CIRM), with its budget of up to $300 million per year in grants, is the paramount funder of pluripotent stem cell research in the world and the energizer that has thrust the field forward. Its priorities, policies, and funding decisions have shaped the pluripotent stem cell field. Proposition 71, whose passage in 2004 created CIRM, has been characterized as “an audacious, unprecedented effort by one state to transform an area of biomedical research, for the benefit of its citizens and of humanity” (Longaker, Baker, and Greely 2007, 520). Chapter Five will provide an overview and ethical analysis of CIRM’s mandate, organizational structure, regulations, and funding priorities. The translation of a discovery into a clinical product requires extensive preclinical research followed by human clinical trials to test the safety and efficacy of the candidate product. Early clinical trials with innovative products often raise complex ethical challenges, particularly early human trials with novel therapies, as the trials with therapeutics developed from pluripotent cells are and will continue to be. Chapter Six will explore the ethical and regulatory issues involved with taking pluripotent stem cells into clinical trials. The chapter will also provide an overview of the initial trials and discuss their outcomes. Which potential applications of pluripotent stem cells are ethically permissible? In the early years of pluripotent stem cell research, a controversy arose as to whether human pluripotent stem cells or their derivatives should be used to create chimeras that combined human and nonhuman cells so as to evaluate how human stem cells function in a developing organism. More recently, the question has arisen as to whether scientists should seek to transform human pluripotent stem cells into human gametes. The development of human gametes from pluripotent stem cells would be a valuable resource for fertility research and the knowledge gained could contribute to the clinical treatment of infertility. However, the next step, the use of pluripotent stem cell–derived gametes for reproductive purposes, would present significant safety risks and ethical challenges. These issues will be the subject of Chapter Seven. Chapter Eight will explore justice issues in the distribution of the potential benefits of pluripotent stem cell research and its translation into therapies. All too often, the benefits of new therapies, even those in which significant public funds have been invested, accrue to a small number of people because the cost associated with them is so high. Scientists and funders rarely factor into their determination of priorities who and how many people are likely to be helped by the development of a potential new therapy. Nor do policy makers attempt to control the high prices typically 20 Chapter One charged for innovative new products that make them well beyond what most individuals can afford and most private and public medical insurers are willing to underwrite. Given the significant public investment in pluripotent stem cell research and the potential of stem cell therapies to advance the welfare of many people, it is important this not happen in the pluripotent stem cell field. One of the fundamental ethical principles informing the International Society for Stem Cell Research (ISSCR)’s Guidelines for Stem Cell Science and Clinical Translation is that the benefits of clinical translation efforts should be distributed justly and globally, with particular emphasis on addressing unmet medical and public health needs (International Society for Stem Cell Research 2016, 5). The Guidelines also affirm that research, clinical, and commercial activities should seek to maximize affordability and accessibility (International Society for Stem Cell Research 2016, Section 3.5.2). Chapter Eight will assess the extent to which research and translation efforts conform with these guidelines.

References

Allum, Nick, Agnes Allansdottir, George Gaskell, Jürgen Hampel, Jonathan Jackson, Andreea Moldovan, Susanna Priest, Sally Stares, and Paul Stoneman (2017) “Religion and the Public Ethics of Stem-Cell Research: Attitudes in Europe, Canada and the United States.” PLOS ONE 12 (4): e0176274. https://doi.org/10.1371/journal.pone.0176274. Chapman, Audrey R., Mark S. Frankel, and Michele S. Garfinkel (1999) “Stem Cell Research and Applications: Monitoring the Frontiers of Biomedical Research.” Washington, DC: American Association for the Advancement of Science; Institute for Civil Society. Cohen, Cynthia B. (2007) Renewing the Stuff of Life: Stem Cells, Ethics, and Public Policy. Oxford, UK: Oxford University Press. Cyranoski, David (2018) “How Human Embryonic Stem Cells Sparked a Revolution.” Nature 555 (March): 427–30. https://www.nature.com/articles/d41586-018-03268-4. Devolder, Katrien, and John Harris (2005) “Compromise and Moral Complicity in the Embryonic Stem Cell Debate.” In Philosophical Reflections on Medical Ethics, edited by Nafsika Athanassoulis, 88– 108. Hampshire, UK: Palgrave Macmillan UK. Doerflinger, Richard M. (1999) “The Ethics of Funding Embryonic Stem Cell Research: A Catholic Viewpoint.” Kennedy Institute of Ethics Journal 9 (2): 137–50. Doerflinger, Richard M. (2010) “Old and New Ethics in the Stem Cell Debate.” Journal of Law, Medicine & Ethics 38 (2): 212–19. Introduction and Overview 21

Fang, Ferric C., and Arturo Casadevall (2010) “Lost in Translation—Basic Science in the Era of Translational Research.” Infection and Immunity 78 (2): 563–66. Farley, Margaret A. (2001) “Roman Catholic Views on Research Involving Human Embryonic Stem Cells.” In The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy, edited by Suzanne Holland, Karen Lebacqz, and Laurie Zoloth, 113–18. Cambridge, MA: MIT Press. Garde, Damian (2019) “Vertex’s Next Act: A Billion-Dollar Bet on a Cure for Type 1 Diabetes.” STAT, September. https://www.statnews.com/2019/09/03/vertexs-next-act-a-billion- dollar-bet-on-a-cure-for-type-1-diabetes/. Geron Ethics Advisory Board (Karen Lebacqz, Michael M. Mendiola, Ted Peters, Ernlé Young, and Laurie Zoloth-Dorfman) (1999) “Research with Human Embryonic Stem Cells: Ethical Considerations.” Hastings Center Report 29 (2): 31–36. “Giving Artificial Priority to Embryonic over Adult Stem Cell Research in State Funding: Hearings on S.B. 59, Before the Senate Finance Committee” (2007). Maryland General Assembly (testimony of Richard M. Doerflinger, Deputy Director of the Secretariat for Pro-Life Activities). Hyun, Insoo (2013) Bioethics and the Future of Stem Cell Research. Bioethics and the Future of Stem Cell Research. New York: Cambridge University Press. International Society for Stem Cell Research (2016) Guidelines for Stem Cell Science and Clinical Translation. http://www.isscr.org/guidelines2016. Katsnelson, Alla (2010) “US Court Suspends Research on Human Embryonic Stem Cells.” Nature, August. Lebacqz, Karen (2001) “On the Elusive Nature of Respect.” In The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy, edited by Suzanne Holland, Karen Lebacqz, and Laurie Zoloth, 149–62. Cambridge, MA: MIT Press. Lewin, Tamar (2015) “Industry’s Growth Leads to Leftover Embryos, and Painful Choices.” The New York Times, June. https://www.nytimes.com/2015/06/18/us/embryos-egg-donors- difficult-issues.html. Longaker, Michael T., Laurence C. Baker, and Henry T. Greely (2007) “Proposition 71 and CIRM—Assessing the Return on Investment.” Nature Biotechnology 25: 513–21. 22 Chapter One

Meilaender, Gilbert (2001) “Some Protestant Reflections.” In The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy, edited by Suzanne Holland, Karen Lebacqz, and Laurie Zoloth, 141–48. Cambridge, MA: MIT Press. National Bioethics Advisory Commission (1999) “Ethical Issues in Human Stem Cell Research, Vol. 1: Report and Recommendations of the National Bioethics Advisory Commission.” Rockville, MD: National Bioethics Advisory Commission. National Center for Health Statistics (2019) “Estimates of Funding for Various Research, Conditions, and Disease Categories.” https://report.nih.gov/categorical_spending.aspx. National Institutes of Health (2009) National Institutes of Health Guidelines for Human Stem Cell Research. National Institutes of Health. https://stemcells.nih.gov/policy/2009-guidelines.htm. National Institutes of Health (n.d.) “Human Embryonic Stem Cell Lines Available Under Former President Bush (Aug. 9, 2001–Mar. 9, 2009).” National Institutes of Health. https://stemcells.nih.gov/research/registry/eligibilitycriteria.htm. Peters, Ted (2007) The Stem Cell Debate. Minneapolis, MN: Fortress Press. Prieur, Michael R., Joan Atkinson, Laurie Hardingham, David Hill, Gillian Kernaghan, Debra Miller, Sandy Morton, Mary Rowell, John F. Vallely, and Suzanne Wilson (2006) “Stem Cell Research in a Catholic Institution: Yes or No?” Kennedy Institute of Ethics Journal 16 (1): 73– 98. Raab, Harriet (1999) “Federal Funding for Research Involving Human Pluripotent Stem Cells.” Memorandum to Harold Varmus, M.D., Director of N.I.H. Ravven, Wallace (2017) “The Stem-Cell Revolution Is Coming — Slowly.” The New York Times, January. https://www.nytimes.com/2017/01/16/science/shinya-yamanaka-stem- cells.html. Robertson, John A. (2001) “Human Embryonic Stem Cell Research: Ethical and Legal Issues.” Nature Reviews Genetics 2: 74–78. Robertson, John A. (2005) “Blastocyst Transfer (sic) Is No Solution.” The American Journal of Bioethics 5 (6): 18–20. Robertson, John A. (2010) “Embryo Stem Cell Research: Ten Years of Controversy.” The Journal of Law, Medicine & Ethics 38 (2): 191–203. Shamblott, Michael J., Joyce Axelman, Shunping Wang, Elizabeth M. Bugg, John W. Littlefield, Peter J. Donovan, Paul D. Blumenthal, George R. Huggins, and John D. Gearhart (1998) “Derivation of